Figure 1. Influence diagram of management of acne
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The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.
We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.
| Director | John M. Eisenberg, M.D. |
| Center for Practice and | Director |
| Technology Assessment | Agency for Healthcare Research |
| Agency for Healthcare Research | and Quality |
| and Quality |
| The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. |
Acne is a common condition, particularly in adolescents and young adults, with potentially significant physical and psychological morbidity from scarring and from adverse effects of treatment, as well as significant economic burdens. The purpose of this review was to provide a comprehensive review of the literature on acne management.
The following reference databases were searched: CENTRAL database of the Cochrane Collaboration (1948 through April, 1999), MEDLINE® (1966 through April, 1999), OLDMEDLINE (1960 through 1965), PsycINFO® (1887 through June, 1999), and CINAHL® (1982 through June 1999). The CENTRAL search strategy was (acne-vulgaris*.me OR acne*.tw). Similar strategies were used for the other databases. The MEDLINE® strategy combined, using a Boolean AND, a topic-specific strategy (acne vulgaris [mh] OR acne* [tw]) with a strategy designed to retrieve all controlled trials. Reference lists from key articles were hand reviewed.
In consultation with our partners and technical experts, the following questions were formulated: What treatments are effective? What is the responsiveness of first-line, second-line, and third-line treatments? What are the side effects of treatment? Controlled trials of acne therapy were sought that presented original, human data, written in English.
Identified articles were screened by independent reviewers in an abstract review process to determine eligibility for full article review. Eligible articles were reviewed serially by two or more abstracters who sought methodological and outcome data. The unit of analysis was the comparison between pairs of treatment arms. Comparisons were qualitatively synthesized into conclusions for which there were varying levels of evidence.
Our searches identified 4,749 articles. After full article review, 250 articles reporting results of 274 controlled trials were included, from 31 countries. Of trials included, 74 percent reported data on subjects' age, 13 percent reported on phase of care at study entry, 8 percent reported on race, and none reported on sexual maturity rating. Investigators used 25 assessment schemes to classify acne severity, and 505 distinctly named outcomes over 4 periods of followup (usually <3 months). Two trials addressed psychological effects and 43 provided data concerning treatment compliance. None reported on cost. Only eight trials stratified results by patient demographics and none by degree or type of prior therapy. Trials that had only strengths numbered 45 (16 percent). Trials that had only weaknesses numbered 106 (39 percent). Trials that had a mix of strengths and weaknesses numbered 101 (37 percent). The remaining 22 (8 percent) were of intermediate quality or did not provide enough information to make a determination.
There were 250 pairwise comparisons of over 140 treatments. In grading the strength of evidence, there were 14 comparisons with Level A, 102 with Level B, and 134 with Level C evidence regarding effectiveness of treatment for acne. The Level A comparisons suggested the greater effectiveness of topical clindamycin, erythromycin, tetracycline, tretinoin, and norgestimate/ethinyl estradiol over vehicle in mild-to-moderate acne; the greater effectiveness of benzoyl peroxide and aluminum chlorhydroxide/sulphur over vehicle in unstated acne severity; and equal effectiveness among topical tretinoin, isotretinoin, and motretinide. The following Level A conclusions demonstrated equivalence: Benzoyl peroxide at various strengths was equally efficacious in mild/moderate acne; adapalene and tretinoin were equally efficacious in unspecificed severity; motretinide and tretinoin were equally effective; adding vitamin A to oxytetracycline conferred no added efficacy; cyproterone was equally effective at two different doses. For side effects data, 88 comparisons provided evidence for withdrawals, severe side effects, or side effects in more than 10 percent of subjects in at least one arm. There were 10 comparisons of Level A strength.
Despite the large number of English-language controlled trials regarding acne therapy, their methodological limitations prevent our ability to evaluate the comparisons among therapies, and may limit the conclusions that others may draw in the future from this evidence base, even when coupled with expert knowledge. Multiple treatments, inconsistent information about baseline characteristics, and heterogeneity of assessment schemes and outcomes make it difficult to synthesize the evidence about best approaches to acne management. For future research to provide results for comparison, standardization among researchers is needed in these different areas. Research is needed to define the optimal sequence of acne therapy, and to define the relative roles of specialists and generalists in the care of acne.
This report was developed using accepted evidence-based techniques; however, as in other areas of research, the methodology was necessarily constrained by issues of feasibility and practicality so that, for example, the analysis was limited to clinical trials reported in the English language. Nonetheless, this report is a systematic effort to collect and summarize the available evidence on the management of acne and represents a potentially powerful resource for the field. As with any systematic review, to be accurate and comprehensive, the generation of guidelines requires additional information, such as expert opinion, to put the evidence into context.
It is estimated that 45 million people in the United States have acne vulgaris, with a prevalence of approximately 85 percent in the population 15-24 years of age. The disease is more common and more severe in males than in females. Morbidity primarily comes from the lesions themselves, which may be painful and tender, as well from scars left by nodules and cysts. Morbidity may be generated by adverse effects of treatments as well. Psychological morbidity has been noted. It is estimated that consumers spend $100 million per year in over-the-counter remedies. Coupled with loss of productivity and unemployment, the direct cost of acne may exceed $1 billion per year in the United States.
Three questions were addressed in the literature abstraction:
What treatments are effective in the management of acne?
What is the responsiveness of acne to first-line, second-line, and third-line (referral) treatments?
What are the side effects of treatment?
Evidence was sought for several subpopulations by acne severity, gender, and race/ethnicity; by outcome (e.g., response to treatment and acne sequelae); and cost.
Working with our partners, the American Academy of Dermatology and the American Academy of Pediatrics, as well as with the American Pharmaceutical Association, the Departments of Dermatology and Pediatrics at Johns Hopkins School of Medicine, the Cochrane Collaboration, and the Society for Investigational Dermatology, we assembled a team of technical experts.
The questions for consideration were developed through discussions with our technical experts, as well as through preliminary searches of MEDLINE® and MicroMedex and a review of consumers' questions submitted to a major consumer health Internet Web site (InteliHealth™).
The following reference databases were searched: CENTRAL database of the Cochrane Collaboration, MEDLINE® (accessed through PubMed), OLDMEDLINE, PsycINFO®, and CINAHL®. The CENTRAL search strategy was (acne-vulgaris*.me OR acne*.tw). Similar strategies were used for the other databases. The search strategy for PubMed combined, using a Boolean AND, a topic-specific strategy (acne vulgaris[mh] OR acne*[tw]) with a strategy designed to retrieve all controlled trials. Reference lists from key articles were reviewed by hand. All unique controlled trials of acne therapy were sought that presented original, human data and were written in English.
Identified articles were screened by independent reviewers in an abstract review process to determine eligibility for full article review. Eligible articles were reviewed serially by two or more abstracters who sought methodological and outcome data.
Studies were qualitatively assessed in terms of methodological strengths and weaknesses. Studies were also classified by the level of acne severity in study patients at enrollment. A combined acne severity classification was created that integrated the 25 schemes found in the literature.
The unit of analysis was the comparison between pairs of treatment arms. Comparisons were qualitatively assessed by addressing methodological issues, by addressing commonality of outcomes across studies, and by addressing results and their statistical significance between arms. The evidence was assessed in terms of strength at Levels A, B, or C as follows:
A -- At least two trials of acceptable quality show moderate to strong statistical evidence for a clinically meaningful endpoint and effect.
B -- Evidence is of modest strength, such as when only one trial addresses a comparison, several trials have different qualitative conclusions, large differences are not statistically significant, or poor trial quality prevents accepting strong statistical evidence at face value.
C -- Evidence does not permit coming to any scientific conclusion because of a paucity of the evidence, conflicting evidence, or very poor quality evidence.
The literature is extremely heterogeneous, severely limiting the number of meaningful conclusions that can be drawn. The 274 trials included reports from 31 countries. There were 140 treatments. There were 505 distinctly named acne outcomes over four periods of followup (usually <3 months). There were 250 pairwise comparisons.
Evidence for subpopulations is either not available or reported in such a varied manner as to prevent meaningful integration. Of the trials, 74 percent reported data on the age of the subjects, 13 percent reported phase of care at study entry, 8 percent reported race, and none reported on sexual maturity rating. Only eight trials stratified their results: four by gender, three by acne type or severity, and one by study location.
Evidence for quality-of-life outcomes and cost is not available. Two trials assessed psychological effects and 43 trials provided anecdotal data on treatment compliance. None reported on cost.
Of 250 comparisons, only 14 had evidence of Level A. These comparisons demonstrated the efficacy over vehicle or placebo control of aluminum chlorhydroxide/sulphur, topical clindamycin, topical erythromycin, benzoyl peroxide, topical isotretinoin, tretinoin, oral tetracycline, and norgestimate/ethinyl estradiol. Level A conclusions demonstrating equivalence include: Benzoyl peroxide at various strengths was equally efficacious in mild/moderate acne; adapalene and tretinoin were equally efficacious in unspecified severity; motretinide and tretinoin were equally effective; adding vitamin A to oxytetracycline conferred no added efficacy; cyproterone was equally effective at two different doses. There were 102 comparisons with Level B evidence and 134 with Level C evidence.
The literature is not organized to differentiate responses to first-line, second-line, or third-line (referral) therapy. Investigators were not systematic in evaluating subjects' prior therapy. There is no basis from controlled trials to judge the efficacy of any treatment in relation to the sequence of therapy.
Regarding side effects, evidence was gleaned for 88 primary comparisons. Of these, 10 provided evidence at Level A. These involved, primarily, adverse local reactions of retinoids. Because of appropriate exclusions, important side effects, like the teratogenicity of isotretinoin, were not documented in these trials.
There is still much work to be done to define the best approach to management of acne in an individual patient based upon his or her specific characteristics. Until this work is done, the process of care for patients with acne vulgaris will remain highly individualized, based upon the experience of the patient and the treating physician. The effectiveness of a more evidence-based, stepwise approach that incorporates several therapies at different points in time still needs to be documented.
Future research on the treatment of acne vulgaris would benefit from:
Population-based studies with detailed information about subjects including age, race, gender, sexual maturity rating, and previous treatment of acne.
Consistent case definitions and methods for assessing acne type and severity.
Greater consistency in outcomes across studies so that trials are comparable.
Standards for assessment of clinical outcomes.
Assessment of outcomes at time points distant from treatment.
Explicit assessment of patients' acceptability of treatment.
More information about psychological outcomes and costs related to treatment.
Attention to the issue of bacterial resistance.
This report was developed using accepted evidence-based techniques; however, as in other areas of research, the methodology was necessarily constrained by issues of feasibility and practicality so that, for example, the analysis was limited to clinical trials reported in the English language. Nonetheless, this report is a systematic effort to collect and summarize the available evidence on the management of acne and represents a potentially powerful resource for the field. As with any systematic review, to be accurate and comprehensive, the generation of guidelines requires additional information, such as expert opinion, to put the evidence into context.
Acne is a very common condition, particularly in adolescents and young adults. While there is virtually no mortality associated with this disease, there is often significant morbidity seen.1 Physical morbidity of acne results from scarring and from the adverse effects of treatment. Also important is the psychological morbidity of the disease on those afflicted, which affects self-esteem and quality of life. The burden of acne in terms of cost to society is not well defined, but the prevalence of the disease suggests that these costs are high.
Because there are several factors involved in the pathogenesis of acne, there are many different approaches to treatment of the disease. Acne patients may treat themselves or may seek care from pediatricians, internists, family physicians or dermatologists. There are many medications available to interrupt or prevent various stages of disease development. These treatments include topical cleansers, topical keratolytic agents, topical and oral antibiotics, topical and oral retinoids, anti-androgen agents, and others. However, there is no single standard approach to care. And, it is not clear to what extent patients are treated optimally. There is some evidence for variations in practice based on the specialty of the treating physician.2
The evidence basis for the treatment of acne has not previously been systematically reviewed. Practice guidelines for the management of acne, based on expert opinion, were published by the American Academy of Dermatology in 1990.3 In addition, some new treatments for acne have become available since that time.
The purpose of this evidence report is to provide clinicians and policymakers with a comprehensive review of the extant literature, albeit limited to English language controlled trials, on the management of acne. This includes both a synthesis of the data on treatment efficacy and side effects as well as a review of other relevant issues, including the characteristics of patients studied, point of contact with the health system, and psychological and economic considerations. This report may be valuable in assisting clinicians in making treatment decisions and in demonstrating areas where evidence is lacking and further research is required.
It is estimated that 45 million people in the United States have acne vulgaris.4 This estimate includes patients afflicted with either the comedonal or inflammatory variants of the disease. Acne occurs at all ages, from infants to adults, but primarily affects adolescents and young adults, with a prevalence of approximately 85 percent in the population ages 15-24 years. Prevalence decreases with advancing age after adolescence with prevalence estimates of 8 percent in the 25-34 years age range and 3 percent in the age 35-44 years age range.5,6 he disease is more common and more severe in males than in females.1 However, young men tend to have their acne resolve by ages 20-25 years, while women are more likely to have their acne persist into their 30s or 40s. In this group of adult women, inflammatory acne is more common than comedonal acne.4
In addition to age and gender, there are several other factors that influence the prevalence and type of acne in subpopulations. For instance, race, stage of pubertal development, skin type, presence of endocrine disease, and geographic location (urban vs. rural, climate) all affect the development of the disease.7
Race may be an important consideration in the management of acne. People with darker skin are more likely to develop post-inflammatory hyperpigmentation (PIH) from any inflammatory skin condition.8 While an acne lesion may last for a few days, the PIH may last for weeks or months. In addition, it has been suggested that many acne treatments including benzoyl peroxide, tretinoin, and glycolic acid may actually exacerbate PIH.9 This treatment-related morbidity has significant implications for choice of treatment in these patients.
It is important to note that there are several diseases, historically termed "acne", which have been reclassified as acneiform eruptions. These are diseases in which the primary lesion of acne, the microcomedo, is not present. These eruptions include acne rosacea, steroid acne, and gram-negative folliculitis.4 These disorders are beyond the scope of this report.
This section does not represent a synthesis of all available evidence; this information has been provided for context and background. Aspects of acne pathogenesis remain controversial. It is beyond the scope of this report to provide the definitive text on the pathogenesis of acne.
The primary skin lesion in acne is the microcomedo. Formation occurs when a keratin plug fills the duct of a pilosebaceous unit, which is comprised of a hair follicle and a sebaceous gland. Sebum is produced in the unit and some may be trapped beneath the keratin plug along with more keratinaceous material, causing enlargement of the follicle. As the lesion enlarges it becomes clinically apparent and becomes a comedo. The comedo may remain functionally closed, appearing as a "whitehead." Or, the dilated follicular orifice may be open to the skin's surface, forming an open comedo or "blackhead." On occasion the comedo may become inflamed and/or enlarge to the point of rupture of the follicular wall. This produces inflammatory papules, pustules, and nodules.1,10
While the exact etiology of acne is unclear, there are three key factors in its pathogenesis. Abnormal follicular keratinization, sebum production, and growth of Propionibacterium acnes (P. acnes) all play a role in the development of this disease at the level of the sebaceous follicle.
Follicular keratinization -- The formation of a keratin plug in the follicle is the result of the abnormal adherence of desquamating keratinocytes. The cause of the plugging is not known. Current areas of research include alterations in keratin expression, cytokine production, and androgen effects.6,11
Sebum production and retention -- Adrenal and gonadal androgens stimulate both the growth of sebaceous glands and sebum production. This explains why acne tends to manifest itself initially during adrenarche. In fact, one study demonstrated that acne could be the first sign of pubertal maturation.12 On average, patients with acne have higher levels of sebum production than those without acne, and disease severity is proportional to sebum production. Sebum is a nutrient source for P. acnes.
Propionobacterium acnes -- P. acnes, a normal part of the skin flora, is an inflammatory stimulus. It activates complement, produces neutrophil hemotactic factors, and stimulates neutrophils to release lysosomal enzymes, causing an inflammatory reaction. While their exact role remains unclear, these factors all influence the developing acne papule.13
These various aspects of the pathogenesis of acne are all targets for different forms of treatment.
The primary morbidity associated with acne is the presence of the lesions themselves. This morbidity may vary by acne type (e.g., comedonal, pustular, nodulocystic), distribution (face, chest, back), and extent (number of lesions). These lesions, particularly the nodulocystic lesions, can be painful, disfiguring, and leave permanent scars. In addition, patients may manipulate their acne lesions for the purpose of expressing the contents of comedones and pustules. This manipulation can lead to scarring, even from the most benign lesions.
In addition to the morbidity seen from acne itself, there is also morbidity associated with treatments and their side effects. Side effects vary based upon the treatment used. While treatments are described in some detail in the Treatment of Acne section of this chapter, there are some common side effects seen with several different therapies. Morbidity may be either an extension of the desired mechanism of action of the drug, such as skin dryness, or it may be an unwanted side effect that is not part of the treatment itself, such as headache. Other unwanted effects seen with different therapies include irritation, skin bleaching, photosensitivity, gastrointestinal distress, and discoloration of the teeth, skin, or nails. The most concerning panel of side effects is seen with oral isotretinoin. And , it has been estimated that isotretinoin is teratogenic in 25 percent of cases of first trimester exposures.6
Acne fulminans is an uncommon disease that consists of ulcerative acne plus systemic symptoms such as fever, weight loss, arthralgias, and/or myalgias. It may lead to sepsis and, rarely, to death.14 Our report does not seek evidence on this rare entity.
The psychological burden of acne may be large. In a small study examining suicide in dermatology patients, patients with severe acne were noted to be one of the groups at high risk for depression and suicide.15
The importance of the psychological impact of acne, particularly on adolescents, is well recognized by clinicians. However, the literature in this area is still in its infancy. One study examined the anxiety level of patients with different dermatologic diseases. It found that patients with cystic acne had the highest level of anxiety.16 Quality of life psychosocial effects have been described in patients with acne, including decreased self-esteem and self-confidence, problems with body image, social withdrawal, depression, anger, preoccupation, confusion, frustration, limitations in lifestyle, and difficulty with family members.17,15,18,19 In a small study of patients with mild to moderate acne, there was a high prevalence of depression before beginning treatment, but the prevalence of depression and anxiety decreased to population norms after treatment.18
The economic costs of acne are not well described in the literature. However, when trying to estimate this burden, both direct and indirect costs must be considered. Direct costs include funds spent on self-care through over-the-counter (OTC) medications, payments for prescription medications and other physician-initiated therapies, and payments for medical visits. Indirect costs such as time lost from work for physician visits and decreased productivity are also important from a societal perspective. While a few studies have examined some of the direct costs of care,20 none has estimated indirect costs.
One review estimates that the average cost of single or combination topical acne therapy ranges from $21to $208 per patient per year. Systemic treatment or the combination of systemic and topical treatment can average as much as $1540 per patient per year. Initial and followup visits with health care providers add another $315 to this cost. In addition, consumers spend over $100 million per year on over-the-counter treatments for acne. Loss of productivity may occur in school or work environments. It has been suggested that the unemployment rate is increased by 50 percent in patients with acne.21 Bearing in mind that approximately 45 million people in this country have acne, these data suggest that the direct cost of acne may exceed $1 billion per year in the United States, with indirect costs due to loss of productivity increasing the cost even more.
Acne is managed by many different types of physicians. Dermatologists provide the majority of acne care, though half of the visits for acne in patients under 15 are with pediatricians. Internists and family physicians also treat acne, though the proportion of care provided by these practitioners is not known. Variations in practice between generalists and specialists have been documented.2 However, there have been no studies exploring differences in outcomes by provider type.
There are several different medications available for the treatment of acne. Broadly, these can be divided into topical therapies and systemic (oral) therapies. In general, mild cases are treated with topical medications, with more severe cases being treated with systemic therapy or a combination of topical and systemic treatments. However, acne treatment tends to be highly individualized due to the spectrum of lesions that may be present in one patient, other patient characteristics, level of patient distress, number of treatments available, and the experience and preference of the physician.
Topical therapies include cleansers, keratolytics, topical antibiotics and topical retinoids. The main action of keratolytics is to increase follicular desquamation and decrease follicular plugging. Common keratolytics include salicylic acid, sulphur, and resorcinol. Antibiotics suppress P. acnes. Common topical antibiotics are erythromycin and clindamycin. Benzoyl peroxide has both antibiotic and keratolytic properties. Its exact mechanism of action in the treatment of acne is unclear, but the antibiotic activity of benzoyl peroxide is believed to predominate. Topical retinoids such as tretinoin and adapalene reduce hyperkeratosis and follicular plugging.6,22,1 In addition to the different active ingredients, topical medications vary by vehicle. This may influence their efficacy. Many of the treatments mentioned above are available in cream, liquid, and gel formulations.
Systemic therapies include oral antibiotics, oral retinoids, and hormonal treatments. Oral antibiotics used to treat acne include tetracyclines, macrolides, and sulfa-containing agents. Some of these agents may have anti-inflammatory activity as well as antibiotic activity. Isotretinoin is currently the only oral retinoid routinely used in the treatment of acne. While its exact mechanism of action is unknown, it decreases both sebaceous gland secretion and keratinization. Estrogens and anti-androgens are systemic medications that may be used in specific cases.1
There are dozens of other treatments for acne that have been used or are currently in use. These include Grenz rays (a type of x-irradiation), anti-fungal treatments, acne surgery, topical and oral steroids, and alternative therapies such as tea tree oil.
This report is intended for use by clinicians, researchers and policymakers. The literature on the management of acne is both vast and heterogeneous, and this report uses accepted evidence-based techniques to summarize the current knowledge. The reader must bear in mind that, as in other areas of research, feasibility and practicality do impact the research methodology. As such, this report is limited to English language reports. This report is also limited to controlled trials, a widely accepted standard for high quality evidence. The authors recognize that there may be several important studies excluded on this basis alone. This caveat aside, the production of this report was a systematic effort to collect and to summarize the available evidence on the management of acne, and, as such, represents a potentially powerful resource for the field. Clinicians can use this report as a supplement to their judgment and experience, being careful to recognize that important aspects of decisionmaking are not addressed here. For researchers, this report may provide a basis and direction for future studies. Finally, for policymakers, including specialty societies, government agencies, and payors, this report can serve as the basis for policy development such as the generation of clinical practice guidelines. To be accurate and comprehensive, the generation of guidelines requires the addition of other information, such as expert opinion to put the evidence in this report into context.
The management of acne was a topic nominated to the Agency for Healthcare Research and Quality (AHRQ, then called the Agency for Health Care Policy and Research [AHCPR]) by the American Academy of Dermatology (AAD) and the American Academy of Pediatrics (AAP). In October 1998, AHRQ awarded a contract to the Johns Hopkins Evidence-based Practice Center (EPC) to prepare an evidence report on this topic. With the assistance from the partners from AAD and AAP, the Johns Hopkins EPC established a team and work plan to develop a report that would identify and synthesize the best available evidence on the management of acne. The project consisted of recruiting technical experts, identifying the patient population, formulating and refining the specific questions, performing a comprehensive literature search, summarizing the state of the literature, constructing evidence tables, and submitting the report for extensive peer review.
Experts were sought who could provide content and/or methodological guidance. The group of experts included representatives from the project partners AAD and AAP, as well as from the American Pharmaceutical Association (AphA), Society for Investigational Dermatology (SID), and the Skin Collaborative Review Group (CRG) from the Cochrane Collaboration. Their input was sought through ad hoc correspondence as well as through more formal requests for feedback during the project. Specific requests for feedback were made for key decisions throughout the project, such question refinement, completeness of literature search, treatment and acne severity classification, and format and layout of evidence tables and synthesis of literature.
Additional representation of AAD, AAP, American Academy of Family Physicians (AAFP), as well as from the Society for General Internal Medicine (SGIM), SID, and Society for Adolescent Medicine (SAM) joined the technical experts as peer reviewers for the report. These reviewers included dermatologists, pediatricians, and generalists (Appendix A).
The target population for this report is all patients with acne who do not have complicating comorbidities such as endocrinopathies. In consultation with the partners and technical experts, we decided to exclude evidence from populations with the following conditions: acne fulminans, acne necroticans, acne venenata, rosacea, and chloracne. We believed that to include endocrinopathies would necessitate an examination of underlying medical conditions that was beyond the scope of this report. The search and synthesis of evidence was not limited by age, gender, or any other patient characteristic, though synthesis includes an analysis by these characteristics, where possible.
The report sought evidence concerning all primary care and dermatology settings. In addition, self-treatment is an important modality for acne therapy. Therefore, the community-based setting in which a consumer of health care acts without the involvement of a health care provider was also considered.
Questions were identified through discussions among the team members, preliminary searches of MEDLINE®, a search of the MicroMedex pharmaceutical database, and consultation with our technical experts. We also reviewed over 14,000 consumer-generated questions posted to a major consumer health Internet Web site (InteliHealth™) for queries about acne. The questions identified through this process formed the basis of a brief questionnaire distributed to the technical experts (Appendix B). The experts were asked to rate the importance of each question, to provide a sense of the data available to address each question, and also to provide any additional comments or suggestions.
Based on the results from the questionnaire, we developed questions in factorial format to embrace the various patient treatments, outcomes, patient characteristics, practice settings, and care providers of interest (Appendix C). The factorial formatted questions, as well as the proposed exclusions, were distributed to the technical experts for feedback (Appendix D). From the factorial questions, the technical experts requested that the evidence report address the following questions:
What treatments are effective in the management of acne?
What is the responsiveness of acne to first-line, second-line, and third-line (referral) treatments?
What are the side effects of treatment?
The following secondary questions were also to be addressed as the evidence allowed:
What baseline characteristics raise the likelihood of acne?
What care do patients provide for themselves at home?
How effective is initial home care?
What is the presentation of acne to physicians?
How compliant are patients with their treatment?
What is the residuum of untreated acne? Of treated acne?
What is the quality of life (psychological morbidity) in untreated acne? In treated acne?
What is the financial cost of therapy?
The accumulation of data alone is not sufficient for decisionmaking. The evidence needs to be organized into meaningful units, and the units must be organized to aid in making decisions. To this end, we structured a causal model, using the conventions of an influence diagram23 (Figure 1
). The diagram is an abstraction
of a decision tree, and, when fully specified, can derive the flowchart of a
practice guideline. For instance, rather than specifying all possible self-care
options, the diagram simply shows that the choice of self-care is influenced by
a patient's baseline characteristics which, in turn, influence the possibility
and choice of initial medical care. It was developed through structured
interviews with two technical experts and a review of the literature, and it was
critiqued by the other technical experts.
Preliminary definitions and assessments were made of the nodes (states or variables) of the influence diagram:
Patient characteristics -- These are characteristics such as race, gender, and skin type.
Self-care -- Refers to over the counter treatments and medications, such as benzoyl peroxide. This also includes self-referral to a medical provider.
Initial acne assessment -- Refers to the acne present at initial assessment. The arrow from baseline characteristics suggests that this acne severity is influenced by baseline characteristics, although our initial review of the evidence suggested that few investigators go beyond lesion count and type in making a severity assessment (see Chapter 3).
Initial medical care -- Represents all possible prescription and non-prescription treatments.
Acne reassessment -- The same as initial acne assessment, but later in time. An arrow is drawn from the initial acne assessment node, suggesting that response to treatment (from initial medical care) is influenced by the initial acne status (or baseline characteristics).
Initial compliance -- Acknowledges that success depends on patient compliance and that initial medical choices must be made keeping compliance in mind.
Followup medical care -- Refers to the provider's options after assessment, including continuing present therapy, changing to another treatment, or referral.
Followup compliance -- Similar to initial compliance.
Followup acne reassessment -- Similar to acne reassessment.
Further medical care -- Focuses on referral if acne reassessment shows no improvement. Refers to the provider's option after assessment, including continuing present therapy, changing to another treatment, or referral. We left the full definition open, hoping to find evidence in the literature that would help us to define the therapeutic choices.
Acne residual -- This is the long-term dermatological morbidity of acne, with or without treatment.
Quality of life -- Outcomes such as self-esteem and social and familial relationships.
Cost -- Includes costs related to loss of productivity in school or work, as well as medical costs.
Other morbidity -- Other morbidity outcomes, such as the presence of lesions themselves, and the possible effects of treatment. Possible treatment effects include sun sensitivity and, of the most concern, more serious side effects such as those related to isotretinoin use.
Influence diagrams terminate in a utility node that integrates the outcomes, their probabilities, and the decisionmaker's valuation of preference for those outcomes. We plan to leave that integration to the users of our final evidence synthesis for creating their guidelines.
Searching the literature included the steps of identifying reference sources, formulating a search strategy for each source, and executing and documenting each search.
Several literature sources were used to identify all studies potentially relevant to our study questions. The first source that we used was the CENTRAL database of the Cochrane Collaboration. This is a database of all clinical trials (primarily randomized controlled trials and controlled clinical trials) identified through the searching efforts of the Cochrane Collaboration. The CENTRAL database includes search results from many electronic databases, including MEDLINE® and EMBASE®, as well as results from the hand searching of more than 1,000 journals, for all publication years starting in 1948. The CENTRAL database also includes the specialized register of controlled trials developed by the Cochrane Skin Collaborative Review Group. The Skin CRG has completed extensive searching of electronic databases including MEDLINE®, MBASE®, Current Contents® in Dermatology, and the American Academy of Dermatology trials register. In addition, members of this CRG hand search a number of key dermatology journals such as Dermatology and Clinical and Experimental Dermatology. The CENTRAL database is made available on The Cochrane Library, which is issued quarterly. Both Issue 4 of the 1998 The Cochrane Library and Issue 1 of the 1999 The Cochrane Library were searched.
Our second source was MEDLINE®, or MEDlars onLINE, the database of bibliographic citations and author abstracts from approximately 3,900 current biomedical journals published in the United States and 70 foreign countries, which dates back to 1966. MEDLINE® was accessed through PubMed, the Internet access to MEDLINE® provided by the National Library of Medicine (NLM), which also includes the PREMEDLINE database of basic citation information and abstracts of full records before they are prepared and added to MEDLINE®. The searching of PubMed helped to confirm the completeness of the search conducted with the Cochrane Collaboration's CENTRAL database and also helped to identify new studies published while we were working on the evidence report. In addition, for the questions where there were few or no controlled clinical trials (i.e., those related to the costs of acne), PubMed was used to identify other types of studies.
Internet GratefulMed, provided as a Web-based service by the NLM, was used to access OLDMEDLINE. OLDMEDLINE contains citations published in the 1960 through 1965 Cumulated Index Medicus and covers the fields of medicine, preclinical sciences, and allied health sciences. We felt it important to include OLDMEDLINE as some of the key articles concerning treatment effectiveness, for instance of benzoyl peroxide, may have been published prior to the MEDLINE® start date of 1966. Internet GratefulMed was also used to access HealthSTAR. This electronic database combines the former HEALTH (Health Planning and Administration) and HSTAR (Health Service/Technology Assessment Research) databases and includes citations from 1975 to present.
Using the access provided by the Johns Hopkins Welch Medical Library, the PsycINFO® and CINAHL® databases were also searched. PsycINFO® covers the professional and academic literature in psychology and related disciplines, including medicine, psychiatry, nursing, sociology, education, pharmacology, physiology, linguistics, and other areas (including literature) from 1887 to present. CINAHL® is a multidisciplinary database covering the nursing, allied health, biomedicine, and consumer health literature from 1982 to present.
Two final steps were taken to ensure a comprehensive literature search. A database of reference material, identified through the electronic searching, through discussions with experts, and by the article review process, was created in the reference management software, ProCite®. A listing of titles and abstracts from this database, the Acne References Database, was reviewed by the investigators to identify key articles. The reference lists from these key articles were then examined to identify any additional articles for inclusion in the Acne Citations Database. Finally, a listing of all identified controlled trials was distributed to our technical experts, and they were asked to identify any additional articles of which they were aware that should be considered for inclusion in the review process.
The search strategies were designed to maximize sensitivity and were developed in consultation with team members. A core search strategy for identifying evidence from the CENTRAL database was developed. PubMed was searched by combining the core search strategy with phases 1 and 2 of a search strategy developed for the optimal identification of controlled clinical trials from PubMed.24 Search strategies were also modified, as needed, based on the source being accessed, with separate strategies developed for OLDMEDLINE, CINAHL®, and PsycINFO®. Because results were limited on this topic, a supplemental search was conducted on PubMed for the retrieval of cost-related articles. (See Appendix E for search strategies.)
The results of the searches of electronic databases were downloaded and, using the duplication check in the bibliographic software ProCite®, articles not previously retrieved were included in the Acne Citations Database. This ProCite® database was used to store citations and to aid in the tracking of search strategies and sources. The use of this software allowed citations and abstracts to be directly imported into a database as well as catalogued with important attributes. The results of the abstract review process were also tracked using ProCite®.
Specific inclusion and exclusion criteria were applied at each of three levels of review, with criteria becoming more stringent as the process moved from use of specific search terms to the review of abstracts to the review of articles. After identifying a citation, its title and abstract were reviewed, and articles were included or excluded from the article review on this basis.
During the abstract review process, the emphasis was placed on identifying all articles that may possibly have original data pertinent to the questions. As previously described, the technical experts were consulted during the development of inclusion and exclusion criteria.
In evaluating titles and abstracts, the following criteria were used to exclude articles from further consideration:
Article does not address management of acne.
Article does not include human data.
Article addresses a topic excluded from this evidence report:
- chloracne
- rosacea
- acne
venanta
- acne fulminans
- acne
necroticans
Article contains no original data.
Article is not in English.
Articles excluded with criterion "no original data" included those that were duplicate publications of the same trial. In those cases, the article with a more comprehensive reporting of the data was kept (if otherwise eligible).
It is recognized that the decision to exclude non-English language reports of trials is a limitation of this report because it means the possible exclusion of potentially high quality and highly relevant reports of trials. Time and other resources, however, prevented this project from searching, retrieving, translating, and then reviewing non-English reports of trials.
The abstract review process was also used to classify the articles by topic and to identify the study design. For those articles without an abstract, the abstract review process was performed using the entire article.
Titles and abstracts for all articles retrieved by the literature search were printed on an abstract form and distributed to two reviewers (Appendix F). When reviewers agreed that, because of insufficient information, a decision regarding eligibility could not be made, the full article was retrieved and then reviewed. The principal investigators reviewed abstracts when abstract reviewers disagreed regarding eligibility of the article.
The results of the abstract review process were entered into the Acne Citations Database. Articles deleted through the abstract review process were tagged with reason for exclusion and removed to the Acne Deletions Database. The maintenance of this database allowed for the ongoing search results to be compared to already retrieved citations (in Acne Citations and Acne Deletions Databases) for the identification of newly retrieved articles and also allowed for the efficient tracking of the abstract review results.
The purpose of the article review was to confirm relevance of each article to the questions at hand, to determine methodological characteristics pertaining to study quality, and to collect evidence pertaining to the questions. Where articles included reports of more than one trial, reviewers were instructed to complete the relevance assessment (i.e., comparison to inclusion and exclusion criteria), quality assessment, and data abstraction for each trial separately.
Forms were developed to confirm eligibility for full article review, assess study characteristics, and abstract the relevant data to address the study questions. The forms were developed through an iterative process including the review of forms used for previous EPC projects, discussions among team members and experts, and through pilot testing.
Three forms were developed and color-coded to aid reviewers and data entry personnel (Appendix G).
The first form completed for all trials comprised three sections. The first section included the same exclusion criteria used during the abstract review phase. In this way, reviewers could confirm the eligibility of the trial before proceeding with the full article review. The second section (questions 1 to 5) contained general study characteristic questions such as the number of treatment groups, number of sites, and location of trial. A classification of study design was also included in this section. Once the decision was made to limit full article review to controlled trials, this question was added to the previous section in that a trial classified as any study design other than a controlled trial would not be reviewed. The final section (questions 6 to 26) contained questions designed to provide an assessment of study quality. The questions were designed to assess characteristics such as research design, treatment allocation, and blinding, as well as the potential for bias and generalizability. These questions allowed for the identification of methodological strengths and weaknesses used in the evidence tables and summary of evidence.
The characteristics of each arm or group in the trial were assessed on the second form. The first section gathered information concerning the treatment or intervention. For example, treatment name and dose were noted. The following pages abstracted information concerning the patients and these 15 questions were completed for each arm and/or for the entire trial, as possible. It was in this section that baseline characteristics such as age and gender, as well as source of care and phase of care, were noted.
Two forms were developed for outcomes: one for discrete outcomes and one for continuous outcomes. These one-page forms gathered definitions and data for each outcome. For discrete outcomes, data collected included the categories and raw numbers for each measurement, while for continuous outcomes the means and standard deviations or standard error were collected. Where available, P-values provided by the investigators were also collected. The number of patients included in outcome assessment, the number of patients based on intention to treat and the number of patients lost to followup were also collected where possible. Finally, reviewers judged the objectivity and consistency of the assessment of each outcome. These questions, combined with those on the study characteristics form, provided the information used to identify the methodological strengths and weaknesses of each trial.
Because of the large number of articles to review, a serial article review process was employed. In this process, the quality assessment and abstraction forms were completed by the primary reviewer. The secondary reviewer, after reading the article, checked each item on the forms for completeness and accuracy. The secondary reviewer also indicated the number of disagreements with the primary reviewer for those items related to study quality. The secondary reviews were completed by the principal investigators. We did not mask reviewers to author, institution, or journal.
All information from the article review process was entered in a Microsoft Access database (Acne Evidence Database) to collect, organize, display, and report the evidence.
Feedback was sought from the technical experts throughout the project through ad hoc and formal requests for guidance. Drafts of the report were sent to technical experts, as well as to peer reviewers identified by AAD and AAP. (See Appendix A for a list of peer reviewers and technical experts who reviewed one or more drafts of this evidence report.) We logged the dates each reviewer's forms were received and entered feedback requiring responses into a database. Revisions were made to the report, as appropriate. Responses to the comments, descriptions of the revisions and/or explanations of decisions, were sent back to reviewers and a conference call was scheduled to discuss the comments and responses. The review process was then repeated with the revised report.
Our results fall into two categories: This chapter addresses assessment of the literature and the evidence; the next chapter provides an exhaustive review of the evidence comparing specific pairs of choices of acne therapy. Chapter 5 reports our answers to the specific questions.
| Source | Date | Retrieved | Unique | Number of citations | Eligible for article review | ||
|---|---|---|---|---|---|---|---|
| Eligible for abstract review | Unable to abstract review | ||||||
| ALL | CTs | ||||||
| CENTRAL Issue 4 1998 | Jan 25, 1999 | 460 | 460 | 375 | 211 | 211 | |
| PubMed core | Jan 27, 1999 | 820 | 312 | 228 | 115 | 55 | |
| OLDMEDLINE | Feb 8, 1999 | 512 | 512a | 126 | 5 | 87 | 39 |
| HealthStar | Feb 25, 1999 | 1,342 | 5a | 0 | 0 | 0 | |
| PsycINFO® | Feb 25, 1999 | 65 | 65a | 25 | 16 | 1 | |
| CINAHL® | Feb 26, 1999 | 125 | 125a | 15 | 0 | 0 | |
| PubMed supplemental search for cost | Feb 26, 1999 | 28 | 25a | 6 | 5 | 0 | |
| PubMed core | Apr 7, 1999 | 835 | 18 | 18 | 10 | 10 | |
| CENTRAL Issue 1 1999 | Apr 27, 1999 | 523 | 30 | 30 | 1 | 13 | 13 |
| Hand Searching reviews | July 1999 | 39 | 6 | 6 | 1 | 3 | 2 |
| TOTAL | 4,749 | 1,558 | 829 | 7 | 460 | 331 | |
Listing reviewed by PIs to identify those to be included in abstract review process
Column Headings:
Source - Name of database searched and, where applicable, version of database and type of search.
Date - Date search completed.
Number of citations: Retrieved - Total number of citations retrieved by search.
Number of citations: Unique - Total number of citations retrieved minus those citations previously retrieved.
Number of citations: Eligible for abstract review - As noted with asterisks, in some cases the PIs reviewed the listing of uniquely retrieved citations to identify those to be included in the abstract review process. The number in this column reflects the citations identified in this manner.
Number of citations: Eligible for article review - Number of citations from abstract review process deemed eligible for article review. This column includes the total number of citations as well as the number of controlled trials (CTs).
We were unable to review 7 citations as they did not have abstracts and we were unable to retrieve the full articles. Of the 822 citations we could review, 460 (56 percent) were classified as eligible for full article review while 362 (44 percent) were determined to be ineligible for full article review. The majority of abstracts were excluded as not addressing management of acne (291 [80 percent]); the next most common exclusion was no original data (75 [21 percent]). Much smaller numbers of abstracts were excluded as not in English language (6), human data not included (4), only addressing excluded topics (5), and as duplicate publications not caught during searching and retrieving process (4).
From the abstract review process, 460 citations were identified for inclusion in the article review phase. Because of this large number, and with consensus from the technical experts, it was decided to focus on the controlled trials. Eligible trials were those where the individuals followed in the trial were definitely or possibly assigned prospectively to one of two or more treatment arms using either random allocation or a quasi-random method of allocation (e.g., date of birth). Of the 460 citations, 331 were identified as reports of controlled trials by the Cochrane Collaboration (citations included in CENTRAL) or by one of the abstract reviewers (for citations from MEDLINE® and other sources).
We were unable to retrieve, and, therefore, unable to complete article review of 12 articles. Of the remaining 319 articles reviewed, 23 (7.2 percent) contained descriptions of more than one trial. Each trial was quality assessed and abstracted separately. There were 351 trials for which a review was completed.
| Reason for exclusion | Number of trials | Percent of trials excluded (n=77) | Percent of all trials reviewed (n=351) |
|---|---|---|---|
| Not management of acne | 16 | 20.8 | 4.6 |
| No human data | 1 | 0.1 | 0.3 |
| Excluded topics only: more than 20% of patients have chloracne, rosacea, venanta, fulminans, necroticans, or agminata | 1 | 0.1 | 0.3 |
| Surrogate measures only (e.g., sebum production, P acnes colony counts) | 12 | 15.6 | 12.0 |
| No original data | 7 | 9.1 | 2.0 |
| Not in English | 4 | 5.2 | 1.1 |
| Fewer than 5 patients | 2 | 2.6 | 0.6 |
| Unable to abstract data | 4 | 5.2 | 1.1 |
| Study design not controlled | 30 | 39.0 | 8.5 |
| Total | 77 | ||
As the article review process progressed, we realized that many studies had multiple time points of outcome assessment (e.g., 2, 4, 6, 8, 10, 12, 14, and 16 weeks in a single trial). It was not feasible to continue collection, or data entry, in this manner nor did it seem likely to add to the value of the evidence synthesis. We conferred with our technical experts on an ad hoc basis and included a proposal for dealing with the time points in a formal request for feedback. Based on this, abstraction of outcome data was collected for the time points corresponding to the following time periods:
Short term -- Longest time interval up to and including 6 weeks (< 6 weeks);
Mid term -- Longest time interval up to and including 12 weeks (>6 to 12 weeks);
Long term -- Longest time point reported by study, if greater than 12 weeks; and
Post-therapy -- Any time period reported after stopping of treatment.
Of the 319 articles reviewed, 296 presented single trials while 23 articles reported multiple trials: 18 articles presented two trials; three articles presented three trials; one article presented four trials; and one article presented six trials.
Figure 2
shows the count of the 274 trials included by
publication year. As illustrated in the graph, the
number of controlled trials published has generally increased since the
mid-1970s.
Study validity is often divided into two parts: external validity and internal validity. Internal validity is the extent to which the methods of the study lead one to trust the results of the study. External validity is the extent to which one may generalize the results beyond the study.
Our method of summarizing methodological strengths and weaknesses is presented in Volume 2 (see Description of the Evidence Tables). Trials that had only strengths numbered 45 (16 percent). Trials that had only weaknesses numbered 106 (39 percent). Trials that had a mix of strengths and weaknesses numbered 107 (37 percent). The remaining 22 (8 percent) were of intermediate quality or did not provide enough information to make a determination.
Funding source is important for assessing bias and in generalizing trial results. Explicit mention of funding source was made in 145 of the trials (53 percent). Of these, 8 were federally funded, 10 reported some other source of funding, and 127 out of 274 trials (46 percent) were drug-company sponsored. We were able to determine additional types of support by drug companies in 113 of the trials, including those where funding source was not clear. Twelve (4 percent of the trials) had a drug-company employee as first author, 38 (14 percent of the trials) had a drug-company employee as co-author, 38 (14 percent of trials) supported the trial by providing medication and one trial (0.4 percent of trials) noted analytic support.
Generalizability also depends on the extent to which results are replicated in multiple locations. The trials spanned the world: Of the 274 included trials for which ata are available, continental Europe accounted for 74 (27 percent); United Kingdom, 56 (20 percent); North America,124 (45 percent -- includes United States, 118 [43 percent], Canada, 5 [2 percent], and Mexico, 1 [0.4 percent]); Asia, 10 (4 percent); Middle East, 2 (1 percent); Oceania, 5 (2 percent); Africa, 1 (0.4 percent); and Iceland, 1 (0.4 percent) for a total of 31 different countries (and one unknown). Although the whole world is represented, patients from American/British Commonwealth countries comprise two-thirds of the trials.
Generalizability is influenced by replication in multiple locations within a trial. Most trials were performed at one study site. Of the 251 trials for which data are available, 177 (71 percent) were single-site, 65 (26 percent) were multi-center, single-country, and 9 (4 percent) were multi-country.
Finally, generalizability is greatly affected by how subjects (patients) are enrolled into a trial. The further away from being a randomly chosen patient and the more selected a subject is through the clinical-care process, the less likely the study patient is to represent other patients. Of 274 trials, fully 203 (84 percent) gave no information regarding patient selection. Of those trials providing information (71), 45 (63 percent) stated that patients were "recruited" (although rarely with further details), and 19 (42 percent) stated that patients were selected as consecutive visitors to the clinic. Seven trials (3 percent) mentioned other methods. Whether subjects were recruited through a dermatology practice, a general practice, or from the general population is also an important consideration. It was rarely possible to determine this with any specificity in the trials reviewed.
Within trials, it is important that the arms be similar in arm comparability, judged on the basis of baseline patient characteristics. For 103 (38 percent) of the trials arm comparability could not be determined. In 90 trials (33 percent) the arms were definitely comparable, and 76 (28 percent) were judged as maybe comparable. Only 5 (2 percent) provided enough evidence to conclude that the arms were not comparable. Further details concerning baseline patient characteristics are provided in the next section (Patient Characteristics).
Trial design is important for internal validity as well. Most of the trials used standard, two-arm, parallel trial designs (259 [94 percent]). Only 15 (5 percent) of the trials used a cross-over design, where patients serve as their own controls over time, 30 (11 percent) were parallel trials with split-face design, where patients serve as their own controls spatially; and 22 (8 percent) were parallel trials with matched controls. While both cross-over and split-face design have the potential to control for baseline characteristics in the most patient-specific manner, it is crucial that, for cross-over studies, there be a wash-out period, and that, for split-face studies, the investigator should anticipate contamination of the opposite side of the face.25 For the most part, we were unable to determine this type of detail from the trials.
Treatment assignment is important for internal validity, with randomized assignment being the current gold standard. Relatively few trials (56, or 20 percent) gave enough information to conclude that the patients were randomly assigned, and 175 (64 percent) were stated to be randomized, with no further details. The rest either used deterministic methods of assignment -- i.e., the treatment was assigned using an attribute known by the investigator, such as date of birth or hospital identification number (9, or 3 percent) -- or gave no information at all (34, or 12 percent).
Treatment blinding is also important for maintaining high internal validity. Only 27 trials (10 percent) gave enough details to convince the abstracters that patient blinding was properly performed; 180 (66 percent) made a statement that blinding was performed, but with no further details; and 45 (16 percent) were explicit that patients were not blinded as to their treatment. Similarly, 41 trials (15 percent) convincingly demonstrated that the enrolling or treating physician was adequately blinded, while 177 (64 percent) only said that they were blinded, and 22 (8 percent) were clearly not blinded.
Compliance of patients with therapy is crucial in determining efficacy or effectiveness, and especially so with topical treatment. Seventy-four trials (27 percent) provided evidence that patients' compliance was addressed prospectively from trial onset. A further 17 (6 percent) discussed compliance retrospectively, 17 (6 percent) made statements suggestive of their concern about compliance, and 8 (3 percent) clearly ignored compliance. Fully 148 trials (54 percent) gave no indication one way or the other of this concern, and for 9 (3 percent), compliance monitoring was not applicable.
Trials varied in mode of treatment administration: 101 trials (37 percent) included systemic therapy, 183 trials (67 percent) included topical facial therapy, and 25 (9 percent) addressed other areas, like the back and chest. (Percent sums to greater than 100 percent because trials could address multiple areas.)
Trials excluded a variety of ancillary therapies used by all trial participants. The excluded ancillary treatments included other medications (110, or 40 percent), soaps (44, or 16 percent), and diet (9, or 3 percent); 129 trials (47 percent) mentioned ancillary therapy, but gave no details. A variety of other therapies were mentioned as being explicitly excluded: radiation therapy, sun bathing, unspecified powder, scalp shampoo, among others. We judged 124 trials (45 percent) as providing evidence that subjects received similar ancillary treatment. Seven trials (3 percent) clearly provided asymmetric ancillary therapy -- that is, the groups did not receive the same reatment, besides the treatment that was the focus of the trial. Fully 119 (43 percent) gave no information at all.
In terms of study execution, 45 trials (16 percent) had major losses to followup, while 107 (39 percent) had minor losses. Ninety-one trials (33 percent) documented virtually no such losses, while 31 (11 percent) did not provide enough data for an assessment. Beyond losses to followup, 7 trials (3 percent) reported protocol departures; 44 (16 percent) had minor such departures but 122 (45 percent) provided too little information to make any assessments. We judged 203 trials (74 percent) to have followed their design in execution and only 4 (1 percent) to definitely not have followed the plan, but this could not be determined for 14 trials (5 percent).
As a summary statement regarding external validity, we judged only 4 trials (1 percent) as being generalizable to the general population; 11 trials (4 percent), to more specific populations; and 9 (3 percent), to local populations. The great majority (152, or 55 percent) do not give enough data, while the remainder can be generalized only to the referral population (22, or 8 percent) or to any group beyond the study participants (76, or 28 percent).
| Patient characteristic cited as exclusion | Number of trials using criterion (percent)a |
|---|---|
| Type of acne | |
| Nodulocystic | 23 (8%) |
| Pustular | 5 (2%) |
| Inflammatory | 5 (2%) |
| Comedonal | 15 (5%) |
| Secondary | 30 (11%) |
| No exclusion based on type | 237 (86%) |
| Severity of acne | |
| Severe | 79 (29%) |
| Moderate | 10 (4%) |
| Mild | 82 (30%) |
| No exclusion based on severity | 124 (45%) |
| Age | |
| < 31 days | 49 (18%) |
| 31 days to 10 years | 39 (18%) |
| 11 to 14 years | 21 (7%) |
| 15 to 18 years | 1 (0.4%) |
| 19 to 34 years | 0 (0%) |
| 35 to 54 years | 28 (10%) |
| > 54 years | 35 (13%) |
| No exclusion based on age | 223 (81%) |
| Sex | |
| Female | 5 (2%) |
| Male | 14 (5%) |
| No exclusion based on sex | 255 (93%) |
| Other conditions | |
| Pregnancy | 63 (23%) |
| Lactation | 39 (14%) |
| Allergy | 45 (16%) |
| Other comorbidity | 68 (25%) |
| No patient characteristic based on exclusion criteria mentioned | 66 (24%) |
A trial may appear several times.
| Patient characteristic | Number of trials providing data (%) |
|---|---|
| Tanner stage | 0 (0%) |
| Age | 204 (74%) |
| Sex | 200 (73%) |
| Race | 23 (8%) |
| Skin type | 6 (2%) |
| Diet | 1 (0.4%) |
| Disease duration | 40 (14%) |
| Insurance status | 0 (0%) |
| Prescription plan | 0 (0%) |
| Source of care | 222 (81%) |
| Practice setting | 220 (80%) |
| Phase of care | 36 (13%) |
Eight trials stratified their results. Trials 35, 293, 111, and 277 stratified by gender. Trials 350, 16, 222, stratified by acne severity, and Trial 55 stratified by location.
As stated above, regarding exclusion criteria, acne severity was the most important patient characteristic, and it is the characteristic our experts raised most often in deciding on individual treatment profiles. In the process of reviewing the literature, 25 different methods of assessment for acne severity were identified. These methods were varied and included lesion counting on all or part of the face, comparison of the patients to a photographic standard, and comparison of the patients to a text description. Many trials did not report their method of assessment. The way in which severity was reported also differed between studies. Many used terminology, "mild, moderate or severe." Others used numerical scores such as 1-4, 0-10, etc. Neither terminology nor score was necessarily consistent across studies; so what was termed "grade 2 acne" in one trial might have been classified as "grade 6" according to a grading system in a different trial.
In our synthesis, an effort was made to standardize the reporting of acne severity so that more accurate comparisons could be made between trials. Terminology used here is the standard "mild, moderate, severe." Each trial was reviewed for the acne severity of the patients included in that study. The reported severity was converted to a "Combined Acne Severity Classification" as follows:
Trials Reporting Lesion
Count
The Combined Acne Severity
Classification was derived from the mean lesion counts and
standard deviations reported in the studies. The definitions
are:
Mild acne -- Fewer than 20 comedones, or fewer than 15 inflammatory lesions, or total lesion count fewer than 30.
Moderate acne -- 20-100 comedones, or 15-50 inflammatory lesions, or total lesion count 30-125.
Severe acne -- More than 5 cysts, or total comedo count greater than 100, or total inflammatory count greater than 50, or total lesion count greater than 125.
Trials Reporting an Acne Severity
Grade
Two reviewers evaluated each
grading system that was described in detail. These grading
systems, a few of which were frequently referenced, were
converted to the Combined Acne Severity Classification based on
how the grading system compared with the above definitions. This
conversion was straightforward in articles that used scoring
based on calculations from lesion counts. Some conversions, such
as the ones from photographic assessment or from text
descriptions, required judgement.
Trials Reporting Both Lesion Count and an Acne Severity
Grade
In some instances, studies
reported both lesion count and a severity grade. In this case,
the lesion count was used to determine the Combined Acne
Severity Classification.
Trials With No Reference to Assessment
Method
In some trials, severity
terminology was used with no reference as to how severity was
actually assessed. In these instances, the severity stated by
the author was kept as the combined acne severity
classification.
When no other information was
provided, the exclusion criteria were used to determine the
Combined Acne Severity Classification. Patients included were
assumed to be all of those not excluded, using the definitions
above to categorize the patients.
| Combined Acne Severity Classification | Allen274 | Burke and Cunliffe (Leeds)275 | Cook276 | Lucky230 | Michaelssona209 | Pochi67 | Pillsbury10 |
|---|---|---|---|---|---|---|---|
| Mild | 0 | 0 | 0 | None | 0-3 | Mild | 1 |
| Very mild | 4-20 | ||||||
| 2 | 0.25-0.5 | 2 | Mild | ||||
| Moderate | 4 | 0.75-1.5 | 4 | Moderate | 20-30 | Moderate | 2 |
| 6 | 6 | ||||||
| Severe | 8 | 2.0-10.0 | 8 | Severe | >30 | Severe | 3 |
| Very severe | 4 |
Michaelsson severity scores based on Cook's descriptions and using the following assumptions:
Cook 0 = 3 papules
Cook 2 = 20 comedones and 10 papules
Cook 6 = 30 papules
for the distribution of the
Combined Acne Severity Classification among the trials included in the
review. The trials were distributed as 21 percent (58) in mild/moderate
category, 49 (18 percent) in moderate/severe category and 51 (19 percent) in
moderate category. Only about 5 percent of the trials had patients
classified at either end of the scale, as either mild or severe. We were
unable to classify severity in about 22 percent (59) of the trials.
), we
needed data conditioned on source of care or practice setting. No trial
noted self-care or HMO as setting of care, 8 (3 percent) were performed
at a health clinic, 21 (8 percent) at a private practice, and 195 (71
percent) of the trials cited study clinic/hospital as practice setting.
Miscellaneous sites included schools or student centers and one military
clinic.Eight trials (3 percent) noted generalist as source of care while 68 trials (25 percent) were determined to have care provided by dermatologists. In 157 trials (57 percent) the source of care could not be determined beyond study clinic.
| Number of trials | Number of outcomes per trial | Total number of outcomes | ||||
|---|---|---|---|---|---|---|
| Average | SD | Median | Range | |||
| Continuous | 203 | 6.3 | 4.5 | 6.0 | 1-21 | 1,282 |
| Discrete | 221 | 2.9 | 3.1 | 2.0 | 1-35 | 637 |
| 1,919 | ||||||
SD - Standard deviation
| Outcome type | Total number of outcomes (percentage of outcomes) | Number of trials (percentage of trials) |
|---|---|---|
| Acne | 888 (70%) | 269 (98%) |
| Adverse effects | 335 (26%) | 174 (64%) |
| Psychological effects | 8 (1%) | 2 (1%) |
| Compliance | 43 (3%) | 43 (16%) |
| Cost | 0 (0%) | 0 (0%) |
| TOTAL | 1,274 | 274 |
| Outcome name | Number of trials | Percent of total trials |
|---|---|---|
| Overall change/physician | 51 | 6% |
| Overall change/patient | 34 | 4% |
| Inflammatory (count) | 33 | 4% |
| Inflammatory change (%) | 33 | 4% |
| Pustules (count) | 30 | 3% |
| Papules (count) | 29 | 3% |
| Comedones (count) | 24 | 3% |
| Non-inflammatory change (%) | 23 | 3% |
| Non-inflammatory (count) | 22 | 2% |
| Total lesions change (%) | 22 | 2% |
| Severity change | 16 | 2% |
| Severity (cook) | 14 | 2% |
| Total lesions (count) | 13 | 1% |
| Pustules change (%) | 12 | 1% |
| Papules change (%) | 12 | 1% |
| Severity (leeds) | 12 | 1% |
| Comedones change (%) | 11 | 1% |
| Open comedones (count) | 10 | 1% |
| Closed comedones (count) | 10 | 1% |
| TOTAL | 411 | 46% |
| Stated region | Number of trials |
|---|---|
| Face | 25 |
| Entire face | 11 |
| Face unspecified | 4 |
| Face excluding nose | 3 |
| 5 cm diameter | 2 |
| Both sides | 2 |
| Half face | 2 |
| Left side | 2 |
| Symmetric area of face | 2 |
| 2 cm worst | 1 |
| 3 + c face | 1 |
| 5 cm worst area | 1 |
| 5cm diameter-worst | 1 |
| Above jawline | 1 |
| Back | 1 |
| Bilateral cheeks | 1 |
| Both halves (except 1/2 midline overlap) | 1 |
| Butterfly | 1 |
| Chest | 1 |
| Designated area of face, chest and/or back | 1 |
| Each side of face | 1 |
| Entire (with estimate) | 1 |
| Entire face chest & back | 1 |
| Entire face-(photos) | 1 |
| Entire face-photo | 1 |
| Face & chest & back | 1 |
| Face (unspecified) | 1 |
| Face + or - other | 1 |
| Face above jawline | 1 |
| Face/neck | 1 |
| Left cheeks | 1 |
| Neck anterior to sternomastoid muscles and face | 1 |
| One side | 1 |
| Right | 1 |
| Selected area | 1 |
| Side of face | 1 |
| Side of face (spilt face trial) | 1 |
| Well defined regions | 1 |
| Witkowski/simons | 1 |
| Worst area | 1 |
| Worst area/5cm diameter | 1 |
| TOTAL | 85 |
For purposes of summarizing the data and for organizing the results, the treatments were divided into a number of classes. This classification was completed by consensus of our technical experts. The basis for the division was (1) similarity of pharmacological mechanism, and (2) similarity of perceived severity for which the treatment would be prescribed. For the first reason, anti-bacterials were grouped together, regardless of the specific class of antibiotic. For the second, topical and oral antibiotics were separated because most physicians would treat topically first, before using systemic therapy. Our goal in separating these classes was to find if the literature supported this established use.
| Treatment | Number of arms |
|---|---|
| Cleanser | 11 |
| Keratolytic | 22 |
| Anti-bacterial (topical) | 83 |
| Anti-bacterial/keratolytic (topical) | 54 |
| Retinoid (topical) | 84 |
| Anti-bacterial/retinoid (topical) | 10 |
| Anti-bacterial (oral) | 98 |
| Anti-bacterial (oral)/keratolytic | 19 |
| Anti-bacterial (oral)/retinoid (topical) | 4 |
| Retinoid (oral) | 26 |
| Anti-androgen | 35 |
| Other | 82 |
| Inert | 130 |
| TOTAL | 659 |
| Treatment | Description | Category | Currently manufactured | U.S. availability | Number of armsa |
|---|---|---|---|---|---|
| 16-epiestriol-3-allyl ether | Epimer of the estrogenic metabolite estriol | AA | No | No | 1 |
| Acidic syndet bar | A detergent that is not a soap, condensed from synthetic detergent | C | Yes | Yes | 1 |
| Adapalene | A topical retinoid-like compound | R | Yes | Yes | 15 |
| Alitretinoin | A natural retinoid with actions similar to all-trans-retinoic acid (tretinoin). | R | Yes | Yes | 1 |
| Aluminum chlorhydroxide | Astringent and antiperspirant properties | C | Yes | Yes | 3 |
| Aluminum chloride | Used in manufacturing, antiperspirants, andastringents | C | Yes | Yes | 1 |
| Azelaic acid | Naturally-occurring, saturated, straight-chained dicarboxylic acid | K | Yes | Yes | 8 |
| Bar soap | The sodium or potassium salts of long chain fatty acids | O | Yes | Yes | 1 |
| Benzoyl peroxide | Antibacterial, mildly comedolytic, and sebostatic agent | AB, K | Yes | Yes | 74 |
| Buttoxethyl nicotinate | Used in topical agents as a rubfacient (to cause redness) | O | Yes | Yes | 1 |
| Chloramphenicol | An antimicrobial agent | AB | Yes | Yes | 7 |
| Chlorhydroxyquinoline | Topical antibacterial, antifungal agent | AB | Yes | Yes | 2 |
| Cimetidine | H2-receptor antagonist | O | Yes | Yes | 2 |
| Clindamycin | A lincosamide antimicrobial agent | AB | Yes | Yes | 21 |
| Clindamycin hydrochloride | A lincosamide antimicrobial agent | AB | Yes | Yes | 6 |
| Clindamycin phosphate | A lincosamide antimicrobial agent | AB | Yes | Yes | 27 |
| Clobetasol propionate | The most potent topical corticosteroid available | O | Yes | Yes | 1 |
| Comedone extraction | Office procedure | O | Yes | Yes | 3 |
| Cotrimoxazole | Antibacterial agent comprised of trimethoprim (dihydrofolate reductase inhibitor antimicrobial agent) and sulfamethoxazole (an intermediate-acting sulfonamide) | AB | Yes | Yes | 4 |
| Cyproterone | An antiandrogen with progestogenic activity | AA | Yes | No | 16 |
| Dapsone | A sulfone antibiotic | AB | Yes | Yes | 2 |
| Delta-0.2%-chlormadione | A progestogen structurally related to progesterone | AA | Yes | No | 1 |
| Delta-5%-chlormadione | A progestogen structurally related to progesterone | AA | Yes | No | 1 |
| Demethylchlortetracycline | A bacteriostatic antimicrobial agent | AB | Yes | No | 6 |
| Desogestrel | A progesten used for contraception | AA | Yes | Yes | 6 |
| Doxycycline | A tetracycline antibiotic with a broad spectrum of activity | AB | Yes | Yes | 6 |
| E-solve | Vehicle for erythromycin/clindamycin | O | Yes | Yes | 1 |
| Electrocautery | Minimal burning of lesions via electricity | O | Yes | Yes | 1 |
| Emollient | An agent that softens or soothes the skin or irritation of the skin | O | Yes | Yes | 1 |
| Epiestriol | Epimer of the estrogenic metabolite estriol | AA | No | No | 1 |
| Erythromycin | A macrolide antibiotic | AB | Yes | Yes | 35 |
| Erythromycin acistrate | A macrolide antibiotic | AB | Yes | No | 1 |
| Erythromycin base | A macrolide antibiotic | AB | Yes | Yes | 2 |
| Erythromycin proprionate | A macrolide antibiotic | AB | No | No | 1 |
| Erythromycin stearate | A macrolide antibiotic | AB | No | No | 2 |
| Ethinyl estradiol | An estrogen component of oral contraceptives | AA | Yes | Yes | 28 |
| Etretinate | A derivative of tretinoin | R | Yes | No | 1 |
| Fractionated human dialyzable transfer factor | Leukocyte extract that passively transfers cell mediated immunity | O | Yes | Yes | 1 |
| Fulguration | A form of electrocautery | O | Yes | Yes | 2 |
| Fusidin cream | A steroidal antibiotic, chemically related to cephalosporin P | AB | Yes | No | 1 |
| Fusidic acid | A steroidal antibiotic, chemically related to cephalosporin P | AB | Yes | No | 2 |
| Gamma-globulin | Antibodies derived from human plasma | O | Yes | Yes | 1 |
| Gestodene | A progestogen structurally related to levonorgestrel | AA | Yes | No | 1 |
| Gluconolactone | Available as part of the orphan drug, glucono-delta-lactone and magnesium carbonate | K | No | Yes | 1 |
| Glycolic acid | An organic acid | K | Yes | Yes | 3 |
| Grenz rays | Superficial irradiation | O | No | No | 6 |
| Group therapy | A psychological method | O | Yes | Yes | 1 |
| Gugulipid | The oleoresin of the Indian herb Commiphora mukul or gum guggul. | O | Yes | Yes | 1 |
| Hexachlorophene | A polychlorinated bisphenol, which is an effective inhibitor of gram positive organisms | O | Yes | Yes | 2 |
| Hydrochlorthiazide | A thiazide diuretic | O | Yes | Yes | 2 |
| Hydrocortisone | A corticosteroid with both glucocorticoid and mineralocorticoid activity | O | Yes | Yes | 14 |
| Hydrocortisone F | A corticosteroid with both glucocorticoid and mineralocorticoid activity | O | Yes | Yes | 1 |
| Hydroxyquinoline | Class of agents with antibacterial, antifungal, and deodorant properties | AB | Yes | Yes | 2 |
| Ibuprofen | A non-steroidal anti-inflammatory drug | O | Yes | Yes | 3 |
| Inactive drug | Drug with no therapeutic effect | O | No | No | 1 |
| Inocoterone acetate | A topical, 5-alpha reductase inhibitor anti-androgen | AA | Yes | No | 1 |
| Ionax | Benzalkonium chloride, coal tar, salicylic acid | K | Yes | No | 1 |
| Isoconazole nitrate | An imidazole antifungal | AB | Yes | No | 1 |
| Isolutrol | Produced in the liver and gallbladder of sharks | O | Yes | No | 1 |
| Isotretinoin | A synthetic analogue of vitamin A | R | Yes | Yes | 28 |
| Komed® | A multiingredient preparation including salicylic acid, sodium thiosulfate, and isopropyl alcohol. | K | No | No | 2 |
| Meclocycline | A tetracycline antibiotic derived from oxytetracycline | AB | Yes | No | 1 |
| Meclocycline sulfosalicylate | A tetracycline antibiotic derived from oxytetracycline | AB | Yes | No | 3 |
| Methyl prednisolone | A corticosteroid and the methyl derivative of prednisolone | O | Yes | Yes | 5 |
| Metronidazole | A synthetic 5-nitroimidazole | AB | Yes | Yes | 4 |
| Miconazole | An antifungal agent | AB | Yes | Yes | 4 |
| Minocycline | A tetracycline antimicrobial agent | AB | Yes | Yes | 10 |
| Motretinide | A retinoid that inhibits the secretion of sebum | R | Yes | No | 5 |
| Neomycin | An aminoglycoside antimicrobial | AB | Yes | Yes | 10 |
| Nicotinamide | The amide metabolite of niacin | O | Yes | Yes | 1 |
| Norethisterone | A synthetic progestin | AA | Yes | Yes | 1 |
| Norgestimate | A progestogen structurally related to levonorgestrel | AA | Yes | Yes | 2 |
| Ocimum basilicum | Oil of sweet basil herb | O | No | No | 1 |
| Oleandomycin | A macrolide antibiotic | AB | Yes | No | 1 |
| Oxytetracycline | A tetracycline antimicrobial agent | AB | Yes | Yes | 8 |
| Petrolatum | A purified semi-solid mixture of hydrocarbons obtained from petroleum | O | Yes | Yes | 2 |
| Phenethicillin | A phenoxypenicillin | AB | Yes | No | 1 |
| Placebo | An inert substance given as a medicine for its suggestive effect | O | No | No | 98 |
| Polyethylene scrub | An abrasive substance used to unseat comedones and deter formation | O | No | No | 2 |
| Polyoprepolymer-2 | A mixture of glycols labeled according to average molecular weight | O | Yes | Yes | 2 |
| Polythionate | Therapeutically active form of sulfur | K | No | No | 2 |
| Potassium hydroxyquinoline | A mixture of potassium sulfate and quinolin-8-ol sulfate monohydrate with antibacterial, antifungal, and deodorant properties | AB | Yes | No | 2 |
| Povidone-iodine | A broad-spectrum germicidal agent | AB | Yes | Yes | 2 |
| Propylene phenoxetol | A preservative with anti-Pseudomonas activity | AB | Yes | Yes | 1 |
| Proteolytic enzymes | A protein that decomposes other enzymes | O | No | No | 1 |
| Pumice | An abrasive | C | Yes | Yes | 1 |
| Quaternary ammonia complex of polythionates | Therapeutically active form of sulfur | AB | No | No | 1 |
| Quinestradol | A synthetic oestrogen | AA | Yes | No | 1 |
| Relaxation-imagery | A psychological method | O | Yes | Yes | 1 |
| Resorcinol | An aromatic alcohol | O | Yes | Yes | 8 |
| Retinyl beta-glucuronide | Vitamin A metabolite | R | No | No | 2 |
| Roxithromycin | A macrolide antibiotic | AB | Yes | No | 2 |
| Salicylic acid | A topical keratolytic agent | K | Yes | Yes | 6 |
| Saline | Sodium is the principle cation of extracellular fluid and chloride is the principle anion of extracellular fluid | O | Yes | Yes | 1 |
| Serum gonadotrophin | Hormones supports and stimulates the function of the gonads (LH and FSH) | AA | No | No | 1 |
| Shankhabhasma vati | A traditional Indian formulation containing minerals derived from conch shells | O | No | No | 1 |
| Silicic acid | A silicon compound that occurs naturally as opal | K | No | No | 1 |
| Sodium fusidate | A steroidal antibiotic | AB | Yes | No | 2 |
| Sodium novobiocin | An antimicrobial which is structurally related to coumarin | AB | Yes | Yes | 1 |
| Sookshama triphala | A traditional Indian formulation containing dried fruits and minerals | O | No | No | 1 |
| Soybean liposome | No description found) | O | No | No | 2 |
| Spironolactone | A synthetic steroid aldosterone antagonist | AA | Yes | Yes | 7 |
| Staphylococcal toxoid | Detoxified toxins which retain their antigenicity and their immunizing capacity | O | No | No | 1 |
| Sulfadimethoxine | A long-acting sulfonamide | AB | Yes | No | 1 |
| Sulfamethoxazole | An intermediate-acting sulfonamide | AB | Yes | Yes | 2 |
| Sulfur | A pure chemical element with keratoplastic and keratolytic, as well as antifungal, antibacterial, and antiscabies activity | K | Yes | Yes | 24 |
| Sulfur-resorcinol salicylic acid | A combination of a pure chemical element with keratoplastic and keratolytic, as well as antifungal, antibacterial, and antiscabies activity, an aromatic alcohol, and a topical keratolytic agent | K | No | No | 1 |
| Sufur/salicylic acid | A combination of a pure chemical element with keratoplastic and keratolytic, as well as antifungal, antibacterial, and antiscabies activity, and a topical keratolytic agent | K | No | No | 1 |
| Sufurated lime | A mixture containing calcium sulfate and not less than 50% of calcium sulfide | K | Yes | No | 1 |
| Sunder vati | A traditional Indian formulation containing dried fruit, bark, and rhizones | O | No | No | 1 |
| Tea tree oil | Obtained by distillation from the leaves of the Australian tea tree, it contains about 50 to 60% of terpenes, cineole (up to 10%), and terpineol | O | Yes | Yes | 1 |
| Tetracycline | A bacteriostatic antimicrobial agent | AB | Yes | Yes | 33 |
| Tetracycline hydrochloride | A bacteriostatic antimicrobial agent | AB | Yes | Yes | 17 |
| Tetracycline phosphate | A bacteriostatic antimicrobial agent | AB | Yes | Yes | 1 |
| Tetracycline-citric acid | A bacteriostatic antimicrobial agent and excipient | AB | Yes | Yes | 1 |
| Tetracycline-novobiocin | Combination of a bacteriostatic antimicrobial agent and a stretomyces antibiotic | AB | Yes | No | 1 |
| Thiostanin | A traditional Indian formulation containing dried fruits, minerals and roots | K | No | No | 1 |
| Tolbutamide | A short-acting sulfonylurea | O | Yes | Yes | 1 |
| Topical treatment | Any traetment applied directly to the skin | O | No | No | 1 |
| Tretinoin | A retinoid derived from naturally occurring all-trans-retinol | R | Yes | Yes | 68 |
| Triacetyl-oleandomycin | An essential trace metal | AB | No | No | 2 |
| Triclosan | An antiseptic used in cosmetics and soaps | AB | Yes | Yes | 3 |
| Trimethoprim | A dihydrofolate reductase inhibitor antimicrobial agent | AB | Yes | Yes | 3 |
| Unfractionated human dialyzable transfer factor | Leukocyte extract that passively transfers cell mediated immunity | O | Yes | Yes | 1 |
| Unknown | Not able to determine what treatment was received | O | Yes | Yes | 1 |
| Untreated | Receiving no treatment | O | Yes | Yes | 3 |
| Urea | An osmotic diuretic, abortifacient, emollient, keratolytic, and diagnostic agent | K | Yes | Yes | 1 |
| Vehicle | A substance without therapeutic action used to administer medication | O | No | No | 78 |
| Vitamin A | A fat-soluble vitamin, it exists within the body as retinol, retinyl esters, retinal, and retinoic acid | R | Yes | Yes | 6 |
| Vitamin A palmitate | A fat-soluble vitamin, it exists within the body as retinol, retinyl esters, retinal, and retinoic acid | R | Yes | Yes | 2 |
| Water avoidance | Avoiding water | O | Yes | Yes | 1 |
| Zinc | An essential trace metal used topically as a drying agent | O | Yes | Yes | 4 |
| Zinc acetate | Mild astringent with inhibitory effects on copper absorption | O | Yes | Yes | 4 |
| Zinc gluconate | Mild astringent with inhibitory effects on copper absorption | O | Yes | Yes | 1 |
| Zinc sulfate | Mild astringent with inhibitory effects on copper absorption | O | Yes | Yes | 10 |
| Zinc sulfate monohydrate | Mild astringent with inhibitory effects on copper absorption | O | Yes | Yes | 1 |
| Zinc sulfate/citrate complex | Mild astringent with inhibitory effects on copper absorption | O | Yes | Yes | 1 |
| Zinc sulfur | Mild astringent with inhibitory effects on copper absorption | O | Yes | Yes | 2 |
| TOTAL | 859 |
Some arms are represented more than once because they employed more than one treatment.
| Target class | Comparator class | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Inert | Cleanser (topical) | Keratolytic (topical) | Anti-bacterial (topical) | Anti-bacterial/keratolytic (topical) | Retinoid (topical) | Anti-bacterial/retinoid (topical) | Anti-bacterial (oral) | Anti-bacterial (oral)/keratolytic (topical) | Anti-bacterial (oral)/retinoid (topical) | Retinoid (oral) | Anti-androgen | Other | Total | |
| Cleanser (topical) | 2 | 2 | --- | 1 | --- | 1 | --- | --- | --- | --- | --- | --- | --- | 6 |
| Keratolytic (topical) | 7 | 1 | 2 | 1 | 4 | 3 | --- | 1 | --- | --- | --- | --- | 1 | 20 |
| Anti-bacterial (topical) | 10 | 1 | 1 | 7 | 6 | --- | --- | 5 | --- | --- | --- | --- | 3 | 33 |
| Anti-bacterial/keratolytic (topical) | 5 | --- | 5 | 6 | 14 | 2 | --- | 2 | --- | --- | 1 | --- | 6 | 41 |
| Retinoid (topical) | 5 | --- | 3 | --- | 2 | 11 | --- | 1 | --- | --- | --- | --- | 2 | 24 |
| Anti-bacterial/retinoid (topical) | 1 | --- | --- | 1 | --- | 1 | --- | --- | --- | --- | --- | --- | --- | 3 |
| Anti-bacterial (oral) | 12 | --- | 1 | 8 | 2 | 1 | --- | 20 | --- | --- | 1 | 1 | 3 | 49 |
| Anti-bacterial (oral)/keratolytic (topical) | --- | --- | --- | --- | --- | --- | 1 | 1 | --- | 1 | --- | --- | --- | 3 |
| Anti-bacterial (oral)/retinoid (topical) | --- | --- | --- | --- | --- | --- | --- | 2 | 1 | --- | --- | --- | --- | 3 |
| Retinoid (oral) | 2 | --- | --- | --- | --- | --- | --- | 2 | --- | --- | 4 | --- | 1 | 9 |
| Anti-androgen | 10 | --- | --- | --- | --- | --- | --- | 2 | --- | --- | --- | 10 | 1 | 23 |
| Other | 16 | --- | 1 | 2 | 5 | 3 | --- | 3 | --- | --- | --- | --- | 7 | 38 |
| TOTAL | 70 | 4 | 13 | 26 | 33 | 22 | 1 | 39 | 1 | 1 | 6 | 11 | 24 | 250 |
Some arms are represented more than once because they employed more than one treatment.
This chapter summarizes the evidence collected. A summary of evidence is presented first, followed by separate discussions of the evidence for each treatment class. Most outcomes relate to therapeutic efficacy. Psychological and compliance outcomes are discussed at the end of the chapter.
We have detailed the evidence into seven types of evidence tables. A summary table lists overall information about every trial included in our synthesis. All two- and three-arm trials are summarized in a heading table, a continuous outcomes table, and a discrete outcomes table. Trials with more than three arms have their results summarized in the multi-arm heading table, multi-arm continuous outcomes table, and multi-arm discrete outcomes table. These tables may be found in Volume 2 of this evidence report, along with a comprehensive index to the evidence tables and a detailed description of the format and contents of each table type.
Our qualitative syntheses have three components. We first describe the trials in the comparison, highlighting from the evidence tables those features important in making our final assessment. For instance, we highlight methodological concerns that influence the assessment of the quality of the evidence. Note that these descriptions may include data from our review that are not presented in the evidence tables, due to space limitations, like funding relationships with pharmaceutical companies. We do not include instances in which it is reported that a pharmaceutical company funded a trial because half of the trials did not report source of funding. However, we do include instances in which a pharmaceutical employee is listed as an author or co-author of a study article because editors quite consistently indicate author affiliation.
Investigators used the term "effective" to cover a range of outcomes. We collected outcomes into three categories: subjective assessment overall (by patient or physician); assessment of severity on observed attributes only (e.g., Leeds score); and lesion count. We call a result in any category as "effective" if the trial demonstrated a statistically significant difference between arms, and we assign the highest assessment of evidence to difference that took baseline values into account (e.g., percent change of lesion counts).
Finally, we summarize the evidence in a table, indicating the direction of the relative effectiveness (> or =), the context of comparison (acne type or severity, if available), and an assessment of the strength of the evidence (levels A, B, and C).
Several criteria are used to determine into what category a given body of evidence lies. Trial quality, trial size, the size of the observed effect, the statistical evidence for effect (i.e., P-values and confidence intervals), and the number of trials all had weight in the summary judgment. In general, the minimum standard for "Level A" evidence is at least two trials of acceptable quality showing moderate to strong statistical evidence for a clinically meaningful endpoint and effect. "Level B" evidence is evidence of modest strength, which can occur when only one trial addresses a comparison, when several trials have somewhat different qualitative conclusions, when there are large differences that fall short of statistical significance, or when poor trial quality prevents accepting strong statistical evidence at face value. "Level C" evidence is evidence that does not permit coming to any scientific conclusion, either because of a paucity of evidence, conflicting evidence, or very poor quality evidence.
Descriptions of the trials focus on a number of features. The following are the default features that we do not comment on:
Parallel design
Mixed gender
Mixed ages (adolescent through adult)
Unless stated otherwise, the trials in the comparisons have these features or do not provide data in age or gender. The remainder of this section describes the features that we do describe.
We categorize sample size as very small (arm size less than 10), small (arm size less than 25), medium (25 to 50), and large (greater than 50). These distinctions are based on the t-test, the core statistical test in two-arm comparisons, and the one used most often in the trials under review here. In a two-sample t-test, 25 subjects in each arm usually suffices to detect a one-standard-deviation difference between groups. For instance, Cunliffe calculated a sample size of 65-75 patients per arm to detect a 15 percent relative difference, so smaller trials may not have enough statistical power to detect desired differences.26 For cross-over and split-face trials, the effective sample size is doubled, because of the increased power from using patients as their own control. Thus, a cross-over trial with 30 patients in each arm is like a two-sample trial with 60 patients in each arm, and we categorize those as large. On the other hand, as the number of arms goes up in a trial, the number of patients in an arm is smaller: A three-arm trial with 120 patients is medium.
The adequacy of sample size depends on the conclusion being sought. The designations in the previous paragraph apply to outcomes that demonstrate a difference. A larger sample size is necessary when drawing conclusions about equivalence. Hence, while we may conclude that sample size is sufficient to lead to a conclusion that one treatment is better than another, we will conclude that the sample size may only lead us to a Level B assessment of the evidence that two treatments are equivalent. Finally, because side effect rates are generally low, and because inference of low-rate events is sensitive to the numerator, we often assess the evidence regarding side effects as Level B or C.
We categorize ages in parallel to the stratification used by the Centers for Disease Control and Prevention: early adolescent, 10-15 years old; late adolescent, 15-19 years old; young adult, 20-24 years old.
Acne severity is discussed more fully in Chapter 3. If we were unable to assign a baseline acne severity category to a trial (i.e., "can't say" in the evidence tables), we will say that "acne severity could not be categorized" or something similar.
| Comparison index | N | Severity | Target | Relative efficacy | Comparator | Evidence strength | Comments |
|---|---|---|---|---|---|---|---|
| A.01.01 | 114 | Mild | Acidic syndet bar (topical) | Soap (topical) | C | ||
| A.01.015 | 50 | mod/sev | Aluminum oxide (topical) | Cleansers (topical) | C | ||
| A.01.02 | Mild/sev | Triclosan (topical) | Hexachlorophene (topical) | C | |||
| A.01.04 | 30 | Mild | Povidone-iodine (topical) | Vehicle (topical) | C | ||
| A.01.05 | 30 | Mod | Silicic acid (topical) | Vehicle (topical) | C | ||
| A.01.06 | Mild/mod | Soybean liposome/glycolic acid (topical) | Soybean liposome (topical) | C | |||
| B.01.01 | 132 | Azelaic acid (topical) | > | Vehicle (topical) | B | ||
| B.01.02 | 309 | Azelaic acid (topical) | = | Benzoyl peroxide (topical) | B | ||
| B.01.03 | Tretinoin (topical) | = | Azelaic acid (topical) | B | |||
| B.01.04 | Tetracycline (oral) | Clindamycin (oral) | C | ||||
| B.02.01 | Tretinoin (topical) | = | Azelaic acid (topical) | B | |||
| B.03.01 | 144 | Mild/mod | Salicylic acid (topical) | > | Placebo (topical) | B | |
| B.03.02 | Mild | Benzoyl peroxide (topical) | Salicylic acid (topical) | C | |||
| B.04.01 | Benzoyl peroxide (topical) | = | Sulfur/resorcinol (topical) | B | |||
| B.04.02 | Vitamin A (topical) | < | Keratolytics (topical) | B | "Keratolytics" includes benzoyl peroxide. From E.06.02. | ||
| B.05.01 | 72 | Mod | Polythionate/quaternary ammonia complex of polythionate (topical) | Polythionate (topical) | C | ||
| B.05.02 | 59 | Mod | Sulfurated lime (topical) | Vehicle (topical) | C | ||
| B.06.01 | 51 | Mild/sev | Komed (sulfur/salicylic acid/resorcinol) (topical) | Placebo (topical) | C | ||
| B.06.02 | 51 | Mild/sev | Komed (sulfur/salicylic acid/resorcinol) (topical) | Proprietary formula (sulfur/salicylic acid/resorcinol) | C | ||
| B.07.01 | 25 | Mild/mod | Aluminum chloride (topical) | Vehicle (topical) | C | ||
| B.07.02 | 776 | Aluminum chlorhydroxide/sulfur (topical) | > | Vehicle (topical) | A | ||
| B.07.03 | Methylprednisolone/neomycin (topical) | < | Aluminum chlorhydroxide/sulfur (topical) | C | |||
| B.07.04 | 150 | Mod/sev | Gluconolactone (topical) | > | Vehicle (topical) | B | inflammatory |
| B.07.05 | Mod/sev | Benzoyl peroxide (topical) | < | Gluconolactone (topical) | B | ||
| B.07.06 | 40 | Mild/mod | Glycolic acid/soybean liposome (topical) | Soybean liposome (topical) | C | ||
| B.07.07 | Mod | Clindamycin (topical) | Nicotinamide (topical) | C | |||
| C.01.01 | 716 | Mild/mod | Clindamycin (topical) | > | Vehicle (topical) | A | Clindamycin phosphate and hydrochoride results combined |
| C.01.02 | 76 | Mod | Clindamycin (topical) | Nicotinamide (topical) | C | ||
| C.01.03 | 753 | Mild/sev | Clindamycin (topical) | Clindamycin (topical) | C | Phosphate vs hydrochoride; lotion vs gel vs solution | |
| C.01.04 | 599 | Mild/sev | Clindamycin (topical) | = | Erythromycin (topical) | B | |
| C.01.05 | 144 | Mild/mod | Clindamycin (topical) | > | Tetracycline (topical) | B | |
| C.01.06 | 532 | Mod | Clindamycin phosphate (topical) | = | Benzoyl peroxide (topical) | B | |
| C.01.07 | 393 | Clindamycin (topical) | < | Clindamycine/benzoyl peroxide (topical) | B | ||
| C.01.08 | Mild/mod | Erythromycin/benzoyl peroxide (topical) | < | Clindamycin phosphate (topical) | B | ||
| C.01.09 | Zinc/erythromycin (topical) | < | Clindamycin phosphate (topical) | B | |||
| C.02.01 | Mod | Clindamycin/benzoyl peroxide (topical) | > | Vehicle (topical) | B | ||
| C.02.02 | Clindamycin (topical) | > | Clindamycine/benzoyl peroxide (topical) | B | |||
| C.02.03 | 472 | Mod | Clindamycin/benzoyl peroxide (topical) | > | Benzoyl peroxide (topical) | B | |
| C.03.01 | 1062 | Mild/mod | Erythromycin (topical) | > | Vehicle (topical) | A | Especially inflammatory |
| C.03.02 | Mild/sev | Clindamycin (topical) | = | Erythromycin (topical) | B | ||
| C.03.025 | 94 | mi/mod/sev | Erythromycin (topical) | Benzoyl peroxide (topical) | C | ||
| C.03.03 | Mod | Zinc/erythromycin (topical) | < | Erythromycin (topical) | B | ||
| C.04.01 | 135 | Fusiden (topical) | = | Vehicle (topical) | B | ||
| C.04.02 | Mild/mod | Doxycycline (oral) | = | Fusidic acid cream (topical) | B | ||
| C.04.03 | Mod/sev | Tetracycline/novobiocin (oral) | < | Placebo (oral) | B | ||
| C.05.005 | 351 | mod/sev | Meclocycline (topical) | > | Vehicle (topical) | B | Inflammatory |
| C.05.01 | 102 | Mod | Meclocycline (topical) | < | Benzoyl peroxide (topical) | B | Comedones |
| C.05.02 | Tetracycline (oral) | = | Azelaic acid (topical) | B | |||
| C.05.02 | Mild/mod | Tetracycline (oral) | = | Meclocycline sulfosalicylate (topical) | B | ||
| C.06.01 | 96 | Metronidazole (topical) | Placebo (topical) | C | |||
| C.07.01 | 79 | Neomycin (topical) | Keratolytics/anti-inflammatory (topical) | C | |||
| C.08.01 | 284 | Mild/mod | Tetracycline (topical) | = | Vehicle (topical) | A | |
| C.08.02 | Mild/mod | Clindamycin (topical) | < | Tetracycline (topical) | B | ||
| C.08.03 | 69 | Mod | Tetracycline (topical) | = | Benzoyl peroxide (topical) | B | |
| C.08.04 | Tetracycline (oral)/povidone-iodine | Tetracycline (oral) | C | ||||
| C.08.05 | Mod | Oxytetracycline (oral) | Tetracycline (topical) (oral) | C | |||
| C.08.05 | Oxytetracycline (oral) | Cotrimoxazole (oral) | C | ||||
| C.09.01 | 72 | Mild/mod | Triclosan (topical) | Vehicle (topical) | C | ||
| C.09.02 | 34 | Mild/sev | Triclosan (topical) | Hexachlorophene (topical) | C | ||
| C.09.03 | 72 | Mild/mod | Triclosan/propylene phenoxetol (topical) | Vehicle (topical) | C | ||
| D.01.01 | 1032 | Benzoyl peroxide (topical) | > | Vehicle (topical) | A | ||
| D.01.02 | Azelaic acid (topical) | = | Benzoyl peroxide (topical) | B | |||
| D.01.03 | 150 | Mod/sev | Benzoyl peroxide (topical) | > | Gluconolactone (topical) | B | |
| D.01.04 | 30 | Mild | Benzoyl peroxide (topical) | Salicylic acid (topical) | C | ||
| D.01.05 | 189 | Benzoyl peroxide (topical) | = | Sulfur/resorcinol (topical) | B | ||
| D.01.06 | Mod | Clindamycin phosphate (topical) | = | Benzoyl peroxide (topical) | B | ||
| D.01.07 | Mod | Meclocycline (topical) | > | Benzoyl peroxide (topical) | B | Comedones. From C.05.01. | |
| D.01.08 | Mod | Tetracycline (topical) | = | Benzoyl peroxide (topical) | B | ||
| D.01.09 | 796 | Mild/mod | Benzoyl peroxide (topical) | = | Benzoyl peroxide (topical) | A | |
| D.01.10 | 39 | Mod | Benzoyl peroxide (topical) | Benzoyl peroxide/urea (topical) | C | ||
| D.01.11 | Mod | Meclocycline/benzoyl peroxide (topical) | > | Benzoyl peroxide (topical) | B | Comedones. From D.06.01. | |
| D.01.12 | Mod/sev | Metronidazole/benzoyl peroxide (topical) | Benzoyl peroxide (topical) | C | |||
| D.01.13 | Mod | Tretinoin (topical) | < | Benzoyl peroxide (topical) | B | ||
| D.01.14 | Vitamin A (topical) | < | Keratolytics (topical) | B | "Keratolytics" includes benzoyl peroxide. From E.06.02. | ||
| D.01.15 | Mod | Oxytetracycline (oral) | Benzoyl peroxide (topical) | C | |||
| D.01.16 | Mild/mod | Isotretinoin (topical) | < | Benzoyl peroxide (topical) | B | ||
| D.01.17 | Mod/sev | Miconazole/benzoyl peroxide (topical) | < | Benzoyl peroxide (topical) | B | ||
| D.01.18 | Mod | Chloramphenicol/hydrocortisone/sulfur | Benzoyl peroxide (topical) | C | |||
| D.01.19 | Mild/mod | Isolutrol (topical) | Benzoyl peroxide (topical) | C | |||
| D.02.01 | Mild/mod | Chloramphenicol/hydrocortisone/sulfur | Chloramphenicol/sulfur (topical) | C | |||
| D.03.01 | 92 | Mild/mod | Benzoyl peroxide/glycolic acid/zinc sulfur (topical) | Placebo (topical) | C | ||
| D.03.02 | 161 | Mild/mod | Benzoyl peroxide/chlorhydroxyquinolone/hydrocortisone (topical) | Benzoyl peroxide/hydroxyquinolone (topical) | C | ||
| D.03.03 | 196 | Mild/mod | Benzoyl peroxide/chlorhydroxyquinolone/hydrocortisone (topical) | = | Benzoyl peroxide/chlorhydroxyquinolone (topical) | B | |
| D.03.04 | 113 | Mild/sev | Benzoyl peroxide/sulfur (topical) | > | Sulfur (topical) | B | |
| D.04.01 | 393 | Mod | Clindamycin/benzoyl peroxide (topical) | > | Vehicle (topical) | B | |
| D.04.02 | Clindamycin (topical) | > | Clindamycine/benzoyl peroxide (topical) | B | |||
| D.04.03 | Mod | Clindamycin/benzoyl peroxide (topical) | < | Benzoyl peroxide (topical) | B | ||
| D.05.01 | 92 | Mild/mod | Erythromycin/benzoyl peroxide (topical) | Placebo (topical) | C | medium | |
| D.05.015 | 177 | mod/sev | Erythromycin/benzoyl peroxide (topical) | Erythromycin, benzoyl peroxide (topical) | C | ||
| D.05.02 | 205 | Mild/mod | Erythromycin/benzoyl peroxide (topical) | > | Clindamycin phosphate (topical) | B | |
| D.05.03 | 92 | Mild | Erythromycin/benzoyl peroxide (topical) | Benzoyl peroxide/glycolic acid/zinc sulfur (topical) | C | medium | |
| D.05.04 | 72 | Erythromycin/benzoyl peroxide (topical) | Erythromycin/zinc (topical) | C | medium | ||
| D.05.05 | Relaxation training/erythromycin/benzoyl peroxide (topical) | Erythromycin/benzoyl peroxide (topical) | C | Similarly for Group therapy control. From N.06.03. | |||
| D.05.06 | Relaxation training/erythromycin/benzoyl peroxide (topical) | Erythromycin/benzoyl peroxide (topical) | C | Similarly for Group therapy control. From N.06.03. | |||
| D.06.01 | 102 | Mod | Meclocycline/benzoyl peroxide (topical) | < | Benzoyl peroxide (topical) | B | Comedones |
| D.07.01 | 43 | Mod/sev | Metronidazole/benzoyl peroxide (topical) | Vehicle (topical) | C | ||
| D.07.02 | 60 | Mod/sev | Metronidazole/benzoyl peroxide (topical) | Benzoyl peroxide (topical) | C | ||
| D.07.03 | Mod/sev | Oxytetracycline (oral) | Benzoyl peroxide/metronidazole (topical) | C | |||
| D.08.01 | 177 | Mod/sev | Miconazole/benzoyl peroxide (topical) | > | Benzoyl peroxide (topical) | B | |
| D.08.02 | 20 | Miconazole/benzoyl peroxide (topical) | Isoconazole/benzoyl peroxide (topical) | C | |||
| E.01.01 | 186 | Mod/sev | Adapalene (0.03%) (topical) | < | Adapalene (0.1%) (topical) | B | |
| E.01.02 | 1880 | Adapalene (topical) | = | Tretinoin (topical) | A | Evidence B that Adapalene more effective for non-inflammatory | |
| E.02.01 | 472 | Mild/mod | Isotretinoin (topical) | > | Vehicle (topical) | A | |
| E.02.02 | 77 | Mild/mod | Isotretinoin (topical) | > | Benzoyl peroxide (topical) | B | |
| E.02.03 | 82 | Isotretinoin (0.05% topical) | = | Isotretinoin (0.1% topical) | B | ||
| E.02.04 | 48 | Isotretinoin (topical) | Tretinoin (topical) | C | |||
| E.03.01 | 276 | Motretinide (topical) | Vehicle (topical) | C | |||
| E.03.02 | 60 | Mod/sev | Motretinide (bid) (topical) | = | Motretinide (qd) (topical) | B | |
| E.03.03 | 354 | Motretinide (topical) | = | Tretinoin (topical) | A | ||
| E.04.01 | 29 | Retinyl beta-glucuronide (topical) | Vehicle (topical) | C | |||
| E.04.02 | 15 | Retinyl beta-glucuronide (topical) | Tretinoin (topical) | C | |||
| E.05.01 | 1248 | Mild/mod | Tretinoin (topical) | > | Vehicle (topical) | A | Evidence type A for non-inflammatory; Type B for inflammatory. |
| E.05.015 | 60 | Tretinoin (topical) | Salicylate/resocinol/sulfur (topical) | C | |||
| E.05.02 | 494 | Mod | Tretinoin (topical) | > | Benzoyl peroxide (topical) | B | |
| E.05.03 | Motretinide (topical) | = | Tretinoin (topical) | A | |||
| E.05.04 | 359 | Tretinoin (topical) | = | Azelaic acid (topical) | B | ||
| E.05.05 | Isotretinoin (topical) | Tretinoin (topical) | C | ||||
| E.05.06 | Retinyl beta-glucuronide (topical) | Tretinoin (topical) | C | ||||
| E.05.07 | 1010 | Mild/sev | Tretinoin (topical) | = | Tretinoin (topical) | B | Compares different strengths. |
| E.05.08 | 68 | Tretinoin (topical) | Methylprednisolone/neomycin (topical) | C | |||
| E.05.09 | 56 | Mod | Tretinoin (topical) | = | Chloramphenical/hydrocortisone (topical) | B | |
| E.06.01 | 147 | Mild/mod | Vitamin A (topical) | > | Vehicle (topical) | B | Papules |
| E.06.02 | 189 | Vitamin A (topical) | > | Keratolytics (topical) | B | "Keratolytics" includes benzoyl peroxide | |
| E.06.03 | 238 | Vitamin A (topical) | = | Oxytetracycline (oral) | B | ||
| G.01.01 | 80 | Tretinoin/erythromycin (topical) | Vehicle (topical) | C | Other comparators as well. | ||
| G.02.01 | 475 | Mod/sev | Tretinoin/clindamycin (topical) | Clindamycin (topical) | B | Non-inflammatory | |
| G.02.02 | 358 | mod/sev | Tretinoin/clindamycin (topical) | > | Tretinoin (topical) | B | Inflammatory |
| G.02.03 | mod/sev | Tretinoin/clindamycin (topical) | Tetracycline (topical) | C | |||
| H.01.01 | 98 | Mod | Clindamycin (oral) | Vehicle (oral) | C | ||
| H.01.02 | 95 | Clindamycin (oral) | = | Tetracycline (oral) | B | ||
| H.02.01 | 401 | Demethylchlortetracycline (oral) | = | Vehicle (oral) | B | ||
| H.02.02 | 66 | Demethylchlortetracycline (oral) | Phenethicillin (oral) | C | |||
| H.02.03 | 250 | Demethylchlortetracycline (oral) | Tetracycline (oral) | C | |||
| H.03.01 | 62 | Mild | Doxycycline (oral) | > | Placebo (oral) | B | More effective for inflammatory. Equally effective in non-inflammatory.' |
| H.03.02 | 110 | Mild/mod | Doxycycline (oral) | = | Fusidic acid cream (topical) | B | |
| H.03.03 | 56 | Mod | Doxycycline (oral) | Erythromycin stearate (oral) | C | ||
| H.03.04 | 140 | Doxycycline (oral) | Minocycline (oral) | C | |||
| H.04.01 | Mod | Doxycycline (oral) | Erythromycin stearate (oral) | C | |||
| H.04.02 | 40 | Erythromycin base oral) | Erythromycin stearate (oral) | C | |||
| H.04.03 | 278 | Erythromycin (oral) | = | Tetracycline (oral) | B | ||
| H.04.04 | 91 | Mod/sev | Erythromycin (oral) | Triacetyl-oleandomycin (oral) | C | ||
| H.04.05 | 30 | Roxithromycin (150 mg) (oral) | Roxithromycin (300 mg) (oral) | C | |||
| H.04.06 | 142 | Oleandomycin (oral) | = | Triacetyl-oleandomycin (oral) | B | ||
| H.05.01 | 43 | Minocycline (oral) | > | Placebo (oral) | B | Inflammatory (P values not given). | |
| H.05.02 | 144 | Mod/sev | Minocycline (oral) | = | Clindamycin phosphate (topical) | B | |
| H.05.03 | Doxycycline (oral) | Minocycline (oral) | C | ||||
| H.05.04 | 266 | Mod/sev | Minocycline (oral) | = | Tetracycline (oral) | B | |
| H.06.01 | 76 | Mod/sev | Oxytetracycline (oral) | > | Placebo (oral) | B | |
| H.06.02 | 69 | Mod | Oxytetracycline (oral) | Benzoyl peroxide (topical) | C | ||
| H.06.03 | 52 | Mod/sev | Oxytetracycline (oral) | Benzoyl peroxide/metronidazole (topical) | C | ||
| H.06.04 | Vitamin A (topical) | = | Oxytetracycline (oral) | B | |||
| H.06.05 | 69 | Mod | Oxytetracycline (oral) | Tetracycline (topical) (oral) | C | ||
| H.06.05 | 69 | Oxytetracycline (oral) | Cotrimoxazole (oral) | C | |||
| H.06.06 | 16 | Mild/sev | Oxytetracycline (oral) | Cotrimoxazole (oral) | C | ||
| H.06.07 | 45 | Oxytetracycline (oral) | Trimethoprim (oral) | C | |||
| H.07.01 | 82 | Cotrimoxazole (oral) | > | Placebo (oral) | B | ||
| H.07.02 | 134 | Sev | Sulfadimethoxine (oral) | > | Placebo (oral) | B | |
| H.08.01 | 945 | Tetracycline (oral) | > | Vehicle (oral) | A | ||
| H.08.02 | 506 | Tetracycline (oral) | = | Clindamycin (topical) | B | ||
| H.08.03 | 54 | Mild/mod | Tetracycline (oral) | = | Erythromycin (topical) | B | |
| H.08.04 | 284 | Mild/mod | Tetracycline (oral) | Tetracycline (topical) | B | ||
| H.08.045 | 85 | Tetracycline (oral)/Tetracycline (topical) | Tetracycline (oral) | C | |||
| H.08.05 | 639 | Tetracycline (oral) | = | Azelaic acid (topical) | B | ||
| H.08.05 | 639 | mod/sev | Tetracycline/sodium novobiocin (oral) | Placebo (oral) | C | ||
| H.08.06 | 60 | Mild/mod | Tetracycline (oral) | = | Meclocycline sulfosalicylate (topical) | B | |
| H.08.07 | Clindamycin (oral) | = | Tetracycline (oral) | B | |||
| H.08.08 | 106 | Tetracycline (oral) | = | Tetracycline (oral) | B | See text for treatment details. | |
| H.08.085 | 42 | Mod/sev | Tetracycline/sodium novobiocin (oral) | Inert (oral) | C | ||
| H.08.09 | Sev | Isotretinoin (oral) | Tetracycline hydrochloride (oral) | C | |||
| H.08.11 | Sev | Gugulipid (oral) | Tetracycline (oral) | C | |||
| H.08.12 | Ocimum basilicum (topical) | Tetracycline (oral) | C | ||||
| H.08.13 | Mod/sev | Zinc sulfate/citrate complex (oral) | = | Tetracycline (oral) | B | ||
| H.08.14 | 30 | Tetracycline (oral)/povidone-iodine | Tetracycline (oral) | C | |||
| H.09.01 | 46 | Dapsone (oral) | Placebo (oral) | C | |||
| H.09.02 | 66 | Phenethicillin (oral) | Placebo (oral) | C | |||
| H.09.03 | Demethylchlortetracycline (oral) | Phenethicillin (oral) | C | ||||
| H.09.04 | 70 | Sodium fusidate (oral) | Sodium fusidate (topical) | C | |||
| H.09.05 | 91 | Mod/sev | Tetracycline/novobiocin (oral) | > | Placebo (oral) | B | |
| I.01.01 | 211 | Cotrimoxazole (oral)/sulfur/resorcinol (topical) | Cotrimoxazole (oral) | C | |||
| I.01.02 | 211 | Cotrimoxazole (oral)/sulfur/resorcinol (topical) | Cotrimoxazole (oral)/tretinoin | C | |||
| I.02.01 | 122 | Tetracycline (oral)/sulfur/salicylic acid/polyethylene scrub | = | Tretinoin/benzoyl peroxide/water avoidance (topical) | B | ||
| J.01.01 | 211 | Cotrimoxazole (oral)/Tretinoin (topical) | Cotrimoxazole (oral) | C | |||
| J.01.02 | 238 | Oxytetracycline (oral)/vitamin A (topical) | = | Oxytetracycline (oral) | A | ||
| J.01.03 | 122 | Tetracycline (oral)/tretinoin/emollient (topical) | > | Tetracycline (oral)/sulfur/salicylic acid/polyethylene scrub (topical) | B | Tretinoin/benzoyl peroxide equally effective (Type B) as tetracyucline/tretinoin. | |
| K.01.01 | Isotretinoin (oral) | Altretinoin (oral) | C | ||||
| K.02.01 | 33 | Sev | Isotretinoin (oral) | Placebo (oral) | C | ||
| K.02.02 | 40 | Sev | Isotretinoin (oral) | Dapsone (oral) | C | ||
| K.02.03 | 30 | Sev | Isotretinoin (oral) | Tetracycline hydrochloride (oral) | C | ||
| K.02.04 | 26 | Isotretinoin (oral) | Altretinoin (oral) | C | |||
| K.02.05 | 56 | Sev | Isotretinoin (oral) | Etretinate (oral) | C | medium | |
| K.02.06 | 378 | Sev | Isotretinoin (oral) | > | Isotretinoin (oral) | B | Some greater efficacy with higher doses |
| K.03.01 | 80 | Vitamin A (oral) | Placebo (oral) | C | |||
| K.03.02 | 64 | Mod/sev | Vitamin A (oral) | Zinc Sulfate (oral) | C | ||
| M.01.01 | 45 | Mild/mod | Cyproterone (topical) | Vehicle (topical) | C | ||
| M.01.02 | 98 | Mild/mod | Cyproterone/ethinyl estradiol (oral) | Minocycline hydrochloride (oral) | C | ||
| M.01.03 | 92 | Cyproterone/ethinyl estradiol (oral) | Tetracycline/placebo (oral) | C | |||
| M.01.04 | 45 | Mild/mod | Cyproterone/ethinyl estradiol (0.035) (oral) | Cyproterone (topical) | C | ||
| M.01.05 | 302 | Mod/sev | Cyproterone/ethinyl estradiol (0.05) (oral) | = | Cyproterone/ethinyl estradiol (0.035) (oral) | A | |
| M.01.06 | 90 | Mod/sev | Cyproterone (2 mg)/ethinyl estradiol (oral) | Cyproterone (0.05 mg)/ethinyl estradiol (oral) | C | ||
| M.01.07 | 411 | Cyproterone/ethinyl estradiol (0.035) (oral) | Desogestrel/ethinyl estradiol (oral) | C | |||
| M.01.08 | 133 | Cyproterone/ethinyl estradiol (0.035) (oral) | = | Levonorgestrel/ethinyl estradiol (0.030) (oral) | B | ||
| M.01.09 | 90 | Cyproterone (50)/ethinyl estradiol (oral) | Norethisterone/placebo/ethinyl estradiol (oral) | C | |||
| M.02.01 | 24 | Mild/mod | Desogestrel/ethinyl estradiol (oral) | Gestodene/ethinyl estradiol (oral) | C | ||
| M.02.02 | 87 | Mild/mod | Desogestrel/ethinyl estradiol (oral) | > | Levonorgestrel/ethinyl estradiol (oral) | B | |
| M.03.01 | 144 | Mild/sev | Spironolactone (oral) | > | Placebo (oral) | B | |
| M.04.01 | 20 | Delta-0.2%-chlormadione (oral) | Vehicle (oral) | C | |||
| M.04.02 | 20 | Delta-5%-chlormadione (oral) | Vehicle (oral) | C | |||
| M.04.03 | Delta-0.2%-chlormadione (oral) | Delta-5%-chlormadione (oral) | C | ||||
| M.04.04 | 134 | 16-epiestriol-3-allyl ether (oral) | = | Placebo (oral) | B | ||
| M.04.05 | 50 | Epiestriol (oral) | Vehicle (oral) | C | |||
| M.04.06 | 153 | Mod | Inocoterone acetate (oral) | > | Vehicle (oral) | B | Inflammatory lesions. Male patients |
| M.04.07 | Cyproterone/ethinyl estradiol (0.035) (oral) | = | Levonorgestrel/ethinyl estradiol (0.030) (oral) | B | |||
| M.04.08 | Cyproterone (50)/ethinyl estradiol (oral) | Norethisterone/placebo/ethinyl estradiol (oral) | C | ||||
| M.04.09 | 507 | Mild/mod | Norgestimate/ethinyl estradiol (oral) | > | Placebo (oral) | A | |
| M.04.10 | 60 | Mild/mod | Quinestradol (oral) | Placebo (oral) | C | ||
| M.04.11 | 40 | Mild/sev | Serum gonadotrophin (oral) | Placebo (oral) | C | ||
| N.01.01 | 82 | Ayurvedic remedies (oral) | Placebo (oral) | C | |||
| N.01.02 | 20 | Sev | Gugulipid (oral) | Tetracycline (oral) | C | ||
| N.01.03 | 70 | Mild/mod | Isolutrol (topical) | Benzoyl peroxide (topical) | C | ||
| N.01.04 | 51 | Ocimum basilicum (topical) | Tetracycline (oral) | C | |||
| N.01.05 | 124 | Mod | Tea tree oil (topical) | < | Benzoyl peroxide (topical) | B | Benzoyl peroxide better for inflammatory, not for non-inflammatory. |
| N.02.01 | 11 | Clobetasol (topical) | Vehicle (topical) | B | |||
| N.02.02 | 267 | Hydrocortisone/neomycin/sulfur/resorcinol (topical) | Components (topical) | C | |||
| N.02.03 | 188 | Hydrocortisone (topical) | Hydrocortisone/sulfur (topical) | C | |||
| N.02.04 | 776 | Methylprednisolone/neomycin (topical) | > | Vehicle (topical) | B | ||
| N.02.05 | 182 | Methylprednisolone/neomycin/sulfur (topical) | > | Vehicle (topical) | B | ||
| N.02.06 | 824 | Methylprednisolone/neomycin (topical) | > | Aluminum chlorhydroxide/sulfur (topical) | C | ||
| N.02.07 | Tretinoin (topical) | Methylprednisolone/neomycin (topical) | C | ||||
| N.03.01 | 40 | Gamma-globulin (parenteral) | Placebo (parenteral) | C | |||
| N.03.02 | 39 | Sev | Unfractionated dialyzable transfer factor (topical) | Fractionated dialyzable transfer factor (topical) | C | Also compared with saline. | |
| N.03.03 | 66 | Staphylococcal toxoid (topical) | Vehicle (topical) | C | |||
| N.04.01 | 32 | Mild/mod | Chloramphenicol/hydrocortisone | Vehicle (topical) | C | ||
| N.04.02 | 120 | Hydrocortisone/buttoxethyl nicotinate/chloramphenicol | > | Vehicle (topical) | B | Comedones | |
| N.04.03 | 50 | Mild/mod | Chloramphenicol/hydrocortisone/sulfur | Chloramphenicol/sulfur (topical) | C | ||
| N.04.04 | 37 | Chloramphenicol/hydrocortisone/sulfur | Hydrocortisone/sulfur (topical) | C | |||
| N.04.05 | 48 | Mod | Chloramphenicol/hydrocortisone/sulfur | Benzoyl peroxide (topical) | C | ||
| N.04.06 | Mod | Tretinoin (topical) | = | Chloramphenical/hydrocortisone (topical) | B | ||
| N.05.01 | 250 | Grenz rays | Sham rays | C | |||
| N.05.02 | 32 | Comedone extraction (cheeks/forehead) | Untreated | C | |||
| N.05.03 | 11 | Fulguration | Tretinoin (topical) | C | |||
| N.05.04 | 12 | Fulguration | Electrocautery | C | |||
| N.06.01 | 50 | Mod/sev | Cimetidine [men] (oral) | Cimetidine [women] (oral) | C | ||
| N.06.02 | 42 | Mod | Contingent contract/benzoyl peroxide (topical) | Benzoyl peroxide (topical) | C | Similarly for non-contingent contract/benzoyl peroxide (topical) | |
| N.06.03 | 30 | Relaxation training/erythromycin/benzoyl peroxide (topical) | Erythromycin/benzoyl peroxide (topical) | C | Similarly for group therapy control | ||
| N.06.04 | 92 | Hydrochlorthiazide (oral) | Vehicle (oral) | C | |||
| N.06.045 | 68 | mild/mod | Ibuprofen/tetracycline (oral) | Placebo (oral) | C | ||
| N.06.05 | 30 | Mod | Tolbutamide (oral) | Vehicle (oral) | C | ||
| N.07.01 | 30 | Mild/mod | Zinc (topical) | Vehicle (topical) | C | ||
| N.07.02 | 515 | Zinc sulfate (oral) | > | Placebo (oral) | B | ||
| N.07.03 | 88 | Mod/sev | Zinc sulfate/citrate complex (oral) | = | Tetracycline (oral) | B | |
| N.08.01 | 244 | Zinc/erythromycin (topical) | Vehicle (topical) | C | |||
| N.08.02 | 167 | Mod | Zinc/erythromycin (topical) | > | Erythromycin (topical) | B | |
| N.08.03 | 103 | Zinc/erythromycin (topical) | > | Clindamycin phosphate (topical) | B | ||
| N.08.04 | 149 | Mild | Zinc/erythromycin (topical)/placebo (oral) | Tetracycline (oral)/placebo (topical) |
NOTE: Some arms are represented more than once because they employed more than one treatment.
| Comparison index | Target arm | Target side effects | Comparator arm | Comparator side effects | Relative efficacy | Assessment of evidence | Comments |
|---|---|---|---|---|---|---|---|
| A.01.01 | Acidic syndet bar (topical) | Itching/redness/scaling (4%: 2/57) | Soap | Itching/redness/scaling (21%: 12/57) | B | ||
| A.01.02 | Hexachlorophene | Withdrew: erythema, soreness (10%: 3/34) | Triclosan (topical) | Withdrew: erythema, soreness (6%: 2/34) | C | From C.09.02. | |
| A.01.03 | Vehicle | ** | Tretinoin (topical) | ** | < | A | Local reactions. From E.05.01. |
| B.01.03 | Azelaic acid | Erythema (15%: 27/177); scaling (14%: 24/177) | Tretinoin (topical) | Erythema (27%: 48/181); scaling (29%:52/181) | < | A | From E.05.04. |
| B.02.01 | Azelaic acid | Erythema (15%: 27/177); scaling (14%: 24/177) | Tretinoin (topical) | Erythema (27%: 48/181); scaling (29%:52/181) | < | A | From E.05.04. |
| B.07.05 | Gluconolactone | Local reactions (14%: 11/75) | Benzoyl peroxide (topical) | Local reactions (29%: 22/75) | < | B | From D.01.03. |
| B.07.05 | Gluconolactone (topical) | Local reactions (25%: 11/45) | Vehicle | Local reactions (11%: 5/45) | > | B | |
| B.07.06 | Soybean liposome (topical) | Withdrawals (0) | Glycolic acid/soybean liposome | Withdrawals (2/20) | C | ||
| B.07.07 | Nicotinanide | Local reactions (26%: 10/38) | Clindamycin (topical) | Local reactions (24%: 9/38) | C | From C.01.02. | |
| C.01.01 | Clindamycin (topical) | Severe: burning (0.2%: 1/539) | Vehicle | Severe: 0 | = | B | |
| C.01.02 | Clindamycin (topical) | Local reactions (24%: 9/38) | Nicotinanide | Local reactions (26%: 10/38) | C | ||
| C.01.04 | Clindamycin (topical) | Withdrew: 0/264 | Erythromycin (topical) | Withdrew (0.4%: 1/252) | = | A | |
| C.01.06 | Clindamycin phosphate (topical) | * | Benzoyl peroxide | * | = | B | |
| C.01.07 | Clindamycin (topical) | Peeling (8%: 7/79) | Clindamycine/benzoyl peroxide | Peeling (22%: 21/95) | < | B | |
| C.01.08 | Clindamycin phosphate | Withdrew (0/100) | Erythromycin/benzoyl peroxide (topical) | Withdrew (3%: 3/99) | = | B | From D.05.02. |
| C.01.09 | Clindamycin phosphate | Withdrew (0/52) | Zinc/erythromycin (topical) | Withdrew (2%: 1/51) | = | B | From N.08.03. |
| C.02.01 | Clindamycin/benzoyl peroxide (topical) | Peeling (22%: 21/95) | Vehicle | Peeling (16%: 9/58) | > | B | |
| C.02.03 | Clindamycin/benzoyl peroxide (topical) | Peeling (22%: 21/95) | Benzoyl peroxide | Peeling (21%: 19/92) | = | B | |
| C.03.01 | Erythromycin (topical) | Withdraw/severe (0.6%: 2/330) | Vehicle | Withdraw/severe (0.3%: 1/330) | = | A | Across 4 studies |
| C.03.02 | Erythromycin (topical) | Withdrew (0.4%: 1/252) | Clindamycin (topical) | Withdrew: 0/264 | = | A | From C.01.04. |
| C.03.025 | Erythromycin (topical) | Withdrew: dermatitis (2%: 1/48) | Benzoyl peroxide (topical) | Withdrew: dermatitis (2%:1/49) | C | ||
| C.03.03 | Erythromycin | Withdrew (2/61) | Zinc/erythromycin (topical) | Withdrew (2/61) | = | B | From N.08.02. |
| C.08.01 | Tetracycline (topical) | Skin discoloration (40%: 17/43); stinging (77%: 33/43) | Placebo | Skin discoloration (10%: 4/42); stinging (77%: 30/42) | > | B | Evidence comparison for skin discoloration |
| C.09.02 | Triclosan (topical) | Withdrew: erythema, soreness (6%: 2/34) | Hexachlorophene | Withdrew: erythema, soreness (10%: 3/34) | C | ||
| D.01.01 | Benzoyl peroxide (topical) | Local reactions (29%: 22/75) | Vehicle | Local reactions (6%: 5/75) | > | B | |
| D.01.03 | Benzoyl peroxide (topical) | Local reactions (29%: 22/75) | Gluconolactone | Local reactions (14%: 11/75) | > | B | |
| D.01.06 | Benzoyl peroxide | * | Clindamycin phosphate (topical) | * | = | B | From C.01.06. |
| D.01.09 | Benzoyl peroxide (2.5%) (topical) | * | Benzoyl peroxide (5%) | * | C | Mix of mild and moderates side effects | |
| D.01.13 | Benzoyl peroxide (alcohol) | Local reactions (16%: 22/137) | Tretinoin (topical) | Local reactions (13%: 13/98) | = | B | Benzoyl peroxide with acetone had apparently fewer local reactions. From E.05.02. |
| D.01.15 | Benzoyl peroxide/placebo (oral) | Severe: Facial reaction (4%: 1/24) | Oxytetracycline (oral)/vehicle | Severe (0/22) | C | From H.06.02. | |
| D.01.16 | Benzoyl peroxide | Erythema (38%: 10/26) | Isotretinoin (topical) | Erythema (0/25) | C | Other side effects recorded. From E.02.02. | |
| D.01.19 | Benzoyl peroxide | * | Isolutrol (topical) | * | C | Local reactions. Between-arm P-values significant. From N.01.03. | |
| D.03.02 | Benzoyl peroxide/hydroxyquinoline +hydrocortisone | * | Benzoyl peroxide/hydroxyquinoline | * | C | ||
| D.04.01 | Clindamycin/benzoyl peroxide | Peeling (22%: 21/95) | Vehicle | Peeling (16%: 9/58) | > | B | |
| D.04.02 | Clindamycine/benzoyl peroxide | Peeling (22%: 21/95) | Clindamycin (topical) | Peeling (8%: 7/79) | > | B | From C.01.07. |
| D.04.03 | Benzoyl peroxide | Peeling (21%: 19/92) | Clindamycin/benzoyl peroxide (topical) | Peeling (22%: 21/95) | = | B | From C.02.03. |
| D.05.01 | Erythromycin/benzoyl peroxide (topical) | Scaling/tightness (30%: 14/46) | Placebo | Scaling/tightness (7%: 3/46) | C | ||
| D.05.02 | Erythromycin/benzoyl peroxide (topical) | Withdrew (3%: 3/99) | Clindamycin phosphate | Withdrew (0/100) | = | B | |
| D.05.03 | Erythromycin/benzoyl peroxide (topical) | Scaling/tightness (44%: 14/32) | Zinc/erythromycin (topical) | Scaling/tightness (13%: 4/30) | C | ||
| D.08.02 | Miconazole/benzoyl peroxide (topical) | Local reactions (38%: 6/16) | Isoconazole/benzoyl peroxide | Local reactions (38% 6/16) | C | ||
| E.01.01 | Adapalene (0.03%) (topical) | Severe erythema (0/24) | Adapalene (0.1%) | Severe erythema (4%: 1/24) | C | ||
| E.01.02 | Adapalene (topical) | * | Tretinoin | * | < | B | |
| E.02.01 | Isotretinoin (0.05%) (topical) | ** | Vehicle | ** | > | A | Erythema and peeling scores give significant P-values between arms |
| E.02.02 | Isotretinoin (topical) | Erythema (0/25) | Benzoyl peroxide | Erythema (38%: 10/26) | C | Other side effects recorded. | |
| E.02.04 | Isotretinoin (topical) | Local reactions+E59 (89%: 93/104) | Tretinoin | Local reactions (62%: 61/98) | > | B | |
| E.03.01 | Motretinide (topical) | * | Vehicle | * | = | B | |
| E.03.03 | Motretinide (topical) | ** | Tretinoin | ** | > | A | Local reactions |
| E.05.01 | Tretinoin (topical) | ** | Vehicle | ** | > | A | Local reactions. |
| E.05.02 | Tretinoin (topical) | Local reactions (13%: 13/98) | Benzoyl peroxide (alcohol) | Local reactions (16%: 22/137) | = | B | Benzoyl peroxide with acetone had apparently fewer local reactions. |
| E.05.04 | Tretinoin (topical) | Erythema (27%: 48/181); scaling (29%:52/181) | Azelaic acid | Erythema (15%: 27/177); scaling (14%: 24/177) | > | A | |
| E.05.05 | Tretinoin | Local reactions (62%: 61/98) | Isotretinoin (topical) | Local reactions+E59 (89%: 93/104) | < | B | From E.02.04. |
| E.05.07 | Tretinoin (0.02% to 0.1%) | ** | Tretinoin (lower strengths) | ** | > | B | Local reactions. One large study with significantly different rates, the other without statistical significance. |
| E.06.01 | Vitamin A (topical) | Erythema (94%: 47/50) | Vehicle | Erythema (0/25) | > | B | |
| G.02.01 | Tretinoin/clindamycin (topical) | * | Clindamycin (topical) | * | = | B | |
| H.01.01 | Clindamycin (oral) | Withdrew: pseudomembranous colitis (2%: 1/42) | Vehicle | Withdrew: 0/39 | C | ||
| H.02.01 | Demethylchlor-tetracycline (oral) | Photosensitivity (64%:46/72) | Placebo | Photosensitivity (5%: 3/56) | > | B | |
| H.02.03 | Demethylchlor-tetracycline (oral) | * | Tetracycline | * | = | B | |
| H.03.04 | Doxycycline/placebo (oral) | Withdrawals: headache/dyspepsia (5%: 2/39) | Minocycline/placebo | Withdrawals: dyspepsia, nausea, vertigo (5%: 3/29) | C | ||
| H.04.01 | Tetracycline | Withdrew: vaginal candidiasis (2% 1/50), visual disturbance 2% (1/50) | Minocycline (oral) | Withdrew: vaginal candidiasis (2%: 1/50), persistent headache (2%: 1/50) | = | B | From H.03.03. |
| H.04.02 | Erythromycin (base) (oral) | Withdrew: gastrointestinal distress (20%: 4/20) | Erythromycin (stearate) | Withdrew: gastrointestinal distress (4%: 1/20) | C | ||
| H.04.03 | Erythromycin (oral) | Withdrew (7%: 7/100) | Tetracycline (oral) | Withdrew (2%: 2/100) | = | B | |
| H.05.01 | Minocycline (oral) | Withdrew: vertigo (4%: 1/19), urticaria (4%: 1/18) | Placebo | Withdrew 0/18 | C | ||
| H.05.03 | Minocycline/placebo | Withdrawals: dyspepsia, nausea, vertigo (5%: 3/29) | Doxycycline/placebo (oral) | Withdrawals: Headache/dyspepsia (5%: 2/39) | C | From H.03.04. | |
| H.05.04 | Minocycline (oral) | Withdrew: Vaginal candidiasis (2%: 1/50), persistent headache (2%: 1/50), hives (1/52) | Tetracycline | Withdrew: Vaginal candidiasis (2% 1/50), visual disturbance 2% (1/50) | = | B | |
| H.06.02 | Oxytetracycline (oral)/vehicle | Severe (0/22) | Benzoyl peroxide/placebo (oral) | Severe: Facial reaction (4%: 1/24) | C | ||
| H.06.07 | Oxytetracycline (oral) | Withdrew (0/8) | Trimethoprim | Withdrew (25%: 2/8) | C | ||
| H.08.045 | Tetracycline (oral)/tetracycline (topical) | Nausea (22%: 9/41) | Tetracycline (oral) | Nausea (12%:5/41) | C | ||
| H.08.09 | Tetracycline | Cheilitis (20%: 5/15) | Isotretinoin (oral) | Cheilitis (100%:15/15) | C | Other side effects recorded. From K.02.03. | |
| H.09.01 | Dapsone (oral) | Side effects (26%: 6/23) | Placebo | Side effects (13%: 3/23) | C | ||
| I.01.01 | Cotrimoxazole (oral)/sulfur/resorcinol (topical) | Withdrew: erythema (7%: 5/71); desquamation (13%: 9/71), erythema (37%: 26/71) | Cotrimoxazole/tretinoin | Withdrew: erythema (28%: 19/69); desquamation (36%: 25/69), erythema (75%: 52/69) | < | B | |
| J.01.02 | Oxytetracycline (oral)/vitamin A (topical) | Erythema or desquamation (84%: 66/79) | Oxytetracycline (oral)/vehicle (topical) | Erythema or desquamation (32%: 25/79) | > | B | |
| K.02.01 | Isotretinoin (oral) | Arthralgia (6%: 1/16) | Placebo (oral) | Arthralgia (0/17) | C | ||
| K.02.02 | Isotretinoin (oral) | Cheilitis (85%:17/20); withdrew (0/20) | Dapsone (oral) | Cheilitis (0/20); withdrew: hypersensitivity (4%: 1/20) | C | ||
| K.02.03 | Isotretinoin (oral) | Cheilitis (100%:15/15) | Tetracycline | Cheilitis (20%: 5/15) | C | Other side effects recorded | |
| K.02.06 | Isotretinoin (0.1) (oral) | Cheilitis (84%:27/32); severe symptoms (14%:3/22) | Isotretinoin (1.0) (oral) | Cheilitis (96%:23/24); severe symptoms (46%:11/24) | C | Other side effects recorded, plus data for 0.5 mg/kg dose | |
| M.01.05 | Cyproterone/ethinyl estradiol (0.05 mg) (oral) | Withdrew (6%: 8/141); severe (6%: 7/141) | Cyproterone/ethinyl estradiol (0.035 mg) (oral) | Withdrew (4%: 6/134); severe (12%: 20/134) | = | B | |
| M.02.02 | Desogestrel/ethinyl estradiol (oral) | Withdrew: worse acne (8%: 2/26) | Levonorgestrel/ethinyl estradiol | Withdrew: worse acne (14%: 4/28) | C | ||
| M.03.01 | Spironolactone (oral) | Withdrew: severe nausea (3%: 2/58); menstrual irregularity (19%: 11/58) | Placebo | Withdrew: severe nausea (0/58); menstrual irregularity (0%: 0/58) | > | B | Menstrual irregularity |
| M.04.06 | Inocoterone acetate (oral) | Local reactions (41% : 32/78) | Vehicle | Local reaction (32% : 24/75) | = | B | |
| M.04.08 | Norgestimate/ethinyl estradiol (oral) | Withdrew (10% : 13/126) | Placebo | Withdrew (4% : 5/129) | > | B | |
| N.01.03 | Isolutrol (topical) | * | Benzoyl peroxide | * | C | Local reactions. Between-arm P-values significant. | |
| N.01.05 | Tea tree oil (topical) | Local reactions (44%: 27/61) | Benzoyl peroxide | Local reactions (82%: 50/61) | < | B | |
| N.04.01 | Chloramphenicol/hydrocortisone | Withdrew (0/15) | Vehicle | Withdrew (33%: 5/15) | C | ||
| N.05.04 | Fulguration | Withdrew: hypopigmentation (18%: 2/11), discomfort (9%: 1/11) | Tretinoin | Withdrew (0/11) | C | ||
| N.06.045 | Ibuprofen/tetracycline (topical) | Withdrew: (6%: 1/17) | Placebo | Withdrew: (6%: 1/17) | C | Similarly for the tetracycline-only and the ibuprofen-only arms. | |
| N.07.02 | Zinc (oral) | Withdrew: gastrointestinal distress (8%: 10/137); gastrointestinal symptoms (16%: 22/137) | Placebo (oral) | Withdrew (0/127); gastrointestinal distress (6%: 6/98) | = | B | Comparison of withdrawals. Comparison is > (Level B) for gastrointestinal distress. Pooled trials that reported side effects. |
| N.08.02 | Zinc/erythromycin (topical) | Withdrew (2/61) | Erythromycin | Withdrew (2/61) | = | B | |
| N.08.03 | Zinc/erythromycin (topical) | Withdrew (2%: 1/51) | Clindamycin phosphate | Withdrew (0/52) | = | B |
*/**Represents multiple outcomes.
NOTE: Some arms are represented more than once because they employed more than one treatment.
There is one medium trial, Trial 197,27 of late adolescents and young adults with mild acne. Although patients were not blinded, the trial was randomized and the enroller was blinded. Both cleansers statistically significantly reduced the count of inflammatory lesions, but there was no statistical difference between the two. The effect on non-inflammatory lesions was not statistically significant. The syndet bar resulted in statistically significantly fewer side effects (itching, redness, scaling).
There was one small five-arm trial, Trial 23928 that studied the cleansers or abradants aluminum oxide, polystyrene, polyethylene, polyester, and pumice in patients with moderate to severe acne. Patients were not randomized, physicians were not blinded, there were no losses to followup, and the arms were not comparable. Outcomes focused on non-inflammatory lesions; differences were not statistically significant.
See C.09.02.
See E.05.01.
There was one small trial, Trial 235,29 of mildly affected patients for which treatment details are not provided and there were major losses to followup. No comparison statistics are provided. There was a single case of itching in the vehicle group.
There was one medium trial, Trial 204,30 of subjects with moderate acne. Although silicic acid produced greater reductions in lesion counts relative to vehicle, these differences were not statistically significant. No data about side effects were reported.
See B.07.06.
There were two trials: one small British trial, Trial 77,31 and one medium Greek trial, Trial 187.32 The Greek trial studied subjects with moderate acne; the British trial matched subjects, but the acne severity cannot be categorized. Both trials were randomized and measured changes in inflammatory and non-inflammatory lesions.
Both trials showed statistically significant reductions in inflammatory and non-inflammatory lesions at 2-3 months in subjects treated with azelaic acid. Trial 187 also showed a significant improvement in physician rating of overall change.
Side effects, including burning, erythema, itching, and scaling were reported in small numbers in both treatment and placebo groups.
There was one large (N = 309) trial, Trial 52.33 Limited information about the subjects and methodology was provided. Although significant changes from baseline were reported in both treatment groups, neither treatment was superior in the short-, medium-, or long-term (maximum followup = 24 weeks). No between-group P-values were reported. The authors reported that benzoyl peroxide produced a more rapid effect.
No specific information about side effects was reported, although the authors stated that azelaic acid applications were "better tolerated."
See E.05.04.
See H.08.05.
See E.05.04.
There were two trials, a large matched-control trial of 114 patients, Trial 95,34 of 2 percent salicylic acid and a medium parallel trial, Trial 294,35 of 1.5 percent salicylic acid. Trial 95 had serious methodological flaws as almost half the subjects departed from protocol at some point secondary to side effects.
Both trials reported greater improvements from baseline in the group treated with salicylic acid. In the matched-control trial, these differences were statistically significant at 12 weeks but not at 4 weeks. In Trial 294, salicylic acid led to an apparently greater improvement in facial oiliness, but comparison statistics were not provided.
The parallel trial reported local reactions (skin and eye burning) in 10 subjects in the salicylic acid group and none in the placebo group. No P-values were provided. No side effects data were reported in the large trial.
See D.01.04.
See D.01.05.
See E.05.015.
See E.06.02.
There was one medium trial, Trial 86,36 where acne severity could not be categorized. Although treatment duration was not specified, data were given at 1 year, at which time overall change was comparable between the two groups. The authors reported that there were no side effects.
There was one medium trial, Trial 101,37 of patients with moderate acne. The single efficacy outcome, subjectively assigned severity change, was statistically significantly better in the treatment group, with two-thirds moderately or excellently improved versus one-quarter in the vehicle group. No side effects data were reported.
There was one large (N=51) split-face trial, Trial 191,38 of subjects with mild, moderate, and severe acne. Subjects were a referral population and there were no reported losses to followup. The one outcome was physicians' assessment of superiority of one face-side versus the other. Komed® was rated as better on both sides of the face, although comparison statistics were not provided. No data about side effects were reported.
There was one large (N=51) split-face trial, Trial 191,38 of subjects with mild, moderate, and severe acne. Subjects were a referral population and there were no reported losses to followup. Treatment was administered for 16 weeks, with followup for up to 36 weeks. The outcome measured was overall change in acne by physician assessment. The one outcome was physicians' assessment of superiority of one face-side versus the other. Komed® was ated as about the same as the proprietary formula, although the numbers are small. No data about side effects were reported.
There was one small split-face trial, Trial 165,39 of patients with mild to moderate acne. Reported data show that patients were blinded. The single outcome, assessment of overall change, was not statistically significantly different. No side effect data were reported.
There was one large (N = 776) multi-center trial, Trial 228.40 The trial was conducted at multiple sites in the United Kingdom and represents pooled data from multiple trials conducted in general practices and dermatologists' offices without specific information about how these data were combined. Characteristics of the subjects and specific methodological information were not reported. No specific information about blinding of subjects or assessors was reported. At 5 weeks, 142 of 201 subjects treated with aluminum hlorhydroxide/sulfur were improved, by physician assessment of overall change in acne, compared to 76 of 151 treated with vehicle alone. This was statistically significant at p<0.001. No information about side effects was reported.
See N.02.06.
There was one large (N = 150) trial, Trial 176,41 of patients with moderate to severe acne. Although subjects in the two groups were reportedly similar in terms of acne duration at enrollment, no data were provided to support this. Although acne severity was assessed at baseline, it was not clear that the groups were comparable. From the lesion count data provided, gluconolactone led to a statistically significant decrease in inflammatory and total lesion counts, with respect to baseline, although only the change in inflammatory lesions was statistically significantly better than the change in subjects treated with placebo. Side effects reported were dryness, scaling, burning, stinging, and redness. These effects were more frequently reported in the gluconolactone group. No P-values were reported.
See D.01.03.
There was one small split-face, multi-center trial, Trial 246,42 of mild-to-moderately affected patients, notable for no losses to followup, and for a pharmaceutical-employee co-author. Both treatments were effective on comedones, papules, and pustules, with the combined treatment being statistically significantly better in each lesion type. There were more withdrawals from the combination group, but the number (2) was small.
See C.01.02.
There were eight trials addressing the effectiveness of topical clindamycin preparations (clindamycin phosphate or clindamycin hydrochloride) versus inert substances (placebos or vehicles): four large (Trial 20,43 Trial 33,44 Trial 99,45 and Trial 21446), two medium (Trial 199,47 Trial 217,48), and two small (Trial 32749 and Trial 14450). These trials included subjects with mild to severe acne and an approximate mean age of 20 years. Seven of the trials were conducted in the USA and one (Trial 33) was conducted in Oslo, Norway. Four trials studied a dose of 1 percent applied twice daily, one studied a dose of 1 percent before bed, and three reported no dose information.
Subjects treated with clindamycin had similar reductions in lesion counts to those treated with inactive substances. Clindamycin tended to produce greater reductions in inflammatory lesions and greater reductions when counts were assessed at later time points, but these results were rarely statistically significant. Clindamycin was more consistently superior to placebo when global measures of acne severity or improvement were measured by subject or physician report. There were limited data reported regarding side effects. These data tended to show similar rates of cutaneous side effects and diarrhea between subjects treated with clindamycin and inactive preparations, although insufficient data were reported for statistical significance. There was one case (Trial 20) of diarrhea attributed to clindamycin; the patient was withdrawn, and it was not pseudomembranous colitis. One patient, in Trial 20, dropped out because of local burning.
There was one medium multi-center trial, Trial 305,51 of patients with moderate acne. The trial was compromised by major losses to followup. While both preparations produced improvement in severity and lesion counts, there were no statistically significant differences between them for any of the outcomes measured. There were no reported differences in local reactions between the two treatments.
There were six parallel trials that reported on the relative effectiveness of different topical clindamycin preparations. Three trials (Trial 2043 Trial 143,52 Trial 22953) tested clindamycin phosphate versus clindamycin hydrochloride. Four trials (Trial 99,45 Trial 131,54 Trial 229,53 Trial 26755) tested clindamycin in different vehicles such as gel, lotion, and solution. All were parallel trials of subjects with acne severity ranging from mild to severe. Two of the trials (Trial 143, Trial 229) used a split-face design.
Trials of topical clindamycin phosphate versus topical clindamycin hydrochloride showed no significant differences in severity or lesion counts between the two preparations.
Trials of topical clindamycin in different vehicles failed to show differences in effectiveness whether the vehicle was a gel, lotion, or solution. Trial 229 showed slightly greater improvement with the Ionax® preparation versus the E-Solve® preparation.
There were no significant differences in side effects between various topical clindamycin preparations. Trial 131 showed slightly less drying and erythema associated with use of lotion versus solution. Across the trials, there were two cases of mild diarrhea that did not lead to discontinuation of treatment.
There were five parallel trials involving subjects that compared topical preparations of clindamycin to topical preparations of erythromycin. There were four large trials, Trial 15856(120 patients), Trial 20857 (109 patients), Trial 24458 (120 patients), and Trial 30359 (178 patients). There was one medium trial, Trial 326.60 These trials generally compared 1 percent clindamycin to 2 percent erythromycin, although one trial (Trial 32660) used 1.5 percent clindamycin and 2 trials (Trial 303,59 Trial 32660) used 1.5 percent erythromycin. All the trials enrolled subjects with mild to severe acne. Trial 158 had blinded ascertainment, but neither physicians nor patients were blinded. In Trial 208, patients were not blinded. Trial 244 had no losses to followup, but the enroller was not blinded, and arms were not comparable.
Although several trials documented differences between the preparations for certain outcomes at certain time points, these differences occurred in favor of each treatment within individual trials and none of the trials showed consistent differences overall. A review of all five trials fails to show that one treatment is superior to the other.
There was very limited information on side effects reported in these trials.
There were two parallel trials that compared the effectiveness of topical clindamycin (1 percent twice daily to topical tetracycline (no dose specified in either trial). One medium trial, Trial 26161 included patients with mild to moderate acne, the other medium trial was of patients with mild acne, Trial 291.62
Although differences in specific lesion counts or changes in lesion counts were insignificant or inconsistent, both trials showed a significant difference in favor of clindamycin in their overall measures of acne severity or improvement. In Trial 261, overall improvement was rated as "poor" in 2 of 22 in the clindamycin group and 13 of 27 in the tetracycline group. In Trial 291, acne severity at 8 weeks was rated as poor in 1 of 44 in the clindamycin group and 11 of 43 in the tetracycline group.
There were no differences in side effects in either trial, although information was limited.
There was one large multi-center, multi-arm trial, Trial 214,46 and two small trials, Trial 32463 and Trial 329,64 of patients with moderate acne. All three trials used 1 percent clindamycin and 5 percent benzoyl peroxide. Trial 324 and Trial 329 studied twice daily application and Trial 214 studied before-bed application.
All three trials demonstrated significant reductions in inflammatory and non-inflammatory lesions from baseline for both treatments. There was no statistically significant difference between the two at any time point except at 12 weeks in Trial 324 when a significantly greater reduction in non-inflammatory lesions was noted in the benzoyl peroxide group. Similarly, in Trial 329, benzoyl peroxide led to a statistically significantly greater reduction in severity, with respect to baseline, than did clindamycin, at 10 weeks.
Except for statistically significantly greater irritancy score for benzoyl peroxide in Trial 329, data about side effects in these trials did not support a statistically significant difference in local reactions such as erythema, peeling, dryness, burning, pruritus, or oiliness.
There was one large (N=393) parallel, multi-center, multi-arm trial, Trial 214,46 that reported on the relative effectiveness of topical clindamycin (1 percent) versus topical clindamycin (1 percent)/benzoyl peroxide (5 percent) applied before-bed for treatment of moderate acne. Both preparations produced significant reductions from baseline of inflammatory and non-inflammatory lesions. These reductions were greater for the combination of clindamycin/benzoyl peroxide than for clindamycin alone. More subjects had their acne rated as good or excellent in the combination group relative to the clindamycin alone group.
Side effects reported were erythema, peeling, burning, dryness, and pruritus. Peeling was reported relatively more often in subjects using the clindamycin/benzoyl peroxide preparation.
See D.05.02.
See N.08.03.
See G.02.01.
See D.04.01.
See C.01.07.
There was one large parallel multi-center, multi-arm trial, Trial 214,46 and one medium trial, Trial 329,64 of patients with moderate acne. In Trial 214, the combination produced statistically significantly greater reductions from baseline of inflammatory and non-inflammatory lesions than benzoyl peroxide alone. However, in Trial 329, the number of lesions appeared comparable (no P-values were provided), and severity was improved to a statistically significant extent with respect to clindamycin, not with respect to benzoyl peroxide. A larger proportion of subjects had their acne rated as good or excellent in the combination group. Side effects reported with relatively equal frequency in both groups were erythema, peeling, burning, dryness, and pruritus.
There were four large parallel trials (Trial 184,65 Trial 205,66 Trial 274,67 and Trial 8968), two medium trials (Trial 27769 and Trial 3970), and two small studies (Trial 15771 and Trial 28572) of patients with mild to moderate acne.
Six trials showed statistically significant improvement in inflammatory lesions by erythromycin. Trial 157 reported that more patients treated with erythromycin assessed their acne as "better" than did those treated with vehicle, but P-values were not provided. Trial 277 failed to show a difference between the preparations in terms of inter-treatment lesion change at 8 weeks.
There were no reported differences in side effects between topical erythromycin and its vehicle.
See C.01.04.
There was one medium, three-arm trial, Trial 39,73comparing erythromycin 1.5 percent twice daily, against benzoyl peroxide 5 percent twice daily. Patients were not randomized. Severity and lesion count changes were comparable in the two arms. One patient withdrew from each arm because of dermatitis.
See N.08.02.
There were two medium trials, Trial 15174 and Trial 315,75of patients with mild to moderate or non-categorizable. No statistically significant differences between topical fusidic acid and inactive preparations were observed.
See H.03.02.
See H.09.04.
There were two large two-arm trials, Trial 19476and Trial 195,76 of patients with moderate to severe acne. Both trials had no losses to followup, but no randomization and inconsistent ascertainment across arms. There was a statistically significantly greater decrease in inflammatory lesions at 5 and 11 weeks in the meclocycline group. The side effect of follicular staining was noted in about 16 percent of anti-bacterial-treated patients, but none in the vehicle group.
There was one large (N=102) trial, Trial 30,77 of young adults with moderate acne. There were no losses to followup, but the outcome assessor was not blinded. Comedone count was statistically significantly fewer in the benzoyl peroxide group, but not for papules and pustules. There were three cases of skin discoloration split between both groups.
See D.06.01.
See H.08.06.
There was one medium trial, Trial 328,78 of patients with mild to moderate acne. No significant differences between topical metronidazole and placebo were observed in this trial.
There was one medium multi-arm trial, Trial 287,79 with patients whose acne status cannot be categorized, whose reported execution differed from the reported design. The following proportions of subjects were classified as improved in each group: neomycin, 10 of 20; vehicle, 14 of 26; hydrocortisone, 14 of 24; sulfur, 11 of 23; resorcinol, 17 of 24; combination, 21 of 32. Differences were not statistically significant.
There were four large parallel trials: Trial 1080 (moderate severity), Trial 2381(moderate), Trial 4082 (cannot determine severity), and Trial 31383 (mild to moderate severity). The first three used topical tetracycline 0.5 percent twice daily. The fourth trial used topical tetracycline 2.2 percent twice daily.
The three trials using 0.5 percent reported no statistically significant differences between topical tetracycline and inactive preparations. In the fourth trial, 25 patients treated with tetracycline were classified as "better" compared to 18 in the placebo group.
In the trial using 2.2 percent, tetracycline was associated with more skin discoloration, placebo with more exfoliation.
See C.01.05.
There was one large (N=69, 45 females, age range 12-33 years) parallel trial, Trial 255,84 comparing the effectiveness of topical tetracycline to topical 5 percent benzoyl peroxide applied once per day for treatment of moderate acne. Outcomes assessed at 8 and 12 weeks were acne severity (by the Leeds method) on back, face, and chest as well as counts of inflammatory and non-inflammatory lesions.
No significant differences were observed between topical tetracycline and topical benzoyl peroxide in any of the outcomes assessed.
See H.08.14.
See H.06.05.
See H.08.04.
There was one medium trial, Trial 114,82 of patients with mild to moderate acne. The trial was conducted using male subjects at a military hospital.
No significant differences were observed between topical triclosan and placebo in any of the outcomes assessed (patients' assessment of change and lesion counts). No side effect data were reported.
There was one medium cross-over trial, Trial 2185(N=34). The trial reported the involvement of a pharmaceutical company. Outcomes assessed at 6 and 12 weeks were overall change as assessed by the subjects and by a physician.
There were no significant differences reported for either of the outcomes (patients' assessment of change and lesion counts) between topical triclosan and topical hexachlorophene. Almost all patients in both arms experienced local drying, scaling, or itching.
There was one medium trial, Trial 40,82 of patients with mild to moderate acne. The trial was conducted using male subjects at a military hospital. No significant differences were observed between topical triclosan and a topical preparation of triclosan and propylene phenoxetol in any of the outcomes assessed (patients' assessment of change and lesion counts). No side effect data were reported.
There were seven parallel trials. Trial 24186, Trial 173,87 and Trial 31488 were medium, two-arm trials; Trial 17641 was a medium, three-arm trial; Trial 17789 and Trial 9790 were medium, four-arm studies, and Trial 21446 was a large, four-arm trial. Each studied the 5 percent concentration of benzoyl peroxide, except for Trial 314, which used 20 percent. Two of these (Trial 173, Trial 314) were specifically designed for this comparison. In each of the others, benzoyl peroxide was used as the control treatment for other active preparations. The trials were conducted in Britain (Trial 173, Trial 177), Australia (Trial 176), and the USA (Trial 214, Trial 241). Four of the trials studied twice daily application of the treatment (Trial 173, Trial 177, Trial 241, and Trial 314), one studied before-bed application (Trial 214), one (Trial 97) had patients applying treatment between once and four times daily, and the other gave no details about how the treatment was used. Acne severity ranged from mild to severe in the trials.
All trials showed improvements from baseline in their measures of acne severity. These changes were consistently superior to the effects of placebo at a statistically significant level.
Side effects such as erythema, peeling, dryness, burning, pruritus, stinging, itching, and soreness were reported more frequently in groups treated with benzoyl peroxide. In Trial 176, of moderately-to-severely affected patients, local side effects were statistically more frequent than in the vehicle group.
See B.01.02.
There was one large trial, Trial 176,41 of patients with moderate to severe acne. Although subjects in the two groups were reportedly similar in terms of acne duration at enrollment, no data were provided to support this. Although acne severity was assessed at baseline, it was not clear that the groups were comparable. The decrease was statistically significantly greater in benzoyl peroxide for inflammatory and non-inflammatory lesions. Side effects reported were dryness, scaling, burning, stinging, and redness. These effects were less frequently reported in the gluconolactone group. No P-values were reported.
There was one medium cross-over trial, Trial 304,91 of mild acne. There were no losses to followup or important protocol departures reported. However, the subjects, enrollers, and outcomes assessors were not blinded to treatment assignment. There were no statistically significant differences in change in comedones between the preparations in either phase of the trial. Information regarding side effects was not reported.
There was one large (N = 189) trial, Trial 272,92 where acne severity could not be categorized. There was very limited information about methodology reported. A greater reduction in total lesions was observed in the benzoyl peroxide group versus the sulfur/resorcinol group, but this difference was not statistically significant. No data about side effects were reported.
See C.01.06.
See C.05.01.
See C.08.03.
There were seven trials that compared various preparations of topical benzoyl peroxide to one another. These comparisons were drawn between benzoyl peroxide in different vehicles (alcohol, water, acetone, gel, lotion) and different concentrations (2.5 percent, 5 percent, and 10 percent).
Trial 35193was a large two-arm trial comparing 2.5 percent with a 5 percent preparation. There were no losses to followup, but physicians were not blinded. Trial 24286 was a medium trial of patients with mild to moderate acne that compared the effectiveness of topical benzoyl peroxide (2.5 percent) and topical benzoyl peroxide (5 percent) applied twice daily. There were no reported losses to followup. Trial 24386 was a medium trial of patients with mild to moderate acne that compared the effectiveness of topical benzoyl peroxide (2.5 percent) and topical benzoyl peroxide (10 percent) applied twice daily. There were no reported losses to followup. Trial 22194 was a large multi-center trial of patients (mean age 46 years) with moderate acne, with daily application of topical 5 percent benzoyl peroxide in either an acetone or alcohol base. This was part of a trial comparing both of these preparations to tretinoin. Subjects, enrollers, and outcomes assessors were not blinded to treatment assignment. Trial 11895 was a medium split-face design where acne severity could not be categorized. The trial compared the effectiveness of topical 5 percent benzoyl peroxide in an alcohol base to the same medication in a water base. Trial 7696 was a medium matched-control trial of patients with moderate acne, with topical 5 percent benzoyl peroxide in a gel and with the same medication in a lotion. Limited information about methodology was reported. Trial 14997was a large five-arm trial of benzoyl peroxide 5 percent and 10 percent alone and with tretinoin.
Of the many outcomes based on lesion counts, there were no statistically significant differences among these different treatments, and there was no dose-response effect demonstrated.
Side effects were numerically almost identical in the 2.5 percent and 5 percent concentration groups in Trial 351. In Trial 243, side effects were more prevalent in the 10 percent group, although P-values were not reported. In Trial 242, side effects were not reported. In Trial 221, side effects were reported and were similar in the two groups. In Trial 118, side effects were reported. Burning and erythema occurred with similar frequency between the groups. Scaling and stinging were reported more frequently with the alcohol-based product. In Trial 76, erythema and scaling were reported with similar frequency in both groups. In Trial 149, there were statistically significantly more side effects in the 10 percent group than in the 5 percent group.
There was one medium split-face trial, Trial 278,98 of patients with moderate acne. Patient education to minimize improper application and translocation was documented in the report. There were minimal losses to followup and only minor protocol departures. There was no statistically significant difference between the preparations for inflammatory and total lesion counts as well as change in inflammatory lesions. No information about side effects was reported.
See C.03.025.
See D.06.01.
See D.07.02.
See E.05.02.
See E.06.02.
See H.06.02.
See E.02.02.
See D.08.01.
See N.04.05.
See N.01.03.
See N.04.03.
There was one medium two-site trial, Trial 310,99 of patients with mild to moderate acne. Data showed that patients and enrollers were blinded to treatment assignment. The performance of outcomes assessors was monitored by a dermatologist. The trial treatment and placebo produced statistically significant improvements in lesion counts in the short (4 weeks) and long (12 weeks) term. However, there was no statistically significant difference between the trial treatment and placebo at either followup time.
Side effects of scaling or tightness of the skin were recorded at 4 and 12 weeks. Although these effects occurred more frequently in the group treated with the trial medication, the difference between this and placebo was not statistically significant.
There were two trials: one medium cross-over trial, Trial 16,100 of patients with mild to moderate acne, and one medium four-arm trial, Trial 177,89 of patients whose acne status could not be categorized. Severity in Trial 177 was statistically significantly improved in every arm, including vehicle. Severity was improved in both arms in Trial 16, without P-values reported. No between-arms P-values were reported in either trial. Inflammatory and cyst counts in Trial 16 were improved in both arms, but no comparison P-values were reported. No data on side effects were reported.
There was one large (N=196) four-arm trial, Trial 97,90 of patients with mild to moderate acne. Overall change and lesion counts improved in all arms, but only statistically significantly greater than vehicle arm. It is not clear if the components beyond benzoyl peroxide added efficacy. There were no side effects data reported.
There was one large trial (N=113), Trial 82,101 of patients with mild, moderate, and severe acne. Subjects and enrollers were blinded to treatment assignment. At 2 weeks, 46 of 56 subjects in the benzoyl peroxide/sulfur group were assessed as either "good' or "excellent" versus 22 of 57 in the sulfur group. This difference was statistically significant at p<0.001. Skin irritation was reported in five subjects in the benzoyl peroxide/sulfur group and two in the sulfur group.
There was one large (N=393) multi-center, multi-arm trial, Trial 21446 of patients with moderate acne. The clindamycin/benzoyl peroxide preparation produced statistically significant reductions from baseline of inflammatory and non-inflammatory lesions; the vehicle did not. More subjects had their acne rated as good or excellent in the clindamycin/benzoyl peroxide group relative to the vehicle group. Side effects reported were erythema, peeling, burning, dryness, and pruritus. Peeling, particularly, was reported relatively more often in subjects using the clindamycin/benzoyl peroxide preparation.
See C.01.07.
See C.02.03.
There was one large four-arm trial, Trial 53102 and one medium trial, Trial 310,99 of patients with mild to moderate acne. Trial 53 had inconsistent ascertainment across arms. In Trial 310, a pharmaceutical company is listed as a co-author. The performance of assessors was monitored by a dermatologist. Data showed that subjects and enrollers were blinded, and there were no reported losses to followup. In Trial 53, erythromycin and benzoyl peroxide, and their combination, produced statistically significant decreases in inflammatory lesions. The combination had a numerically larger effect than either constituent, although statistics were not provided for that comparison. The effect was smaller, and statistically significant only at 10 weeks for non-inflammatory lesions. In Trial 310, both benzoyl peroxide/erythromycin and placebo produced significant reductions from baseline in lesion counts at 4 and 12 weeks. However, neither preparation was superior to the other at either time point. In Trial 310, scaling or tightness was reported more often in the group treated with benzoyl peroxide/erythromycin.
There was one large, three-arm trial, Trial 53,102of moderately to severely affected adolescents to young adults. There was inconsistent ascertainment across arms. Improvement in non-inflammatory and in inflammatory lesions was numerically greater with the combination that with either constituent, although the statistical significance is given with respect to vehicle. No other side effects were reported.
There was one large (N=205) multi-center trial, Trial 260,103 of young and older adult women with mild to moderate acne. A pharmaceutical company employee was the primary author. Inter-site differences in baseline severity were reported to significantly influence the results and were controlled for in the analysis. Data showed that the subjects, enrollers, and assessors were blinded to treatment assignment, but assignment was deterministic.
Counts of comedones at 4 and 10 weeks and counts of inflammatory lesions at 10 weeks were statistically significantly lower in the group treated with benzoyl peroxide/erythromycin than in the group treated with clindamycin phosphate. Overall change scores were similar in both groups at all timepoints. There were few reported side effects. Three subjects in the benzoyl peroxide/erythromycin group withdrew from the trial compared to none in the clindamycin phosphate group.
There was one medium trial, Trial 310,99 of patients with mild to moderate acne. A pharmaceutical company employee was listed as a co-author. The performance of assessors was monitored by a dermatologist. Data showed that subjects and enrollers were blinded, and there were no reported losses to followup. Both benzoyl peroxide/erythromycin and placebo produced significant reductions from baseline in lesion counts at 4 and 12 weeks. Benzoyl peroxide/erythromycin produced greater reduction in inflammatory lesions at 4 and 12 weeks than benzoyl peroxide/glycolic acid/zinc sulfur. Scaling or tightness was reported more often in the group treated with benzoyl peroxide/erythromycin.
There was one medium trial, Trial 62,104 of patients whose acne severity could not be categorized. There were no significant differences between the two preparations for physicians' perceived changes in comedones. Benzoyl peroxide/erythromycin produced greater reductions in inflammatory lesions and superior clinical assessment scores than did zinc/erythromycin. A greater number of subjects improved by "50 percent or more" in the benzoyl peroxide/erythromycin group at all time points. Dryness and irritation was reported by four subjects in the zinc/erythromycin group and by one subject in the benzoyl peroxide/erythromycin group.
See N.06.03.
See N.06.03.
There was one large (N=102) trial, Trial 30,77 of young adults with moderate acne. There were no losses to followup, but the outcome assessor was not blinded. Comedo count was statistically significantly fewer in the benzoyl peroxide-only group, but not for papules and pustules. There were two cases of skin discoloration split between both groups.
There was one medium trial, Trial 121,105 of patients with moderate to severe acne. A statistically significantly greater number of subjects in the benzoyl peroxide/metronidazole group were improved by self-assessment and by photographic assessment than in the vehicle group. No evidence about side effects was reported.
There was one medium trial, Trial 121,105 of patients with moderate to severe acne. There were no reported losses to followup. A statistically significantly greater number of subjects in the benzoyl peroxide/metronidazole group were improved by self-assessment and by photographic assessment than in the benzoyl peroxide group. No data about side effects were reported.
See H.06.03.
There were three trials, Trial 85,106 Trial 111,107 and Trial 231,108 of patients of mostly late adolescents with moderate to severe acne. While the largest trial (Trial 85) had no losses to followup, the second largest (Trial 111) did, and both had pharmaceutical industry employees as co-authors. All three compared the same concentrations of miconazole and benzoyl peroxide, all applied twice daily.
Against non-inflammatory lesions, in large-sized Trial 85, not only did both treatments reduce the count within each arm (although P-values are not provided), but the anti-fungal combination was more effective than benzoyl peroxide. Both treatments conferred what the authors in Trial 111 called a "statistically significant" rate at 4 and 12 weeks, although no P-value was provided. In Trial 231, there was a similar response of comedones; the effect appears large, but no P-value was provided.
In the comparison against inflammatory lesions, the results were similar to those seen in non-inflammatory lesions: within arms, a statistically significant response, but no difference between arms. There were similar results for total lesions. However, although a medium-sized trial, Trial 111 is one of the few trials that stratified results by gender, and females got a better response in terms of total lesion from the combination treatment. In Trial 231, the effect of both treatments was large, but no P-values were reported.
Patients' and physicians' overall assessment in Trial 231 gave the combination statistically significantly better results than benzoyl peroxide alone. In the same trial, physician's and patients' overall assessment were numerically similar, but no P-values were reported.
The side effect of irritation was worse in the benzoyl peroxide only arm in Trial 85, about 10 percent versus 1 percent. While the outcome assessment was different in Trial 111, the conclusion was the same: that benzoyl peroxide alone caused more irritation. The rate was comparable between males and females in that trial. The side effect rates reported in Trial 231 were about 10 percent for both arms.
There was one small split-face trial, Trial 335,109 of mostly females with mild to moderate acne. The isoconazole arm led to a statistically significant decrease in closed comedones, while the miconazole did not, but the difference between the two arms was not statistically significantly different. This pattern was the same for open comedones, papules, and pustules. The miconazole preparation led to a statistically significant decrease in pustules, and open comedones. The rates of erythema, scaling, and itching were about 50 percent in both groups. Comparison P-values were not provided.
Adapalene is currently available only as 0.01 percent.
There were three trials, Trial 78110 and Trial 338,111 comparing 0.1 percent versus 0.03 percent, and Trial 92,112 a split-face trial comparing immediate versus delayed adapalene. Patients' acne severity varied from mild to severe; there were moderately severely affected patients in all trials. Although statistics with respect to baseline are not available, both concentrations reduced total lesion counts. The higher concentration reduced Leeds severity more in Trial 78, although this trial had major losses to followup. The higher concentration also yielded a higher percent change in inflammatory lesion count in Trial 338. In the split-face trial, Trial 92, erythema and dryness were low and the same.
There were 11 trials. Seven trials had two-arm design: Trial 49,113 Trial 80,110 and Trial 93114 (split-face), Trial 63,115 Trial 100,116 Trial 140,117 and Trial 306.118 These all involved the same concentration of tretinoin, 0.025 percent. There were four multi-arm trials: Trial 78,110 comparing doses 0.1 percent, 0.03 percent, and tretinoin 0.025 percent with adapalene; Trial 119,119 a seven-arm trial with a range of concentrations from 0.025 percent to 0.1 percent in different vehicles; Trial 338,111 a three-arm trial of 0.03 percent to 0.025 percent; and Trial 120,119 a six-arm, split-face trial, with tretinoin concentration of 0.025 percent to 0.1 percent and vehicles (gel and cream). The total is over 1,700 patients, with about one-third in Trial 63. The patients studied varied in severity from mild to severe; all trials had moderately affected subjects. Most of the trials were demonstrably randomized.
Across outcomes, the two treatments were mostly comparable in efficacy. The effect was about 50 percent reduction in total lesions, requiring between 4 weeks (Trial 78) and 12 weeks (Trial 338) to achieve this effect. Adapalene had greater intra-patient percent change in non-inflammatory lesions in one trial (Trial 306) and in inflammatory lesions in two (Trial 306 and Trial 338).
Adapalene fared better in terms of side effects. Tretinoin had more patients with desquamation (a score of 1 versus adapalene's 0) and slightly more total adverse skin symptoms (Trial 93), more scaling (Trial 306, Trial 80) or dryness (Trial 80) or "tightness" (Trial 49), more burning (Trial 80, Trial 49) at 2 and at 12 weeks, more "adverse reactions" (Trial 63), and more patients discontinuing therapy because of adverse effects. In one trial, adapalene caused more burning or itching (Trial 100). In a split-face trial (Trial 93), patients were more often intolerant of tretinoin; and of patients asked their preferences after trial completion, more favored adapalene or the method of application (P = 0.001), although patients were not blinded and the trial was funded by adapalene's producers.
There were three trials, Trial 54,120 Trial 173,87 and Trial 202121 (the last two being three-arm trials), of patients with mostly mild to moderate severity. Topical isotretinoin proved to be statistically significantly more effective (although the authors make the claim without providing the actual significance levels) in terms of Cook or Leeds severity change, inflammatory lesions, and non-inflammatory lesions, starting at 4 weeks and extending to 14 weeks. In Trial 202, there was no statistical difference with respect to papules or to comedones. The effect was on the order of 40 percent change in severity or lesion count. In terms of adverse effects, there was no statistically significant difference between the therapies.
There was one comparison, Trial 173,87 two arms of a three-arm trial. In this trial of 77 mild and moderately affected patients, benzoyl peroxide conferred mildly better improvement (P = 0.01). For both treatments, Leeds severity dropped to a mean of 1 after 4 weeks, and 0 after 12 weeks. Both inflammatory and non-inflammatory lesions were improved. The improvement in counts was on the order of 20 percent for both. Local reactions (roughness) were few and similar.
There was one medium trial, Trial 202.121 Each concentration had a statistically significant effect on papule and comedo counts, and that effect was statistically equivalent between the arms. Side effects were limited to one patient dropping out due to erythema in the 0.05 percent group.
There were two small trials, Trial 90122 and Trial 98,123 of patients with moderate acne in Trial 90, but not categorizable in Trial 98. Trial 90 had no losses to followup, but patients and providers were not blinded adequately, while Trial 98 had arms that were not completely comparable. Decrease in counts of comedones and inflammatory lesions at 4 and 12 weeks were large and comparable. Only Trial 90 provides data on adverse reactions. The rate of side effects (irritation) was about 50 percent in isotretinoin patients, and about 65 percent (stinging, erythema, and desquamation) in the tretinoin patients. Comparison P-values were not provided.
There are two trials: Trial 61,124 a small trial with major losses to followup, noncomparability of the arms, and the execution differing, thereby, from the design; and a large trial, Trial 60,125 by the same authors, of mild through moderate acne in a three-arm trial. Although motretinide led to statistically significant changes with respect to baseline in Trial 61, the sample size was so small that the decrease was not statistically significantly different from the vehicle effect. In the larger trial, the subjective rating of total lesions change was not statistically significantly different from vehicle. There was a high incidence, but no statistically significant differences, in side effects (erythema, desquamation, pruritus, burning).
There was one medium trial, Trial 253,126 of patients with moderate through severe acne. Motretinide twice daily was compared against itself as a once daily administration. Both led to statistically significant and meaningful decreases in papules and pustules, and in overall change, but neither was better than the other. Side effects were not reported.
There were three trials, Trial 59,127 Trial 253,126 and Trial 60,125 of patients with the full range of acne severity. Trial 60, being the largest, had mild through moderate degrees of severity. Trial 59 had arms comparable on a number of characteristics beyond age and severity, but the trial was weakened by major losses to followup.
The improvement in total lesion count in each arm was statistically significant in Trial 59, but not statistically significantly different between arms. Papule and pustule counts were similarly effectively reduced in Trial 253, with no statistically significant difference between arms. In Trial 60, over half the patients in the two arms had a 50 percent or more improvement, and, again, there was no statistically significant difference between the two arms.
Side effects (pruritus, burning, erythema, and desquamation) occurred in most patients in the tretinoin group in Trial 60, and statistically significantly less so, but still very often, in the motretinide group. The absolute rate was lower in Trial 59, but tretinoin's rate was still statistically significantly greater than motretinide's.
There was one small trial, Trial 145,128 a split-face trial of males with mild to moderate acne using stratified randomization and no losses to followup. The retinoid conferred a statistically significant decrease in non-inflammatory lesions at 18 weeks. Most other outcomes were equivalent numerically and statistically. Adverse reactions were equivalent.
There was one small trial, Trial 146,128 including patients with mild to moderate acne. Both treatments led to a statistically significant decrease in physicians' rating of overall change. No outcome differed in a statistically significant way between the treatments. Almost all tretinoin-treated patients had erythema, drying, peeling or cracking, while the retinyl group did not.
The strengths of tretinoin examined ranged from 0.025 percent to 0.1 percent, and included both gel and cream. There were six trials: five three-arm trials, Trial 58,129 Trial 60,125 Trial 198,130 Trial 220,131 and Trial 219,132 and one two-arm trial, Trial 270,133 comprising 10 relevant comparisons. Trial 58, Trial 60, and Trial 198 all involved a comparison with 0.05 percent; the remaining comparison concerned the weaker 0.025 percent strength. Trial 58, Trial 220, and Trial 219 were multi-center trials. Most patients had mild to moderate acne, except for patients in Trial 58, where the acne was severe, and in Trial 198, where we could not categorize the severity.
Four trials assessed global, overall change. In three (Trial 60, Trial 198, and Trial 270), the change was large and statistically significant. In Trial 219, the change was large, but not statistically significant. Most trials measured lesion counts. Total lesion counts were statistically significantly improved only in one trial (Trial 219), where there was borderline statistical significance at 12 weeks. The magnitude was fairly large (about 40 percent), however. Tretinoin led to a greater decrease in non-inflammatory lesions in all trials, although statistically significantly in only three of the four trials. Inflammatory lesions decreased as well, but fewer trials achieved a statistically significant result compared with vehicle. Only Trial 59 and Trial 270 distinguished papules from pustules, and papules were statistically significantly improved only with the higher tretinoin dose in the first trial, but both pustules and papules were improved in the second.
Side effects were frequent. In two trials (Trial 58 and Trial 60), erythema and other local symptoms were almost universal early on, but then dropped off. Local symptoms included erythema, peeling, pruritus, burning, and irritation. The frequency was almost always statistically significantly greater than in the inert control. The frequency was not insignificant, however, in the control groups. One trial (Trial 220) reported on systemic symptoms, which occurred about one-third of the time, but not statistically significantly more often in the tretinoin group.
There was one medium trial, Trial 84,134 of tretinoin at 0.05 percent and 0.02 percent strengths, and the keratolytic. Numerous methodological qualifications included lack of blinding, major losses to followup, noncomparable arms, and inconsistent ascertainment across arms. The single outcome of qualitative improvement appeared greater for the higher tretinoin concentration, but P-value was not provided. Side effects were comparable.
There were three trials. Trial 149 97was a large five-arm trial of benzoyl peroxide 5 percent and 10 percent alone and with tretinoin in Indonesian patients where acne severity cannot be categorized. There was one medium trial, Trial 38,135 and one large trial, Trial 221,94 of patients with moderate acne. The first trial used lower strength (0.025 percent) and the second, higher (0.1 percent).
In Trial 38, there was early increase in papules in tretinoin (data abstracted but not shown in the evidence table), but statistically significant improvement in comedones, papules, and pustules by 12 weeks. The decrease was statistically significantly greater in the tretinoin group for comedones and papules, but the differences were small. Both patients and clinicians rated the tretinoin group as more improved. In Trial 221, there was over a 30 percent decrease (after 8 weeks) in the tretinoin group for papules, pustules, and, most strongly, for comedones. The benzoyl peroxide groups had a greater effect on papules, but otherwise had a statistically significant equivalent effect. Qualitative assessment of severity change was the same in both groups. In Trial 149, the amount of time to 75 percent or more improvement was not statistically significantly greater in the benzoyl peroxide group. Overall change was highest in the tretinoin/benzoyl peroxide 5 percent group, and statistically significantly greater than the other groups.
Side effects (erythema, irritation, soreness) were few in Trial 38 and the same in the two arms. In Trial 221, the rate of these side effects was about 20 percent and not statistically significantly different for the two arms.
See E.01.02.
There were two large trials, Trial 18832and Trial 316.136 Acne severity was mild in the second trial and could not be categorized in the first. Trial 188 used a higher strength of tretinoin, and treatment continued for 6 months.
Change in non-inflammatory lesions was comparable in the tretinoin arms of the two trials, although neither within- or between-arm P-values are supplied. Change in papules was greater and statistically significantly so in the azelaic group in Trial 316.
In Trial 188 (higher strength, longer duration of treatment), side effects of erythema and scaling occurred in about 30 percent of subjects, and were statistically significantly greater than in the azelaic (about 20 percent) group. In Trial 316, the same side effects occurred and statistically significantly more frequently in the tretinoin than in the azelaic group.
See E.02.04..
See E.04.02..
There were eight trials. Three trials were large three-arm trials: Trial 58,129 Trial 220,131 and Trial 219.132 There were two medium three-arm trials, Trial 84134 and Trial 198.130 There were three small multi-arm trials: Trial 119119(seven arms), Trial 120119 (six arms), and Trial 302137 (four arms). Trial 119, Trial 120, and Trial 302 were very small (less than 10 patients per arm) and very short (3-week) multi-arm trials. Trial 58 and Trial 220 were multi-center trials. One-quarter of the patients had severe acne (Trial 58); one-third had mild acne (Trial 220); one-quarter had mild to moderate acne (Trial 219); and for the remainder, severity could not be categorized. In fact, not all subjects in Trial 119 and Trial 120 had acne, since these were trials to evaluate tolerability and not effectiveness. Pharmaceutical employees were co-authors in these two trials. Trial 302 suffered from major protocol departures, although losses to followup were minor. Trial 84 reported comparable improvement, but no P-values, between the two strengths of tretinoin. The strengths of tretinoin examined ranged from 0.025 percent gel through 0.1 percent cream.
Two trials evaluated overall change. In Trial 198, both lower and higher dose tretinoin conferred improvement or marked improvement that was not statistically significant between the two groups. In Trial 219, the addition of polyolprepolymer-2 did not increase overall improvement. The three trials that reported total lesion count change (Trial 58, Trial 198, and Trial 220) showed no statistically significantly different change across tretinoin strengths. Four trials reported on non-inflammatory lesions specifically (Trial 58, Trial 198, Trial 220, and Trial 302). One trial (Trial 58) yielded a statistically greater decrease from the 0.05 percent preparation compared with the 0.025 percent, but the absolute difference was small. The same trials reported on inflammatory lesions. Only two trials demonstrated statistically significant differences in efficacy, and the magnitude of these differences was small.
All trials reported on side effects. There was a strength-response relationship demonstrated in Trial 58, in Trial 119, and in Trial 120. Side effects from 0.1 percent strength were so frequent and severe that most subjects stopped using the treatment. Side effects noted included erythema, peeling, and irritation. The addition of polyolprepolymer-2 in Trial 219 did not improve the side effect rate.
See G.02.02.
See E.03.03.
There was one medium multi-center, split-face trial, Trial 13,138 of patients with the full range of acne severity. Although 18 centers were involved, the authors reported no details regarding baseline characteristics, beyond gender and age; so it is difficult to assess the generalizability of their findings. The outcomes are hard to interpret in the absence of baseline data, but the actual change scores and comedo counts appear the same in the two groups. No comparison statistics were provided. Qualitative assessment (number of patients comedo-free, inter-treatment patient preference) was the same in both groups. Side effect rates of burning, stinging, dry skin, and erythema are equal in the two groups.
There was one medium multi-center trial, Trial 37,139 of patients with moderate acne. Evidence of randomization is good, but there were major losses to followup, and the paper was co-authored by a pharmaceutical employee. Patients rated statistically significantly "marked improvement" after 12 weeks in both groups, with no statistical difference between the groups. Both groups had decreases in all lesion types (including cysts), but the baseline numbers were small. Qualitative assessment of improvement was the same in both group. The authors provided no data on side effects.
There were two medium trials, Trial 35140 and Trial 34,141 of patients with mild to moderate acne. Trial 34 had no losses to followup. Trial 35 used a matched-control design.
In Trial 35, there was a marked difference numerically between the groups for comedones and papules, although P-values were not provided and cannot be calculated. Subjective assessment of overall change was statistically significant. There does not appear to be a difference with respect to pustules, but the absolute number of pustules is small, meaning a larger sample size would be needed to discern a difference. This is one of the few trials to stratify findings by sex. The effect of vitamin A appears to have been different for males and females: papules were reduced in males, but not in females, while comedo counts were reduced a similar proportion (60-80 percent). Assessments of overall change were statistically significant in both strata. In Trial 34, assessed response was better in the treated group; our calculated P-value demonstrated statistical significance.
In Trial 34, every patient treated with vitamin A had erythema, while the control group had none. Trial 35 provided no side effect data.
There was one large three-arm trial, Trial 27292 (N=189), with benzoyl peroxide and with sulfur/resorcinol as comparators. Percent change at 14 weeks was numerically markedly better in the vitamin A arm than in either comparator arm, although P-values were not provided nor could be calculated. No side effect data were provided.
There was one large multi-center trial, Trial 57142 at 2 university clinics and 13 private clinics, for a total of 238 patients 11 to 44 years old, where acne severity cannot be categorized. The enroller/treater was adequately blinded, and the arms were comparable by age, sex, skin color, skin type, and number and type of acne, but there were major losses to followup. The trial compared topical vitamin A, oral oxytetracycline, and the two together.
Across the three groups, improvement in inflammatory and non-inflammatory lesions was high (over half of patients achieving over 50 percent improvement), but no differences were statistically significant. The rate of side effects was high: up to 25 percent with erythema and desquamation in the vitamin A group and about 8 percent in the antibiotic group, but the between-arm P-value addresses all side effects together and is not statistically significant.
No comparisons are available.
There was one small four-arm trial, Trial 238143 of patients with moderate to severe acne. Physicians' assessment of overall change appeared greater in the combination group, less so in each component group, and least in the vehicle group. No comparison P-values were reported. No side effect data were reported.
There were two small trials, two-arm Trial 46144 and three-arm Trial 283,145 and two large two-arm trials, Trial 45144 and Trial 47,144 all of adolescents and young adults with moderate to severe acne (some patients with mild acne in Trial 283). In Trials 45, 46, and 47 (performed by the same investigators), there were no losses to followup, but inconsistency in outcome ascertainment and noncomparable arms. In Trial 283, recruitment and treatment assignment were stratified by gender.
The combination treatment resulted in statistically significant, but small, improvements in non-inflammatory, but not inflammatory, acne in Trials 45 and 47. The overall severity score was also statistically significant, but small, in these two trials. Only Trial 283 reported on side effects, which were numerically fewer in the clindamycin group but statistically different across the three arms of that trial.
There were two large trials, Trial 43144 and Trial 44,144 and one medium trial, Trial 42,144all two-arm trials of moderately to severely affected adolescents to young adults. All had no losses to followup but had noncomparable arms and inconsistent ascertainment across arms.
Of severity, inflammatory, and non-inflammatory changes, inflammatory change with respect to baseline was greater in the combination group in Trials 42 and 43, but not statistically greater in Trial 44. Severity change was statistically significantly greater in the combination group only in Trial 43, at 12 weeks. Side effects were not reported.
There was one small three-arm trial, Trial 283,145 of adolescents and young adults, stratified by gender recruitment and treatment assignment. There were no statistically significant differences in effectiveness or in side effects.
See D.01.09.
There was one medium trial, Trial 56,146 of adolescents with moderate acne. Changes in non-inflammatory and inflammatory lesions were large (48 percent and 75 percent decrease, respectively) and statistically significant at 6 and 13 weeks. Adverse reactions, gastrointestinal in particular, were the same; there was numerically more mild diarrhea in the clindamycin group. P-values were not provided.
There were two small trials, Trial 265147 and Trial 275,148 of moderately affected patients (adolescents exclusively in Trial 265). Trial 265 was afflicted with major losses to followup, while Trial 275 made explicit its education of patients for applying the medication.
In Trial 265, efficacy was numerically equivalent for overall change, for severity, and for lesion count, at 4 and at 8 weeks, but no P-values were provided or could be calculated. In both treatments, the effect was about a 50 percent decrease in lesion counts, using group means. In Trial 275, overall change, according to patients, were equivalent for the two groups, about two-third of patients having been "much improved."
In Trial 265, esophagitis or mild diarrhea/cramping was present in equal, small numbers in both groups. In Trial 275, two patients withdrew from the clindamycin group, none from the tetracycline group.
There was one small trial, Trial 162,149 one medium trial, Trial 192,150 and three large trials, Trial 312,151 Trial 193150 and Trial 71,152 the last two being cross-over trials. Acne severity was moderate to severe in one trial (Trial 162), mild through severe in another (Trial 312), and not categorizable in the others. Only one trial (Trial 71) provided the gender breakdown. Although it had a cross-over design, Trial 71 had enough errors in assignment that it had, effectively, non-random assignment. Trial 162, a parallel-design trial, had too many placebo patients receive the anti-bacterial (unplanned cross-over). In two trials, the dose was 150 mg once daily; in the other two, 150 mg four times daily.
Assessment of relative improvement was statistically significantly greater for demethylchlortetracycline only in Trial 162. The difference was not statistically significant in the other four trials.
In Trial 162 (higher dose), about one-third of patients reported photosensitivity; other patients report gastrointestinal (GI) disturbance and photo-onycholysis, none of which occurred in placebo-treated patients (P=0.01). In Trial 71 (higher dose), 10 percent of patients complained of photosensitivity (versus less than 1 percent in the placebo group).
There was one medium trial, Trial 312,151 of patients with mild through severe acne. Physicians' assessment of overall change was numerically and statistically the same. Similarly, patients' assessment and photo-based severity assessment were both the same in the two treatment groups.
There were two large trials, Trial 70153 and Trial 71,152 of patients with non-categorizable acne severity. Trial 70 had biased ascertainment because more severely affected patients finished their course of antibiotics earlier. Treatment assignment in Trial 71 was made incorrectly in about one-quarter of the patients.
In Trial 70 (lower dose), physicians' assessment of overall change was better in the tetracycline group (P=0.01), although there were eight (about 10 percent) relapses 15 weeks after therapy in the tetracycline group. In Trial 71 (higher dose), severity change was not statistically significantly different. The actual improvement rate was higher in Trial 70 than in Trial 71.
In Trial 71 (higher dose), 10 percent of demethylchlortetracycline assigned patients complained of photosensitivity. In Trial 70, there were numerically more side effects (all GI-based) in the tetracycline group, but no statistics are provided.
There was one large cross-over trial, Trial 273,154 of patients with mild acne. The trial was limited by major losses to followup. Decreases in inflammatory counts was statistically significant in the doxycycline arm in both phases. Assessment of improvement, however, was not different for comedones or for cysts. There were zero side effects in either group.
There was one large trial, Trial 1155 (N=110), of late adolescents with mild-moderate acne. Patients were not blinded, and a co-author was a pharmaceutical employee. Total lesion count, at 6 and 10 weeks, dropped significantly in both groups so that the effectiveness was statistically significant within each arm, but not statistically significant across arms. Assessments of overall change, by patient and by investigator, were also not statistically different. There were numerically more side effects in the fusidic acid group (4 vs.1), but no P-values were reported.
There was one medium two-site trial, Trial 25,156 of young adults with moderate acne. The trial had excellent methodological control. Severity decreased to mild in both groups; P-value was not provided. Change in inflammatory lesions was large and statistically significant within each group, but not statistically different across groups.
There was one medium trial, Trial 257,157 and two small trials, Trial 311158 and Trial 155,159 of patients with a full range of acne severity. In Trial 257, a co-author was a pharmaceutical employee. In Trial 155 there were major losses to followup.
In Trial 311, there was no difference in severity at 12 weeks. In Trial 257 and Trial 155, there were many lesion-based outcomes. In Trial 155, investigators attempted to obtain patients' preferences on a 100 cm visual analogue scale, but the responses were too inconsistent to be usable. Although no differences were statistically significant, both treatments were effective, decreasing counts by about 50 percent by 12 weeks for both inflammatory and non-inflammatory lesions; P-values were not supplied by the authors.
Side effects (dyspepsia, headache, nausea, vertigo) were few and comparable in the two groups.
See H.03.03.
There were two trials: one small trial, Trial 24,160 of patients with moderate acne over only 2 weeks, and one small seven-arm trial, Trial 340,161 of patients with moderate to severe acne treated between 6 and 18 months. In Trial 340, preference over placebo was evaluated, but difficult to interpret. In Trial 24, only papule counts were reported. The counts were significantly (and statistically) decreased with respect to baseline in each arm, although the stearate did statistically significantly better. Side effects (gastrointestinal distress) appeared in both groups, but the difference was not statistically significant.
There were four trials: two small trials (Trial 6162 and Trial 36140), one small seven-arm trial (Trial 340161), and one large multi-center trial (Trial 125163). Severity ranged from mild to moderate (Trial 125) to moderate (Trial 36), to severe (Trial 340); baseline acne severity could not be categorized in Trial 6. Trial 36 included student health centers, in addition to dermatologists' offices and academic clinics, but had a pharmaceutical co-author. Doses varied: Trial 6 compared erythromycin 250 mg twice daily with tetracycline, 250 mg twice daily; Trial 36, erythromycin acistrate 200 mg once daily versus tetracycline 250 mg once daily; and Trial 125, erythromycin 500 mg once daily versus tetracycline of unknown dose.
Trial 36 reported that, on the face, back, and chest, severity improved at 12 and 24 weeks, with a within-group P-value of 0.05, but between groups, the between-arm P-value was not statistically significant. Trial 125 provided no P-values, but numerically, the effects were the same for both treatments for comedones, papules, and pustules. Patients' subjective assessments of change were numerically similar for the two treatments as well. Trial 6 also did not present P-values but presented numerically similar assessments of severity change in the two treatments. Trial 340 presented inter-treatment comparison. Although difficult to interpret (they are based on comparison to placebo), a few more patients preferred two different types of tetracycline (phosphate, citric acid, but not novobiocin) than preferred erythromycin.
Trial 6 had about 8 percent of patients with side effects, equal in the two groups. Trial 36 had up to 20 percent side effects, again equal in the two groups numerically. In Trial 125, there were again about 8 percent side effects. Numerically, more patients dropped out of erythromycin due to side effects, but these are probably statistically not significant.
There was one small seven-arm trial, Trial 340,161 of patients with moderate to severe acne treated between 6 and 18 months. Preference over placebo was evaluated, but difficult to interpret. More patients preferred triacetyl-oleandomycin over placebo than preferred erythromycin over placebo. No side effect data were reported.
There was one small trial, Trial 4,164 where acne severity cannot be categorized. A single outcome, severity change, was high for both groups, and not statistically significantly different. No side effect data were reported.
There is one large trial, Trial 247165 (N=142), of patients where acne severity cannot be categorized. The authors reported only one outcome, physicians' perception of overall change, which was "excellent" in about one-quarter of cases in each arm, and not statistically significantly different. No data on side effects were reported.
There was one medium cross-over trial, Trial 161,166 and one large cross-over trial, Trial 273.154 Acne severity was mild in Trial 273, and could not be categorized in Trial 161. The high-dose trial (Trial 273) was weakened by major losses to followup.
Acne severity in Trial 161 improved within the minocycline arm to a statistically significant extent and it improved, but not to a statistically significant extent in the placebo arm, in both phases of the cross over. However, a between-arm P-value was not provided. Inflammatory lesion counts in Trial 273 are improved by minocycline to a statistically significant extent in both phases. Non-inflammatory lesions, nodules, and cysts were improved, but not apparently more than by placebo; between-arm P-values were not provided.
There were two side effects (vertigo and urticaria) leading to patient withdrawals in Trial 161, and zero side effects reported in Trial 273.
There were two medium trials, Trial 268167 and Trial 307,168 of patients with moderate to severe acne. Trial 268 was a multi-center trial of student health centers that used balanced, block randomization. Trial 307 was a matched-control trial.
Overall assessment at 4 and 12 weeks was equivalent between the two groups in Trial 268, and was highly statistically significant within each group. Severity was not statistically significantly different between arms in Trial 307. Lesion-count decreases were equivalent between the two groups in both trials. Only Trial 268 documented statistically significant decreases within each group.
Side effects (six patients with allergy, diarrhea, impetiginization, dryness, and stinging) were few and similar between the groups.
See H.03.04.
There were two large two-arm trials, Trial 72169 and Trial 171,170 and one medium trial, Trial 298,171 of patients with moderate to severe acne. Trials 72 and 298 evidenced good blinding, and in Trial 298, agreement in assessment among patients, reviewers, and investigator was measured and was high (between 60 and 86 percent). Trial 171 had major losses to followup and inconsistent ascertainment across arms.
Severity change was not statistically significantly different between the two arms in Trial 298 or Trial 171. Lesion counts were improved by both treatments in Trial 72, having reduced comedones, papules, and pustules about 30 percent by 19 weeks; P-values were not provided.
Side effects (nine total in Trial 298) were not statistically significantly different between the arms, including GI and vaginal symptoms. There was one case of hives in the minocycline group in Trial 171.
There was one large cross-over trial, Trial 250172 (N=76), in patients with moderate to severe acne. There were major losses to followup and there were irregularities in execution. Severity change favored oxytetracycline in both phases of the cross-over (by our calculated chi-square test). Over half the patients had an "excellent" response in the oxytetracycline arm. No side effect data were reported.
There was one small three-arm trial, Trial 255,84 of patients with moderate acne. Data were provided on many outcomes on the face, chest, and back. For oxytetracycline, many of these results were statistically significant within its arm. Although the benzoyl peroxide arm had no P-values listed, the numerical values were similar to those in the anti-bacterial group. The differences between the two arms were not statistically significant. There were six side effects reported (GI symptoms, severe facial reaction, vaginal candidiasis).
There was one medium trial, Trial 123,105 of young adults with moderate to severe acne. Assessments of overall change by both patient and physician were about the same in the two groups (about one-third "much improved") and not statistically significantly different. No side effect data were reported.
See E.06.03.
There was one small three-arm trial, Trial 255,84 of patients with moderate acne. Both treatments reduced face severity and comedonal count with statistical significance. Both also reduced the inflammatory lesion count, although only tetracycline's effect reached statistical significance, but the difference between the two groups was not statistically significant. There were four side effects (GI symptoms).
There was one small matched-control trial, Trial 152,173 of only 16 patients with mild through severe acne. There was no statistically significantly different preference for one treatment over the other. There was one report of side effects (flatulence/abdominal pain).
There was one small trial, Trial 128.174 Overall change was mostly "fair," but not statistically significantly different between arms. Lesion counts were statistically significantly reduced in both arms, with no statistically significant difference between the arms. Side effects (five patients) reported were not statistically significantly different between arms.
There were two medium cross-over trials, Trial 160175 and Trial 223.176 Neither trial specified the patients' acne severity, and Trial 223 did not provide a sex and age breakdown, but did provide evidence of good blinding. In Trial 160, improvement in severity was large and statistically significant, whether treated first or second with the antibiotic. There was no improvement from the vehicle. No between-arm P-value was provided. In Trial 223, the way that the lesion data were reported precludes our making a comparison. However, that trial provided some side effect data (dizziness, headaches, red macular rash), which were too few to make inferences.
There was one large cross-over trial, Trial 44,177 of patients with severe acne. There were no losses to followup. The only outcome is physicians' preference across the two treatment phases, comparing treatments within patients. The P-value we calculated for the authors (based on chi-square) is 0.001. There were no data on side effects.
There were nine trials of tetracycline 250 mg at different dosing schedules. Trials of twice daily administration were: Trial 69,178 Trial 201,179 Trial 10,80 Trial 33,44 Trial 23,81 Trial 313,83 and Trial 136, 180 the last five being three-arm trials. Trials of four-times-daily administration were Trial 71152 and Trial 349,181 a four-arm trial. Six trials gave baseline severity information: Trial 33 studied mildly affected patients; Trial 10, Trial 23, Trial 249, and Trial 136 studied moderately affected subjects; Trial 313 patients had mild to moderate acne. Of the trials that provided ages, all were late adolescent/young adult. Trial 71 and Trial 313 were generalizable to college or local populations of young adults. Trial 23 and Trial 349 were properly randomized and Trial 201 had proper blinding. Trial 71 was a cross-over trial; but because of errors in randomization, almost all subjects received tetracycline first. Trial 23 had a pharmaceutical employee as a co-author.
For outcomes of relative improvement, and in all nine trials, tetracycline conferred statistically significantly greater improvement than placebo as early as 6 weeks and as late as 13. The magnitude of the improvement cannot be summarized from the data reported. Trial 33 provides some lesion count data: by 8 weeks, the decrease in inflammatory lesions was statistically significantly different from placebo.
Five trials (Trial 33, Trial 69, Trial 201, Trial 349, and Trial 136) reported on side effects; the total number of affected patients was 15.
There were five trials: Trial 29,182 Trial 33,44 Trial 186,183 Trial 318184 and Trial 136,180 of patients with mild, moderate, unspecified (two trials), and moderate to severe acne. Trial 136 was a three-arm trial. Trials 29 and 33 both used complementary placebos (topical and oral) to ensure patient blinding. Trial 186 suffered from major losses to followup.
Trial 186 resulted in equal numbers, and statistically nonsignificant differences, in many lesion-based outcomes, ranging from comedones to cysts. In Trial 136, papule and pustule counts were reduced equally, but physicians rated clindamycin as leading to statistically significantly greater improvement than tetracycline, while patients rated themselves as improved to the same degree. In Trial 33, there were statistically significant changes within each group. Clindamycin conferred a statistically significantly greater decrease in inflammatory lesions at 8 weeks, but conferred no advantage in Trial 29 at 4 weeks. Overall changes, as determined by patients or physicians, were better in the tetracycline group, although P-values were not provided. In Trial 318, there was no statistically significant difference in pustules counts.
Side effects included diarrhea in both groups (Trial 33) or erythema (Trial 186), for a total of four cases.
There was one medium trial, Trial 279,185 of patients with moderate to severe acne. Overall assessment was that patients were improved in both arms, with no statistically significant difference. Counts of many lesion types were presented. For many of them, within-arm improvement was statistically significant, but the difference between arms was not statistically significant.
Two patients withdrew because of adverse reactions.
There were two small trials and one medium trial, Trial 10,80 Trial 23,81 and Trial 313,83 all three-arm trials of mild to moderately affected patients. Trial 23 reported evidence of randomization but had a pharmaceutical-company as co-author, and Trial 313 was generalizable to the local population.
Only relative improvement outcomes were provided. Patients improved in all arms, with a statistically significant difference between oral and topical treatment in only one trial, Trial 23.
No side effect data were reported.
There was one medium study, Trial 40,82 of young adults and late adolescents of undetermined severity. Severity decreased in both arms, but comparison P-values were not provided. Gastrointestinal symptoms were apparently comparable; P-values were not provided.
There was one small trial, Trial 22,186 and two large trials, Trial 167187 and Trial 166,187 of patients with mild through severe acne. Trials 167 and 166 were adequately randomized. Trial 22 suffered from major losses to followup.
Relative improvement was "excellent" or "good" in the majority of patients in both arms in Trial 167 and Trial 166. Lesion counts were reduced in both arms in Trial 22 and Trial 166. Only the former, the smallest trial, found a statistically significant difference between the treatments in one comparison of lesion counts, out of a total of nine count-based outcomes.
A single case of abdominal pain, in Trial 22, was reported.
See H.05.04.
There was one medium trial, Trial 164,188 of young adults with mild to moderate acne. Of the many outcomes assessed, both treatments reduced all lesions about 70 percent. Tetracycline was statistically significantly better in treating open comedones. Otherwise, the reduction was the same in the two groups. The authors report that there were no side effects, but they provide no specific data.
See H.01.02.
There were two medium trials that compared different regimens of tetracycline. Trial 212,189 where acne severity could not be discerned, compared tetracycline sustained release 250 mg once daily with tetracycline 250 mg twice daily in young adults. The trial was limited by major losses to followup. Trial 317,190 of severely affected patients, compared tetracycline 250 mg four times daily with a similar tetracyline regimen plus proteolytic enzymes in severely affected patients.
In Trial 212, two-thirds of patients were improved at 12 weeks, but there was no statistically significant difference between treatments. In Trial 317, patients were much improved in both groups at 12 weeks, but with no statistically significant difference between treatments.
Side effects were few (diarrhea [1] and sore mouth [1]) in Trial 212.
There was one small two-arm trial, Trial 299,191of adolescents and young adults with moderate to severe acne. Blinding is documented and there were no losses to followup, although arms were not comparable. Patients treated with anti-bacterial combination reported greater overall improvement (and statistically significantly more) than patients treated with placebo. Side effects data were not provided.
See K.02.03.
See M.01.03.
See N.01.02.
See N.01.04.
See N.06.045.
See N.07.03.
See N.08.04.
There was one small trial, Trial 236,29 of moderately to severely affected patients notable by the absence of treatment information regarding povidone-iodine and by major losses to followup. No comparison statistics were provided, but outcomes were comparable. There were zero side effects reported.
Although dapsone is an anti-microbial, it does not have activity against P. acnes.
There was one small trial, Trial 293.192 There were no losses to followup. There was a statistically significant difference in severity change favoring dapsone. This is one of the few trials to stratify results by gender. The results were about the same for each sex, although P-values were not reported. Side effects were numerically greater in dapsone, but not statistically significantly different.
There was one medium trial, Trial 312,151 of mixed acne severity, where patients were not blinded. Physicians' assessment of overall change was that most patients were judged to be unchanged, and overall change for the treatment arm was not statistically significantly different from control.
See H.02.02.
There was one medium trial, Trial 344,193 of all levels of acne severity. Treatment assignment was not properly randomized and patients and care provider were not blinded. There was a blinded outcome assessment made, however. The numbers in each improvement category were similar, although no between-arm P-values were provided. There was about a 10 percent side effect rate in the oral group and zero percent in the topical, but numbers were small.
There were two trials: one small trial, Trial 279,191 and one small seven-arm trial, Trial 340,161 with treatment between 6 and 18 months; both trials had patients with moderate to severe acne. There were no losses to followup in Trial 279 and there was well-executed blinding. On physicians' evaluation, the antibiotic group improved statistically significantly more than the placebo group. Side effects were comparable but infrequent. In Trial 340, the outcome was inter-treatment comparison against placebo. The tetracycline-novobiocin arm had the fewest number of patients rating it as the preferred treatment.
There was one large multi-center, three-arm trial, Trial 126 (N=211).194 Methodological issues included 22 percent of enrolled patients not randomized, subjects' baseline acne severity not ascertainable, major losses to followup, and patients and outcome assessors were not blinded. There were many outcomes, including severity assessments and lesion counts, showing no statistically significant difference between the groups. Erythema appeared more frequent (about one-third) in the treatment group, but a P-value was not provided.
There was one large multi-center, three-arm trial, Trial 126 (N=211).194 Methodological issues included 22 percent of enrolled patients not randomized, subjects' baseline acne severity not ascertainable, major losses to followup, and patients and outcome assessors not blinded. All efficacy differences (severity change and lesion counts) had P-values of 0.001. Desquamation and erythema appeared comparable, but P-values were not provided.
There was one medium three-arm trial, Trial 323,195 that included many patients of a narrow age range, but a wide range of acne severity. The report shows evidence of good randomization, blinding, and no losses to followup. There were many efficacy outcomes. The tetracycline/keratolytic combination achieved significant within-arm P-values for total lesion change, for comedo change, and for papule+pustule change. The tretinoin/keratolytic combination achieved a significant within-arm P-value for comedo change. The between-arm P-values were not significant, however. Ratings of side effects were low, but standard deviations were not provided to enable a comparison between the arms.
There was one large multi-center, three-arm trial, Trial 126 (N=211),194 where acne severity cannot be categorized. Only 78 percent of recruited patients were enrolled, patients were not blinded, outcome assessor was not blinded, and there were major losses to followup, as well as other major protocol departures. The outcomes were discretized improvement in pustule counts (statistically significant difference in favor of the combination therapy), in papule counts (not statistically significant), and in severity (statistically significant). Side effects of erythema and desquamation appear comparable in the two groups, although comparison statistics are not provided.
There was one large multi-center, three-arm trial, Trial 57,196 where the subjects in arms were similar along many dimensions, but where there were major losses to followup (N=238). Most patients were judged to have had 75-100 percent reduction in lesions, but P-values were not reported. No comparison between arms reached statistical significance. Over two-thirds of patients had local side effects in each group. The difference between arms is not statistically significant.
There was one three-arm trial, Trial 323,195 that included many patients of a narrow age range, but a wide range of acne severity. The report shows evidence of good randomization, blinding, and no losses to followup. All arms yielded changes in comedones and inflammatory lesions of about 40 percent. The tretinoin/benzoyl peroxide arm resulted in decreases that were statistically significantly larger. No side effects data were reported.
See K.02.04.
The teratogenic effect of isotretinoin is well known. None of the trials reviewed reported births or birth defects. The trials excluded women or women who were pregnant or lactating, and the trials reported contraceptive precautions.
There was one small trial, Trial 269,197 that compared isotretinoin to placebo in patients with severe acne. Patients in the isotretinoin arm had a decrease in the number of cysts while patients in the placebo arm had an increase in the number of cysts. This difference was statistically significant. Side effects of cheilitis (1), dermatitis (1), and arthralgia (1) were reported in the treatment arm.
There was one small trial, Trial 276,198 which evaluated males with severe acne. In the isotretinoin arm, there was statistically significant overall change as rated by the patient on a visual analogue scale beginning at 4 weeks of followup. Improvement in overall severity was statistically significant beginning at week 8. Statistically significant improvement in chest/back and face/neck were seen at week 16. All of these improvements persisted post-therapy. In the dapsone arm, there was some statistically significant improvement over baseline as rated by the patient in overall change and in face/neck count beginning at week 16. The isotretinoin arm had more improvement than the dapsone arm in the post-therapy face/neck count, though P-values for comparison between the treatment arms were not always provided. Other comparisons such as 16-week chest/back lesion count and total severity were not statistically significant. Cheilitis was reported in 17 patients in the isotretinoin arm but none in the dapsone arm.
There was one small trial, Trial 206,199 that evaluated patients with severe acne. This trial had major losses to followup. Patients in both treatment arms had improvement in the number of cysts, cyst diameter, and comedones and pustules present, though no P-values were provided. There were no statistically significant differences between the arms at 12 weeks; however, at post-therapy followup, the patients in the isotretinoin arm had statistically significantly greater improvement in cyst count, cyst diameter, and comedo and pustule count than patients in the tetracycline arm. More local side effects were reported in the isotretinoin arm (70 vs. 11) and more systemic side effects were reported in the isotretinoin arm (9 vs. 6), although no P-values were provided.
There was one small trial, Trial 127.200 In this trial, males received either alitretinoin or isotretinoin. Patients in both treatment arms reported side effects including abdominal pain or diarrhea (2 vs. 0), dryness of various membranes (20 vs. 23), headache (5 vs. 1) and red face (6 vs. 10). Overall, similar numbers of side effects were reported, although no P-values were provided.
There is one medium trial, Trial 130,201 of patients with severe acne. While patients in both arms showed improvement, isotretinoin was statistically significantly more effective in reducing inflammatory nodules at the end of treatment and 8 weeks of post-therapy than was etretinate. Improvement for both treatments was notable on the face more than on the chest or back. Side effects of cheilitis were noted in all patients, and conjunctival injection was noted in 25 percent of patients in each treatment group.
There were six trials. Trial 5202 was a small trial of patients with severe acne, while Trial 185203 was a medium trial of patients with moderate acne, Trial 332204 was a medium trial of patients with severe acne, and Trial 320205 was a large multi-center trial of patients with severe acne. Trial 106206 was a small three-arm trial as was Trial 190.207 Examined together, these trials evaluate isotretinoin at different doses, comparing 0.1mg/kg to 0.3, 0.5 and 1.0 mg/kg, and comparing 0.3 to 0.5 and 0.5 to 1.0 mg/kg. In Trials 5, 185, and 332, the higher dose of isotretinoin was associated with either more patients rated as "very good" or "good" improvement, or with greater percent change in non-inflammatory lesions. However, in Trials 320 and 332, there was statistically significant improvement in all treatment groups, with no significant differences in improvement between the different dosage groups.
In Trials 5, 106, 185, and 332, the higher doses were also associated with more side effects, with cheilitis, facial dermatitis, desquamation and epistaxis being the most common complaints. Taken together, these side effects were reported at least 14 times per arm in Trial 5. In Trial 320, there were minor differences in the side effect profiles at different doses, but 42 percent of patients given the lowest dose of 0.1 mg/kg/day required treatment. Similarly, a dose response for side effects was suggested by Trial 106, but P-values were not provided. More systemic side effects were noted at the 1.0 mg/kg dose. No P-values were presented.
There was one medium trial, Trial 12,208 comparing vitamin A to placebo. Similar numbers of patients were rated "improved" (34 vs. 33) and "no change" (23 vs. 17), with more patients being identified as "worse" in the placebo arm (3 vs. 22). No P-values were presented. No side effect data were presented.
There was one small four-arm trial, Trial 233,209 that evaluated vitamin A palmitate (oral), zinc sulfate (oral), their combination, and placebo in patients with moderate to severe acne. Severity change was numerically similar in the vehicle and vitamin A groups, and greater (and equal) in the zinc and combination group. No comparison statistics were provided. There were no patients with dry skin in the vehicle and vitamin A group, and four each in the other two groups. No comparison P-values were available.
No comparisons are available.
There was one small trial, Trial 141.210 Women with mild and moderate acne were evaluated. Neither the patient nor the outcome assessor was blinded. At 12 weeks, there was improvement in the face severity, total lesion count and total lesion percent change compared to baseline but no within-arm P-values were provided. There were statistically significant differences between the treatment arm and the vehicle arm in terms of severity change and total lesions percent change. No side effect data were provided.
There was one medium trial, Trial 245,211 that evaluated women with mild or moderate acne. This trial was not blinded and had major losses to followup. Both treatments demonstrated statistically significant reductions in the papule, pustule, and comedo mean counts at week 24 compared to baseline. No P-values for between group comparisons were provided. Side effects of nausea, vomiting, giddiness, bleeding problems, and headaches were reported in both arms. In addition, diarrhea, heartburn, and depression were reported in the minocycline arm. Differences in the number of patients reporting side effects were not statistically significant.
There was one medium trial of female patients, Trial 137,212 a three-arm trial of cyproterone/ethinyl estradiol with tetracycline or the tetracycline placebo versus tetracycline (with placebo for birth control pills). This trial had major losses to followup. In all arms, there were statistically significant improvements in the inflammatory lesion change, total severity change, and face severity change at all time points. The improvement in non-inflammatory lesions was numerically different, but not statistically significantly different. In the tetracycline arm, there was statistically significant improvement in all of the outcome measures over baseline. At week 24, there was no statistically significant difference between the arms in terms of inflammatory lesion change, but the cyproterone/ethinyl estradiol arm shows statistically significantly greater improvement in total severity. Side effects of hypertension (1) and dysmenorrhea (1) were reported in the cyproterone/ethinyl estradiol arm. Side effects of chest pain (1), headache (1), menstrual irregularity (1), and breast tenderness (1) were reported in the cyproterone/ethinyl estradiol/tetracycline arm. No side effects were reported in the tetracycline arm.
There was one small trial, Trial 141.210 Women with mild and moderate acne were evaluated. Neither the patient nor the outcome assessor was blinded. At week 12, both arms showed improvement in face severity, total lesion count and percent change, although no P-values were provided for comparison to baseline. There were statistically significant differences between the topical cyproterone arm and the cyproterone/ethinyl estradiol arm in terms of total severity change and Leeds severity score, with the topical cyproterone showing greater improvement. However, there were no statistically significant differences between the arms in total lesion count. No side effect data were provided.
There were three medium and large trials which evaluated the combination of cyproterone/ethinyl estradiol in various strengths in women: Trial 48,213 Trial 66,214 and Trial 117.215 The studies evaluated the combination of 2 mg cyproterone with 0.035 mg vs. 0.050 mg of ethinyl estradiol in women with moderate to severe acne. The trials demonstrated statistically significant improvement in severity within both arms with respect to baseline. No statistically significant difference between the arms was found. Systemic side effects were noted once in 22 patients in each arm, and more than once in at least 10 patients in each arm, although no P-values were provided.
There was one medium trial, Trial 237,216 of female patients with mild to moderate acne. The trial demonstrated statistically significant improvement in face papule count, face severity, and total severity by week 26. There was no numerical difference between the two arms in papule or nodule count, but there was a numerical difference in face severity, with the high cyproterone dose demonstrating greater improvement. P-values between the two arms, however, were not available and could not be calculated.
There was one small trial, Trial 55,217 and two large trials, Trial 87218 and Trial 103219 (all women), some with mild acne (Trial 55) and the remainder unspecified, that compared cyproterone/ethinyl estradiol to desogestrel/ethinyl estradiol at different doses. In Trial 55, there was no blinding. The trial was administered at two sites. Trial 87 had major losses to followup. In both trials, both treatment arms demonstrate some improvement in severity of acne. By long term followup, this improvement is statistically significant for both cyproterone sites in the cyproterone arm, but only for one site in the desogestrel arm. P-values were not provided in Trial 87. Comparing the two treatment arms, there was statistically greater improvement in the cyproterone arm at one site, but no difference between the arms at the other site or in Trial 87. No side effect data were presented.
There was one large trial of female patients with unspecified acne severity, Trial 48213 (N=133). It compared cyproterone with low-dose and high-dose ethinyl estradiol to levonorgestrel/ethinyl estradiol. Results show that both cyproterone/ethinyl estradiol and levonorgestrel/ethinyl estradiol improved total lesion percent change, but no P-values were given in the comparison to baseline. The cyproterone/ethinyl estradiol arm had a statistically significantly greater decrease in total lesion change at 16 weeks than the levonorgestrel/ethinyl estradiol arm, but there was no statistically significant difference between the arms at 24 weeks. No side effect data were presented.
There was one medium trial of women with moderate to severe acne, Trial 237.216 Comparison of cyproterone/ethinyl estradiol to norethisterone/ethinyl estradiol demonstrated statistically significant reduction of face severity and total severity in both arms by week 26. Papule count was only statistically significantly reduced in the cyproterone/ethinyl estradiol arm. There were no statistically significant differences between the arms in nodule count or papule count. There was statistically significantly more improvement in the norethisterone arm in total severity and face severity. No side effect data were presented.
There was one trial, Trial 225,220 a small trial of patients with mild and moderate acne. This trial had limitations including lack of blinding and major losses to followup. Both treatments showed statistically significant improvement in acne severity grade at 36 weeks compared to baseline. The patients that received desogestrel/ethinyl estradiol had more improvement than those in the gestodene/ethinyl estradiol arm, although no P-values were provided. Similar numbers of patients reported systemic side effects in the desogestrel/ethinyl estradiol arm (6) and in the gestodene/ethinyl estradiol arm (4).
There were two trials. Trial 264221 was a small trial of women with mild and moderate acne. Trial 263222 was a medium trial. Trial 264 demonstrated statistically significant improvement in acne severity over baseline in both treatment arms, with the desogestrel arm having statistically significantly greater improvement than the levonorgestrel arm. Similarly, in Trial 263 there were patients in both arms who were rated "improved" at 24 weeks, but there were statistically significantly more improved patients in the desogestrel arm. Side effects were reported in Trial 263. Two patients in the desogestrel arm and three patients in the levonorgestrel arm reported irregular bleeding. Two patients in the desogestrel arm and four in the levonorgestrel arm reported that their acne was worse and dropped out. While these numbers were similar, no P-value was provided.
There were three trials. One was a small four-arm trial, Trial 156,223 of patients with moderate to severe acne, limited by the absence of blinding. Results were stratified by gender. Women seemed to have lower severity scores than men, but no comparison statistics were reported. The second was a large cross-over trial, Trial 249,224 of 200 mg daily in women with mild-to-moderate acne (N=58 in each arm). The third was a very small five-arm trial, Trial 132,225 of four doses of spironolactone tested (50, 100, 150, and 200 mg daily) in a mixed-gender pool of patients with severe acne. Trial 249 was weakened by major losses to followup.
In Trial 249, spironolactone provided greater improved lesion counts (75 percent vs. 20 percent), greater improvement in patients' perceived severity (90 percent vs. 10 percent) and in photography-based severity assessment (55 percent vs. 20 percent). There were side effects deemed "positive" by the authors (decreased oily skin and breast enlargement) as well. In Trial 132, the higher doses of spironolactone may have led to higher assessments of overall change, but the numbers were very small.
There was a high rate of menstrual irregularity in Trial 249 and about a 10 percent rate of severe nausea, bad enough to lead to patient withdrawal; but the actual numbers are small. Trial 132 did not report any side effects.
There was one small trial, Trial 2.226 There were no patients who had any change in their acne reported by either physician or patient, although no P-values were provided. No data on side effects were reported.
There was one small trial, Trial 2.226 There were no patients who had any change in their acne reported by either physician or patient, although no P-values were provided. No data on side effects were reported.
There was one small trial, Trial 2.226 There were no patients who had any change in their acne reported by either physician or patient, although no P-values were provided. No data on side effects were reported.
There was one large trial (N=134). Trial 19227 compared the synthetic estrogen 16-epiestriol-3-allyl ether to placebo. After 12 weeks of treatment, there was no statistically significant difference in acne severity between the treatment arm and the placebo arm, with similar numbers of patients rated as "no change" (31 vs. 34), "improved" (19 vs. 26) and "marked improvement" (16 vs. 8). Similar number of patients also reported improvement in oiliness in both groups.
There was one small split-face trial, Trial 295.228 After 12 weeks, more patients were termed "better" in terms of severity in the placebo arm than in the treatment arm, though no P-values were provided. Both arms had the same number of patients rated as "worse" (7), "unchanged" (18), and "improved" (19) in terms of overall change as rated by the physician at 12 weeks. No side effect data were provided.
There was one large trial (N=153), Trial 213,229 that evaluated male patients with moderate acne. While there was no statistically significant difference in the inflammatory lesion count or the comedo count between the treatment arm and the placebo arm at 4 weeks, there was a statistically significantly greater decrease in the inflammatory lesion count at weeks 12 and 16 in the treatment arm. There remained no statistically significant difference between the two arms in terms of comedo count at 12 or 16 weeks. The number of inflammatory lesions decreased steadily from baseline through week 16 in the treatment arm, but no P-values were provided for within group comparison. Local reactions in the treatment arm included burning (32), stinging (18), itching (10), redness (19), and peeling (27). There were no statistically significant differences between the two arms with respect to the number of patients reporting local adverse reactions.
See M.01.08.
See M.01.09.
There were two large trials of women, Trial 218230 (moderate acne) and Trial 280 (mild to moderate acne).231 While Trial 218 had major losses to followup, it did demonstrate decreases in total lesions, comedo count, and inflammatory lesion count at 26 weeks compared to baseline although no P-values were provided. The differences were statistically significant compared to placebo. There was no statistically significant improvement in the number of nodules compared to placebo. Similarly, Trial 280 demonstrated change in total lesion count, inflammatory lesions, and comedones, although no P-value was provided for comparison to baseline. The percent change, both in inflammatory lesions and in total lesions, was statistically significant compared to placebo. Both trials demonstrate statistically significant overall change reported by both investigator and patient. Trial 280 reported similar numbers of adverse events reported between treatment arm and placebo arm, with 13 patients discontinuing therapy and 113 patients reporting events in the treatments arm, and 5 patients discontinuing therapy and 119 other events reported in the placebo arm. No P-values were presented.
There was one medium trial of women with mild to moderate acne, Trial 248,232 with major losses to followup. After 8 weeks, patients in the treatment arm demonstrated a statistically significant decrease in the comedo count and total lesion count compared to baseline. However, there were no statistically significant differences demonstrated between the treatment arm and the placebo arm in terms of either outcome. No side effect data were presented.
There was one small trial, Trial 271,233 a trial of patients with mild, moderate, and severe acne. In addition to serum gonadotropin (with unclear proposition of luteinizing hormone and/or follicle stimulating hormone) or placebo, patients received ancillary treatments including ultraviolet light and antibiotics. Similar numbers of patients were rated as "improved" (8 vs. 9), "no change" (9 vs. 9), and "worse" (2 vs. 3) in the treatment and placebo arms after 12 weeks of treatment, although no P-values were provided. No side effect data were presented.
There was one medium trial, Trial 266,234 that compared three oral Indian ayurvedic remedies, sookshama triphala, shankhabhasma vah, and sunder vati, with placebo and the keratolytic, thiostanin. The trial is notable in that the investigators used a government agency to assure the constituents of the treatments. Only the effectiveness with respect to baseline of sunder vati reached statistical significance for non-inflammatory and inflammatory lesions. No data on side effects were reported.
There was one small trial, Trial 325,235 of severely affected late adolescents/young adults. Effect of both treatments was to reduce counts of inflammatory and non-inflammatory lesions, but within-group P-values are not provided. Differences between groups were not statistically significant, except for severity change at 12 weeks. No data were provided on side effects.
There was one medium trial, Trial 94,236 of late adolescents with mild to moderate acne. Based on group data, inflammatory and non-inflammatory lesions were reduced statistically significantly in the benzoyl peroxide group; only non-inflammatory counts in the isolutrol were statistically significantly reduced, and only at 12 weeks. Local side effects (burning, dryness, erythema, pruritus, and scaling) appeared in about half the benzoyl peroxide patients and in only about one-fifth of the isolutrol group.
There was one small trial, Trial 17,237 with patients of a wide age and severity spectrum, where design was weakened by the absence of blinding and by major losses to followup. For the single outcome, severity change, comparison P-values were not provided, although the numbers appear comparable. There were no data on side effects.
There was one large trial (N=124), Trial 18,238 of late adolescents with moderate acne, notable for good blinding and the absence of losses to followup, but weakened by absence of randomization. Both treatments were effective with respect to baseline. Benzoyl peroxide bested tea tree oil at 4 and at 12 weeks on inflammatory, but not non-inflammatory, lesions. The rate of side effects was about 50 percent for tea tree oil and 80 percent for benzoyl peroxide, with large numbers and a statistically significant difference.
There was one very small, split-face trial, Trial 175,239 of patients with moderate to severe acne. No dose information was provided. Change in severity appears better in clobetasol, but between-group P-value was not significant.
There were two small multi-arm trials, Trial 28779 and Trial 288,79 both with little methodological information, and uncertain duration. These trials examined different combinations of the components of this treatment. Each component, and their aggregate, yielded a subjective "improved" rating in about half the patients in each arm. Sulfur and resorcinol resulted in itching or erythema in more patients than any other treatment, but there were few patients with any side effects.
There was one medium multi-arm trial, Trial 288,79 with little methodological information. In the single efficacy outcome, physician's assessment of overall change, about half the patients improved in these two arms. No comparison P-values were provided. There were few side effects, but numbers were too small for comparison.
There was one large multi-center, three-arm trial (N=776), Trial 228,40 that amalgamated several double-blind trials (five trials involving dermatologists and seven trials involving general practice centers) so that patients' severity and many other details are not determinable and arm sizes are not equal. Physicians' assessment of overall change was dramatically different: 84 percent improvement versus 50 percent in the vehicle group; P = 0.001. No side effect data were provided.
There was one large trial, Trial 102,240 of patients with unstated acne severity and no other patient data, and one medium trial, Trial 346,241 of patients with comedonal acne. In Trial 102, for the single outcome "overall change," the difference was statistically significant in favor of the treatment. In Trial 346, active treatment was statistically significantly better as regards patient acceptance and physician evaluation.
There was one large multi-center, three-arm report, Trial 228,40 that amalgamated several double-blind trials (five trials involving dermatologists and seven trials involving general practice centers) so that patients' severity and many other details are not determinable and arm sizes are not equal. There was also one medium trial, Trial 347,241 of patients with comedonal acne. The steroid/anti-bacterial treatment gave statistically significantly better results in Trial 228 but gave equal results in Trial 347.
See E.05.08.
There was one small trial, Trial 189,242 of subjects with wide age range and severity spectrum. Patients received variable numbers of injections, and there is no information on when outcomes were assessed. The outcomes were numerically similar.
There was one small trial, Trial 15,243 of severely affected young adults. Relative improvement was similar in all groups, although P-values were not provided; about half the patients were not improved in any group.
There was one small trial, Trial 222,244 of Royal Air Force males with a wide spectrum of acne severity, although results were stratified by acne severity. Numbers appear similar, although no P-values were provided. Adverse reactions were reported only for week 1 of therapy.
There was one small trial, Trial 297,245 of patients with mild to moderate acne. A pharmaceutical employee was a co-author. A number of subjective assessments, by patients and by physicians, and objective severity score yielded statistically significant differences in favor of the combination treatment. Statistically significantly more patients withdrew from vehicle treatment, presumably because of lack of efficacy. No side effects data were reported.
There was one large cross-over trial (N=120), Trial 224,246 of patients with the full spectrum of acne severity. The data show that patients were blinded, but there were major losses to followup and the trial staff was not blinded. The combination was statistically significantly more effective in reducing comedones, but not inflammatory lesions. Side effects (itchiness/dryness) were few and comparable.
There was one medium trial, Trial 142,247 of patients with mild to moderate acne. Pharmaceutical employee was first author. Severity, improvement, and lesion count change were the same. No side effect data were reported.
There was one small two-center trial, Trial 115,248 where acne severity cannot be determined. The trial was randomized; pharmaceutical employee was co-author. Both treatments led to statistically significant improvements in severity scores. The combination with chloramphenicol yielded a statistically significantly greater improvement at 4 weeks, but the difference became statistically nonsignificant at 12 weeks. Side effects (irritation and poor cosmesis) were few and numerically similar.
There was one small matched-control trial, Trial 75,249 of late adolescents with moderate acne. There were no losses to followup but degree of blinding is not clear, since the treatment regimen (frequency) may have been different for the two arms. Both treatments led to statistically significant improvements in severity and lesion count outcomes for inflammatory and non-inflammatory lesions. The differences between the treatments, however, did not reach statistical significance. Side effects (erythema or scaling leading to treatment reduction) were about 10 percent in each group, but there was no statistically significant difference between the arms.
See E.05.09.
There were five trials: Trial 138,70 Trial 139,70 Trial 179,250 Trial 180,250 and Trial 350.251 Including multi-arm Trial 350 of severely affected patients, these were all split-face trials, but the baseline characteristics were not made explicitly, and not all were randomized; there were major losses to followup in one trial (Trial 139), and in two trials, outcome assessments were biased in favor of radiotherapy (Trial 138, Trial 139). The total irradiated doses differed across the trials. In two trials (Trial 138, Trial 139), the results favored Grenz rays (also called bucky rays), although no comparison P-values were provided, while in Trials 179 and 180, the numbers appear equivalent. In Trial 350, hexachlorophene added to the Grenz rays led to numerically greater severity improvement, although the authors did not report comparison statistics.
There was one small and one medium split-face trial, Trial 215252 and Trial 216,252 of patients of unknown acne severity and unknown gender. The second trial lists its ages (14-18 years). A serious concern is that "some patients" were offered or were taking oral anti-bacterials at the same time. No P-values were reported; our calculated one shows a nonstatistically significant relationship.
There was one very small split-face trial, Trial 31,253 of patients with closed comedonal acne. There was a statistically significantly greater improvement on the side of face treated with fulguration than that by tretinoin. There were no data on side effects.
There was one very small split-face trial, Trial 32,253 of patients with closed comedonal acne. There were statistically significant improvements for large, but not for small, lesions. The differences in qualitative improvement and patients' preferences were not statistically significant. Three patients out of 15 total withdrew from the trial because of hypopigmentation or discomfort.
There was one small four-arm trial, Trial 156,223 of patients with moderate to severe acne, weakened by the absence of blinding. Results were stratified by gender. Women seem to have lower severity scores than men, but no comparison statistics were reported.
There was one small multi-arm trial, Trial 109,254 of patients with moderate acne, testing these different motivating techniques. Group-based total lesion counts were statistically significantly decreased in all groups, and statistically significantly decreased with respect to the no-treatment group. There were no reported statistical comparisons, however, among the different interventions.
There was one trial, Trial 172,142 a three-arm, matched-control trial of paid adults (mostly women), where the erythromycin/benzoyl peroxide group was a second set of observational controls that received dermatology care in clinic but no other intervention. The relaxation group, that included biofeedback and erythromycin/benzoyl peroxide, had the best outcome (P-value across three groups, 0.01), both at the end of therapy and after cessation of treatment.
There were two trials, Trial 178255 and Trial 284.256 The first was a cross-over trial of women with peri-menstrual acne exacerbation, limited by major losses to followup. The second included children as young as 8, was not randomized, and was not blinded.
Overall severity was either unchanged or even worse in the hydrochlorthiazide arms, although no comparison P-values were reported. Side effects were numerically similar to those of inert treatment in Trial 284.
There was one small two-arm trial, Trial 349,181 of young adults with mild to moderate acne. The arms were ibuprofen/tetracycline, tetracycline, ibuprofen, placebo. (Each arm had appropriate placebo to make two medications for each patient.) Patient blinding was documented, but physicians were not. At 8 weeks, total change was statistically significantly greater for the combination over the other three arms. While the change in single-treatment arms was greater than in placebo arm, P-values were not provided for those comparisons. Side effects data were not provided.
There was one small trial, Trial 110,257 of moderately affected patients, where subjects were not randomized. Dose information was not provided. P-values were not provided, but outcomes appear the same in both groups.
There was one small trial, Trial 64,258 where subjects had mild to moderate acne. Severity was not improved any more over vehicle, while side effects (irritancy) were statistically significantly greater in the zinc group.
There were nine trials: four small, Trial 3,259 Trial 259,260 Trial 211,261 and Trial 342262; four medium, Trial 91,263 Trial 133,264 Trial 336,265 Trial 341266; and one large, Trial 163.267 Three trials (Trial 91, Trial 163, and Trial 259) were multi-center. The trials were mostly of moderately affected patients, but included mild to severe. Three trials had major losses to followup (Trial 259, Trial 341, and Trial 342); one had pharmaceutical employee co-authors (Trial 133). One trial, Trial 133, is notable for documenting inter-rater reliability (between 0.54 and 0.68). The doses across the trials are comparable, usually 200 mg (45 mg elemental zinc), but ranging from 137 mg to 600 mg.
Out of 46 efficacy outcomes, including severity, lesion count, and photograph-based counts, 8 differences reached statistical significance, all in favor of zinc. The authors reported a range of side effects: nausea, diarrhea, oiliness, irritancy. There were few reported comparison statistics, and none was significant.
There were two small trials, Trial 74268 and Trial 232,186 of patients with moderate to severe acne. One trial (Trial 74), comparing zinc against tetracycline, had no patient blinding, while the other one (Trial 232), comparing zinc against oxytetracycline, had no losses to followup.
Out of multiple outcomes, only one yielded a statistically significant difference: In Trial 74, severity was improved more in the tetracycline arm. There were no side effects data.
There were three trials. Trial 108269 was a medium four-arm trial of males, 18-26 years old, with comedonal acne, that compared zinc/erythromycin gel and lotion against tetracycline and against placebo, and was notable for its explicit procedure to blind the participant. There was one medium trial, Trial 301,270 of females with moderate acne with major losses to followup, non-comparable arms, and unintended cross-overs from placebo to treatment group. Trial 321277 was a small two-arm trial of patients with mild to moderate acne that documented randomization and had no losses to followup, but had inconsistent ascertainment across arms.
In Trial 301, the combination was statistically significantly better than placebo for papules at 6 and 12 weeks. In Trial 321, there was statistically significant, and large, difference in inflammatory change with respect to baseline at 10 weeks. In Trial 108, the statistically significant results were that, in terms of severity, gel was more effective than lotion, which was as effective as tetracycline, and both were more effective than placebo. In terms of papules, the placebo fared poorer than the other three arms. No data on side effect events were reported.
There were two trials, single-site Trial 28271 and multi-country Trial 147,272 of patients with mostly moderate acne. Neither trial had methodologic limitations, although Trial 28 did not specify the concentration of the erythromycin product.
Lesion counts in both treatment arms were statistically significantly reduced for non-inflammatory and inflammatory lesions in both trials. The combination appears to have had an effect on nodules that erythromycin alone did not in Trial 147, but the actual number of nodules was small and no between-arm P-values were reported. The combination was reported to have been better for comedones, for inflammatory lesions, and for overall severity assessment, reaching statistical significance in the larger, but not the smaller, trial. Mild side effects appeared about twice as often in the combination group, but numbers are too small for valid P-value calculations.
There were two withdrawals from each arm due to local side effects.
There was one large trial, Trial 300.273 Both treatments were effective on their own (although the authors simply state "significant," without specifying a significance level). The differences were in favor of erythromycin/zinc for changes in comedo, inflammatory lesions, and overall severity. One patient from the erythromycin/zinc arm withdrew due to burning/redness.
There was one study, Trial 108,269 a medium four-arm trial of males 18-26 years old with comedonal acne. The two treatments were comparable in percent change in papules and in general severity. No data on side effects were reported. (See N.08.01 for further information on this trial.)
During review, two trials provided data for outcomes classified as psychological, beyond assessment of patient preference or satisfaction. Trial 316,136 in comparison E.05.04, compared topical azelaic acid/glycolic acid versus topical tretinoin. Subjects rated the effect of each treatment on a 6-point scale for the following factors: perceived attractiveness, self-confidence, comfort in social situations, satisfaction with their appearance, ease in a physical relationship, embarrassment, and degree to which acne negatively affected performance in work or at school. There were no differences detected between the treatments for these outcomes. Trial 40,82 in comparison H.08.045, assessed cosmetic acceptability in patients treated with tetracycline orally alone or in combination with topical tetracycline; acceptability was equivalent. No trials reported outcomes related to longer-term psychological morbidities of acne or its treatment.
Although 43 trials provided some data on treatment compliance, only 12 trials (Trial 1,155 Trial 30,77 Trial 69,178 Trial 110,257 Trial 121,105 Trial 122,105 Trial 123,105 Trial 162,149 Trial 189,242 Trial 247,165 Trial 280,231 and Trial 338111) reported that they monitored compliance and provided explicit data regarding patients' compliance. The detailed results are scattered across treatments and serve only as anecdotal data.
The following discussion is organized around our findings, characterizing the state of the acne literature, stating overarching conclusions from the evidence synthesis, providing answers to our primary and secondary questions as the evidence allows, describing limitations of the conclusions, and pointing to future research.
The literature regarding the treatment of acne vulgaris is characterized by a wide range of treatments, outcomes, study designs, and methods of assessment. These characteristics render synthesis of evidence difficult. We chose to focus on evidence presented in controlled clinical trials as the most efficient and defensible method for identifying which treatments are superior to others.
| Treatment class | Number of comparisons by evidence level | |||
|---|---|---|---|---|
| A | B | C | Total | |
| Cleanser (topical) | 0 | 0 | 6 | 6 |
| Keratolytic (topical) | 1 | 9 | 10 | 20 |
| Anti-bacterial (topical) | 3 | 20 | 11 | 34 |
| Anti-bacterial/keratolytic (topical) | 2 | 19 | 19 | 40 |
| Retinoid (topical) | 4 | 11 | 8 | 23 |
| Anti-bacterial/retinoid (topical) | 0 | 2 | 2 | 4 |
| Anti-bacterial (oral) | 1 | 22 | 25 | 48 |
| Anti-bacterial (oral)/keratolytic | 0 | 1 | 2 | 3 |
| Anti-bacterial (oral)/retinoid | 1 | 1 | 1 | 3 |
| Retinoid (oral) | 0 | 1 | 8 | 9 |
| Anti-androgen | 2 | 6 | 15 | 23 |
| Other | 0 | 10 | 27 | 37 |
| TOTAL | 14 | 102 | 134 | 250 |
Some arms are represented more than once because they employed more than one treatment.
In our report, we present the evidence as we encountered it in our reading of the literature. To enhance comparability across studies, we have attempted to classify subjects studied in terms of acne severity and have grouped outcomes at consistent time points where possible. We have grouped individual treatments by treatment class.
Of the 14 comparisons with Level A evidence, half refer to trials where mild or moderate acne was studied; only one refers to patients with moderate to severe acne; and the remainder, to studies where acne severity could not be ascertained. The majority of these are efficacy results - comparison to vehicle or placebo, rather than to some standard of care.
The results are sparse, and, in some cases, surprising. There are no cleanser or keratolytic products in the list of Level A evidence comparisons. Of the topical anti-bacterials, clindamycin and erythromycin demonstrate evidence of superiority in mild/moderate acne over vehicle. The evidence alone suggests that topical tetracycline is no better than vehicle. The treatment mainstay benzoyl peroxide has both anti-bacterial and keratolytic activity, and the evidence indicates effectiveness with respect to vehicle, although the severity context is not explicit. The evidence suggests that the three topical retinoids, tretinoin, adapalene, and motretinide are equally effective. Of the oral anti-bacterials, the evidence is clear only for tetracycline. Surprisingly, oral isotretinoin does not appear on this list, although it is generally perceived by clinicians, including the reviewers of this report, as the most potent acne treatment. This absence, and others, may result from limitations of our review, including bias introduced through the exclusion of non-English language reports of trials. In the case of isotretinoin, this absence is also a function of limiting the review to controlled trials as such trials are difficult to design for isotretinoin because of the side effect pattern seen. Of the anti-androgens, the birth-control pill norgestimate/ethinyl estradiol was demonstrated more effective than placebo. No comparison of the "miscellaneous" class is represented in this group of comparisons with Level A evidence.
There were 102 comparisons of Level B evidence. In these comparisons, expert opinion is especially necessary to evaluate the implications for clinical care. In the case of the 134 comparisons of Level C evidence, our results suggest that further research is required to evaluate the place of those treatments in clinical care.
| Treatment class | Index | Severity | Target treatment | Relative efficacy | Comparator Treatment | Evidence Level | Comments |
|---|---|---|---|---|---|---|---|
| Keratolytic | B.07.02 | Aluminum chlorhydroxide/sulfur (topical) | > | Vehicle (topical) | A | ||
| Anti-bacterial (topical) | C.01.01 | Mild/mod | Clindamycin (topical) | > | Vehicle (topical) | A | Clindamycin phosphate and hydrochloride results combined |
| C.03.01 | Mild/mod | Erythromycin (topical) | > | Vehicle (topical) | A | Especially inflammatory | |
| C.08.01 | Mild/mod | Tetracycline (topical) | = | Vehicle (topical) | A | ||
| Anti-bacterial/keratolytic (topical) | D.01.01 | Benzoyl peroxide (topical) | > | Vehicle (topical) | A | ||
| D.01.09 | Mild/mod | Benzoyl peroxide (topical) | = | Benzoyl peroxide (topical) | A | ||
| Retinoid (topical) | E.01.02 | Adapalene (topical) | = | Tretinoin (topical) | A | Evidence B that adapalene more effective for non-inflammatory | |
| E.02.01 | Mild/mod | Isotretinoin (topical) | > | Vehicle (topical) | A | ||
| E.03.03 | Motretinide (topical) | = | Tretinoin (topical) | A | |||
| E.05.01 | Mild/mod | Tretinoin (topical) | > | Vehicle (topical) | A | Evidence type A for non-inflammatory; type B for inflammatory. | |
| Anti-bacterial (oral) | H.08.01 | Tetracycline (oral) | > | Placebo (oral) | A | ||
| Anti-bacterial (oral)/retinoid (topical) | J.01.02 | Oxytetracycline (oral)/vitamin A (topical) | = | Oxytetracycline (oral) | A | ||
| Anti-androgen | M.01.05 | Mod/sev | Cyproterone/ethinyl estradiol (0.05) (oral) | = | Cyproterone/ethinyl estradiol (0.035) (oral) | A | |
| M.04.09 | Mild/mod | Norgestimate/ethinyl estradiol (oral) | > | Placebo (oral) | A |
Note: Some arms are represented more than once because they employed more than one treatment.
The variable study quality, as well as the noncomparability of studies due to lack of standardization, prevented us from performing quantitative meta-analyses to answer this question, which was our initial intent. In particular, we cannot make general statements about classes of treatment.
Many trials documented decreases in lesion counts with respect to baseline. However, because improvements from baseline were documented in both the active and placebo arms of many trials, we deemed treatment was "effective" only if it was deemed so in comparison to another treatment.
These conclusions are all based on severity or lesion-count based outcomes. As noted in Chapter 4, only two trials reported on psychological outcomes, beyond globally assessed patient preference.
There were few trials involving procedural, or nonmedical, treatment and the level of evidence for these trials was rated at Level C. No trials addressed diet.
Although clinicians and practice guidelines often discuss management of acne using this approach, the literature is not organized to answer this question. Investigators were not systematic in evaluating subjects' prior therapy. There is no basis from controlled trials to judge the efficacy of any treatment in relation to the sequence of therapy.
| Treatment class | Index | Target treatment | Side effects | Comparator treatment | Side effects | Relative side effects | Level of evidence | Comments |
|---|---|---|---|---|---|---|---|---|
| Anti-bacterial (topical) | C.01.04 | Clindamycin (topical) | Withdrew: 0/264 | Erythromycin (topical) | Withdrew (0.4%: 1/252) | = | A | |
| Retinoid (topical) | E.02.01 | Isotretinoin (0.05%) (topical) | ** | Vehicle | ** | > | A | Erythema and peeling scores give significant P-values between arms |
| E.03.03 | Motretinide (topical) | ** | Tretinoin | ** | > | A | Local reactions | |
| E.05.01 | Tretinoin (topical) | ** | Vehicle | ** | > | A | Local reactions | |
| E.05.04 | Tretinoin (topical) | Erythema (27%: 48/181); scaling (29%:52/181) | Azelaic acid | Erythema (15%: 27/177); scaling (14%: 24/177) | > | A |
Readers are directed to package inserts and post-marketing data that provide further information concerning possible adverse effects. This is especially important for the teratogenic oral isotretinoin. Because appropriate exclusions were made, the teratogenicity of isotretinoin was not documented in the controlled trials reviewed.
Because of the volume of literature available, this review focused on controlled clinical trials, rather than observational, laboratory, or other designs. Answers to our secondary questions require such designs (e.g., epidemiological observational studies for the residuum of untreated acne). Because of our focus, this report cannot be definitive on such issues as the true teratogenicity risk of isotretinoin, or the risk of depression in patients treated with oral retinoids.
None of the controlled trials related evidence on risk factors for the development of acne.
We reviewed trials specifically for locus of care but found none where "home" was the focus of care. It may be that this type of question is best addressed by other study designs that were not included in this evidence review.
None of the reviewed trials provided information addressing this question.
The term "presentation" suggests ways of describing acne and its natural history. These are acne duration, lesion type and count, severity, and prior therapy. Only 40 trials (14 percent) provided data on acne duration in describing their study sample at baseline. Most studies provided some information about lesion type, count, or severity. However, because these were controlled trials, where patients volunteered or were recruited in unstated ways, we do not know if the acne experienced by these subjects present the experience of all patients, and we therefore cannot say how these findings generalize. In some cases, the acne may be recent, in which case high spontaneous remission ("placebo") rates may be seen, while in others, it may be only subjects with refractory acne that are referred and recruited. A few trials included information on what treatments had been received prior to enrollment. No study quantified this information, and none stratified their results based on prior treatment. There are no standard ways of documenting "refractory" acne.
Also implicit in this question is the issue of how acne presents to dermatologists as opposed to primary care providers. Only 29 studies had patients seen in primary care offices or health clinics; so our data cannot provide a generalizable description of the patients seen in primary care.
Measuring compliance is difficult in acne studies. The most commonly used method is to require the volunteers to bring back the used containers of medication at the time of a study visit. However, one never knows if the subjects are emptying the containers at home in order to demonstrate compliance or otherwise not taking the medication as prescribed and few of the studies documented even attempting any measure of compliance. Seventy-four trials (27 percent) provided information to conclude that they monitored compliance prospectively and only 39 of these provided some documentation of the degree of compliance (36 saying 80 percent compliance or greater and 3 trials reporting 50-80 percent compliance).
Only 15 studies observed their subjects for more than 6 months: Trial 52,214 Trial 70,36 Trial 86,219 Trial 97,215 Trial 115,212 Trial 123,128 Trial 154,203 Trial 160,242 Trial 173,199 Trial 185230 Trial 191,220 Trial 202,216 Trial 237,198 Trial 241,231 and Trial 278.235 None assessed scarring or long-term morbidity.
As described in Chapter 4, only two trials provided specific evidence.
As described in Chapter 3, no studies provided evidence.
Our conclusions must be qualified because of the great heterogeneity present in the acne literature at all levels: there are a large number of treatments, compared in multiple ways; although there are a limited number of primary acne outcomes, there are a large number of ways of defining on what part of the body lesions are counted (over 30 ways); there are a large number (25) of ways of classifying severity; and there are many ways that these outcomes were expressed (raw measures, absolute change with respect to baseline, and percent change with respect to baseline). There is no standard approach to describing side effects. Similarly, there is no standardization of followup times. Our division into short-term, mid-term, long-term, and post-therapy, while a result of consensus among our technical experts, is still an arbitrary arrangement.
The practical decision to focus on English language reports of trials meant that potentially high quality non-English studies were not included in this review. Syntheses on more focused questions (e.g., a synthesis on isotretinoin alone) should include a search for and inclusion of non-English language reports of trials.
While some effort was made to use sources that may provide nonpublished reports of trials (such as the use of the Cochrane Collaboration's CENTRAL database, which contains hand searching results as well as ongoing trials, and our own searching of reference lists of key articles) we must also recognize that this report is open to publication bias-that is, trials with positive results are more likely to be published, thereby potentially leading to an overestimation of the true effects of the treatments. This report summarizes the available evidence as found in published reports of trials and, as such, may not include all of the relevant evidence. We might expect publication bias in the field of acne, since so much of the research is industry-sponsored, and pharmaceutical companies may be less motivated to publish negative results than researchers without a commercial interest in the results. Syntheses on more focused questions should include a more intensive search for nonpublished reports of trials. This may include a hand search of proceedings of relevant conferences and contacting key researchers in the field to ask if they know of any completed or ongoing unpublished trials.
At the same time, there were some surprises. Some treatments currently in use or soon to be in use had little to no evidence in the literature reviewed. For instance, although tazarotene was recently approved by the FDA for use in acne, we found no published trials in our search procedure that included asking our technical experts for controlled trials we might have missed. (One trial on tazarotene has been published since the literature review for this report was completed.)
Industry plays a major role in acne research. Of the 145 trials (out of 274) that reported funding, 127 were pharmaceutical company funded, and an additional 113 trials mentioned other forms of support from drug companies, such as provision of medicine. Because these companies design their research to comply with FDA requests (in the United States), these requests have a great influence on the nature and scope of the trials on acne. Such requests could encourage pharmaceutical companies to support trials that not only establish the efficacy versus safety of their product but also provide clinicians with the evidence they need to make rational therapeutic decisions.
The heterogeneity of the literature makes it very difficult to pool any results, and, therefore, precludes quantifying the conclusions. We focused on assessing the level of evidence available for any treatment comparison, and we based all assessments of the efficacy of a treatment in terms of comparisons with other treatments, including placebos. Improvements relative to baseline were commonly seen for both active treatments and placebo treatments. This suggests that acne may improve spontaneously and mitigates against drawing conclusions about efficacy from the results of a single arm of a trial, even if large and statistically significant differences were documented with respect to baseline status.
Generally, controlled trials provide limited information on side effects. Readers are cautioned to check other sources for side effect data such as drug inserts.
Finally, the nature of acne itself may be changing. A number of our technical experts expressed concern about bacterial resistance of P acnes, especially to clindamycin and erythromycin. This issue has major consequences for treatment recommendations and for future research.
During the peer review process, the contents of this report proved to be controversial because of the surprise to find well established therapies not strongly supported by evidence from controlled trials. These surprises point to the need for studies concerning apparently established therapies. For instance, peer reviewers were surprised that doxycycline, one of the most favored anti-bacterials used in the treatment of acne, had so little evidence of superior efficacy in English language controlled trials.
For researchers investigating acne therapies, this evidence synthesis points to a number of recommendations. Given the many different treatments for acne, it would be impossible to compare new therapies with one another. The research community must lay out a chain of evidence across therapies that would enable clinicians to make rational choices. A core factor in this strategy is to choose an anchor of evidence. For instance, for mild to moderate acne, inert control and benzoyl peroxide suggest themselves as candidates for comparison. For severe acne, isotretinoin may be the appropriate comparison.
The question of bacterial resistance suggests further questions: To what extent must "established" therapies (both clindamycin and erythromycin were two of the few treatments that had evidence of Level A documenting their efficacy) be revisited? To what extent must multi-drug therapy be used, in place of monotherapy? To what extent must P. acnes baseline status be assessed by generalists?
Future trials should address the following methodological issues:
Explicit description of how patients are recruited for a study, and from what population they are chosen.
Explicit exclusion and inclusion criteria, using a standard method for describing patient characteristics, such as acne severity, acne duration, prior therapy, and colonization with P. acnes.
Stratified randomization by acne severity, sexual maturity, race, and sex, as appropriate based on the sample.
Explicit method of randomization.
Psychometric measurement for quality of life at baseline and at termination.
Explicit assessment of patients' acceptability of treatment.
Explicit and standard method of lesion counting.
Explicit and standard method of severity rating.
Explicit and standard method of compliance monitoring.
Explicit procedures to ensure consistent outcome assessments across investigators especially in multi-site studies.
Sample size assessment to be made before the study, with an explicit statement regarding the minimal difference desired by either the investigator or the patients.
Statistical analysis to use at least analysis of covariance with baseline lesions as the covariate or analysis of variance with discrete assessment of severity as a factor.
Standard followup periods, including post-therapy.
Percentage change with respect to baseline within each patient as the primary acne outcome.
Subgroup analyses by sexual maturity, acne severity, sex, race, and prior therapy.
While the information contained in this report will be useful in selecting specific treatments for their documented effectiveness, there is still much work to be done to define the best approach to management of acne in an individual patient based upon their specific characteristics. Until this work is done the process of care for patients with acne vulgaris will remain highly individualized, based upon the experience of the patient and the treating physician. The effectiveness of a more evidence-based, stepwise approach that incorporates several therapies at different points in time still needs to be documented.
Future research on the treatment of acne vulgaris would benefit from:
Population-based studies with detailed information about subjects including age, race, gender, sexual maturity rating, and previous treatment of acne.
Consistent case definitions and methods for assessing acne type and severity.
Greater consistency in outcomes across studies so that trials are comparable.
Standards for assessment of clinical outcomes.
Assessment of outcomes at time points distant from treatment.
More information about psychological outcomes and costs related to treatment.
Attention to the issue of bacterial resistance.
Research is needed to define what the sequence of acne therapy (first-line, second-line, and third-line) ought to be. This research needs to take into account baseline characteristics that we have discussed, as well as treatment effectiveness and side effects. Patient and physician preferences must be elicited explicitly. Although we have defined 'sequence' in terms of level of care, other categorization may be useful, like 'active' and 'maintenance'. In any event, attention needs to be made to a therapeutic strategy, not just to drug efficacy.
A question posed by many experts at the start of this project - "When should acne be referred to a dermatologist"? - still stands, and requires explicit research. This research involves assessing the relative outcomes of patients cared for by primary care physicians and by dermatologists for patients with equally severe acne. British researchers (e.g., Trial 11208) have put together networks of primary care providers, but they have not explicitly compared outcomes of primary care providers with those of dermatologists. We recommend that a controlled trial be considered that would compare the outcomes (acne and psychological) of patients treated on basis of a clinical practice guideline by primary care providers with the outcomes of patients cared for by dermatologists. The guideline would have to account for prognostic characteristics that we have outlined, and would have to take into account the myriad of treatments that we have summarized. A formal decision analysis could then be performed, utilizing the causal model detailed in this report.
Another area for further research is the optimal duration for acne therapy. The time points in the trials we reviewed had more to do with study design and resources then consideration of therapeutic effect. Furthermore, consistent time points for outcome assessment would allow for more direct comparison of results from multiple trials. An outcome not captured in the current literature is the relative speed of therapeutic action. A treatment that works more quickly would be more desirable than a treatment that is equally effective but takes longer to reach effectiveness.
It has been suggested that future research would do well to focus on more severe cases of acne. including those that have been resistant to treatment. These cases are more likely to cause scarring, and cause the most frustration for patients and physicians.
Acne is a prevalent condition which can lead to significant morbidity. A variety of therapies are effective, but further research is needed to define which patients might be expected to benefit the most from specific schedules of treatment.
Nancy Barnett
Johns Hopkins Evidence-based Practice Center
Bob Bryant
American Pharmaceutical Association
Mary-Margaret Chren
American Academy of Dermatology
Tsu-Yi Chuang
American Academy of Dermatology
Bernard Cohen
Johns Hopkins Evidence-based Practice Center
Anne Eady
Skin Collaborative Review Group, Cochrane Collaboration
Evan R. Farmer
American Academy of Dermatology
James Herbert
American Academy of Pediatrics/Committee on Practice and Ambulatory Medicine
Alain Joffe
Johns Hopkins Evidence-based Practice Center
Daniel Krowchuk
American Academy of Pediatrics
Anne W. Lucky
American Academy of Dermatology
Gary Peck
American Academy of Dermatology
John Strauss
Society for Investigational Dermatology
American Academy of Dermatology
Pat Alguire
Society for General Internal Medicne
Martin Fisher
Society for Adolescent Medicine
Kathleen C. Teets Grimm
American Academy of Pediatrics/Committee on Practice and Ambulatory Medicine
Martin Mahoney
American Academy of Family Practitioners
Alan Moshell
National Institute of Arthritis, Musculoskeletal, and Skin Diseases
Alan R. Shalita
American Academy of Dermatology
Diane Thiboutot
Society for Investigative Dermatology
Jonathan D.K. Trager
Society for Adolescent Medicine
Barbara Yawn
American Academy of Family Practitioners
Dear <<Technical Advisor>>,
A major responsibility in this project is to help us refine the topics and questions for evidence review. Please complete this questionnaire. Feel free to call or email us with questions. There are strict time constraints from the AHCPR. We need a RAPID response. Please FAX your responses by DEC 18 (410 614-9878).
Below is a non-prioritorized list of questions elicited
from experts, professional organizations, and consumers. For
each question, please
- Rate the Importance to your constituency of the
questions, from 1 (Unimportant) to 10 (Vitally Important).
- Rate your sense of the Data Availability to answer the
questions, from 1 (Unavailable) to 10 (Available through a
simple Medline query).
- Provide some Comments, giving a sense of what you think
the answer will be, or how established the answer might
already be.
| Question | Importance | Data Availability | Comments |
|---|---|---|---|
| Are there predictors of acne severity (race, time with acne, history of treatment, diet, hygiene)? | |||
| Does acne treatment effectiveness vary by severity/type of acne? | |||
| To what extent does health insurance cover acne treatment? | |||
| At what point do patients seek, or want to seek, medical care? | |||
| How do generalists and specialists compare in their ability to diagnose acne and its severity? | |||
| What is the effectiveness of OTC preparations and their combinations in treating acne? | |||
| What is the efficacy of FDA-approved drugs for treating acne, and the efficacy of their combinations? | |||
| What is the efficacy of treatments not FDA approved in treating acne? | |||
| What is the efficacy of treatments used outside the United States in treating acne? | |||
| What treatments are known not to be effective in treating acne? | |||
| How do generalists and specialists differ in their manageent (appropriate or otherwise) of acne? | |||
| What should be the first-line, second-line, and third-line treatments for acne? | |||
| Does response to second-line therapy depend on prior length of time with acne and response to first-line treatment? | |||
| At what point in the treatment process should men receive isoretinoin (Accutane)? | |||
| At what point in the treatment process should women receive isoretinoin (Accutane)? | |||
| At what point in the treatment process should a patient be referred to a dermatologist? | |||
| What are the frequencies of side effects of treatment? | |||
| Does the type of acne remain constant within an individual? | |||
| To what extent does antibiotic resistance develop in patients treated with oral or topical antibiotics for acne? | |||
| What are patient preferences regarding acne treatment? | |||
| How cost-effective are different acne treatment strategies? | |||
| How should patients with acne be treated in whom isoretinoin (Accutane) fails? | |||
| How should post-treatment scarring and hyperpigmentation be treated? |
2. Please write any further questions, their importance, data availability, and sense of the answer:
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
3. We will be searching MEDLINE, COCHRANE, HEALTHSTAR, and PSYCHINFO. Do you have any further suggestions for searching?
______________________________________________________________________________
______________________________________________________________________________
4. How would you or your group use the evidence report? Please check all that apply.
___ For internal guideline
___ For collaborative guideline with other organizations
___ Disseminating management plan
___ Other (please specify) ________________________________________________________
___ Other (please specify) ________________________________________________________
___ Other (please specify) ________________________________________________________
5. Complete by (Name, phone, fax, and email, if we don't already have them):
_____________________________________________________________________________
_____________________________________________________________________________
| What is the effect on | acne sequelae of acne costs psychological effects adverse effects 1 | of | treatment 2 | in | children adolescents young adults older adults 3 | with |
| mild moderate severe 4 | nodulocystic comedonal pustular 5 | acne, and with | race skin type duration of disease diet geographic environment insurance status 6 | , who are treated by | self generalist dermatologist 7 | ? |
| What are the | economic costs physical effects psychological effects 8 | of acne and its sequelae in a population? |
| January 25, 1999 | Management of Acne AHCPR Evidence Report | FAX to: 410-614-9878 |
Feedback Regarding Study Questions and Exclusions
| Feedback from: | ______________________________________________________ | |
| First Name | Last Name | |
| Date: | _______________________ | |
| Number of pages (including this one): _______ | ||
| _____________________________________________________________________________ | ||
Study Questions:
We have enclosed the study questions for this project. These questions were developed based upon a preliminary review of the evidence and feedback from our Partners and Technical Experts. Please provide comments regarding the study questions by writing on and faxing back the page(s) with the questions and/or provide comments here:
_____________________________________________________________________________
_____________________________________________________________________________
_____________________________________________________________________________
Exclusions:
As outlined in deliverable 5a (enclosed), our literature search and review will be guided by the study questions, and by inclusion and exclusion criteria. We would like your confirmation that we have made appropriate decisions, based upon previous feedback and the preliminary review, regarding the exclusion criteria we have set.
In general, we feel that it is beyond the scope of this evidence
report to examine endocrinopathies; to do so would necessitate an
examination of underlying medical conditions. Do you agree that this
report should focus on the management of acne in patients whose exam
and medical condition is otherwise normal? (circle one)
Yes
No Comments: __________________________________________________
We have set specific exclusions and include these below.
Please place a check beside those you agree shouldbeexcluded from this report:
 chloracne |
acne
rosacea |
|
acne venanta |
acne
fulminans |
|
acne necroticans |
acne
agminata |
| Others? Please specify: | |
|
_________________________ |
_________________________ |
Notes for study questions:
Outcomes: Outcomes of interest include acne residual, quality of life, cost and other morbidities. Sequelae of acne (acne residual) include scarring and hyperpigmentation.
Treatment: Includes the following:
Pharmaceutical interventions:
FDA approved prescription drugs
FDA approved OTC
Alternative therapies
Pharmaceutical treatments used outside of the United States
Surgical interventions
Patient Age: We will include all ages in our search. Where possible, we will stratify by age. For instance, based on the preliminary literature review, we may stratify Tanner Stage V by age (adolescents, young adults and older adults).
Acne Severity
Acne Type
Patient Characteristics: We have listed in the question, patient characteristics that appear to have an influence on the management of acne. Insurance status of an individual may be MCO, fee-for-service, no insurance and public assistance.
Source of care: Includes issue of variation of practice.
Population outcomes
CENTRAL Core Search Strategy
acne-vulgaris*.me
acne*.tw
#1 or #2
PubMed Core Strategy
(((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR (clinic* [tw] AND trial* [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (latin [tw] AND square [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp]) NOT (animal [mh] NOT human [mh]))) AND (acne vulgaris[mh] OR acne*[tw])
OLDMEDLINE Core Search Strategy
acne vulgaris (kw) OR (acne (tw) and vulgaris (tw))
OLDMEDLINE Text Search Strategy
acne (kw) OR acne (tw)
CINAHL® Core Search Strategy
Acne/or acne vulgaris.ti,sh,ab,it
PsycINFO® Core Search Strategy
acne vulgaris [words anywhere] OR acne [words anywhere]
Supplemental Search Strategy: Cost
(acne vulgaris [mh] OR acne [tw]) AND ("economics"[Subheading] OR "financial management"[mh] OR "economics"[mh] OR economics[tw] or "costs and cost analysis"[mh] OR cost*[tw])
Acne Abstract Review Form
Reviewer: _________
Entered: __________
| Delete, because article (check one): | Study areas addressed (check all that apply): |
|
did not address
management of acne
did not include
human data
only addressed
chloracne, acne rosacea, acne venanta, acne fulminans, acne
necroticans, acne agminata
no original
data
article not in
English
Specify language:__________________
Do not go on if any of above are checkedType of
evidence:
controlled
trial
cohort
study
case-control
study
case-series/case-report
review
opinion/editorial
unclear |
Medical
outcomes
Treatment
Cost
Psychological
morbidities
Acne
severity
Acne
type
Patient
characteristics
Source of care
None of the
above
None of the
above, but relevant to:
___________________________________________
Unclear,
retrieve article
Comments:
________________________________________________
________________________________________________ |
Acne: STUDY ARTICLE ID_________REVIEWER A___________ B________ YEAR:
_________
Date
Exclude: Check ANY that apply
| Does not discuss acne management |
|
| No human data |
|
| More than 20% of the patients have chloracne, rosacea, venanta, fulminans, necroticans, agminata |
|
| Patients are not baseline normal (e.g., industrial-caused acne) |
|
| Surrogate outcome measures only (e.g., sebum production, P acnes colony counts) |
|
| No original data |
|
| Article not in English |
|
| Fewer than 5 patients |
|
| DO NOT PROCEED FURTHER IF ANY ITEMS CHECKED ABOVE!!! |
READ PAPER BEFORE ANSWERING THE FOLLOWING QUESTIONS.............................USE PENCIL!!!!!!
QUESTIONS FOR
PI:(Harold and John)
Experts
STUDY CHARACTERISTICS
| 1. Design | ||
| Treatment was assigned prospectively, randomly or no | Controlled trial |
 |
| Group of patients followed prospectively without treatment assignment | Cohort study |
|
| Groups defined as those with or without outcome | Case-control |
|
| One or more groups of patients are examined at one point in time | Cross-sectional |
|
| Data are available on a single group of patients before and after/during the intervention | Before-after |
|
| Single-arm study with more than four patients (note subjectivity) | Case series |
|
| You cannot say based on the information provided | Unspecified |
|
| 2. Arms | ||
| How many distinct treatment groups were there? | Number of arms | _______ |
| 3. Dates | ||
| From first patient enrolled to last data collected (xx/19xx or ??? if unclea)r You can enter only the year if that's all you know | Enrollment | ____/_____ |
| xx/19xx or ??? if unclear | End of data collection | ____/_____ |
| If dates aren't given, perhaps the duration is | Study duration | __________ |
| Units | Wks
Mos
Yrs
| |
| 4. Number of sites | ||
| Single city/locale | Single |
|
| One country | Multicenter |
|
| Multiple countries | Multicountry |
|
| Not enough data | Can't say |
|
| 5. Location | ||
| Primary, or coordinating (for multistudy), country of the study | Country | ____________ |
| Primary, or coordinating (for multistudy) state/province of the study | State/Province | __________ |
| Primary, or coordinating (for multistudy) city of the study | City | __________ |
| Inferred from author address only |
| |
STUDY QUALITY
| How did patients get into this study? | 6. Assembly | ||
| All patients who came in through the door were enrolled/included | Consecutive |
| |
| Do the authors state the patients were recruited? | Recruited |
| |
| Other |
| ||
| Can't say |
| ||
| What patients were excluded from this study, according to the design description? | 7. Exclusion criteria | |||||
| Tanner I |
| Female |
| Mild acne |
| |
| Tanner II |
| Male |
| Moderate acne |
| |
| Tanner III |
| Severe acne |
| |||
| Tanner IV |
| Asian |
| Secondary acne |
| |
| Tanner V |
| Black |
| |||
| Hispanic |
| Pregnancy |
| |||
| Other race |
| Lactation |
| |||
| _______________ | Allergy to study meds |
| ||||
| < 31 days |
| White |
| |||
| 31 d to 10 y |
| |||||
| 11 y to 14 y |
| Other comorbid condition |
| |||
| 15 y to 18 y |
| ____________________ |
| |||
| 19 y to 34 y |
| Dry skin |
| |||
| 35 y to 54 y |
| Oily skin |
| Comedonal acne |
| |
| > 54 y |
| Inflammatory acne |
| |||
| Pustular acne |
| |||||
| Nodularcystic acne |
| |||||
| None listed |
| |||||
| For what prior treatment regimens were patients excluded? | 8. Treatment Exclusion criteria | ||
| Treatment | Duration | Units | |
| ______________________________________ | ___________________ |
Days
Weeks
Months | |
| ______________________________________ | ___________________ |
Days
Weeks
Months | |
| ______________________________________ | ___________________ |
Days
Weeks
Months | |
| ______________________________________ | ___________________ |
Days
Weeks
Months | |
| ______________________________________ | ___________________ |
Days
Weeks
Months | |
| None listed
| |||
| 9. Research design | ||
| The standard CCT | Parallel |
|
| With or without initial washout | Cross-over |
|
| There was only one group of patients | Single-arm |
|
| There are not enough data to make a determination | Can't say |
|
| 9a. Matched control | ||
| One or more controlled patient(s) were specified in each experimental patient | Yes |
|
| Design is called matched ,but their are few data or no data to support that | Maybe |
|
| No mention or evidence of matching | No |
|
| Can't say |
|
| 10. Research funding | ||
| NIH, etc. | Federal |
|
| Drug-company funded, but evaluated in usual peer way | Drug/peer-eval |
|
| Drug-company funded and published in a supplement or worse | Drug/supplement |
|
| There are not enough data to make a determination | Can't say |
|
| E.g., Foundation | Other _______________ | |
| How were patients assigned to treatment | 11. Assignment across patients | |
| Based on random numbers, from a table or computer | Randomized |
|
| The authors decoration: call it "randomized," but give no details | Maybe Randomized |
|
| A method that results in assignment that is clearly known in advance, e.g., odds/even clinic days, birthdays, odd/even clinic numbers | Deterministic |
|
| Not enough information to say how assignment was actually made | Can't say |
|
| There were no assignments made to treatment in a prospective manner | Not applicable |
|
| Were different sides of the face (back, etc.) treated differently? | 12. Assignment within patient | ||
| Split face (or other body part), random |
| ||
| Split face (or other) deterministic |
| ||
| Can't say |
| ||
| There was no such assignment made | Not applicable |
| |
| Were the patients ignorant about what treatment they got? | 13. Patient blinded | |
| There is clear attempt at documenting whether they knew, and it shows that theydidn't | Yes |
|
| There may be documentation, and it shows that they didn't know, or, from implicit data, you infer that there was fair patient blinding (also if author says "double blind" but no other information provided) | Somewhat |
|
| There is clear attempt at documenting whether they knew, and it shows that they did | No |
|
| There are no implicit or explicit data | Can't say |
|
| Not applicable |
| |
| Was the person enrolling patients ignorant about what treatment would be assigned? This is somewhat dependent on the method of treatment assignment | 14. Enroller blinded | |
| There is clear attempt at documenting whether they were ignorant, and it shows that they were ignorant | Yes |
|
| Either the method (based on your background knowledge) or the data suggest that there was some unblinded enrollment (also if author says "double blinded" but no other information provided) | Somewhat |
|
| The method or the data make it clear that enrollers knew the prospective enrollment | No |
|
| There are no implicit or explicit data | Can't say |
|
| There was no assignment made | Not applicable |
|
| Was compliance of the patients to their assigned treatment monitored? | 15. Compliance monitoring | |
| Monitoring was planned from the outset and was followed | Prospectively |
|
| Although not planned, there are data about compliance | Retrospectively |
|
| There was a plan for monitoring, but the results are not reported or no plan and no data reported | Maybe |
|
| Neither explicit (e.g., survey) nor implicit (e.g., side effect rates) data are available to make this assessment | Can't say |
|
| There was no assignment made | Not applicable |
|
| What part(s) of the body was treated? | 16. Body area | ||
| Face |
| ||
| Chest |
| ||
| Back |
| ||
| Systemic |
| ||
|
| |||
| Other | |||
| What was the nature of the medical care that patients received in ALL arms? | 17. Type of care | ||
| Community office | Clinic visits |
| |
| Includes academic clinic | Hospital visits |
| |
| Home |
| ||
| Other | |||
| ________________________________________ | |||
| Can't say |
| ||
| What was the nature of the things excluded from ALL arms? | 18. Ancillary Rx: Excluded Rx | ||
| Medication |
| ||
| Soaps |
| ||
| Diet |
| ||
| Other |
| ||
| ___________________________________________ | |||
| Can't say |
| ||
| Was ancillary treatment similar across arms? | 19. Equal ancillary Rx across arms | |
| Yes |
| |
| Some doubt about the consistency, based on data or your background knowledge | Maybe |
|
| Clearly differences in ancillary treatment that are important | No |
|
| There are not enough data to determine | Can't say |
|
| There was no assignment made | Not applicable |
|
| "LTFU" includes any patient for whom (primary) outcome data are NOT available | 20. Losses to follow-up | |
| The number of patients LFTU comprise less than 5% of the sample, and were evenly distributed across arms | None |
|
| LTFU comprises between 5 and 20%, evenly distributed | Minor |
|
| LTFU comprise greater than 20% or grossly asymmetric | Major |
|
| There are no data on LTFU | Can't say |
|
| This was a retrospective study | Not applicable |
|
| "PD" includes dropouts, withdrawals, and unintended cross-overs for whom outcome data ARE available | ||
| 21. Protocol departures | ||
| The number of PD comprise less than 5% of the sample, were evenly distributed across arms, and outcome data are available on any that did depart. | None |
|
| PD comprises between 5% and 20%, are evenly distributed, and outcome data are 80% known. | Minor |
|
| PD comprises greater than 20% or what PD there is unaccounted for or outcome data are not known and could subvert the study's conclusion so | Major |
|
| There are no data on protocol departures | Can't say |
|
| There was no protocol | Not applicable |
|
| Was the process by which patient came to have their outcomes assessed consistent across arm? Examples of not consistent would be inpatients vs outpatients or other more subtle differences | ||
| 22. Ascertainment consistent across arms | ||
| No doubt about the consistency | Yes |
|
| Some doubt about the consistency | Maybe |
|
| Clearly differences in ascertainment | No |
|
| There are not enough data to determine | Can't say |
|
| There was no assignment made | Not applicable |
|
| Were the person/people assessing the outcomes blinded to assignment? These may be the same as the treaters. If there was blinding for some outcomes, but not for others, list here the best level of blinding, and make a Comment about the worse level on the data table about that outcom (in ARM form) | ||
| 23. Outcomes assessor blinded | ||
| Totally blinded | Yes |
|
| Some degree of blinding, but the lack of blinding is unimportant (also if author says "double blinded" but no other information provided) | Somewhat |
|
| Clearly differences in ascertainment | No |
|
| There are not enough data to determine | Can't say |
|
| There was only one arm | Not applicable |
|
| Based on your judgment, paying attention especially to "Table 1," the table of baseline characteristics of the patients in each arm. If a couple of characteristics are statistically significantly different between the groups, they may still be comparable if those characteristics are unimportant. | ||
| 24. Comparability of the arms. | ||
| Many important characteristics were assessed, and they are equally represented in the different arms | Yes |
|
| Some important characteristics were not assessed, or at most one or two of those characteristics that were assessed are different among the groups, but probably not important | Maybe |
|
| Several characteristics are different, and they are important | No |
|
| There are not enough data about the execution to permit a conclusion | Can't say |
|
| There is only one arm in this study | Not applicable |
|
| Based upon your judgment. This judgment synthesizes what you've read | ||
| 25. Execution true to study design | ||
| The execution followed the design, and any problems you detected do not detract from inferences assuming that that study was performed ideally | Yes |
|
| The execution essentially followed the design, but some departures from design may invalidate the results | Somewhat |
|
| The study as executed is different enough from design that inferences are called fundamentally into question | No |
|
| There are not enough data about the execution to permit a conclusion | Can't say |
|
| What is the most general group of patient for which this study's results are valid, in your opinion, taking the design and results into account | ||
| 26. Generalizability | ||
| E.g., all peoples | General population |
|
| E.g., all white 14-year olds | Specific population |
|
| E.g., all white 14 olds in Baltimore | Local population |
|
| E.g., all patient referred to a specialty clinic | Referral population |
|
| E.g., patients in the study only, because selection bias or other issues prevents generalizability | Study patients |
|
| There are not enough data about the execution to permit a conclusion | Can't say |
|
| SECONDARY REVIEWER ONLY!!! | 27. Number of Disagreements | |
| Compare your review with the primary review. Include all study areas(i.e,on green form only) where your changes made substantive changes. Addenda, misspelling, etc., are not included in this assessment | Number | _________ |
| Please enter one sentence summary of the conclusions of the study. | 28. Bottom line |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| Please add any additional information you think a reader of the evidence report wouldlike to know about this study. | 29. Comments |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| _______________________________________________________________________ | |
| ARM NAME:(Prefer use treatment name here) |
| 1.Generic name | |||
| 2.Type | Med
Surg
Altern
| Med
Surg
Altern
| Med
Surg
Altern
|
| 3.Avalability (in 1999) | OTC
Rx
Study
| OTC
Rx
Study
| OTC
Rx
Study
|
| 4.Brand name | |||
| 5.Route | Topical
po
Other
Specify
(if other) | Topical
po
Other
Specify
(if other) | Topical
po
Other
Specify
(if other) |
| 6.Vehicle | ConstituentPercent _______________ ____________ __________ Can't
say
| ConstituentPercent _______________ ____________ __________ Can't
say
| ConstituentPercent _______________ ____________ __________ Can't
say
|
| 7.Dose | Can't say
| Can't say
| Can't say
|
| 8.Units(e.g., mg/kg) | |||
| 9.Frequency (e.g., tid) | qd
bid
tid
qid
qhs
other | qd
bid
tid
qid
qhs
other | qd
bid
tid
qid
qhs
other |
| 10.Compliance (if monitored). | >80%
50-80%
<50%
Can't say
| >80%
50-80%
<50%
Can't say
........................ | >80%
50-80%
<50%
Can't say
........................ |
| 11.Ancillary treatment | |
| 12.Comments |
| ||||||||
| Intent to treat is preferred | 1. Source of data | |
| Characteristics of patient as they entered the study | Intent to treat |
|
| Characteristics of patients during the study | Interim |
|
| Characteristics of the patients left at the end of the study | Terminal |
|
| Can't say |
| |
| 2. Tanner stage (# pts) |
| Tanner I ____________ |
| Tanner II____________ |
| Tanner III____________ |
| Tanner IV____________ |
| Tanner V____________ |
| Unspecified
|
| 3. Age (#pts.) |
| < 31 days__________ |
| 31 d to 10 y _________ |
| 11 y to 14 y__________ |
| 15 y to 18 y__________ |
| 15 y to 18 y__________ |
| 19 y to 22 y__________ |
| 23 y to 26 y__________ |
| 27 y to 34 y__________ |
| 35 y to 54 y__________ |
| > 54 y__________ |
| __________________________________ |
| Or, if there is no breakdown.. Mean (yrs)_________ |
| Standard Deviation (yrs)_________ |
| Range (yrs)_________ to_________ |
| Can't say
|
| 4. Sex (#pts.) |
|---|
| Female __________ |
| Male __________ |
| Can't say
|
| 5. Race (#pts.) |
|---|
| Asian __________ |
| Black __________ |
| Hispanic __________ |
| White __________ |
| Other_______________ __________ |
| Can't say
|
| 6.Skin Type(#pts.) |
|---|
| Dry ___________ |
| Oily __________ |
| Normal __________ |
| Can't say
|
| 7.Diet (#pts.) | |
|---|---|
| Was this group constituted on the basis of diet, or did they share a similar diet? | Diet_______________ __________ |
| No, or there are no data | Can't say
|
| 8. Disease duration | |||
|---|---|---|---|
| 9. Acne severity (# pts.) | |||
| Mean | SD | Units | |
| What was the mean and SD of the duration of disease before patients came to treatment in this study; include time of prior treatment Include units (years, months..). If there are no data on disease duration, check this radio button. | __________ | __________ | _______________ |
| Can't say |
| ||
| Mild | __________ | ||
| Moderate | __________ | ||
| Moderately severe | __________ | ||
| Severe | __________ | ||
| Other______________________________________________ | __________ | ||
| Other______________________________________________ | __________ | ||
| Other______________________________________________ | __________ | ||
| Can't say | __________ | ||
| Mean | __________ | ||
| SD | __________ | ||
| # Lesions, type
| |||
| Indicate the WAY that acne severity was assessed (include brief citation, if available). Select "subjective" if only "mild," etc, used without a formal citation | Method of assessment | Subjective
Other
___________ | |
| Citation | |||
| ______________________________________________ | |||
| 10. Insurance (#pts.) |
|---|
| Fee for service __________ |
| Capitation __________ |
| None __________ |
| Can't say
|
| Even if patients said they had insurance, does their coverage include the drugs OF THIS STUDY |
| 11. Prescription plan (#pts.) |
|---|
| Yes __________ |
| No __________ |
| Can't say
|
| Number of lesions per patient | 12. Acne Type | ||||||
| Mean | SD | Range | |||||
| Open Comedones | |||||||
| Close Comedones | |||||||
| Non-inflammatory | Total Commedones | ||||||
| Other non-Inflammatory | |||||||
| Total Non-Inflammatory | |||||||
| Papules | |||||||
| Inflammatory | Pustules | ||||||
| Other Inflammatory | |||||||
| Total Inflammatory | |||||||
| Mixed Inflammatory/non-inflammatory | |||||||
| Nodules | |||||||
| Nodulocystic | Cysts | ||||||
| Nodulocysts | |||||||
| Other______________________ | |||||||
| If another way of describing acne type was used, write the method here (along with a citation, if available) | Can't say |
| |||||
| Citation ______________ | |||||||
| Method of assessment____________________________________ | |||||||
| _________________________________________________________________________ | |||||||
| Self ___________ | |||||||
| Generalist ___________ | |||||||
| Dermatologist ___________ | |||||||
| Study clinic ___________ | |||||||
| Can't say
| |||||||
| If a multicenter site, use the majority type of practice setting) 14. Practice Setting (#pts.) |
|---|
| Self ___________ |
| Private practice ___________ |
| College/school health clinic ___________ |
| Staff HMO ___________ |
| Study site ___________ |
| Hospital ___________ |
| Can't say
|
| At start of study, the patients were at what-15. Phase of Care (#pts.) |
|---|
| Before first MD visit ___________ |
| After initial MD care ___________ |
| After follow-up visit ___________ |
| After further care ___________ |
| After referral ___________ |
| Can't say
|
| COMMENTS | |
| __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ | |
| CONTINUOUS OUTCOME NAME: |
ONE PAGE FOR EACH OUTCOME. For a single outcome with multiple times, use SEPARATE PAGES for each time.
| 1. Outcome Type | Acne
| Psychological
| Adverse effect
|
| Economic
| Compliance
| ||
| 2. Outcome DefinitionOperational definition as defined in the study, e.g., how was lesion severity assessed; what instrument was used? | |||
| 3.Outcome Definition Citation | |||
| 4.Objectivity of assessment In your judgment, was the method of assessment objective or not (subjective) | Yes
| No
| |
| Somewhat
"Somewhat" = Although subjective, assessment was
systematic | Can't say
| ||
| 5.Consistency of assessmentWas the assessment made the same way in all patients in this arm? | Yes
| No
| |
| Somewhat
| Can't say
| ||
| 6. Denominator USED BY AUTHOR FOR STUDY where denominator for each arm not available | Can't say
| ||
| ARM (Treatment Name) | |||
| 1. Denominator by ITT Intention to treat | Can't say
| Can't say
| Can't say
|
| 2. Denominatorused by author/ | Can't say
| Can't say
| Can't say
|
| 2a. Number lost to follow-up | Can't say
| Can't say
| Can't say
|
| 3. Outcome Mean | |||
| 4. Outcome SD | |||
| 5. Follow up duration, mean | |||
| 6. Follow up duration, standard deviation | Can't say
| Can't say
| Can't say
|
| 7. Follow up duration, units | |||
| 8. Raw data cannot be reconstructed |
|
|
|
(std dev = std error * sqrt(arm size)
| 9. Data source (Page #/Table #) | |
| 10. Comments (over if necessary) |
| DISCRETE OUTCOME NAME: |
| 1. Outcome Type | Acne
| Psychological
| Adverse effect
|
| Economic
| Compliance
| ||
| 2. Outcome DefinitionOperational definition as defined in the study, e.g., how was lesion severity assessed; what instrument was used? | |||
| 3.Outcome Definition Citation | |||
| 4.Objectivity of assessment In your judgment, was the method of assessment objective or not (subjective) | Yes
| No
| |
| Somewhat
"Somewhat" = Although subjective, assessment was
systematic | Can't say
| ||
| 5.Consistency of assessmentWas the assessment made the same way in all patients in this arm? | Yes
| No
| |
| Somewhat
| Can't say
| ||
| 6. Denominator USED BY AUTHOR FOR STUDY where denominator for each arm not available | Can't say | ||
| ARM (Treatment Name) | ||||
| 1. Denominator by ITT Intention to treat | Can't say
| Can't say
| Can't say
| |
| 2. Denominatorused by author/ | Can't say
| Can't say
| Can't say
| |
| 2a. Number lost to follow-up | Can't say
| Can't say
| Can't say
| |
| 3. Numerators | Labels | |||
| Category 1 | ||||
| Category 2 | ||||
| Category 3 | ||||
| Category 4 | ||||
| Category 5 | ||||
| Category 6 | ||||
| Category 7 | ||||
| Category 8 | ||||
| 4. Follow up duration, mean | ||||
| 5. Follow up duration, standard deviation | Can't say
| Can't say
| Can't say
| |
| 6. Follow up duration, units Preference 6 & 12 weeks | ||||
| 7. Raw data cannot be reconstructed |
|
|
| |
std dev = std error * sqrt(arm size)
| 9. Data source (Page #/Table #) | |
| 10. Comments (over if necessary) |
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