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Prasterone (Intrarosa): CADTH Reimbursement Review: Therapeutic area: Post-menopausal vulvovaginal atrophy [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 Jun.
An overview of the submission details for the drug under review is provided in Table 1.
Submitted for Review.
The vagina, vulva, lower urinary tract, and pelvic floor of patients contain hormone receptors to estrogen, androgen, or both. Genitourinary syndrome of menopause (GSM) describes the consequences of hormone deficiency which affect urogenital tissues and result in genitourinary symptoms that patients with menopause experience.1,2 GSM is a broader term for vulvovaginal atrophy (VVA),the latter of which focuses on changes in the genital tissues and related symptoms.3 Symptoms of GSM can be grouped as genital, including dryness, burning, and irritation; sexual, including lack of lubrication, discomfort or pain, and impaired function; and urinary, including urgency, dysuria, and recurrent urinary tract infections. Signs of GSM can be observed through physical examination, as there may be changes in the colour, size, and integrity of the anatomy of the vagina. There may also be signs of decreased lubrication and an increase in vaginal pH; typically a pH of greater than 5.0 would be considered abnormal.1
The prevalence of patients who experience VVA or GSM is uncertain, as estimates are largely dependent on reporting of symptoms from patients. A recent study of 4,246 women from Sweden, Finland, the US, the UK, and Canada reported varying prevalence of VVA; in Canada, 34% of post-menopausal women reported having VVA.4 It is suggested that many aging patients will experience GSM, with vaginal dryness being the most commonly reported symptom. Estimates of prevalence are likely underestimates, as menopausal and post-menopausal patients attribute their symptoms to changes associated with normal aging; these patients may be hesitant to report symptoms to their treating health care providers. Previous literature estimates that 60% to 90% of post-menopausal patients may suffer from VVA, and experience important deficits in their quality of life because of it.5 Due to the potential for underreporting, and consequently undertreatment, it may be important for health care providers to take the initiative and ask post-menopausal patients about symptoms related to GSM to identify the condition as early as possible and provide optimal care.
Prasterone is a synthetic form of dehydroepiandrosterone (DHEA), which is a natural steroid compound with no estrogenic, androgenic, or other hormonal activity. When prasterone is administered intravaginally, the cells in the vagina convert it into estrogen and androgens.6 The recommended dosage is 1 ovule, containing 6.5 mg prasterone, administered intravaginally once a day.6 Prasterone is indicated for the treatment of post-menopausal VVA. The sponsor has requested the reimbursement of prasterone as per the Health Canada indication. Prasterone has not been previously reviewed by CADTH.
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from the clinical expert consulted by CADTH for the purpose of this review.
Input was received from 1 patient group, the Women’s Health Coalition of Alberta (WHC). The WHC advocates, raises awareness, and educates about uro-gynecological and reproductive health of patients of all ages. The WHC noted the overall lack of awareness and understanding of uro-gynecological health, the limited therapeutic options for peri- and post-menopausal conditions (e.g., post-menopausal VVA), and potential inequity in accessing preferred treatments when they are not reimbursed by public drug plans. The WHC emphasized that clinical and psychological impacts caused by untreated menopausal conditions are often overlooked and dismissed and expressed the expectation that a positive reimbursement recommendation for prasterone would improve treatment options for patients and potentially raise clinician awareness of the importance of treating menopausal conditions.
To provide additional background on lived experience, values, and preferences of patients with VVA, patient group websites were sought for original experiences of patients with VVA. Healthtalk.org is a non-profit organization that has collected hundreds of stories from patients with any health condition.7 Information from Healthtalk.org pertaining to VVA was obtained, assessed, and synthesized by the CADTH review team. This included video interviews with 13 British patients. Among the interviewed patients, vaginal dryness, decline in libido, and urinary problems were reported as some of the complications experienced after entering menopause. Most patients reported a decline in sexual activity due to loss of libido. Vaginal dryness was another issue patients reported encountering during menopause. Comments also acknowledged the importance of sex in a marriage and the important complications that can happen within a relationship over time due to decreased sexual activity and symptoms of VVA. During the interview, 1 woman indicated that she was not aware of the effects of hormone replacement therapies, and that treatment with hormone replacement therapies may not prevent the “thinning of the vaginal wall.” The thinning of vaginal tissue was stated to cause severe discomfort for many of these patients resulting in tears and bleeding. Patients also commented on how the decline in their estrogen levels affected the pelvic floor, bladder, uterus, vagina, and bowel leading to urinary and bowel problems. Comments on difficulty with incontinence, and the impacts on quality of life were echoed many other patients.
One clinical specialist with expertise in the diagnosis and management of VVA provided input for this review.
The clinical expert consulting with CADTH for this review indicated that as many as 70% of women are expected to have GSM by the age of 70. Over-the-counter moisturizers and lubricants may help provide patients with some symptomatic relief, but these treatments do not affect the underlying disease mechanism and can also be expensive for patients. Vaginal estrogen treatment was identified as being the most effective treatment option for patients. However, all estrogen-based products (despite being systemic or local) have a black box warning issued from Health Canada for several disease risks, limiting its use for some patients. The clinical expert consulting with CADTH for this review stated that prasterone would provide patients with another treatment option as it can help to improve their physiology and sexual function. In addition, prasterone could be an option for patients with contraindications to estrogen therapies, including patients with breast cancer or other estrogen-based cancers, and patients with cardiovascular disease risk.
The dosing schedule of prasterone was acknowledged to be different compared to other estrogen-based therapies; other therapies are prescribed to patients at an interval of twice weekly which some patients may easily forget, compared to prasterone which is administered daily. Patients who would benefit from treatment with prasterone would be identified by an experienced clinician both by a physical exam and by asking patients about symptoms of GSM and sexual function. According to the clinical expert, a patient’s response to treatment can be assessed through self-reported symptoms and a clinical examination of vaginal colour, lubrication, sensation, and pain. Any reduction on GSM symptoms (for example, dyspareunia, dryness, pain, discomfort, burning, itch, dysuria) was stated to be considered a clinically meaningful response to treatment. Response to treatment was stated by the expert to be assessed 3 to 4 months following treatment initiation, although some studies suggest that patients may improve dramatically within the first month of treatment. After an initial assessment of treatment, it may not be necessary to continue assessing patient’s response to treatment unless a new symptom occurs, or symptoms worsen again. Adverse events (AEs) were stated to be of little worry as the clinical expert believed that prasterone is a very well-tolerated treatment. The clinical expert confirmed that prasterone may be prescribed by family physicians or at specialty clinics including gynecology, urology, or urogynecology clinics. Diagnosis of post-menopausal VVA can be made by a family physician, nurse practitioner, or a specialist if the patient is referred to 1 (i.e., gynecologist or urologist).
Input was received from 2 clinician groups: Cleopatra (prepared by 2 registered nurses) and the Society of Obstetricians and Gynaecologists of Canada (SOGC; prepared by 1 physician). No significant contrary views were presented. Both clinician groups highlighted that many patients may suffer from VVA and that prasterone may provide a useful treatment option for patients to treat symptoms and the underlying condition.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for prasterone:
A total of 3 studies were summarized and critically appraised in this CADTH report: the ERC-238, ERC-231, and ERC-230 trials. The ERC-238 trial was a phase III, double-blind (DB), placebo-controlled, multi-centre trial that aimed to confirm the efficacy of 12 weeks of treatment with once-daily administration of an intravaginal 0.5% prasterone ovule (N = 374) compared to once-daily administration of an intravaginal placebo ovule (N = 180) on pain with sexual activity (dyspareunia) among post-menopausal patients aged 40 to 80 years who had dyspareunia as their most bothersome symptom of VVA. The ERC-231 trial was a phase III, DB, placebo-controlled, multi-centre trial assessing the efficacy of intravaginal prasterone 6.5 mg (N = 87), or 3.25 mg compared to placebo (N = 80) among post-menopausal patients having moderate to severe dyspareunia as their most bothersome symptom of VVA at baseline. Only the prasterone (6.5 mg) group was considered relevant for this CADTH review as this is the dose approved by Health Canada. The duration of the trial was 12 weeks. The ERC-230 trial was a phase III, open-label, single-group study (N = 521) which examined the long-term safety of daily treatment with intravaginal prasterone (6.5 mg). The trial duration was 52 weeks.
The 4 coprimary end points of the ERC-238 and ERC-231 trials included percentage of parabasal cells, percentage of superficial cells, vaginal pH, and severity score of dyspareunia. Secondary end points included sexual function (measured using the Female Sexual Function Index [FSFI]), vaginal dryness, vaginal irritation or itching, and safety. The primary objective of the ERC-230 trial was to evaluate the long-term safety of prasterone among post-menopausal patients with VVA; safety was assessed through AEs, mammography, Papanicolaou (Pap) smear, endometrial biopsy, and other outcomes. Secondary end points of the ERC-230 trial included percentage of parabasal cells, percentage of superficial cells, vaginal pH, severity score of dyspareunia, sexual function (measured using the FSFI), vaginal dryness, and vaginal irritation or itching.
Baseline characteristics were similar between the prasterone and placebo groups in the ERC-238 and ERC-231 trials as well as across the 2 trials. In all 3 trials, the median age of patients was between 57 years and 59 years. Overall, the majority of patients were White (> 85%) and non-Hispanic or Latino (≥ 88%). Patients reported both natural and surgical causes of their last menstruation, which occurred at a mean age of between 44 and 50 years. Previous hormone therapy was reported by approximately half of patients across all trials. Key differences across trials included mean years since last menstruation (between 13 and 14 years for patients in the ERC-238 and ERC-231 trials, versus approximately 8 years in the ERC-230 trial), proportion of patients reporting a hysterectomy (38% in the ERC-238 trial versus 61% in the ERC-231 trial; patients in ERC-230 were non-hysterectomized), and oophorectomy (26% to 33% in the ERC-238 and ERC-231 trials, respectively, compared to 5% in the ERC-230 trial).
Key efficacy results are summarized in Table 2. A summary of the 4 coprimary end points of the ERC-238 and ERC-231 trials are summarized here, along with the corresponding results for the ERC-230 trial.
In the ERC-238 trial, the mean change from baseline in severity score of dyspareunia was greater for the prasterone group (–1.42; standard deviation [SD] = 1.00) compared to the placebo group (–1.06; SD = 1.02) at 12 weeks; the mean difference [MD] for the prasterone group versus the placebo group was –0.35 (SD for MD not reported; P = 0.0002) in favour of prasterone. In the ERC-231 trial, the mean change from baseline in severity score of dyspareunia was greater for the prasterone group (–1.27; SD = 0.99) compared to the placebo group (–0.87; SD = 0.95) at 12 weeks; the MD for the prasterone group versus the placebo group was –0.40 (SD for MD not reported; P < 0.0001) in favour of prasterone. In the ERC-230 trial, the mean severity score of dyspareunia was reported for patients who had moderate to severe dyspareunia as their most bothersome symptom at baseline while also meeting VVA criteria for superficial cells (≤ 5%) and vaginal pH (> 5.0) (n = 183). The severity score of dyspareunia was 2.57 (SD = 0.50) at baseline and 0.87 (SD = 0.96) at week 52; the mean change from baseline was –1.69 (SD = 0.97). The mean severity score of dyspareunia was also reported for patients who had moderate to severe dyspareunia at baseline while also meeting VVA criteria for superficial cells (≤ 5%) and vaginal pH (> 5.0) (n = 240). The severity score of dyspareunia was 2.53 (SD = 0.50) at baseline and 0.85 (SD = 0.95) at week 52; the mean change from baseline was –1.68 (SD = 0.95).
Vaginal cell maturation was assessed using the change from baseline in the percentages of parabasal and superficial cells. In the ERC-238 trial, the mean change from baseline in the percentage of parabasal cells was greater for the prasterone group (–41.51%; SD = 36.26%) compared to the placebo group (–11.98%; SD = 29.58) at 12 weeks; the MD for the prasterone group versus the placebo group was –29.53 (SD for MD not reported; P < 0.001) in favour of prasterone. In the ERC-231 trial, the mean change from baseline in the percentage of parabasal cells was greater for the prasterone group (–47.40%; SD = 42.50) compared to the placebo group (–1.62%; SD = 28.22) at 12 weeks; the MD for the prasterone group versus the placebo group was –45.77% (SD for MD not reported; P < 0.0001) in favour of prasterone. In the ERC-230 trial, the mean change from baseline to week 52 in percentage of parabasal cells among all patients who were treated with prasterone was –42.67 (SD = 39.23). The mean change in percentage of parabasal cells was also analyzed in a group of 292 patients who had dyspareunia, vaginal dryness, or vaginal irritation or itching as their most bothersome symptom. The mean change from baseline to week 52 in percentage of parabasal cells among all patients treated with prasterone was –49.14 (SD = 37.91).
The mean change from baseline in the percentage of superficial cells was greater for the prasterone group (10.20%; SD = 10.35) compared to the placebo group (1.75%; SD = 3.33) at 12 weeks in the ERC-238 trial; the MD for the prasterone group versus the placebo group was 8.46% (SD for MD not reported; P < 0.001) in favour of prasterone. In the ERC-231 trial, the mean change from baseline in the percentage of superficial cells was greater for the prasterone group (5.62%; SD = 5.49) compared to the placebo group (0.91%; SD = 2.69) at 12 weeks; the MD for the prasterone group versus the placebo group was 4.71% (SD for MD not reported; P < 0.0001) in favour of prasterone. In the ERC-230 trial, the mean change from baseline to week 52 in percentage of superficial cells among all patients who were treated with prasterone was 7.41% (SD = 8.06). The percent change in superficial cells waw also analyzed in a group of 292 patients who had dyspareunia, vaginal dryness, or irritation/itching as their most bothersome symptom. The mean change from baseline of superficial cells among all patients treated with prasterone was 7.85% (SD = 7.15).
In the ERC-238 trial, the mean change from baseline in vaginal pH was greater for the prasterone group (–0.94; SD = 0.94) compared to the placebo group (–0.27; SD = 0.74) at 12 weeks; the MD for prasterone versus placebo was –0.67 (SD for MD not reported; P < 0.0001) in favour of prasterone. In the ERC-231 trial, the mean change from baseline in vaginal pH was greater for the prasterone group (–1.04; SD = 1.00) compared to the placebo group –0.21; SD = 0.69) at 12 weeks; the MD for prasterone versus placebo was –0.83 (SD for MD not reported; P < 0.0001) in favour of prasterone. In the ERC-230 trial, the mean chance from baseline to week 52 in vaginal pH among all patients who were treated with prasterone was –1.14 (SD = 0.96). The percent change in parabasal cells were also analyzed in a group of 293 patients who had dyspareunia, vaginal dryness, or irritation/itching as their most bothersome symptom. The mean change from baseline to week 52 of parabasal cells among all patients treated with prasterone for this subgroup was –1.27 (SD = 0.90).
The proportions of patients reporting at least 1 AE in the ERC-238 trial were similar between treatment groups, with 179 patients (47.9%) in the prasterone group and 77 patients (42.8%) in the placebo group reporting at least 1 AE. There was a higher proportion of patients in the prasterone group with at least 1 AE than the placebo group in the ERC-231 trial; 46 patients (52.9%) in the prasterone group and 35 patients (43.8%) in the placebo group reported at least 1 AE. A greater proportion of AEs were reported in the ERC-230 trial with 418 patients (80.2%) experiencing AEs. In general, application site discharge (ERC-238: 6.1% in the prasterone group versus 5.6% in the placebo group; ERC-231: 5.7% versus 6.3%, respectively; ERC-230: 14.0% in the prasterone group) and urinary tract infections (4.5% in the prasterone group versus 2.8% in the placebo group; ERC-231: 5.7% versus 5.0%, respectively; ERC-230: 10.2% in the prasterone group) were the most commonly reported AEs across all trials.
Serious AEs (SAEs) were infrequently reported across trials. In the ERC-238 trial, 1.6% of patients in the prasterone group experienced an SAE compared to 0 patients in the placebo group. In the ERC-231 trial, 1.1% of patients in the prasterone group experienced an SAE compared to 0 patients in the placebo group. In the ERC-230 trial, SAEs occurred in 3.5% of patients.
Few patients discontinued treatment due to an AE across all trials and reporting of these AEs was generally consistent across treatment groups. In the ERC-238 trial, 1.3% of patients in the prasterone group versus 2.8% of patients in the placebo group discontinued treatment due to an AE. In the ERC-231 trial, 1.1% of patients in the prasterone group and 1.3% of patients in the placebo group discontinued treatment due to an AE. In the ERC-230 trial, 6.0% of patients discontinued treatment due to an AE.
There were no deaths in any of the trials.
Notable harms identified in the CADTH systematic review protocol included vaginal hemorrhage, endometrial dysplasia, cervical dysplasia, and breast mass. In general, few patients experienced notable harms reported as AEs across the ERC-238, ERC-231, and ERC-230 trials, and there was little-to-no difference in reporting of notable harms across treatment groups. Vaginal hemorrhage was reported among 1.1% of patients in both the prasterone and placebo groups in the ERC-238 trial, 0 patients and 2.5% of patients in the prasterone and placebo groups, respectively, in the ERC-231 trial, and 2.5% of patients in the ERC-230 trial. Cervical dysplasia was reported among 1.9% of patients in the prasterone group versus 0 patients in the placebo group in the ERC-238 trial, 3.4% of patients in the prasterone group versus 2.5% of patients in the placebo group in the ERC-231 trial, and 3.8% of patients in the ERC-230 trial. Breast mass was reported in 0.3% of patients in the prasterone group versus 0 patients in the placebo group of the ERC-238 trial, 0.4% of patients in the ERC-230 trial, and 0 patients in the ERC-231 trial.
The ERC-230 trial also reported on breast, endometrial, and cervical safety. Endometrial safety was also reported in the ERC-231 trial. Breast examinations were conducted using mammograms at screening and at week 52. A total of 451 patients (98%) had a mammogram; of these patients 455 patients (99%) showed normal or no significant findings. Significant breast pathology was observed among 2 patients which included 1 case each of atypical ductal hyperplasia and infiltrating carcinoma. Undetermined status was reported among 2 patients; 1 patient refused follow-up and findings from the other patient were reported as being probably benign. The results of the remaining 15 patients were reported to be benign. In general, normal breast findings were observed for patients who received long-term treatment with prasterone. In general, long-term administration of prasterone in the ERC-230 trial was not associated with cervical dysplasia. Papanicolaou (Pap) smears were conducted for patients who received prasterone for at least 26 weeks. A Pap smear was conducted for 430 of 432 patients who received prasterone for 52 weeks (90%). A total of 13 patients yielded results of atypical squamous cells of uncertain significance (ASCUS), low grade squamous intraepithelial lesion, or high grade squamous intraepithelial lesion. Of these 13 patients, 7 had a negative HPV test or colposcopy.8 In the ERC-231 trial, approximately 40% of patients were non-hysterectomized and underwent an endometrial biopsy at screening (31 to 25 patients per treatment group). Almost all non-hysterectomized patients (99%), including 28 patients in the prasterone group and 27 patients in the placebo group, underwent an endometrial biopsy at week 12; 5 patients in the prasterone group and 2 patients in the placebo group did not have sufficient tissue for biopsy at this time. At week 12, the endometrium of all evaluable patients was atrophic, and the sponsor reported no clinically significant results.9 In the ERC-230 trial, endometrial biopsies were performed for patients who received prasterone for at least 3 months. For patients with unevaluable endometrial biopsies or who refused endometrial biopsies at the end of treatment, transvaginal ultrasounds were performed; these were performed for 43 patients. In total, 457 patients (94%) had a biopsy at the end of the 52-week study period. Among patients who underwent a biopsy, the endometrium of most patients (91%) was atrophic. Among the 43 patients who underwent a transvaginal ultrasound, the average endometrial thickness was 2.2 mm (SD = 1.4). There were no clinically significant histological findings in the ERC-230 trial with long-term use of prasterone.8
Summary of Key Results From Pivotal and Protocol Selected Studies.
The ERC-230 trial used an open-label single-group design to evaluate treatment with prasterone among post-menopausal patients with VVA. Since this study lacks a comparison (control) group and there is no control for potential confounding variables, causal relationships cannot be established. All efficacy end points in the ERC-230 trial were secondary and no adjustments were made for multiplicity. In addition, the placebo used in the trials may have had an effect on patients. Placebo ovules were administered in a capsule which may have had some moisturizing effects for patients. Therefore, the treatment effects of the prasterone ovule compared to a true placebo may be underestimated. In fact, results from efficacy analyses did reveal that patients in the placebo groups also experienced some benefit from the placebo as patients in the placebo group also reported improved symptoms, albeit not as great as patients in the prasterone group.
Both the ERC-238 and ERC-231 trials were placebo-controlled trials. Although it was stated by the sponsor that placebo was an appropriate comparator, the CADTH team noted that estrogen-based therapies would have been available during the inception of these trials and the clinical expert consulted by CADTH for this review agreed that a comparison with a vaginal estrogen therapy would have been of value. It is typical that trial eligibility criteria can be restrictive and, ultimately, not representative of all patients in clinical practice. That eligibility criteria were overly restrictive is likely evident from the large number of patients who were considered screen failures across the trials; the high rate of screen failures may partially be due to guidance from the FDA recommending that patients adhere to a number of clinical criteria. Patients with comorbidities were excluded from the ERC-238, ERC-231, and ERC-230 trials. In particular, patients with a history of cancer were excluded from the trials; this was considered a population of interest as post-menopausal women with history of cancer are still at risk for VVA and may benefit from non-hormonal therapies such as prasterone. The impact of treatment on patients with comorbidities is not clear. The duration of the ERC-238 and ERC-231 trials was only 12 weeks. As the trial durations were short, the long-term benefits and harms of prasterone on patients is uncertain, and patients who are prescribed prasterone in clinical practice are likely to take this treatment for longer than 12 weeks. The ERC-230 trial was conducted for 52 weeks; however, the study is lacking a control group which does now allow for definitive conclusions to be drawn about the effects of longer-term treatment.
The CADTH literature search identified 1 network meta-analysis (NMA) publication by Li et al.11 Li et al. conducted several NMAs to indirectly compare treatment with prasterone to other treatments for VVA among people with menopause. A total of 29 trials which incorporated 8,311 patients were included in the indirect treatment comparison (ITC) by Li et al. evaluating the following treatments: laser therapy, vaginal estrogen, ospemifene, vaginal DHEA, and moisturization/lubrication.11
Characteristics of study design revealed inclusion of both open-label and blinded randomized controlled trials (RCTs). Trials were published between 1992 and 2020. All patients included in the trials had a mean age between 58 years and 60 years of age. All trials except 312-14 excluded patients with breast or gynecological cancers. Treatment duration was heterogeneous, with most trials assessing treatment for 12 weeks. Outcomes assessed included urinary and sexual outcomes (i.e., dryness, itching, dyspareunia, urinary tract infections), AEs, and health-related quality of life assessed through various tools. Different doses of treatments were also used in the 29 trials; specifically regarding DHEA, studies assessing doses of 0.5% (6.5 mg) and 0.25% (3.25 mg) were included.11 The authors did not report on the number of studies included for the NMAs conducted for each end point (vaginal dryness, vaginal burning and itching, dyspareunia, sexual function, vaginal pH, proportion of parabasal cells, and AEs) nor on their risk of bias. It is not clear how the nodes were created, though it appears that similar treatments were merged regardless of dose and duration. The tool used to measure the end points across the included trials was not specified. The network structure was not described. The authors indicated that the model converged “adequately” but relevant data were not provided to support this assertion.
No differences were observed between DHEA and vaginal estrogen therapy (MD = 0.32; 95% credible interval [CrI], −8.54 to 8.77). The I2 value for heterogeneity was 0%, but the pairwise frequentist analyses showed high heterogeneity. Subgroup analyses did not seem to explain the heterogeneity for the comparisons of interest (DHEA versus other treatments). There did not appear to be any sensitivity analyses performed for this comparison. Publication bias was not detected.
Little-to-no difference was observed between DHEA and vaginal estrogen therapy (−4; 95% CrI, −13.88 to 4.46). The I2 value for heterogeneity was 11%.
No differences were observed between DHEA and vaginal estrogen therapy (MD = 1.04; 95% CrI, –1.99 to 3.93). The I2 value for heterogeneity was 0%.
The I2 value for heterogeneity was 4%. Vaginal estrogen therapy (MD = 0.4; 95% CrI, 0.11 to 0.69) was favoured over DHEA.
No differences were observed between DHEA and vaginal estrogen therapy (MD = 1.6; 95% CrI, −12.45 to 13.84). The I2 value for heterogeneity was 9%.
No difference was found between DHEA and vaginal estrogen therapy (odds ratio = 1.54; 95% CrI, 0.91 to 2.62). The I2 value for heterogeneity was less than 25% among treatments.
Though several databases were searched for the systematic review, the authors did not search other sources (e.g., clinical trial registries) so it is possible that some relevant studies were missed. Methods of data extraction were not described, so error within the findings is possible. Studies were assessed for risk of bias, but it is not clear how this assessment was carried out, so it is difficult to assess the validity of these assessments. Differences in trial and baseline characteristics are likely to have impacted the indirect comparisons, although the exact effect of these difference is unclear. An assessment of similarity across trials in each NMA was not conducted; therefore, whether underlying assumptions of the NMAs (i.e., homogeneity and transitivity) have been met are uncertain. There was a lack of clear reporting regarding the construction of nodes in the NMAs. However, based on reported information it was assumed that treatment doses, durations, and outcomes measures for single treatments were combined into single nodes. The combination of different doses, durations, and outcomes measures for treatments is likely to have introduced bias, as the efficacy and safety of treatments which may not have been administered or measured in the same way is uncertain. CrIs were also wide, indicating the potential for substantial uncertainty between treatment comparisons, including the comparisons between DHEA and vaginal estrogen therapies. Subgroup and sensitivity analyses revealed sources of variation for each end point. It is probable that heterogeneity across trials affects the confidence of results of the NMA.
The following studies were included as additional evidence: the ERC-210 trial,15 the Estip-Es study,16 and a study by Barton et al.12 The ERC-210 trial was a multi-centre, DB, randomized, placebo-controlled, phase III trial to determine the dose response of prasterone on symptoms and vaginal mucosa parameters in post-menopausal women with VVA. The Estip-Es study was an observational study conducted in Spain which evaluated the effectiveness and safety of prasterone in a real-world clinical setting.16 The study by Barton et al.12 examined the use prasterone for treatment of post-menopausal symptoms of VVA in patients with a history of breast or gynecological cancer.
The ERC-210 trial, which started in June 2007 and was completed in October 2008, was a multi-centre (US and Canada), prospective, DB, randomized, parallel assignment, placebo-controlled, phase III trial to determine the dose response of prasterone on symptoms and vaginal mucosa parameters in post-menopausal women with VVA. The study informed the dose of prasterone to use for the subsequent phase III studies. Patients were randomized to receive prasterone at 3.25 mg (n = 53), 6.5 mg (n = 56), or 13.0 mg (n = 54), or placebo (n = 53). Only the 6.5 mg dose of prasterone was relevant to this review.
The Estip-Es study was a multi-centre, prospective, noncomparative, observational study with 184 adult post-menopausal patients who were routinely seen in medical centres throughout Spain for GSM. Patients had used vaginal moisturizers/lubricants and/or vaginal hormone therapy and switched to intravaginal prasterone without a washout period.
The study by Barton et al.12 was a multi-centre (US and Canada), 3-group, DB, parallel group RCT where 443 patients were randomized to receive either 3.25 mg (n = 147) or 6.5 mg of prasterone (n = 149) in a plain bioadhesive moisturizer, or a plain bioadhesive moisturizer alone (n = 147). Only the 6.5 mg dose of prasterone was relevant to this review.
The percentage of superficial cells were measured to be 0.62% (SD = 1.02) at baseline and 0.54% (SD = 0.95) at week 12 (P = 0.7460 versus baseline) for the placebo group. The percentage of superficial cells were measured to be 0.40% (SD = 0.62) at baseline and 5.20% (SD = 6.54) at week 12 for the prasterone group. The MD in change was 4.88% (P = 0.0111) of superficial cells in prasterone group compared to the placebo group at week 12.
The percentage of parabasal cells were measured to be 46.73% (SD = 44.05) at baseline and 47.81% (SD = 38.36) at week 12 (P = 0.7686 versus baseline) for the placebo group. The percentage of parabasal cells were measured to be 53.40% (SD = 41.01) at baseline and 11.00% (SD = 18.77) at week 12 for the prasterone group. The MD in change was 43.48% (P < 0.0001) of parabasal cells in the prasterone group compared to the placebo group at week 12.
In the placebo group, the mean vaginal pH was 6.49 (SD = 0.69) at baseline and 6.01 (SD = 1.12) at week 12 (P = 0.005 versus baseline). In the prasterone group, the mean vaginal pH was 6.64 (SD = 0.51) at baseline and 5.17 (SD = 0.91) at week 12. At week 12, there was a mean 0.99 greater change (P = 0.0001) in pH in the prasterone group compared to the placebo group.
The mean severity score of dyspareunia was 2.77 (SD = 0.43) at baseline and 2.35 (SD = 0.94) at week 12 (P = 0.0132 versus baseline) for the placebo group. The mean severity score of dyspareunia was 2.73 (SD = 0.45) at baseline and 1.10 (SD = 1.18) at week 12. There was a mean 1.21 greater change (P < 0.0001) in symptom score in prasterone group compared to the placebo group at week 12.
In the overall study population, the total FSFI score increased from 15.7 (SD = 6.3) to 19.9 (SD = 5.38) with the mean change of 4.2 over 30 days. Increased scores from baseline to post-treatment with prasterone were observed in all the FSFI domains with variable magnitudes. A visual analogue scale (VAS) was administered to assess the self-reported impact on GSM across 19 items, encompassing symptoms including dryness, dyspareunia, bleeding, burning, itching, urinary problems and infections, and abdominal pain. There was a numerical decrease (improvement) in all symptoms assessed using the VAS except for vaginal discharge; however, it should be noted that application site discharge is an expected AE related to use of prasterone.
The primary end point was self-rated severity of patients’ most bothersome symptom, either dryness or dyspareunia using an ordinal scale of none, mild, moderate, severe, or very severe. There was no difference (P = 0.08) between the 6.5 mg prasterone (mean = 1.8; 95% confidence interval [CI], –1.97 to –1.54) and plain moisturizer (mean = –1.5; 95% CI –1.74 to –1.27) groups in changes of either dryness or dyspareunia at week 12.
Of patients who received prasterone, 47 (84%) patients experienced at least 1 AE, compared to 35 (65%) patients in the placebo group. The most common AEs (≥ 5%) reported in the prasterone group were cough (11%), headache (9%), and vaginal discharge (9%). The percentage of patients who withdrew from treatment due to an AE was 4% for both the placebo and prasterone groups. For the prasterone group, 1 (2%) patient had cervical dysplasia, and none had vaginal discharge.
In the overall population, 6.5% of patients reported AEs (e.g., blisters on the face, hair loss, constipation, leukorrhea, and dizziness) during follow-up at 30 ± 7 days. No further detail regarding these AEs was provided in the published paper.
The most common clinician-graded AEs (reported in > 5% of any treatment group) included headache and breast pain, which were not different between treatment groups.
The plan for the primary analysis was amended following feedback from the FDA to restrict to the subgroup of patients who identified dyspareunia as their most bothersome symptom at baseline. This revision was post hoc and in a subgroup of patients, thereby breaking randomization. The direction and extent of any selection bias related to imbalances in characteristics is unclear because updated baseline characteristics for the subgroup were not reported. However, the Bonferroni adjustment for the coprimary analyses was a conservative approach to help mitigate the potential bias introduced by the revised analysis. The differences between prasterone 0.5% and placebo groups were statistically significant following the Bonferroni adjustment. The sample sizes of patients randomized to the prasterone and placebo groups were 56 and 54, respectively. The amendment of the analysis to a subgroup of these patients means that the sample sizes were reduced to 30 patients and 26 patients, respectively, with no information regarding baseline characteristics of this subgroup population provided. Since moisturizer (placebo) may have some effect on vaginal parameters and symptoms, the treatment effect of the prasterone ovule may have been smaller versus the placebo ovule than it would have been versus a true placebo. The relatively short follow-up and small number of patients in the ERC-210 study are inadequate to confirm the long-term benefits of prasterone beyond 12 weeks and assess rare, long-term harms.
The Estip-Es study was an observational study with the objective of evaluating the efficacy, safety, and tolerability of prasterone for the treatment of post-menopausal women with GSM in clinical practice. As there was no comparator group, the efficacy of prasterone relative to other therapies was not clear based on data from this study. In addition, the nature of this study design may introduce bias due to the inability to control for confounding patient characteristics. The lack of blinding to treatment allocation and the subjective nature of all of the outcomes could have contributed to patients reporting greater improvements with a switch to prasterone than they would have in a DB RCT. Patients enrolled in the Estip-Es study were not subject to a washout period; therefore, it is possible that residual effects from previous treatments may have carried over and affected patient outcomes while receiving treatment with prasterone. The study used “a validated short version with 7 items” for FSFI; however, no references were provided related to the validity and reliability of the short form. Due to the lack of detailed information on patient’s baseline characteristics, it is difficult to ascertain to what extent the enrolled population reflects the Canadian population who are eligible for treatment with prasterone. The small sample size further limits generalizability of this study to the Canadian population. The Estip-Es study enrolled women from medical centres throughout Spain for GSM; therefore, these women were seeking medical intervention for symptoms related to VVA; due to this, there is a possibility for selection bias, as patients who were dissatisfied with their previous treatments were likely to have been enrolled in the Estip-Es trial and may view treatment with prasterone more positively. Follow-up visits for patients were conducted approximately 1 month after recruitment into the Estip-Es study. This short-term follow-up may not be an optimal time frame to capture benefits and harms related to treatment with prasterone.
The study was conducted for a period of 12 weeks. The 12-week duration may not be ideal for capturing the efficacy and safety and treatment with prasterone among post-menopausal women with history of breast and gynecological cancers. Treatment with prasterone may occur for longer periods of time, and longer-term data would be necessary for understanding the long-term impact of treatment in this patient population with a history of hormone-dependent cancers. For the primary outcome, approximately 20% and 25% patients discontinued before completion of the study in the plain moisturizer and 6.5 mg prasterone groups, respectively. Primary analysis was based on a completed analysis set (“primary end point” data) and was not done in an intention-to-treat (ITT) method. Therefore, the high rate of study discontinuations (missing data of ≥ 20% in each group) introduces uncertainty in the results and it is unclear how the last value carried forward missing data imputation method may have biased the results. Also, it is unclear if the last value carried forward missing data imputation method was used for all the other analyses besides primary outcomes (i.e., FSFI and quality of life). After all the losses to follow-up, the “primary end point data” set did not meet its intended sample size (i.e., 145 patients in each arm), so the study is at risk of being underpowered. This study specified that patients administer compounded intravaginal prasterone in a gel formulation using a syringe (without a needle) whereas the Health Canada product monograph specifies that prasterone be administered as an ovule and inserted using an applicator. Therefore, comparability across other studies which assess prasterone as an ovule versus the gel is limited.
Three trials, including 2 multi-centre, randomized, DB, placebo-controlled trials (ERC-238 and ERC-231), and 1 multi-centre, single-group, open-label study (ERC-230) provided evidence on the safety and efficacy of prasterone for post-menopausal patients with VVA. Compared to placebo, prasterone 6.5 mg showed greater improvements after 12 weeks of treatment in percentage of parabasal cells, percentage of superficial cells, vaginal pH, dyspareunia, and vaginal dryness that were clinically meaningful according to the clinical expert consulted by CADTH. The ERC-230 trial provided long-term data on the use of prasterone; however, the lack of a comparator precluded the ascertainment of causal relationships, and the study did not adjust for multiple comparisons. The findings over a treatment period of 52 weeks; however, seemed similar to the findings of the 2 shorter-term trials, suggesting that it is possible that the benefits would be sustained with continued treatment. While the results for sexual function measured using the FSFI in the ERC-238 trial also favoured the prasterone group compared to the placebo group, these results were unadjusted for multiplicity and should be considered exploratory. Safety data from the ERC-238 and ERC-231 trials showed similar proportions of patients with AEs between the prasterone and placebo groups; the ERC-230 trial reported higher proportions of patients of AEs compared to the ERC-238 and ERC-231 trials, which may be expected due to the longer exposure to prasterone. However, due to the lack of a control group, it is unclear whether AEs may be associated with prasterone itself. AEs identified in the ERC-230 trial were mostly similar to those identified in the ERC-238 and ERC-231 trials; all trials reported application site discharge and urinary tract infections as the most commonly reported AEs. Comparison of prasterone to other therapies was assessed through a published ITC. In general, the ITC did not provide evidence for a difference in efficacy between prasterone and vaginal estrogen therapies (grouped as a single comparator), though there was considerable uncertainty in the treatment effect estimates. Limitations related to reporting of the NMA and heterogeneity across the included studies that could not be resolved precluded drawing strong conclusions about the comparative effectiveness and safety of prasterone versus other treatments for VVA. Additional evidence was identified to inform on the safety and efficacy of prasterone: the ERC-210 trial, the Estip-Es study, and a study by Barton et al. While the results of the ERC-210 trial were supportive of those from the 3 pivotal trials mentioned above, limitations of the design and analyses of the Estip-Es and Barton et al. studies precluded drawing concrete conclusions regarding the efficacy or safety of prasterone versus vaginal estrogen therapies or moisturizers/lubricants. The study by Barton et al. enrolled patients with history of breast and gynecological cancers, but did not find a difference between DHEA 6.5 mg daily and placebo in most bothersome symptom (dyspareunia or vaginal dryness) and did not assess the notable harms identified for this review outside of AE reporting over the 12-week treatment period.
Due to aging and changes during menopause, some patients may experience symptoms of VVA. Hormonal changes, particularly the decrease in estrogen, may result in symptoms such as vaginal dryness, irritation, dyspareunia, and recurrent urinary tract infections. The pelvic floor is particularly susceptible to changes related to menopause as there are estrogen receptors in the vulva, vaginal, bladder, urethra, and pelvic floor musculature.1 VVA may refer more specifically to symptoms of dyspareunia and may be limited to patients who are sexually active. GSM is a broader term which encompasses other genitourinary symptoms and may not be limited to patients are sexually active.1 Symptoms of GSM can be grouped as genital, including dryness, burning, and irritation; sexual, including lack of lubrication, discomfort or pain and impaired function; and urinary, including urgency, dysuria, and recurrent urinary tract infections. Signs of GSM can be observed through physical examination conducted by an experienced health care provider, as there may be changes in colour, size, and integrity of the anatomy of the vagina. There may also be signs of decreased lubrication and an increase in vaginal pH; typically a pH of greater than 5.0 would be considered abnormal.1
While no official estimates of VVA among Canadians are available, a study which included 1,016 Canadians reported a prevalence of VVA of 34%.4 However, estimates regarding the prevalence of patients who experience VVA or GSM may be underreported. Many patients will not report changes they experience as they will associate changes with normal aging. Previous literature suggests that 60% to 90% of post-menopausal patients may suffer from VVA, and experience significant deficits in their quality of life because of it.5 Due to underreporting, it may be important for health care providers to take the initiative and ask post-menopausal patients about symptoms related to GSM to identify the condition as early as possible and provide optimal care.
The treatment goals for post-menopausal VVA are to improve patients’ symptoms and sexual function with minimal side effects and thereby improve patients’ quality of life. Current treatments for post-menopausal VVA currently include moisturizers, lubricants, and vaginal estrogen. According to the clinical expert consulted by CADTH for this review, moisturizers and lubricants may benefit patients in providing them with some relief from symptoms; however, moisturizers and lubricants do not affect the underlying disease mechanism and can also be costly for patients. Estrogen treatment favourably alters patients’ physiology to treat the underlying disease and targets disease symptoms. However, vaginal estrogen therapies also have a black box warning issued from Health Canada for several disease risks (myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis for most products) based on evidence for oral estrogen plus progestin therapy and oral estrogen-alone therapy. They are also contraindicated in patients with known or suspected estrogen-dependent malignant neoplasia and patients with known, suspected, or past history of breast cancer, also based on evidence for systemic therapies. According to the clinical expert, it is possible for some patients with these contraindications to be treated with vaginal estrogen, though the product monograph warnings can lead to hesitancy among these patients to use vaginal estrogen. Estrogen hormonal therapies may be administered to patients vaginally as creams, tablets, capsules, or a ring, or as an oral therapy. Some patients may prefer products other than vaginal creams as they can be messy. Due to patient needs that are unmet by currently available treatment options, some patients face a great impact on their quality of life.
Prasterone is a synthetic form of DHEA, which is a natural steroid compound inactive by itself. DHEA has no estrogenic, androgenic, or other hormonal activity. When prasterone is administered intravaginally as an ovule, the cells in the vagina transform it into estrogen and androgens.6 The recommended dose of prasterone is 0.5%, or 6.5 mg, approved by Health Canada.6 Prasterone has not been previously reviewed by CADTH. The sponsor has requested the reimbursement of prasterone as per the Health Canada indication.
Key Characteristics of Treatments for Vulvovaginal Atrophy.
This section was prepared by CADTH staff based on the input provided by patient groups and on information from a patient group website that was sought for original experiences from patients with VVA. The original patient group submission can be found in the Stakeholder Input section at the end of this report.
Input was received from 1 patient group, the Women’s Health Coalition of Alberta (WHC). The WHC advocates, raises awareness, and educates about uro-gynecological and reproductive health of patients of all ages. WHC is committed to empowering people to speak openly about patients’ reproductive and sexual health, as well as encouraging people to address barriers, gaps, policies, and unconscious bias impacting this population. WHC is also committed to ensuring access to the right treatment at the right time to improve patients’ health outcomes.
The WHC noted the overall lack of awareness and understanding of uro-gynecological health, the limited therapeutic options for peri- and post-menopausal conditions (e.g., post-menopausal VVA), and potential inequity in accessing preferred treatments when they are not reimbursed by public drug plans. The WHC emphasized that clinical and psychological impacts caused by untreated menopausal conditions are often overlooked and dismissed and expressed the expectation that a positive reimbursement recommendation for prasterone would improve treatment options for patients and potentially raise clinician awareness of the importance of treating menopausal conditions.
To provide additional background on lived experience, values, and preferences of patients with VVA, patient group websites were sought for original experiences of patients with VVA. Healthtalk.org is a non-profit organization that has collected hundreds of stories from patients with any health condition.7 Information from Healthtalk.org pertaining to VVA were obtained, assessed, and synthesized by the CADTH review team. This included video interviews with 13 British patients.
Among the interviewed patients, vaginal dryness, decline in libido, and urinary problems were reported as some of the complications experienced after entering menopause. Patients reported mixed reactions regarding the decline in libido after menopause. While 1 patient reported that the changes in the libido did not impact her sexual activity, others reported a decline in sexual activity due to loss of libido. Vaginal dryness was another issue patients reported encountering during menopause. One patient reported negative impacts on her sexuality due to decreased vaginal lubrication. She also pointed out the importance of sex in a marriage and the important complications that can happen within a relationship over time due to decreased sexual activity and symptoms of VVA. During the interview, 1 woman indicated that she was not aware of the effects of hormone replacement therapies, and that treatment with hormone replacement therapies may not prevent the “thinning of the vaginal wall.” The patient had expected that use of hormone replacement therapy “would protect from vaginal problems.” Another woman commented on the discomfort experienced during a vaginal smear, and the need for use of an estrogen cream to “get a correct reading from the cervix.” The thinning of vaginal tissue was stated to caused severe discomfort for many of these patients. One patient mentioned about her vaginal tissue getting “very, very thin,” resulting in tears and bleeding. Another patient described the chain of effects created by the lack of estrogen in the whole body after menopause, affecting the collagen, the pelvic floor, bladder, uterus, vagina, and bowel leading to urinary and bowel problems. The patient stated, “So you can get fecal incontinence, which is mortifying, bladder irritability or incontinence, and also your womb can come down, or your vagina can come down and that’s called a prolapse.” Comments on difficulty with incontinence, and the impacts on quality of life were echoed many other patients; patients also reported that they were likely to attribute this problem to the onset of menopause. Patients also expressed the importance of the support they get from their spouses during the difficult times, which helps them tackle the everyday difficulties and brings them hope.
All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of post-menopausal VVA.
The clinical expert consulting with CADTH for this review indicated that recognition of symptoms and identifying VVA or GSM is paramount for patients as it is underreported among patients, but very common as 70% of patients are expected to have GSM by the age of 70 years. Over-the-counter moisturizers and lubricants may help provide patients with some symptomatic relief, but these treatments do not affect the underlying disease mechanism and can also be expensive for patients. Vaginal estrogen treatment was identified as being the most effective treatment option currently available for patients. However, all estrogen-based products (despite being systemic or local) have a black box warning issued from Health Canada for several disease risks, limiting its use for some patients. The clinical expert stated that estrogen treatment favourably alters patients’ physiology to treat the underlying disease and target disease symptoms; however, the clinical expert did not consider it to be effective for improving some aspects related patient’s sexual function.
The clinical expert stated that there were unmet needs for patients for whom estrogen therapy is contraindicated, or who do not want to take this treatment. In addition, some patients do not like using creams as they can be very messy. Tablets or suppositories can be less messy compared to currently available therapies and may help to improve patient compliance and convenience. Currently available treatment options also do not address the androgen component which is provided with DHEA.
The clinical expert consulting with CADTH for this review stated that prasterone would provide patients with another treatment option as it can help to improve their physiology and sexual function. In addition, prasterone could be an option for patients with contraindications to estrogen therapies, including patients with breast cancer or other estrogen-dependent cancers, and patients with cardiovascular disease risk.
The clinical expert indicated that prasterone would be suitable as a first-line treatment for patients with post-menopausal VVA. Since prasterone is converted into estrogens and androgens, it is believed to target both GSM and sexual function; based on this, the clinical expert suggested that prasterone may be preferred over currently available estrogen-based treatments. The dosing schedule of prasterone was acknowledged to be different compared to other estrogen-based therapies; other therapies are prescribed to patients at an interval of twice weekly which some patients may easily forget, compared to prasterone which is administered daily.
Patients may consider trying other therapies first primarily due to cost; conjugated estrogen cream (Premarin cream) and vaginal estradiol inserts (Vagifem) are treatment options which are currently covered under public drug plans and accessible to many patients. However, should prasterone be covered and accessible to patients, then it was stated to be an appropriate first-line therapy for patients.
Patients who would benefit from treatment with prasterone would be identified by an experienced clinician both by a physical exam and by asking patients about symptoms of GSM and sexual function. The clinical expert stated that post-menopausal VVA is likely underdiagnosed as approximately 20% to 25% of affected patients tend to seek treatment. The clinical expert stated that all patients who are post-menopausal should be asked about their genitourinary health and sexual health; this is something that is often overlooked among this population of patients. Patients with a history of breast cancer or estrogen-dependent cancers were identified as being a group of interest for treatment with prasterone. As the vulva and vagina have androgen receptors, the clinical expert believed that patients with vulvodynia who are refractory to other treatments may benefit from prasterone as an additional treatment option.
The clinical expert stated that patients who are pre-menopausal and patients who do not complain of GSM symptoms should not be offered treatment with prasterone.
The clinical expert stated that, while it is not possible to identify the patients who would be most likely to respond to treatment with prasterone, most patients who experience symptoms of GSM would be expected to experience some improvement.
According to the clinical expert, a patient’s response to treatment can be assessed through self-reported symptoms and a clinical examination of vaginal colour, lubrication, sensation, and pain. Any reduction in GSM symptoms (e.g., dyspareunia, dryness, pain, discomfort, burning, itch, dysuria) was stated to be considered a clinically meaningful response to treatment.
Response to treatment was stated by the expert to be assessed 3 months to 4 months following treatment initiation, although some studies suggest that patients may improve dramatically within the first month of treatment. After an initial assessment of treatment, if patients are happy with their treatment, then it may not be necessary to continue assessing patient’s response to treatment unless a new symptom occurs, or symptoms worsen again.
AEs related to prasterone were stated to be of little worry as the clinical expert believed that prasterone is a very well-tolerated treatment. The clinical expert noted that some patients may find the discharge associated with treatment with prasterone to be bothersome; these patients may wish to discontinue treatment. Some patients may also choose to discontinue treatment if they stop having sexual intercourse and no longer experience dyspareunia.
The clinical expert confirmed that prasterone may be prescribed by family physicians or at specialty clinics including gynecology, urology, or urogynecology clinics. Diagnosis of post-menopausal VVA can be made by a family physician, nurse practitioner, or a specialist if the patient is referred to 1 (i.e., gynecologist or urologist).
This section was prepared by CADTH staff based on the input provided by clinician groups. The original clinician group submissions can be found in the Stakeholder Input section at the end of this report.
Input was received from 2 clinician groups: Cleopatra (prepared by 2 registered nurses) and the SOGC (prepared by 1 physician).
Cleopatra is a virtual clinic with the goal of raising awareness about patients’ intimate health issues, including, but not limited to, vaginal dryness, painful sex, and urinary tract infections. The SOGC is 1 of Canada’s oldest national specialty organizations. The goal of the SOGC is to lead the advancement of patients’ health, working with obstetricians, gynecologists, family physicians, nurses, midwives, and allied health professionals working in the field of patients’ sexual and reproductive health.
According to the clinician groups, approximately 70% of women will experience some degree of VVA. Symptoms of post-menopausal VVA were stated to lead to recurrent urinary tract infections and low sexual desire. Once dermatological conditions have been ruled out, both medical and non-medical treatment choices were stated to be used as treatments for VVA. Non-medical treatment options were stated to include good hydration, avoidance of irritants, and correction of contributing conditions (e.g., urinary incontinence). Pelvic floor physiotherapy was also stated to be another treatment option, especially if patients are experiencing dyspareunia or incontinence. While physiotherapy can be effective, it can also be costly for patients if they are not covered by insurance.
According to the SOGC, medical interventions can include vaginal lubricants, vaginal moisturizers (i.e., polycarbophil, polyacrylic aid, hyaluronic acid with or without vitamin E), vaginal estrogen, prasterone, ospemifene, or laser therapy. Cleopatra also listed vaginal moisturizer, prasterone, vaginal estrogen, and laser therapy as treatment options. Vaginal lubricants were stated by the SOGC as being useful for patients whose predominant symptom was dyspareunia. Some vaginal moisturizers, such as polycarbophil or polyacrylic acid, were stated to be unpleasant to patients. Vaginal estrogens were identified as being a common treatment for patients as they correct both symptoms of VVA, and can reverse underlying atrophic changes. When vaginal estrogens are used as directed, they were stated by the SOGC as being safe with minimal systemic absorption of estrogen. Prasterone and ospemifene were listed by the SOGC as new therapies in Canada, with no experience with them outside of clinical trials for prasterone. Vaginal laser therapy was also mentioned by both groups as a therapy for VVA; however, the SOGC noted that RCT evidence suggests that it is not a suitable treatment option for VVA.
Treatment goals for this patient population include improvement in patients’ overall health, bladder health, relationships, and overall quality of life. As many patients will experience vaginal dryness and recurrent urinary tract infections, the condition may impact a patient’s self-esteem and is a significant contributor to a diminished quality of life.
Both the SOGC and Cleopatra stated that not all patients with VVA will respond to available treatments. Many treatment options are estrogen based. The clinician groups highlighted that many patients express trepidation about taking estrogen treatment. Cleopatra stated that some patients with a history of breast cancer may not be comfortable taking estrogen-based treatments. Vaginal laser therapy, while being experimental and potentially damaging to patients, is an expensive therapy and unavailable in certain geographic areas and was stated by the SOGC to be gaining popularity due to fears related to estrogen. In addition, vaginal moisturizers are available to patients as over-the-counter medications but may contain some ingredients that are not suggested for patients with sensitive vaginal issues.
Overall, the SOGC stated that there may be unexpected treatment benefits related to prasterone which are not currently offered to patients through available treatments for VVA.
Before seeking intervention from a medical physician, the SOGC stated that it is common for many patients to try lubricants and moisturizers. The SOGC stated that prasterone could be used as a first-line treatment in patients who seek medical help. Cleopatra stated that prasterone or vaginal estrogen are appropriate treatment options if over-the-counter products do not help. Prasterone was also stated to address the underlying disease condition and have a minimal toxicity profile. In particular, prasterone would be preferred for patients who complain of VVA side effects related to sexual desire, and who prefer not to take estrogen-based therapies. In general, SOGC stated that patient preference plays an integral role in patients’ health care. The SOGC also stated that concomitant lifestyle advice would also be recommended to patients.
Prasterone would be used for post-menopausal patients with VVA whose quality of life is impacted due to symptoms of VVA. In particular, the SOGC highlighted patients who are unable to have sexual intercourse due to symptoms of VVA, patients who are unable to have intercourse because of partner issues or are at risk of having vaginal strictures and adhesions which can lead to permanent loss of use of the vagina; these patients should be treated to restore the vaginal mucosa to a state of health.
Patients suitable for treatment with prasterone were stated to be identified by their treating physicians or nurses during an assessment. Both Cleopatra and the SOGC highlighted the underdiagnosis of patients with this condition and stated that more patients need to be treated for VVA and GSM as many patients suffer from this condition needlessly; some patients may be reluctant to seek help, putting the onus on the health care providers to enquire about VVA and identifying patients who could benefit from treatment. SOGC stated that a clinical examination will usually reveal the problem; however, decreased frequency of Pap screening and a shift away from annual clinical examinations may result in symptoms being ignored until patients become highly symptomatic. By the time a diagnosis of VVA is made for patients, there may be sexual health and relationship issues for patients to deal with. SOGC highlighted a need for early recognition of symptoms for patients to have optimal care.
Patients least suitable for treatment with prasterone were stated to include pregnant patients or those who have a sensitivity to prasterone or any ingredient in the product. The SOGC also acknowledged that patients using systemic menopausal hormone treatment may also be candidates for local treatment as the doses of systematic treatment currently used are not always adequate to reverse VVA.
Assessing a patient’s response to treatment was stated to be based on symptom reporting or clinical examination. For example, reductions in urinary tract infections, painless sex, and vaginal comfort were identified as being markers for treatment response. A clinically meaningful response to treatment would include improvement in intimate health, ability to resume sexual relations, and reduction in symptoms during daily living. Both Cleopatra and SOGC stated that an annual assessment of patient’s response would be sufficient after diagnosis.
Discontinuation of treatment would be based on patients’ self-monitoring their symptoms and responses to treatment. If patients experience a reaction or lack of response to treatment, they may discontinue treatment. If patients no longer have a need for addressing symptoms, they may also stop treatment for VVA.
Both clinician groups acknowledged that prasterone could be prescribed to patients either in primary or specialty clinics.
Both clinician group inputs stated that prasterone would be a welcome addition to the current treatment options available to patients.
The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.
Summary of Drug Plan Input and Clinical Expert Response.
The clinical evidence included in the review of prasterone (Intrarosa) is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that met a priori selection criteria according to the protocol. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the protocol. The third section includes additional relevant studies that did not meet the a priori selection criteria but were considered to address important gaps in the evidence included in the systematic review.
To perform a systematic review of the beneficial and harmful effects of prasterone at 6.5 mg per day administered as an ovule intravaginally for the treatment of post-menopausal vulvovaginal atrophy.
Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.
Inclusion Criteria for the Systematic Review.
The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.20
Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were prasterone and vulvovaginal atrophy. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.
No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.
The initial search was completed on October 29, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on February 23, 2022.
Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist. Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.
Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the pre-determined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.
A focused literature search for NMAs dealing with prasterone was run in MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid on October 29, 2021. No limits were added to limit the search.
A total of 193 records were identified from the literature and screened for relevance; of these 15 were reviewed by full text and 9 reports of 3 unique studies were included in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.
Flow Diagram for Inclusion and Exclusion of Studies.
Detail of Included Studies.
The ERC-238 trial was a phase III, DB, placebo-controlled, multi-centre (38 sites in Canada and US) trial that aimed to confirm the efficacy of 12 weeks of treatment with once-daily intravaginal DHEA at 0.5% (6.5 mg) compared to once-daily intravaginal placebo ovule for pain at sexual activity (dyspareunia) among post-menopausal patients aged 40 years to 80 years who had moderate to severe dyspareunia as their most bothersome symptom of VVA. A total of 558 patients were randomized 2:1 to prasterone (6.5 mg) or matching placebo centrally using a permuted block design. Main outcomes included change from baseline in percentage of superficial and basal cells, vaginal pH, and severity score of dyspareunia.
The ERC-231 trial was a phase III, placebo-controlled, multi-centre trial assessing the efficacy of intravaginal prasterone at 6.5 mg or 3.25 mg compared to placebo among post-menopausal patients experiencing moderate to severe dyspareunia as their most bothersome symptom of VVA at baseline. The trial was conducted in 33 sites including 24 sites in the US and 9 sites in Canada. The trial consisted of a screening period lasting between 4 weeks to 6 weeks, followed by a 12-week treatment period. Patients were randomized in 1:1:1 ratio to receive each treatment. Randomization was conducted centrally by Veristat Inc. using permuted block design. Blocks of 3 patients were generated with each block sequence randomly allocated. Main outcomes included change from baseline in percentage of superficial and basal cells, vaginal pH, and severity score of dyspareunia. For this CADTH review, only the prasterone group treated at 6.5 mg (0.5%) was considered relevant as this is the Health Canada–approved dose; data from patients who received prasterone at 3.25 mg are not summarized in this report.
The ERC-230 trial was a phase III, open-label, single-group study which examined the long-term safety of daily treatment with intravaginal prasterone (6.5 mg). The duration of the trial was 12 months (52 weeks). The study was conducted in 10 sites in Canada and 31 sites in the US. There were 2 phases of the trial, including a screening period of 4 weeks to 6 weeks, and a treatment period of 52 weeks. All patients received treatment with DHEA. As the main purpose of this trial was to evaluate the long-term safety of prasterone, the main outcomes included AEs, SAEs, and mortality.
Inclusion criteria across the ERC-238, ERC-231, and ERC-230 trials included post-menopausal patients with VVA who self-identified dyspareunia as moderate to severe and as their most bothersome symptom. Patients also had 5% of less superficial cells on vaginal smear, a vaginal pH greater than 5, a normal mammogram and physical breast examination, and a normal Pap smear. The ERC-238 and ERC-231 trials enrolled patients regardless of whether they were hysterectomized and non-hysterectomized, while the ERC-230 trial enrolled only non-hysterectomized patients. Patients in the ERC-230 trial could also report moderate to severe vaginal dryness or irritation/itching in addition to dyspareunia.
Exclusion criteria included a previous diagnosis of cancer and having history of significant or uncontrolled comorbidities (i.e., thromboembolic disease, endocrine disease, diabetes mellitus, depression). In addition, patients were excluded if they received vaginal hormonal products, DHEA, or estrogen or progestin therapies (local or systemic) within 8 weeks or within 6 months of study entry, depending on the specific type of product.
A summary of baseline characteristics is shown in Table 7. Baseline characteristics were similar between the prasterone and placebo groups in the ERC-238 and ERC-231 trials as well as across the 2 trials. In all 3 trials, patients had a mean age of between 58 years and 60 years and were mostly White (> 85%) and non-Hispanic or Latino (≥ 88%). Patients reported both natural and surgical causes of their last menstruation, which occurred at a mean age of 44 years to 50 years. Previous hormone therapy was reported by approximately half of patients across all trials.
There were a few key differences across trials. The mean years since last menstruation was 13 years to 14 years for patients in the ERC-238 and ERC-231 trials, versus approximately 8 years in the ERC-230 trial. More than 1-third of patients in the ERC-238 trial reported having a hysterectomy, versus 2-thirds of patients in the ERC-231 trial; patients in the ERC-230 trial were non-hysterectomized. Oophorectomy was performed in approximately 1-quarter to 1-third of patients in ERC-238 and ERC-231, compared to 5% in the ERC-230 trial.
Summary of Baseline Characteristics (Safety Population).
In the ERC-238 and ERC-231 trials, patients received either prasterone 0.5% (6.5 mg) solubilized in Witepsol (hard fat) as a vaginal ovule (suppository) or matching placebo (Witepsol only). Patients in the ERC-230 trial all received prasterone 0.5% (6.5 mg) solubilized in Witepsol (hard fat) as a vaginal ovule (suppository); there was no comparison group. In all trials, patients inserted their assigned therapy intravaginally using a single-use applicator daily before bedtime (usually in the evening) for 12 weeks. Instructions and a demonstration regarding proper administration of study treatment were given to patients before their first administration. Patients were instructed not to take a bath or shower for at least 1 hour after application for adequate absorption, and to not use any vaginal care product on the vagina or vulva during the treatment period. If a day of therapy was forgotten, patients were instructed to insert it immediately, but a minimum interval of 8 hours should be observed between doses. Patients were required to return all boxes at week 6 and 12 to count the vaginal ovules and assess adherence. Treatment adherence was also assessed using a diary card where patients would record the frequency of treatment application.
Concomitant treatments which were necessary for the patient’s well-being were allowed during the study. The following concomitant medications were not permitted in all trials: hormone replacement therapy, progestogen medication, natural oral “estrogenic” products, vaginal cream or gel, vaginal lubricant, or vaginal douching.
A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized below. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.
The 4 coprimary end points of the ERC-238 trial and the ERC-231 trial were change from baseline to week 12 in each of the following: percentage of parabasal cells, percentage of superficial cells, vaginal pH, and severity score of dyspareunia as the most bothersome self-reported VVA symptom.10 The main purpose of the ERC-230 trial was to evaluate the long-term (52 week) safety of intravaginal DHEA; however, efficacy variables were evaluated as secondary end points.
Summary of Outcomes of Interest Identified in the CADTH Review Protocol.
Dyspareunia was assessed as part of the Vaginal Atrophy Symptom Questionnaire (VASQ) which consists of items evaluating dryness, soreness, irritation, dyspareunia, and vaginal discharge (detailed description and appraisal in Appendix 3). The VASQ was used to evaluate the severity score of symptoms of VVA associated with menopause in all 3 trials and was administered at screening, baseline, week 6, and week 12 in the ERC-238 and ERC-231 trials and at screening, baseline, week 12, week 26, week 39, and week 52 in the ERC-230 trial. Patients who discontinued from the trial were assessed at their discontinuation visit. Data from the VASQ were self-reported by patients. The severity of each VVA symptom was recorded as none, mild, moderate, or severe and were analyzed using scores of 0, 1, 2, or 3, respectively. No minimal important difference (MID) has been established for the VASQ. Construct validity was demonstrated with the VASQ; however, populations assessed included patients treated with systemic hormonal therapy, and did not include post-menopausal patients.30 Reliability of the VASQ has not been well established.
Vaginal dryness was assessed as 1 of the symptoms in the VASQ.
Vulvovaginal irritation or itching was assessed as 1 of the symptoms in the VASQ.
Sexual function was measured using the FSFI which contains 19 items and can be used to assessed 6 key domains, including arousal/lubrication, subjective arousal (psychological), satisfaction, desire, pain at sexual activity, and orgasm, over the past 4 weeks (detailed description and appraisal in Appendix 3). Patients’ total FSFI scores could range from 2.0 to 36.0 with higher scores indicating greater sexual function. Female sexual dysfunction is defined in the FSFI as a total score of less than 26.5. For the ERC-238 and ERC-231 trials, the FSFI questionnaire was completed by patients at their screening visit, baseline, week 6, and week 12 (or discontinuation visit). For the ERC-230 trial, the FSFI was completed at screening, baseline, week 26, and week 52 (or discontinuation visit). Under the original protocols of the ERC-231 and ERC-230 trials, patients were to complete the Menopause-Specific Quality of Life questionnaire (MENQOL). In updated versions of these trials’ protocols patients were to complete the FSFI instead of the MENQOL. Validity and reliability of the FSFI has been demonstrated in peri- and post-menopausal women. No MIDs have been established for the FSFI.
In the ERC-238 and ERC-231 trials, the vaginal cell maturation index was determined from vaginal smears collected at baseline, week 6, and week 12 (or discontinuation visit) of the trial. In the ERC-230 trial the vaginal cell maturation index was determined at screening, baseline, week 26, and week 52. Patients who discontinued therapy were to complete their vaginal smears at their discontinuation visit. Vaginal smear samples were examined by experienced cytopathologists who were blinded to treatment assignment of patients. A 100-cell count was performed to classify cells as parabasal (including basal), intermediate, and superficial squamous cell types. A greater number of cells were usually counted, and the numbers obtained for each of the 3 cell populations were divided to be reported as a total of 100.
Vaginal pH was determined by using a pH strip which was applied to an Ayre spatula (or equivalent) to the opposite lateral wall of the vagina. The change in colour on the indicator strip was compared to a colour chart to determine the pH. The pH numbers were read on the ColourpHast, an indicator with a range from pH 4.0 to 7.0. In the ERC-238 and ERC-231 trials, vaginal pH of patients was determined at screening, baseline, week 6, and week 12. In the ERC-230 trial, vaginal pH was measured at screening, baseline, week 26, and week 52. For patients who discontinued the trial, vaginal smears were conducted at their discontinuation visit.
In all trials, harms outcomes included reporting of all AEs (including SAEs, unexpected AEs, withdrawal due to AEs, and mortality). AEs included all and any medical experiences, regardless of their relationship to the study treatment. SAEs included any occurrences that resulted in death, were immediately life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, were a congenital anomaly or birth defect, or were an important medical event that the investigator considered serious.10 All AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03). AEs were tabulated if they started or worsened after the start of treatment (after first dose) through 30 days after the last dose of the study treatment.
Regarding the ERC-230 trial, breast, endometrial, and Pap smear safety were assessed. Breast safety was assessed through mammograms at screening and at week 52 in the ERC-230 trial. Pap smears were conducted for patients who received prasterone for 26 weeks or longer. Endometrial biopsies were performed for patients who received prasterone for 3 months or longer. Endometrial safety was also assessed in the ERC-231 trial among patients who were non-hysterectomized and underwent an endometrial biopsy at screening and at week 12. For all trials, Pap spears and endometrial biopsy samples were assessed by a central laboratory.
In general, for the ERC-238, ERC-231, and ERC-230 trials, observations conducted at baseline (day 1) were used for analyses related to change from baseline parameters. If no sexual activity occurred between screening and baseline, the screening value for vaginal pain associated with sexual activity was used for the baseline value. For other analyses, the screening value was used as the baseline value if there were missing data at baseline.
Determination of sample size for the ERC-238 trial was based on results from the ERC-231 trial. The sample size required to detect the same differences between DHEA 0.5% and placebo as seen in the ERC-231 trial was based on a 1-sided alpha of 0.025 and an overall power of 97.7% across all end points, or greater than 99.99% for each coprimary end point. Based on a randomization of 2:1 for prasterone to placebo, the largest required sample size out of all coprimary efficacy end points was 274 patients in the prasterone group and 137 patients in the placebo group, based on the end point of severity of dyspareunia. An allowance for 15% loss to follow-up resulted in an expected 322 patients in the prasterone group and 161 patients in the placebo group. In addition, the sample size of 322 patients treated with prasterone allowed for the sponsor to achieve the total number of 1,500 patients exposed to intravaginal prasterone across all trials, as in accordance with the International Conference on Harmonization E1 guidelines.
The ITT populations were used for analyses of efficacy variables, with the per-protocol (PP) population also analyzed as supportive evidence. The primary analysis of the 4 coprimary end points (change from baseline to week 12 in vaginal pH, percent parabasal cells, percent superficial cells, and symptom score of dyspareunia) was based on data pooled across all sites with results presented separately for each treatment group. An analysis of covariance model was used, with the treatment group as the main factor and the baseline value as the covariate. The P value for the baseline adjusted least squares MD between groups was presented for prasterone versus placebo. The P values of the coprimary end points were not adjusted for multiplicity as statistical significance of each coprimary end point was required to form a conclusion of superiority of prasterone over placebo. No other approaches to adjust for multiplicity were applied to the coprimary end points. Each of the coprimary end points were analyzed as continuous variables. Statistical analyses were performed at a 2-sided significance level of 0.05 unless otherwise specified.
The symptom scores of vaginal dryness and vaginal irritation or itching were tested as second- and third-order end points, respectively, and were tested among patients who identified these symptoms as being moderate or severe at baseline. To control for the potential for type I error due to multiple end points, the primary symptom score of dyspareunia had to be statistically significant before testing of vaginal dryness, which had to be statistically significant before testing of vulvovaginal irritation or itching.
In the ERC-238 trial, to assess change in sexual function, the mean changes from baseline to week 12 in the following sexual domains of the FSFI were evaluated: arousal/lubrication, subjective arousal (arousal/psychological), desire, satisfaction, and orgasm. No adjustments for multiplicity were conducted for analyses of the FSFI. While the pain at sexual activity domain was used for calculation of the total score of the FSFI, the individual domain of pain at sexual activity was not a secondary end point since pain was evaluated as a coprimary end point using the VASQ. For FSFI analyses, a computational formula reported in Rosen et al.31 was used to derive the individual domain scores and full-scale scores of the FSFI. Individual domain scores were obtained by adding the scores of the individual items that comprise the domain and multiplying the sum by the domain factor (a detailed description and appraisal of the FSFI is provided in Appendix 3). The total score was obtained by summing the 6 domain scores. A score of 0 for each domain indicated that no sexual activity was reported during the past month. When an individual domain question had “missing” as the reported value at baseline, both the domain score and the total score were not calculated for this patient at baseline. The individual domain scores and the global score of the FSFI questionnaire were analyzed using analysis of covariance for the difference in change from baseline between prasterone treatment and placebo.
Patients who were lost to follow-up or discontinued were not replaced. Missing safety data were not imputed.
The last observation carried forward (LOCF) approach was used for efficacy end points in the ITT population when there were missing time points due to discontinuation of a patient, or from missing samples or data for efficacy parameters. In patients who reported pain at sexual activity as their most bothersome symptom at baseline but did not engage in sexual activity after baseline, the baseline value for severity of dyspareunia was carried forward through week 12 and was used for analysis. Also, the evaluation of dyspareunia at week 6 was carried forward if not available at week 12 or discontinuation. Similarly, if the sample for pH, parabasal cells, or superficial cells was missing at day 1, the screening value was used for baseline.
For the FSFI questionnaire, if a patient did not answer 1 or more questions at baseline, the answer(s) given at screening was used for baseline calculations. If a patient had missing answers at both screening and baseline, then the domain score (if applicable) containing a missing answer(s) as well as the full-scale score (total score) of the patient were not calculated and not included in the analysis for the baseline and post-baseline time points.
The sample size calculations for the ERC-231 trial were based on results of the ERC-210 trial,15 which demonstrated a statistically significant improvement in all prasterone groups compared to placebo for change from baseline to 12 weeks in change in severity score of dyspareunia, vaginal dryness, vaginal irritation or itching, and vaginal pH. The sample size requirements for tests of the coprimary outcomes were based on comparisons to placebo for both prasterone groups (0.25% and 0.5%); a 2-sided alpha level of 0.025 was used to control for the 2 comparisons versus placebo. The power for all tests was set at 95%. The largest required sample size out of all coprimary efficacy end points was 60 per treatment group; the sponsor planned to have 70 patients to be enrolled into each treatment group to account for drop-outs and to provide increased safety data.
The ITT populations were used for analyses of efficacy variables, with the PP population also analyzed as supportive evidence. The analyses of efficacy end points, including adjustments for covariates and handling of missing data, for the ERC-231 trial were conducted in the same manner as the ERC-238 trial which are reported above (in the ERC-238 section). Adjustments to multiplicity were the same as those used in ERC-238, except that ERC-231 also adjusted for the multiple doses of prasterone assessed using the Hochberg modification of the Bonferroni procedure. This procedure was used to preserve the overall type I error of 0.05 for testing of the 2 doses of prasterone versus placebo.
There were 450 patients enrolled to have data from 300 or more patients at 12 months; this was conducted in agreement with International Conference on Harmonization E1 recommendations and requirements for regulatory agencies.
For the ERC-230 trial, efficacy variables were analyzed using the “Safety Population for Efficacy Analysis” Set. Data from across all study sites was pooled for safety and efficacy analyses. No adjustments for multiplicity to P values were used for analyses of secondary efficacy outcomes. For efficacy end points, mean values at each visit and changes from baseline were reported using continuous descriptive statistics where appropriate, and t-tests were used to assess the change from baseline to each visit. Vaginal cell maturation index change was analyzed in the following manner: change from baseline to week 26 and week 52 (in percentage of basal or parabasal and superficial cells). The vaginal pH change was evaluated as follows: change from to week 26 and week 52.
Regarding the FSFI, the FSFI parameters were tested using change from baseline to week 26 and week 52. Actual values were also summarized. For FSFI analyses, a computational formula reported in Rosen et al.31 was used to derive the individual domain scores and full-scale scores of the FSFI. Individual domain scores were obtained by adding the scores of the individual items that comprise the domain and multiplying the sum by the domain factor. The total score was obtained by adding the 6 domain scores. A score of 0 for each domain indicated that no sexual activity was reported during the past month. When a question for an individual domain had missing as the reported value at baseline, both the domain score and the total score were not calculated for this patient at baseline. A statistical hierarchy was not implemented for the ERC-230 trial, as the main objective of the study was to evaluate the safety of prasterone. As the original protocol of the trial, dated October 25, 2020, specified use of the MENQOL, only patients enrolled after a change was made to the protocol, dated March 7, 2011, which switched to use of the FSFI, were included in these analyses.
Patients who were lost to follow-up or discontinued were not replaced. Missing safety data were not imputed. For efficacy outcomes with missing data, the last observation was carried forward for the analysis only if patients had at least 1 post-baseline measurement. When no post-baseline efficacy data were evaluated for an end point, the patient was not included in the analysis of that end point. If an efficacy parameter was missing at baseline, the screening value was used as the baseline value.
In general, disposition of patients did not differ between treatment groups within trials. Disposition of patients was generally consistent across trials, though the percentages of randomized patients discontinuing the study were highest in the ERC-230 trial (18%), followed by the ERC-231 trial (11% to 13%), and then the ERC-238 trial (5% to 6%). While almost all randomized patients in the ERC-231 trial were included in the ITT population, a notable proportion of randomized patients in the ERC-238 trial were not included in the ITT population. In the ERC-238 trial, there were 23 patients in the placebo group and 49 patients in the prasterone group who were excluded from the ITT population because at least 1 study eligibility criterion was not met at baseline.
A total of 1,226 patients were screened for eligibility; of these, 558 were enrolled and randomized into the trial with 376 patients in the prasterone group and 182 patients in the placebo group.10 Screen failures were mainly due to |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (||||||%).32 Most patients (94%) completed the study. Few patients discontinued from the trial (5% in the prasterone group and 6% in the placebo group); reasons for discontinuation from the trial included patient’s withdrawal of consent (40% versus 18% of patients who discontinued in the prasterone and placebo groups, respectively), AEs (25% versus 45%, respectively), lost to follow-up (15% versus 18%, respectively), non-compliance (5% versus 9%, respectively), investigators’ decision (5% versus 0%, respectively), or other (10% versus 9%, respectively). In general, no major differences in patient disposition were noted between treatment groups.10
A total of 464 patients were screened for eligibility; of these patients, 87 patients were randomized into the DHEA 0.5% group and 81 were randomized into the placebo group.9 Screen failures were mainly due to ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (||||||%).32 Most patients completed the trial, including 87% of patients in the prasterone group and 89% of patients in the placebo group. The primary reasons for discontinuing were due to “other” (64% versus 33% of patients who discontinued in the prasterone and placebo groups, respectively), patients withdrawing consent (18% versus 44%, respectively), and AEs (18% versus 11%, respectively).9
A total of 798 patients were screened for eligibility; of these patients, 530 were enrolled into the study.8 Screen failures were primarily due to |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (||||||%).32 Few patients discontinued from the ERC-230 trial; reasons for discontinuation were mostly due to patients withdrawing consent (33% of discontinuations) and AEs (31%).8
Patient Disposition.
Major protocol deviations were reported in 35 patients (9.3%) in the prasterone group and 11 patients (6.0% in the placebo group). The sponsor reported these deviations not to have affected the integrity of the study data. There was no premature unblinding of patients in the study.10
There were 4 (4.6%) major protocol deviations reported in the prasterone 0.5% group and 5 (6.2%) protocol deviations in the placebo group. These deviations were reported by the sponsor not to have affected the integrity of the study data, and there was no premature unblinding of patients in the study.9
There was a total of 36 patients with major protocol deviations in the ERC-230 trial. Major protocol deviations were reported by the sponsor not to have affected the integrity of the trial data.8
A summary of patients’ exposure to study treatments is reported in Table 11. The mean duration of treatment was similar between the treatment with prasterone and placebo groups in the ERC-238 trial (82.3 days versus 82.4 days, respectively) and the ERC-231 trial (76.2 days versus 76.6 days, respectively) trials, that is, approximately 11 to 12 weeks. The mean total exposure to treatment was also similar between the prasterone and placebo groups in the ERC-238 (79.9 days versus 80.4 days, respectively) and ERC-231 (74.5 days versus 74.5 days, respectively) trials. As the ERC-230 trial was conducted over a longer period of time (52 weeks), the overall duration of exposure to DHEA was greater. The mean duration of treatment for patients in the ERC-230 trial was 325.0 days with a mean total exposure of 316.0 days, corresponding to over 45 weeks.
Exposure to Study Treatments (Safety Population).
Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following.
Health-related quality of life was not assessed in the ERC-238, ERC-231, and ERC-230 trials.
A summary of results for change from baseline to week 12 of dyspareunia in the ERC-238 and ERC-231 trials is reported in Table 12. The summary of results for change from baseline to the end of treatment period of dyspareunia in the ERC-230 trial is reported in Table 13. It should be noted that in the ERC-238 and ERC-231 trials, eligibility criteria specified that patients report having pain at sexual activity (dyspareunia) of moderate to severe intensity being perceived as the most bothersome symptom of VVA both at the time of screening and at baseline. Change from baseline in symptom score of dyspareunia was a coprimary end point in the ERC-238 and ERC-231 trials, and a secondary end point in the ERC-230 trial. The PP analyses results were similar to those for the ITT analyses in the ERC-238 and ERC-231 trials.
The mean change from baseline in severity score of dyspareunia was greater for the prasterone group (–1.42; SD = 1.00) compared to the placebo group (–1.06; SD = 1.02) at 12 weeks; the MD for prasterone versus placebo was –0.35 (SD for MD not reported; P = 0.0002). The results in the modified ITT population were similar to those in the ITT population.
The mean change from baseline in severity score of dyspareunia was greater for the prasterone group (–1.27; SD = 0.99) compared to the placebo group (–0.87; SD = 0.95) at 12 weeks; the MD for prasterone versus placebo was –0.40 (SD for MD not reported; P < 0.0132).
The mean severity score of pain at sexual activity was reported for patients who had moderate to severe dyspareunia as their most bothersome symptom at baseline while also meeting VVA criteria for superficial cells (≤ 5%) and vaginal pH (> 5.0) (n = 183). The baseline score severity score of dyspareunia was 2.57 (SD = 0.50) at and 0.87 (SD = 0.96) at week 52; the mean change from baseline was –1.69 (SD = 0.97).
The mean severity score of dyspareunia was reported for patients who had moderate to severe dyspareunia at baseline while also meeting VVA criteria for superficial cells (≤ 5%) and vaginal pH (> 5.0) (n = 240). The severity score of dyspareunia was 2.53 (SD = 0.50) at baseline and 0.85 (SD = 0.95) at week 52; the mean change from baseline was –1.68 (SD = 0.95).
Dyspareunia Symptom Score — ERC-238 and ERC-231 (ITT Population).
Dyspareunia Symptom Score — ERC-230.
Vaginal dryness was tested as a second-order end point dependent on statistical significance of change in symptom score of dyspareunia in the ERC-238 and ERC-231 trials. As both the ERC-238 and ERC-231 trials demonstrated statistically significant improvement with prasterone in symptom score for dyspareunia, vaginal dryness was tested. A summary of change from baseline in vaginal dryness among patients who had moderate to severe dyspareunia and who also had moderate to severe vaginal dryness at baseline for the ERC-238 and ERC-231 trials is reported in Table 14; the corresponding data for the ERC-230 trial are reported in Table 15. The PP analyses results were similar to those for the ITT analyses in the ERC-238 and ERC-231 trials.
The mean change from baseline in severity score of vaginal dryness was greater for the prasterone group (–1.44; SD = 0.93) compared to the placebo group (–1.17; SD = 0.99) at 12 weeks; the MD for prasterone versus placebo was –0.27 (SD for MD not reported; P = 0.004). The PP analyses results were similar to those for the ITT analyses.
The mean change from baseline in severity score of vaginal dryness was similar for the prasterone group (–1.45; SD = 0.95) compared to the placebo group (–1.02; SD = 1.08) at 12 weeks; the MD for prasterone versus placebo was –0.43 (SD for MD not reported; P = 0.0128). The PP analyses results were similar to those for the ITT analyses.
The severity score of vaginal dryness among patients who reported moderate to severe vaginal dryness at baseline while also meeting criteria for superficial cells (≤ 5%) and vaginal pH (> 5.0) and who reported vaginal dryness as their most bothersome symptom were summarized (n = 81). The severity score of vaginal dryness at baseline was 2.19 (SD = 0.39) and 0.67 (SD = 0.81) at week 52; the mean change from baseline was –1.52 (SD = 0.78).
The severity score of vaginal dryness among patients who reported moderate to severe vaginal dryness at baseline were summarized (n = 251). The severity score of vaginal dryness at baseline was 2.22 (SD = 0.42) and 0.59 (SD = 0.74) at week 52; the mean change from baseline was –1.63 (SD = 0.79).
Vaginal Dryness (ITT Population With Moderate to Severe Vaginal Dryness at Baseline) — ERC-238 and ERC-231.
Vaginal Dryness — ERC-230.
In the ERC-238 and ERC-231 trials, vaginal irritation or itching was tested as a third-order end point dependent on statistical significance of vaginal dryness; as vaginal dryness demonstrated statistical significance in these trials, analyses of vaginal irritation or itching were conducted. This was a secondary end point in the ERC-230 trial and was not adjusted for multiplicity. A summary of change from baseline in vaginal irritation or itching for the ERC-238 and ERC-231 trials is reported in Table 16; the corresponding data for the ERC-230 trial are reported in Table 17. The PP analyses results were similar to those for the ITT analyses in the ERC-238 and ERC-231 trials.
The mean change from baseline in moderate to severe vulvovaginal irritation or itching was greater for the prasterone group (–1.56; SD = 0.99) compared to the placebo group (–1.36; SD = 1.11) at 12 weeks; the MD for prasterone versus placebo was –0.06 (SD for MD not reported; P = 0.6404). The PP analyses results were similar to those for the ITT analyses.
The mean change from baseline in moderate to severe vulvovaginal irritation or itching was greater for the prasterone group (–1.36; SD = 1.11) compared to the placebo group (–1.09; SD = 0.90) at 12 weeks; the MD for prasterone versus placebo was –0.27 (SD for MD not reported; P = 0.1976). The PP analyses results were similar to those for the ITT analyses.
A total of 23 patients reported moderate to severe irritation or itching at baseline as the most bothersome symptom at baseline. The mean severity score was 2.13 (SD = 0.34) at baseline and 0.74 (SD = 0.69) at week 52; the mean change from baseline was –1.39 (SD = 0.78).
A total of 86 patients reported moderate to severe irritation or itching at baseline while meeting the criteria for superficial cells (≤ 5.0%) and vaginal pH (> 5.0) at baseline. The mean severity score of moderate to severe itching was 2.10 (SD = 0.31) units at baseline and 0.60 (SD = 0.74) at week 52; the mean change from baseline was –1.50 (SD = 0.82).
There was a total of 63 patients who had moderate to severe irritation or itching at baseline but who did not consider moderate to severe itching as their most bothersome symptom at baseline. The mean severity score of moderate to severe itching was 2.10 (SD = 0.76) at baseline and 0.56 (SD = 0.84) at week 52; the mean change from baseline was –1.54 (SD = 0.84).
Vulvovaginal Irritation or Itching (ITT Population With Moderate to Severe Vulvovaginal Irritation or Itching at Baseline) — ERC-238 and ERC-231.
Vulvovaginal Irritation or Itching — ERC-230.
A summary of results for the ERC-238 and ERC-230 trials are reported in Table 18 and Table 19, respectively. Sexual function was considered a secondary outcome and was not controlled for multiplicity.
The mean baseline scores for the FSFI total score were 14.29 (SD = 6.49) and 14.25 (SD = 6.50) in the prasterone and placebo groups, respectively. Both groups showed improvement with increased total scores of 23.14 (SD = 8.11) in the prasterone group and 20.53 (SD = 8.43) in the placebo group at week 12. The mean change from baseline was greater in the prasterone group (8.85; SD = 7.85) than the placebo group (6.28; SD = 8.31). The trend of improvement from baseline to week 12 was consistent for both treatment groups for all domains of the FSFI; in addition, the mean change from baseline was greater for the prasterone group than the placebo group for all domains. The PP analyses results were similar to those for the ITT analyses.
The mean baseline score for the FSFI total score was 13.43 (SD = 7.54) and 21.50 (SD = 9.96) at week 52; the mean change from baseline was 8.08 (SD = 8.84). Findings for individual domains of the FSFI are shown in Table 26.
FSFI (ITT Population) — ERC-238.
Female Function Sexual Index — ERC-230.
Urinary symptoms were not assessed in the ERC-238, ERC-231, and ERC-230 trials.
Depression was not assessed in the ERC-238, ERC-231, and ERC-230 trials.
Anxiety was not assessed in the ERC-238, ERC-231, and ERC-230 trials.
Vaginal cell maturation was assessed using the change from baseline in percentages of parabasal and superficial cells. These end points were 2 of 4 coprimary end points of the ERC-238 and ERC-231 trials. A summary of results for change from baseline to the end of treatment period (week 12) of parabasal cells in the ERC-238 and ERC-231 trials is reported in Table 20. The summary of results for change from baseline to the end of treatment period of parabasal and superficial cells in the ERC-230 trial is reported in Table 21. The PP analyses results were similar to those for the ITT analyses in the ERC-238 and ERC-231 trials.
The mean change from baseline in the percentage of parabasal cells was greater for the prasterone group (–41.51%; SD = 36.26%) compared to the placebo group (–11.98%; SD = 29.58) at 12 weeks; the MD for prasterone versus placebo was –29.53 (SD for MD not reported; P < 0.001).
The mean change from baseline in the percentage of superficial cells was greater for the prasterone group (10.20%; SD = 10.35) compared to the placebo group (1.75%; SD = 3.33) at 12 weeks; the MD for prasterone versus placebo was 8.46% (SD for MD not reported; P < 0.001).
The mean change from baseline in the percentage of parabasal cells was greater for the prasterone group (–47.40%; SD = 42.50) compared to the placebo group (–1.62%; SD = 28.22) at 12 weeks; the MD for prasterone versus placebo was –45.77% (SD for MD not reported; P < 0.0001).
The mean change from baseline in the percentage of superficial cells was greater for the prasterone group (5.62%; SD = 5.49) compared to the placebo group (0.91%; SD = 2.69) at 12 weeks; the MD for prasterone versus placebo was 4.71% (SD for MD not reported; P < 0.0001).
The mean chance from baseline to week 52 in percentage of parabasal cells among all patients who were treated with prasterone was –42.67% (SD = 39.23). The percent change in parabasal cells were also analyzed in a group of 292 patients who had dyspareunia, vaginal dryness or irritation, or itching as their most bothersome symptom. The mean change from baseline to week 52 of parabasal cells among all patients treated with prasterone was –49.14% (SD = 37.91).
The mean change from baseline to week 52 in percentage of superficial cells among all patients who were treated with prasterone was 7.41% (SD = 8.06). The percent change in superficial cells was also analyzed in a group of 292 patients who had dyspareunia, vaginal dryness or irritation, or itching as their most bothersome symptom. The mean change from baseline of superficial cells among all patients treated with prasterone was 7.85% (SD = 7.15).
Percentage of Parabasal and Superficial Cells (ITT Population) — ERC-238 and ERC-231.
Percentage of Parabasal and Superficial Cells — ERC-230.
A summary of results for change from baseline to week 12 of vaginal pH in the ERC-238 and ERC-231 trials is reported in Table 22. The summary of results for change from baseline to the end of treatment period of parabasal cells in the ERC-230 trial is reported in Table 23. The PP analyses results were similar to those for the ITT analyses in the ERC-238 and ERC-231 trials.
The mean change from baseline in vaginal pH was greater for the prasterone group (–0.94; SD = 0.94) compared to the placebo group (–0.27; SD = 0.74) at 12 weeks; the MD for prasterone versus placebo was –0.67 (SD for MD not reported; P < 0.001).
The mean change from baseline in vaginal pH was greater for the prasterone group (–1.04; SD = 1.00) compared to the placebo group (–0.21; SD = 0.69) at 12 weeks; the MD for prasterone versus placebo was –0.83 (SD for MD not reported; P < 0.001).
The mean chance from baseline to week 52 in vaginal pH among all patients who were treated with prasterone was –1.14 (SD = 0.96). The percent change in parabasal cells were also analyzed in a group of 293 patients who had dyspareunia, vaginal dryness or irritation, or itching as their most bothersome symptom. The mean change from baseline to week 52 of parabasal cells among all patients treated with prasterone for this subgroup was –1.27 (SD = 0.90).
Vaginal pH (ITT Population) — ERC-238 and ERC-231.
Vaginal pH — ERC-230.
Only those harms identified in the review protocol are reported below. See Table 24 for detailed harms data.
Summary of Harms (Safety Population).
The proportion of patients reporting at least 1 AE between treatment groups in the ERC-238 trial were similar between treatment groups, with 179 patients (47.9%) in the prasterone group and 77 patients (42.8%) in the placebo group reporting at least 1 AE of any grade. There was a higher proportion of patients in in the prasterone group with at least 1 AE than in the placebo group in the ERC-231 trial; 46 patients (52.9%) in the prasterone group and 35 patients (43.8%) in the placebo group reported at least 1 AE of any grade. A greater proportion of AEs were reported in the ERC-230 trial with 418 patients (80.2%) experiencing AEs of any grade.
The most commonly reported (≥ 3% in any treatment group) AEs in the ERC-238 trial included application site discharge (6.1% of patients in the prasterone group and 5.6% in the placebo group), urinary tract infection (4.5% versus 2.8%, respectively), weight gain (4.0% versus 2.2%, respectively), weight loss (2.9% versus 3.3%, respectively), and hot flush (1.6% versus 3.9%, respectively). The most commonly reported AEs in the ERC-231 trial included application site discharge (5.7% versus 6.3% in the prasterone and placebo groups, respectively), urinary tract infection (5.7% versus 5.0%, respectively), nasopharyngitis (1.1% versus 6.3%, respectively), headache (5.7% versus 1.3%, respectively), nausea (4.6% versus 1.3%, respectively), arthralgia (2.3% versus 3.8%, respectively), and vulvovaginal candidiasis (3.4% versus 0%, respectively). The most commonly reported AEs in the ERC-230 trial included application site discharge (14.0%), urinary tract infection (10.2%), weight loss (3.8%), nasopharyngitis (9.8%), cervical dysplasia (3.8%), abdominal pain (3.1%), headache (3.6%), hot flush (4.4%), nausea (3.1%), back pain (4.2%), and sinusitis (3.8%). In general, application site discharge and urinary tract infections were the most commonly reported AEs across all trials.
SAEs were infrequently reported across trials. In the ERC-238 trial, 1.6% of patients in the prasterone group experienced an SAE compared to 0 patients in the placebo group. In the ERC-231 trial, 1.1% of patients experienced an SAE compared to 0 patients in the placebo group. In the ERC-230 trial, SAEs occurred in 3.5% of patients.
Few patients discontinued treatment due to an AE across all trials. In the ERC-238 trial, 1.3% of patients in the prasterone group versus 2.8% of patients in the placebo group discontinued treatment due to an AE. Of these patients, 0.5% in the prasterone group discontinued treatment due to an SAE. In the ERC-231 trial, 1.1% of patients in the prasterone group and 1.3% of patients in the placebo group discontinued treatment due to an AE. In the ERC-230 trial, 6.0% of patients discontinued treatment due to an AE.
There were no deaths in any of the trials.
Notable harms identified in the CADTH systematic review protocol included vaginal hemorrhage, endometrial dysplasia, cervical dysplasia, and breast mass. In general, few patients experienced notable harms reported as AEs across the ERC-238, ERC-231, and ERC-230 trials, and there was little-to-no difference in reporting of notable harms across treatment groups. Vaginal hemorrhage was reported among 1.1% of patients in the prasterone and placebo groups in the ERC-238 trial, 0 patients and 2.5% of patients in the prasterone and placebo groups, respectively, in the ERC-231 trial, and 2.5% of patients in the ERC-230 trial. Cervical dysplasia was reported among 1.9% of patients in the prasterone group versus 0 patients in the placebo group in the ERC-238 trial, 3.4% of patients in the prasterone group versus 2.5% of patients in the placebo group in the ERC-231 trial, and 3.8% of patients in the ERC-230 trial. Breast mass was reported in 0.3% of patients in the prasterone group versus 0 patients in the ERC-238 trial, 0.4% of patients in the ERC-230 trial, and 0 patients in the ERC-231 trial.
The ERC-230 trial also reported on breast, endometrial, and Pap smear safety. Endometrial safety was also reported in the ERC-231 trial.
Breast examinations were conducted using mammograms at screening and at week 52 in the ERC-230 trial. A total of 451 patients (98%) had a mammogram; of these patients, 455 patients (99%) showed normal or no significant findings. Significant breast pathology was observed among 2 patients which included 1 case each of atypical ductal hyperplasia and infiltrating carcinoma. Undetermined status was reported among 2 patients; 1 patient refused follow-up and findings from the other patient were reported as being probably benign and this patient was instructed to have a follow-up exam 6 months later. The results of the remaining 15 women were reported to be benign. In general, normal breast findings were observed for women who received long-term treatment with prasterone.
In general, long-term administration of prasterone in the ERC-230 trial was not associated with cervical dysplasia. Pap smears were conducted for patients who received prasterone for 26 weeks or longer. A terminal Pap smear was conducted for 430 of 432 patients who received prasterone for 52 weeks (90%). A total of 13 patients yielded results of ASCUS, low grade squamous intraepithelial lesion, or high grade squamous intraepithelial lesion. Of these 13 patients, 7 had a negative HPV test or colposcopy.8
In the ERC-231 trial, approximately 40% of patients were non-hysterectomized and underwent an endometrial biopsy at screening (31 to 25 patients per treatment group). Almost all non-hysterectomized patients (99%), including 28 patients in the prasterone group and 27 patients in the placebo group, underwent an endometrial biopsy at week 12; 5 patients in the prasterone group and 2 patients in the placebo group did not have sufficient tissue for biopsy at this time. At week 12, the endometrium of all evaluable patients was atrophic, and the sponsor reported no clinically significant results.9 In the ERC-230 trial, endometrial biopsies were performed for patients who received prasterone for 3 months or longer. For patients with unevaluable endometrial biopsies or who reused endometrial biopsies at the end of treatment, transvaginal ultrasounds were performed; this was performed for 43 patients. In total, 457 patients (94%) had a biopsy at the end of the 52-week study period. The endometrium of most patients (91%) was atrophic. Among the 43 patients who underwent a transvaginal ultrasound, the average endometrial thickness was 2.2 mm (SD = 1.4). There were no clinically significant histological findings in the ERC-230 trial with long-term use of prasterone.8
Both the ERC-238 and ERC-231 trials were DB, randomized, phase III trials; features of the randomization (computer-generated permuted block design) and central allocation mean that the trials are unlikely to be affected by selection bias. Additionally, the lack of important differences in baseline characteristics across groups signal that the randomization was successful. The DB (patients, personnel and investigators) nature of the trials is advantageous in reducing the risk of performance and detection bias related to knowledge of treatment assignment from patients and investigators. The sponsor reported that no unintentional unblinding occurred for either the ERC-238 or ERC-231 trials, and since the treatment administration of both prasterone and placebo were identical and the AEs were similar between treatment groups, it is unlikely that unblinding occurred. The ERC-230 trial used an open-label, single-group design to evaluate treatment with prasterone among post-menopausal patients with VVA. Since this study lacks a comparison (control) group and there is no control for potential confounding variables, causal relationships cannot be established. The trial was open label; therefore, all patients were aware of treatment assignment, and all patients received the same therapy. It is possible that knowledge of the treatment would lead patients to overestimate both its potential benefits and potential harms. A greater proportion of patients in the ERC-230 trial reported AEs as compared to the other 2 trials, but it is not clear whether this is related to the open-label design, increased duration of exposure to placebo as compared to the ERC-231 and ERC-238 trials, or other factors.
Eligibility criteria specified that patients were to be excluded if they received hormonal therapy within 6 months of the start of the trial. This was considered appropriate given the potential for residual treatment effects from hormonal therapy to influence trial results; however, the clinical expert consulted by CADTH for this review stated that a length of 3 months may have been sufficient to prevent any residual effects of prior hormonal therapies on patient outcomes in these trials.
The 4 coprimary end points of the ERC-238 and ERC-231 trials were change from baseline to 12 weeks in the following: percentage of parabasal cells, percentage of superficial cells, vaginal pH, and severity score of dyspareunia. No adjustments were made for multiple testing of these coprimary end points; this was appropriate because end points were required to be statistically significant in favour of DHEA to conclude superiority of DHEA over placebo. Further, secondary end points assessing vaginal dryness and vaginal irritation or itching were tested as second- and third-order end points, respectively; testing vaginal dryness was specified to occur only if the primary symptom score of dyspareunia was statistically significant, and testing of vaginal irritation or itching was specified to occur only if testing of vaginal dryness was statistically significant. This testing hierarchy allowed for control of type I error for these secondary end points. However, sample size calculations did not consider secondary end points of vaginal dryness and vaginal irritation or itching, these end points were only measured in patients with these symptoms as moderate to severe at baseline, and randomization methods did not incorporate stratification by these symptoms. The results of these end points should be interpreted with caution.
In efficacy analyses which compared changes from baseline to later time points, missing data were handled by using the LOCF method. It is possible that use of this method for handling of missing data may over- or underestimate the effectiveness of therapies. The exact impact of this potential source bias is uncertain, though the use of LOCF is less likely to lead to bias in favour of prasterone if treatment benefit is expected to improve over the course of the treatment period.
The FSFI was used to analyze sexual function in post-menopausal patients with VVA. In both the ERC-231 and ERC-230 trials, patients were to complete the MENQOL under the original protocol of these trials. After protocol amendments, patients were to instead complete the FSFI. No justification was provided as to why protocols were amended to use the FSFI instead of the MENQOL. Results were reported for patients in the ERC-230 trial; as only 29% of enrolled patients provided data for analyses related to the FSFI, these results are likely not powered and may be biased as data from most patients were unavailable. Results from the ERC-230 trial provide an indication of impacts of long-term treatment with DHEA on patients; however, the ERC-230 trial did not have a comparator group making interpretation of results difficult. Due to the limited number of patients who completed the FSFI in the ERC-231 trial, the results for these data were not provided. While the results of the ERC-231 trial were not available, results of the ERC-238 trial (for which the FSFI was a part of the original protocol) were reported and provide an indication of how treatment with prasterone may impact patients’ sexual function compared to placebo. In addition, no adjustments for multiplicity for these analyses were made as part of the overall testing scheme in any of the trials and results should be considered exploratory.
In addition, the placebo used in the trials may have had a beneficial effect on patients. Placebo ovules were administered in a capsule which may have had some moisturizing effects for patients. Therefore, the treatment effects of the prasterone ovule compared to a true placebo may be underestimated. In fact, results from efficacy analyses did reveal that patients in the placebo groups also experienced some benefit from the placebo as patients in the placebo group also reported improved symptoms, albeit not as great as patients in the prasterone group.
Both the ERC-238 and ERC-231 trials were placebo-controlled trials. It was stated by the sponsor that placebo was an appropriate comparator as there is no standard funded therapy for treatment of post-menopausal VVA. Patients may use over-the-counter therapies, such as moisturizers and lubricants, to combat symptoms of VVA. However, the CADTH team noted that estrogen-based therapies are also available for post-menopausal patients with VVA. Specifically, Vagifem, an estradiol vaginal insert, would have been available during the inception of these trials. The clinical expert consulted by CADTH for this review agreed that there may have been other appropriate comparators that would have been of value to use in the trials, to allow for a better understanding of the efficacy of prasterone compared to other therapies that are available to patients.
The eligibility criteria of the trial were considered to be mostly appropriate and reflective of post-menopausal patients with VVA. However, it is typical that trial eligibility criteria can be restrictive and, ultimately, not representative of all patients in clinical practice. That eligibility criteria were overly restrictive is likely evident by the large number of patients who were considered screen failures; the high rate of screen failures may partially be due to guidance from the FDA recommending that enrolled patients identify at least 1 moderate to severe symptom that is most bothersome, have 5% or less superficial cells on a vaginal smear, and a vaginal pH of greater than 5.0. Patients with comorbidities were excluded from the ERC-238, ERC-231, and ERC-230 trials. In particular, patients with a history of cancer were excluded from the trials; this was considered a population of interest as post-menopausal women with history of cancer are still at risk for VVA and may benefit from non-hormonal therapies such as prasterone. The impact of treatment on patients with comorbidities is not clear. Although, based on comments from the clinical expert consulted by CADTH for this review, the findings are likely to be generalizable to patients seen in Canadian clinical practice.
In general, baseline characteristics of the trials were considered to be reflective of post-menopausal patients with VVA. However, it was noted that the majority of patients enrolled in all trials were mostly White and non-Hispanic or Latino. The clinical expert consulted by CADTH for this review commented that, while it is typical for clinical trials to enroll mostly White patients, this may not be reflective of all patients who may also be diagnosed with VVA. In particular, Canada is a multicultural and diverse population. Many Canadian patients who suffer from VVA and who are not White are likely not represented by the patients enrolled in the ERC-238, ERC-231, and ERC-230 trials.
The interventions assigned in the trials included prasterone and placebo. The protocols of the trials specified that patients should not take concurrent treatment with other moisturizers or lubricants. However, it was noted by the clinical expert consulted by CADTH for this review that patients may use these therapies in combination in the real world. The efficacy of prasterone in combination with moisturizers or lubricants is unknown.
The duration of the ERC-238 and ERC-231 trials was only 12 weeks. As the trial durations were short, the long-term benefits and harms of prasterone on patients is uncertain, and patients who are prescribed prasterone in clinical practice are likely to take this treatment for longer than 12 weeks. The ERC-230 trial was conducted for 52 weeks; however, the study is lacking a control group and thus does not allow for definitive conclusions about the effects of longer-term treatment to be drawn.
The 4 coprimary end points of the ERC-238 and ERC-231 trials, and secondary end points of the ERC-230 trial were decrease in percentage of parabasal cells, increase in the percentage of superficial cells, decrease in vaginal pH, and improvement in the severity score of dyspareunia as the most bothersome self-reported VVA symptom. The 4 coprimary end points also align with recommendations from the FDA which specify that these outcomes should be used for studies of this indication.33 Other secondary end points included analyses of vaginal dryness, vaginal irritation or itching, and sexual function assessed using the FSFI. The clinical expert consulting with CADTH for this review agreed that these outcomes were important for consideration to patients and clinicians in the treatment of post-menopausal VVA. However, end points such as the change of parabasal and superficial cells may not typically be assessed in clinical practice. End points which assess symptoms and severity of symptoms may be more relevant to patients.
The objective of this section is to summarize and critically appraise available indirect evidence comparing DHEA to other relevant treatments (identified in the protocol) for post-menopausal women experiencing VVA.
A focused literature search for NMAs dealing with prasterone was run in MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid on October 29, 2021. No limits were added to limit the search. Of 8 records identified by the CADTH literature search, 1 published NMA by Li et al.11 was included.
Li et al. conducted several NMAs to indirectly compare treatment with prasterone to other treatments for VVA among post- menopausal people. Selection criteria for studies to be included in the NMAs are described in Table 31.
Study Selection Criteria and Methods for ITC.
The aim of the NMA conducted by Li et al.11 was to identify the safest and most effective treatments for post-menopausal women having symptoms of GSM.
The NMA by Li et al. was informed by an a priori registered protocol. A description of the eligibility criteria used to identify relevant studies in each of the NMAs is reported in Table 25. To identify relevant articles for inclusion in their NMA, Li et al.11 conducted a literature search in the following electronic databases from inception to March 2020: PubMed, Embase, Scopus, Cochrane Library, Web of Science, and ScienceDirect. The target population included women with symptoms of GSM. Interventions and comparators were not specified in by the authors, but it appears that any treatment for VVA was eligible. Included study designs were limited to RCTs published in any language.
A literature search was conducted based on criteria reported in Table 25. Studies were screened by title and abstract by 2 independent reviewers, and then considered further for inclusion into the NMA. A third independent reviewer conducted arbitration.11 Methods for data extraction were not reported. Risk of bias was appraised using the Cochrane Risk of Bias tool; the methods (e.g., number of reviewers involved) were not described.
Details of the methodology used for the sponsor’s ITC are provided in Table 26. NMAs were undertaken using Bayesian random effects models, employing non-informative priors for the overall mean effect and between-study SDs. It is not clear how the authors assessed clinical and methodological heterogeneity across the studies within the NMAs. Nodes appear to have included similar treatments regardless of dose and duration. Model geometry was not shown and assessment of model fit was not reported; convergence was assessed using the Brooks-Gelman-Rubin method. Node splitting was used to assess consistency between direct and indirect effect estimates. Statistical heterogeneity was assessed using the I2 statistic: I2 less than 25% was considered by the authors to indicate no heterogeneity, 25% to 50% to indicate moderate heterogeneity, 50% to 75% to indicate high heterogeneity; and greater than 75% to indicate extremely high heterogeneity. Heterogeneity was explored using subgroup analyses and meta-regressions. The authors indicate that sensitivity analyses were performed to estimate the stability of the meta-analyses.
ITC Analysis Methods.
The literature search identified 29 trials which incorporated 8,311 patients evaluating the following treatments: laser therapy, vaginal estrogen, ospemifene, vaginal DHEA, and moisturization/lubrication.11 Vaginal DHEA and vaginal estrogen were relevant to this review.
Characteristics of study design revealed inclusion of both open-label and blinded RCTs. Trials were published between 1992 and 2020. All patients included in the trials had a mean age of 58 years to 60 years. All trials except 312-14,34 excluded patients with breast or gynecological cancers. Treatment duration was heterogeneous, with most trials assessing treatment for 12 weeks. Outcomes assessed included urinary and sexual outcomes (i.e., dryness, itching, dyspareunia, urinary tract infections), AEs, and health-related quality of life assessed through various tools. Different doses of treatments were also used in the 29 trials; specifically regarding DHEA, studies assessing doses of 0.5% (6.5 mg) and 0.25% (3.25 mg) were included.11
The authors did not report on the number of studies included for the NMA of any end points assessed (vaginal dryness, vaginal burning and itching, dyspareunia, sexual function, vaginal pH, proportion of parabasal cells, and AEs) nor on their risk of bias. It is not clear how the nodes were created, though it appears that similar treatments were merged regardless of dose and duration (including all vaginal estrogen therapies). The tool used to measure the end points across the included trials was not specified. The network structure was not described. The authors indicated that the model converged “adequately” but relevant data were not provided to support this assertion.
The risk of bias assessment revealed that most trials showed low or unclear risk of bias in the domains assessed (random sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias). There was high risk of bias reported for random sequence generation for 4 studies, allocation concealment for 3 studies, blinding of patients for 6 studies, blinding of outcome assessment for 1 study, and incomplete outcome data for 3 studies.11
The following treatments were considered in the NMA by Li et al.11: laser therapy, vaginal estrogen, ospemifene, vaginal DHEA, and moisturization/lubrication. As DHEA (prasterone) is the main treatment of consideration for this CADTH review, only results of comparisons between DHEA and other relevant treatments specified in the protocol (i.e., vaginal estrogen therapies) are presented.
No differences were observed between DHEA and vaginal estrogen therapy (MD = 0.32; 95% CrI, −8.54 to 8.77). The I2 value for heterogeneity was 0%, but the pairwise frequentist analyses showed high heterogeneity. Subgroup analyses did not seem to explain the heterogeneity for the comparisons of interest (DHEA versus other treatments). There did not appear to be any sensitivity analyses performed for this comparison. Publication bias was not detected.
Little-to-no difference was observed between DHEA and vaginal estrogen therapy (−4.00; 95% CrI, −13.88 to 4.46). The I2 value for heterogeneity was 11%.
No differences were observed between DHEA and vaginal estrogen therapy (MD = 1.04; 95% CrI, −1.99 to 3.93). The I2 value for heterogeneity was 0%.
The I2 value for heterogeneity was 4%. Vaginal estrogen therapy (MD = 0.4; 95% CrI, 0.11 to 0.69) was favoured over DHEA.
No differences were observed between DHEA and vaginal estrogen therapy (MD = 1.6; 95% CrI, −12.45 to 13.84). The I2 value for heterogeneity was 9%.
No difference was found between DHEA and vaginal estrogen therapy (odds ratio = 1.54; 95% CrI, 0.91 to 2.62). The I2 value for heterogeneity was less than 25% among treatments.
The systematic review to locate studies for inclusion in the NMAs followed an a priori developed protocol. Though several databases were searched up to March 2020, the authors did not search other sources (e.g., clinical trial registries) so it is possible that some relevant studies were missed, and those published after March 2020 would not have been included. Methods of data extraction were not described, so error within the findings is possible. Studies were assessed for risk of bias, but it is not clear how this assessment was carried out, so it is difficult to assess the validity of these assessments.
The eligibility criteria for inclusion of studies in the NMAs appears relevant, though these are described in minimal detail within the publication. All studies included in the NMA were RCTs. Characteristics of studies included in the NMA were somewhat varied as some trials were open-label while others were blinded. In addition, few trials also included patients who had history of breast and gynecological cancers; the clinical expert consulted by CADTH for this review suggested that patients with history of cancers may have worse outcomes compared to patients without history of cancers, which could potentially underestimate treatment effects. In addition, there may be additional concerns for safety due to contraindications with estrogen-based therapies among cancer patients, especially if they are hormone dependent. Treatment duration varied across trials with durations between 4 weeks and 52 weeks; most trials were 12 weeks. It is possible that patients who underwent longer durations of therapy experienced greater benefit from treatment. However, the main eligibility criteria of the trials suggest that, in general, all trials enrolled post-menopausal women with symptoms of GSM and that populations of women across trials may generally be consistent. Differences in trial and baseline characteristics are likely to have impacted the indirect comparisons; although, the exact effect of these difference is unclear. An assessment of similarity across trials in each NMA was not conducted; therefore, whether underlying assumptions of the NMAs (i.e., homogeneity and transitivity) have been met are uncertain.
The risk of bias assessment conducted by the authors suggested that most trials included in the NMA had low or unclear risk of bias. Of the 29 trials, few of them revealed high risk of bias; domains which were determined to have high levels of bias were regarding random sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessment, and incomplete outcome data among 11 of the trials. As it was not always clear which studies and how many patients were included within each NMA, it was not always possible to fully quantify the extent of potential bias within the analyses. It is possible in these cases that analyses were affected by substantial bias. Publication bias was not detected in any of the NMAs.
There was a lack of clear reporting regarding the construction of nodes in the NMAs. However, based on reported information, it was assumed that treatment doses, durations, and outcomes measures for single treatments were combined into single nodes. The combination of different doses, durations, and outcomes measures for treatments is likely to have introduced bias, as the efficacy and safety of treatments which may not have been administered or measured the same is uncertain. In particular, formulations of placebo were not consistent across trials and may not be considered equivalent. Combination of different placebo groups across different trials is likely not appropriate given the potentially different effects they may have in treating symptoms of VVA. No sensitivity analyses were conducted to explore the effects of treatments at different formulations, doses, durations, or measurements. The effect of this bias is unclear.
A number of outcomes were assessed in the NMAs including vaginal dryness, vaginal burning, vaginal itching, dyspareunia, FSFI, urinary incontinence, pH, vaginal health index (VHI), AEs, and endometrial thickness. However, DHEA was not incorporated in the analyses for some of these outcomes, including vaginal burning, vaginal itching, urinary incontinence, VHI, and endometrial thickening, likely due to lack of available data. The outcomes assessed in the NMA which included DHEA in the analyses are useful for patients and clinicians, as they captured efficacy, safety, and health-related quality of life. Conclusions cannot be drawn for comparisons between DHEA and other therapies for end points which did not include DHEA in the analyses.
The NMA by Li et al.11 was conducted using a random effects models. The random effects model is likely to be appropriate as it incorporates the assumption that studies are measuring different but related treatment effects. Because the authors provided no measures of model fit, it is unclear whether the random effects models would have been preferred over fixed effects models.
In many instances, the results of the NMAs showed a lack of difference between treatments, as CrI included values of 0 for associated MDs. CrIs were also wide, indicating the potential for substantial uncertainty between treatment comparisons. In general, the results of the NMA suggested that DHEA was favoured over placebo; these results are aligned with results from the ERC-238 and ERC-231 trials which are discussed in the main body of this CADTH report. Comparisons of DHEA to other therapies should be interpreted with caution, as it is uncertain how DHEA may compare to vaginal estrogen therapies if directly compared.
Statistical heterogeneity was assessed using an I2 statistic. I2 values less than 25% were pre-specified by the authors to indicate no heterogeneity. For analyses of end points which included DHEA, the I2 values were less than 25%, suggesting little or no heterogeneity. All models were also reported to have adequate convergence; however, data regarding convergence was not provided. The authors also conducted meta-regressions on demographic variables and study characteristics to identify sources of variation. The meta-regression revealed that dryness, pH, VHI, and proportion of parabasal cells showed high heterogeneities among frequentist pairwise comparisons. Subgroup and sensitivity analyses revealed sources of variation for each end point. It is probable that heterogeneity across trials may affect the confidence of results of the NMA.
This section includes additional relevant studies included in the sponsor’s submission to CADTH, and additional studies identified in the CADTH literature search that were considered to address important gaps in the evidence included in the systematic review. The following studies were included as additional evidence: the ERC-210 trial,15 the Estip-Es study,16 and a study by Barton et al.12 The ERC-210 trial was a multi-centre, DB, randomized, placebo-controlled, phase III trial to determine the dose response of prasterone on symptoms and vaginal mucosa parameters in post-menopausal women with VVA. The Estip-Es study was an observational study conducted in Spain which evaluated the effectiveness and safety of prasterone in a real-world clinical setting.16 The study by Barton et al.12 examined the use prasterone for treatment of post-menopausal symptoms of VVA in patients with a history of breast or gynecological cancer. A summary and critical appraisal of these studies are provided below.
The ERC-210 trial is summarized here as supportive evidence for the efficacy and safety of prasterone 0.5% as it included patients with symptoms other than dyspareunia as the most bothersome symptom and had a placebo control group (unlike the ERC-230 trial).
The ERC-210 trial, which started in June 2007 and was completed in October 2008, was a multi-centre (US and Canada), prospective, DB, randomized, parallel assignment, placebo-controlled, phase III trial to determine the dose response of prasterone on symptoms and vaginal mucosa parameters in post-menopausal women with VVA. The study informed the dose of prasterone to use for the subsequent phase III studies. Post-menopausal women who self-identified as having at least 1 moderate to severe symptom of VVA were enrolled. A total of 217 patients were centrally randomized using a permuted block randomization scheme to receive prasterone at 1% (13 mg), 0.5% (6.5 mg), 0.25% (3.25 mg), or placebo. Only the data for prasterone at a dose of 0.5% are relevant to this review and reported here. The study was divided into 2 phases: a screening period of 4 weeks to 6 weeks followed by a treatment period of 12 weeks.
The inclusion and exclusion criteria for the ERC-210 trial were mostly the same as those for the ERC-231 and ERC-238 trials, which are described in Table 6. Briefly, the inclusion criteria of the ERC-210 trial specified post-menopausal women aged 40 years to 75 years who self-identified to have at least 1 moderate to severe symptom of VVA. Women had to have a low maturation index (≤ 5% of superficial cells on a vaginal smear) and a vaginal pH of greater than 5 at baseline. Exclusion criteria included undiagnosed abnormal genital bleeding, uncontrolled hypertension, endometrial hyperplasia, endometrial cancer, and use of estrogen or progesterone products in the 4 weeks to 6 weeks before study entry.
Baseline characteristics of randomized patients are presented in Table 27. Characteristics were similar between the prasterone 0.5% and placebo groups. Most patients were White (96%), most were non-hysterectomized (59%), most were non-ovariectomized (70%), and most had received previous hormone replacement therapy (72%). The most bothersome symptom that was most commonly self-identified by patients at the start of treatment was dyspareunia (61%).
Summary of Baseline Characteristics (ITT Population) — ERC-210.
Patients received a daily dose of 1 1.3 mL vaginal suppository (ovule) of the following prasterone concentrations: 0.0% (placebo or 0 mg), 0.25% (3.25 mg), 0.5% (6.5 mg), or 1.0% (13 mg). Treatments were applied daily intravaginally, in the evening or at bedtime. The prasterone ovules contained a lipophilic base as non-active ingredient.
Concomitant medications necessary for the patients’ well-being were allowed during the study except for vaginal creams, gels, or lubricants, vaginal douching, and natural “estrogenic” products (unless they were already on the natural “estrogenic” products before study initiation, in which case they were allowed to continue).
The 4 coprimary end points were change from baseline to week 12 in percent parabasal cells, percent superficial cells, vaginal pH, and most bothersome symptom based on patients’ self-assessment. These outcomes were assessed as previously described for the ERC-238 and ERC-231 trials. Assessments of these outcomes occurred at screening, baseline, as well as weeks 2, 4, 8, and 12.
Health-related quality of life was assessed using the MENQOL questionnaire and Psychological General Well-Being questionnaire and sexual function was assessed using the Abbreviated Sexual Function questionnaire. End points based on these outcomes were secondary end points.
Tolerability and AEs were assessed at baseline and weeks 2, 4, 8, and 12, or discontinuation visit following at least 1 month of treatment and at discretion of physician. Endometrial biopsy was examined at central lab at screening, week 12, and discontinuation visit following at least 1 month of treatment and at discretion of physician.
The trial was designed for 50 patients per treatment group for a total of 200 patients.
Efficacy analyses were pre-specified to be performed on the ITT population, defined as treated patients who had a baseline and at least 1 post-baseline efficacy assessment. Missing follow-up observations for the coprimary end points among patients included in the ITT analysis were imputed using the LOCF method, in which missing efficacy data for patients who discontinued the study were imputed using the last non-missing evaluation before discontinuation. The primary statistical analyses were performed using analysis of covariance, with the baseline value used as the covariate and a 2-sided significance level of 0.05. There was no P value adjustment for multiplicity, as significance of all of the 4 primary end points was needed to demonstrate efficacy.
The study was originally designed to evaluate the aggregate most bothersome symptoms of VVA in addition to the other 3 coprimary end points. However, following feedback from the FDA, the primary analyses were redone (post hoc) on a subgroup of patients (n = 114; 64% of those randomized) who had a vaginal pH of greater than 5 and superficial cells of 5% or less and who self-identified as having dyspareunia as their most bothersome symptom at baseline. Given this amendment, an adjustment for multiplicity was performed to account for the choice of dyspareunia out of the 3 potential most bothersome symptoms of vaginal dryness, vaginal itching or irritation, and dyspareunia. A Bonferroni correction was applied, where the P value for statistical significance for each of the 4 coprimary end points was 0.05 divided by 3, equalling 0.0167.
Safety analyses were performed on the safety population, defined as all patients who received any of the study treatments and had safety information available. Analysis was based on the treatment actually received and missing safety data were not imputed.
A total of 403 patients were screened and 217 (54%) were randomized to treatment groups; 54 and 56 patients were randomized to the placebo and prasterone 0.5% groups, respectively (Table 28).
Patient Disposition in the ERC-210 Trial.
Patients received treatment for a mean of 76 days (range: 15 to 91 days) in the placebo group and 80 days (range: 14 to 86 days) in the prasterone group. Adherence to treatment was a mean of 99% (SD = 2.35) based on patient diary, or 100% (SD = 2.97) based on medication count for the placebo group. Similarly, adherence was 99% (SD = 3.88) based on patient diary, or 100% (SD = 5.18) based on medication count for the prasterone group.
This report will focus on the primary outcomes due to the dose response design, limited sample size, and the amendments which restricted the primary end point analyses to a subgroup of patients with dyspareunia as the most bothersome symptom (Table 29).
The percentage of superficial cells were measured to be 0.62% (SD = 1.02) at baseline and 0.54% (SD = 0.95) at week 12 (P = 0.7460 versus baseline) for the placebo group. The percentage of superficial cells were measured to be 0.40% (SD = 0.62) at baseline and 5.20% (SD = 6.54) at week 12 for the prasterone group. The MD in change was 4.88% (P = 0.0111) of superficial cells in prasterone group compared to the placebo group at week 12.
The percentage of parabasal cells was measured to be 46.73% (SD = 44.05) at baseline and 47.81% (SD = 38.36) at week 12 (P = 0.7686 versus baseline) for the placebo group. The percentage of parabasal cells was measured to be 53.40% (SD = 41.01) at baseline and 11.00% (SD = 18.77) at week 12 for the prasterone group. The MD in change was 43.48% (P < 0.0001) of parabasal cells in the prasterone group compared to the placebo group at week 12.
In the placebo group, the mean vaginal pH was 6.49 (SD = 0.69) at baseline and 6.01 (SD = 1.12) at week 12 (P = 0.005 versus baseline). In the prasterone group, the mean vaginal pH was 6.64 (SD = 0.51) at baseline and 5.17 (SD = 0.91) at week 12. At week 12, there was a mean 0.99 greater change (P = 0.0001) in pH in the prasterone group compared to the placebo group.
The mean severity score of dyspareunia was 2.77 (SD = 0.43) at baseline and 2.35 (SD = 0.94) at week 12 (P = 0.0132 versus baseline) for the placebo group. The mean severity score of dyspareunia was 2.73 (SD = 0.45) at baseline and 1.10 (SD = 1.18) at week 12. There was a mean 1.21 greater change (P < 0.0001) in symptom score in prasterone group compared to the placebo group at week 12.
Summary of Coprimary End Points From ERC-210 (ITT Population Meeting Baseline Criteria With Dyspareunia as MBS).
Of patients who received prasterone, 47 (84%) patients experienced at least 1 AE, compared to 35 (65%) patients in the placebo group. The most common AEs (≥ 5%) reported in prasterone group were cough (11%), headache (9%), and vaginal discharge (9%). The percentage of patients who withdrew from treatment due to an AE was 4% for both the placebo and prasterone groups. For the prasterone group, 1 (2%) patient had cervical dysplasia and none had vaginal discharge. Adverse events of endometrial dysplasia and breast mass were not reported (Table 30).
Summary of Harms.
The plan for the primary analysis was amended following feedback from the FDA to restrict to the subgroup of patients who identified dyspareunia as their most bothersome symptom at baseline. This revision was post hoc and in a subgroup of patients, thereby breaking randomization (i.e., the characteristics of the treatment groups may no longer have been similar with respect to known and unknown confounding and prognostic variables). The direction and extent of any selection bias related to imbalances in characteristics is unclear because updated baseline characteristics for the subgroup were not reported. However, the Bonferroni adjustment for the coprimary analyses was a conservative approach to help mitigate the potential bias introduced by the revised analysis. The differences between the prasterone 0.5% and placebo groups were statistically significant following the Bonferroni adjustment.
The sample sizes of patients randomized to the prasterone and placebo groups were 56 and 54, respectively. The amendment of the analysis to a subgroup of these patients means that the sample sizes were reduced to 30 patients and 26 patients, respectively, with no information regarding baseline characteristics of this subgroup population provided. In addition, greater than 90% of patients were White. Taken together, it is unclear whether the results are generalizable to post-menopausal patients with VVA in Canada due to limited representativeness of the sample population.
Since moisturizer (placebo) may have some effect on vaginal parameters and symptoms, it is possible that the treatment effect of the prasterone ovule was smaller versus the placebo ovule than it would have been versus a true placebo.
Finally, the clinical expert consulted by CADTH for this review expected that patients would be on prasterone treatment indefinitely unless they wish to discontinue and/or significant harms occur. A relatively short follow-up and small number of patients in the ERC-210 trial are inadequate to confirm the long-term benefits of prasterone beyond 12 weeks and assess rare, long-term harms.
The objective of the observational “Estip-Es” study from Spain was to evaluate the effectiveness, safety, and tolerability of prasterone in a real-world clinical setting.16 This study is summarized here for supportive evidence as it evaluated relevant outcomes in patients who switched from previous vaginal hormonal therapy to prasterone.
The Estip-Es study was a multi-centre prospective, noncomparative, observational study with 184 adult post-menopausal patients who were routinely seen in medical centres throughout Spain for GSM. The enrolment period was from August 2019 to December 2019.
Patients included post-menopausal women with GSM confirmed by a gynecological examination (including determination of vaginal pH and cytology, if necessary). Exclusion criteria included starting other treatments for GSM during the study; previous treatment for GSM with an expected long-term residual effect (except for vaginal hormonal therapies); starting therapies that may worsen GSM; and contraindication for the use of intravaginal prasterone.
The mean age of patients at baseline was 57.98 (SD = 6.06) years and the mean time since menopause was 7.56 years (SD = 6.23). Of 184 patients, 42.9% were using vaginal hormonal therapy and 32.1% were using vaginal moisturizers or lubricants. The overall FSFI score for the total population (n = 184) at baseline was 15.7 (SD = 6.3).
Patients had used vaginal moisturizers or lubricants and/or vaginal hormone therapy and switched to intravaginal prasterone without a washout period. No information about specific prasterone doses or frequency of administration was provided.
Outcomes were assessed at baseline and after 30 ± 7 days of treatment with prasterone.
Sexual function was self-reported on a validated short version of the FSFI with 7 items. Each item ranged from never (score 0) to always (score 5). Higher scores indicate better sexual function. A score between 0 and 20 suggests that sexual dysfunction may be present. An increase of greater than 3 points was interpreted as considerable clinical improvement, an increase between 2 and 3 points as moderate, and an increase of 1 point as mild clinical improvement.
A VAS was administered to assess the self-reported impact on GSM across 19 items, encompassing symptoms including dryness, dyspareunia, bleeding, burning, itching, urinary problems and infections, and abdominal pain. Each item ranged from 0 (absence of discomfort) to 10 (extreme discomfort). Higher scores indicate more discomfort. A decrease of greater than 3 points was interpreted as considerable improvement, 2 to 3 points as moderate improvement, 1 point as mild clinical improvement, and less than 1 point as absence of clinical improvement.
There was no a priori sample size reported. Categorical variables were expressed as frequencies (n, %) and changes from baseline to follow-up were assessed using the chi-square test or the Fisher exact test when appropriate. Continuous variables were expressed as mean (SD) and changes between baseline and follow-up were assessed using the Student t-test or the Mann–Whitney U test, as applicable. Missing data or lost values were not imputed. The authors mentioned that missing data for important variables were controlled for using filters when collecting data from the case report form. However, it is unclear exactly how they performed this filtering to control for missing data. Statistical significance was set at P less than 0.05 compared to baseline. No information regarding adjustment for multiplicity was found in the published paper.
At the end of the study, 78.4% of patients remained on prasterone. The primary reason for patients withdrawing from the trial was AEs (6.5%).
A total of 184 post-menopausal women with GSM were enrolled and treated with intravaginal prasterone, including 59 women who were taking vaginal moisturizers or lubricants and 79 women taking vaginal hormonal therapy. The mean age of women was 57.98 years (SD = 6.06) with a mean time since onset of menopause of 7.56 years (SD = 6.23). Few women (6.1%) were smokers or had diabetes (6.1%). Just under half of patients (42.9%) were taking vaginal hormonal therapy and 32.1% were taking vaginal moisturizers or lubricants. The authors noted that there was less frequent use of vaginal hormonal therapy among the subgroup of patients who were taking vaginal moisturizers or lubricants (27.1%) compared to the overall patient population (42.9%); no other differences were noted.
In the overall study population, the total FSFI score increased from 15.7 (SD = 6.3) to 19.9 (SD = 5.38) with the mean change of 4.2 (P < 0.01) over 30 days (Table 31). Increased scores from baseline to post-treatment with prasterone were observed in all the FSFI domains with variable magnitudes.
There was a numerical decrease (improvement) in all symptoms assessed using the VAS except for vaginal discharge; however, it should be noted that application site discharge is an expected AE related to use of prasterone. Likewise, there was a numerical increase (improvement) in all FSFI domain scores.
Short FSFI and Symptoms (VAS) at Baseline and After Treatment With Prasterone.
In the overall population, 6.5% of patients reported AEs (e.g., blisters on the face, hair loss, constipation, leukorrhea, and dizziness) during follow-up at 30 ± 7 days. No further detail regarding these AEs was provided in the published paper.
The Estip-Es study was an observational study with the objective of evaluating the efficacy, safety, and tolerability of prasterone for the treatment of post-menopausal women with GSM in clinical practice. As there was no comparator group, the efficacy of prasterone relative to other therapies was not clear based on data from this study. The lack of blinding to treatment allocation and the subjective nature of all of the outcomes could have also contributed to patients reporting greater improvements with a switch to prasterone than they would have in a DB RCT. Patients enrolled in the Estip-Es study were not subject to a washout period; therefore, it is possible that residual effects from previous treatments may have carried over and affected patient outcomes while receiving treatment with prasterone.
Greater than 29% of patients discontinued treatment and an ITT approach was not used. Therefore, the analysis is based on data from a select patient population. There is a potential for selection bias since the authors do not report anything about using a consecutive sample. Since there is not a prior protocol available, there is a potential for selective reporting bias as well. Moreover, numerous statistical analyses were conducted without adjustment for multiple comparisons.
There was limited reporting of safety data for this study. It was unclear how safety data were collected (i.e., solicitation from each patient or voluntary reporting).
Lastly, the study used “a validated short version with 7 items” for FSFI; however, no references were provided related to the validity and reliability of the short form. Use of this questionnaire may also be subject to bias as this was an open-label trial without a comparator group.
Due to the lack of detailed information on patient’s baseline characteristics, it is difficult to ascertain to what extent the enrolled population reflects the Canadian population who are eligible for treatment with prasterone. Also, this study was performed in Spain where cultural perception of VVA may differ from those in Canada. The small sample size further limits generalizability of this study to the Canadian population. The Estip-Es study enrolled women from medical centres throughout Spain for GSM; therefore, these women were seeking medical intervention for symptoms related to VVA. For this reason, there is a possibility for selection bias, as patients who were dissatisfied with their previous treatments were likely to have been enrolled in the Estip-Es trial and may view treatment with prasterone more positively.
The Estip-Es study failed to report details about the intervention, such as the dosage and frequency of administration of prasterone, and whether they aligned with those specified in the product monograph for prasterone.
Follow-up visits for patients were conducted approximately 1 month after recruitment into the Estip-Es study. This short-term follow-up may not be an optimal time frame to capture benefits and harms related to treatment with prasterone. In particular, as patients may be on treatment with prasterone for long periods of time, the 1-month follow-up may not be reflective of true patient experiences.
Barton et al.12 conducted a study in post-menopausal women with a history of breast or gynecological cancer. Post-menopausal women with a history of breast or gynecological cancer who have VVA are an important subgroup with the unmet need for VVA therapies that are not estrogen based. Patients with a previous diagnosis of cancer were excluded from the ERC-231, ERC-238, and ERC-230 trials.
This study was a multi-centre (US and Canada), 3-group, DB, parallel group RCT where 443 patients were randomized to receive either 3.25 mg or 6.5 mg of DHEA in a plain bioadhesive moisturizer, or a plain bioadhesive moisturizer alone (placebo). Randomization was accomplished using the Pocock-Simon dynamic allocation procedure stratified by hysterectomy status (yes or no), cigarette smoking history (current, past, or never), use of aromatase inhibitors (anastrozole, letrozole, exemestane, or none), and the current use of tamoxifen (yes or no). The primary aim of this study was to compare 3.25 mg or 6.5 mg prasterone contained in plain moisturizer versus plain moisturizer alone over 12 weeks for the alleviation of the most bothersome vaginal symptom. This summary focuses on the comparison between the approved prasterone 6.5 mg dose and placebo.
Patients eligible for inclusion were post-menopausal women with a history of breast or gynecologic cancer and no current evidence of disease, who had completed chemotherapy and/or radiation. Patients had to report either dyspareunia or vaginal dryness of at least moderate severity and this symptom had to have been present for at least 2 months. Patients could be receiving treatment with tamoxifen or an aromatase inhibitor for at least 8 weeks before enrolment, without plans to change treatment during the study to minimize any changes in important variables. Patients could not use vaginal products other than water-based lubricants during intercourse.
Patients were not eligible for the study if they had prior pelvic surgery resulting in anatomic changes, had prior radiation to the pelvis, active vaginal infections, or had used any (systemic or local) hormonal product (including soy or any compounded hormones) in the preceding 4 weeks.
The active ingredient, DHEA, was added to a bioadhesive base to result in either 3.25 mg/0.4 mL or 6.5 mg/0.4 mL gel. The bioadhesive base was used as the plain moisturizer in the control group. Study patients inserted 1 syringe (without needle) of gel daily right before going to bed and after any sexual activity for 12 weeks.
The primary end point was self-rated severity of patients’ most bothersome symptom, either dryness or dyspareunia using an ordinal scale of none, mild, moderate, severe, or very severe.
Secondary outcomes included AEs measured by provider-reported CTCAE version 4.0. In addition, an investigator-developed, patient self-reported questionnaire asked patients to report on 8 potential toxicities and overall quality of life, using a numeric analogue scale from 0 (“not at all”) to 10 (“as bad as it can be”). For the analysis, these numbers were inverted such that negative numbers indicate worsening of symptoms and positive numbers indicate improvement. Another secondary outcome was overall sexual function, measured using the FSFI.
A total of 145 patients in each group were required to provide 80% power to detect a difference of 0.36 SD with a type I error of 2.5%. An effect size of 0.36 SD was selected based on previous work by Labrie et al. which demonstrated safety and improved symptoms among post-menopausal women treated with prasterone for VVA.35,36
For the primary analysis (“primary end point set”), the mean change from baseline to week 12 in the severity of vaginal dryness or dyspareunia for each prasterone dose was considered a continuous variable (derived from an ordinal scale). Doses of prasterone were compared to plain moisturizer using 2 independent t-tests with a Bonferroni correction due to having 2 correlated primary hypothesis tests, 3.25 mg prasterone versus plain moisturizer and 6.5 mg prasterone versus plain moisturizer. The study results were also analyzed using logistic regression when considering the end point as ordinal in nature and using the LOCF missing data imputation method.
Other analyses were not adjusted for multiplicity, including analyses conducted at multiple time points and questionnaires. Also, information regarding how the authors treated missing data with respect to secondary outcome analyses were missing.
A total of 464 patients were screened for eligibility; of these 21 patients withdrew consent or failed to meet eligibility criteria. A total of 149 patients were randomized into the 6.5 mg DHEA group and 147 patients were randomized into the plain moisturizer group. Most patients completed the study. A total of 35 patients (24%) in the DHEA group discontinued the study, mainly due to AEs (11%), refusal to continue (11%), and unspecified reasons (0.01%). In the plain moisturizer group, 29 patients (20%) discontinued from the study due to AEs (10%), refusal to continue (10%), and receiving an alternative treatment (0.01%). Patient who discontinued were not included in the sample of patients used for primary and secondary analyses, leaving 112 patients in the DHEA group and 118 patients in the plain moisturizer group. It should be noted that 2 additional patients in the DHEA group were excluded from the analyses; reasons for exclusion were not provided.
A total of 464 patients were enrolled, with 149 patients enrolled to the DHEA 6.5 mg group and 147 enrolled in the plain moisturizer group. Baseline characteristics of the patients were similar between the DHEA and placebo groups (Table 32). Dryness was reported as the most bothersome symptom for 42% of patients in the prasterone group and 49% in the plain moisturizer group and dyspareunia was reported as the most bothersome symptom for 58% and 51% of patients in the DHEA and plain moisturizer groups, respectively. The mean severity score of the most bothersome symptom for either dryness or dyspareunia was 4 out of 5 for the DHEA group, and 4.1 for patients in the plain moisturizer group; the severity of dryness or dyspareunia was considered severe at baseline for patients in this study.
Most patient had history of breast cancer (97% in each group); few patients had history of ovarian (2% in each group) or endometrial (1% in each group) cancers. The mean age was 57.3 years (SD = 8.2) in the DHEA group and 58.0 years (SD = 7.3) in the plain moisturizer group. Most patients were White (95% versus 93% in the DHEA and plain moisturizer groups, respectively). More than half of patients had naturally occurring menopause (59% in the DHEA group versus 65% in the plain moisturizer group). Patients reported concomitant aromatase inhibitor use including anastrozole or letrozole (48% versus 49% in the DHEA and plain moisturizer groups, respectively) and exemestane (7% versus 6%). A proportion of 16% in each group reported currently taking tamoxifen therapy. Patients reported a mean time of 24.5 months (SD = 18) and 22.0 months (SD = 18.7) of current therapy in the DHEA and plain moisturizer groups, respectively.
Baseline and Treatment Characteristics.
There was no difference (P = 0.08) between the DHEA (mean = –1.8; 95% CI –1.97 to –1.54) and plain moisturizer (mean = –1.5’ 95% CI –1.74 to –1.27) groups in changes of either dryness or dyspareunia at week 12.
Patients using DHEA reported numerically improved scores for all domains of FSFI and total FSFI score at week 12 compared to baseline and the improved scores were numerically greater compared to those in plain moisturizer group. For quality of life, the score increased at week 12 compared to baseline in DHEA group; however, it decreased at week 12 compared to baseline in the plain moisturizer group (Table 33).
FSFI and Quality of Life.
The most common clinician-graded CTCAE side effects (> 5%) included headache and breast pain, which were not different between study groups. Providers graded hirsutism and specific components of hirsutism (voice alteration, increased body hair and acne) primarily as grade 1 (98%) and there were no differences between study groups. No further data regarding clinician-graded CTCAE side effects were reported in the published paper.
Self-reported side effect changes were not different between the plain moisturizer and DHEA groups (Table 34). However, statistically significant (P ≤ 0.02) voice change was observed in patients receiving DHEA (change from baseline: –0.2, 95% CI, –0.4 to 0.0) compared with plain moisturizer (change from baseline: 0.2, 95% CI, 0.0 to 0.4).
Summary of Harms.
For the primary outcome, approximately 20% and 25% patients discontinued before completion of the study in the plain moisturizer and DHEA groups, respectively. Primary analysis was based on a completed analysis set (“primary end point” data) and was not done in an ITT method. Therefore, the high rate of study discontinuations (missing data of ≥ 20% in each group) introduces uncertainty in the results and it is unclear how the last value carried forward missing data imputation method may have biased the results. Also, it is unclear if the last value carried forward missing data imputation method was used for all the other analyses besides primary outcomes, (i.e., FSFI and quality of life). After all the losses to follow-up, the “primary end point data” set did not meet their intended sample size, (i.e., 145 patients in each arm), so the study is at risk of being underpowered.
For secondary outcomes of self-reported side effects and quality of life, the study used investigator-developed questionnaires. No information was provided that the questionnaires have been validated for their psychometric properties.
Moreover, Barton, et al. stated that most bothersome symptom, either dryness or dyspareunia, was rated as none, mild, moderate, severe, or very severe with no specific indication as to how this descriptive rating scale corresponds to the numerical rating scale as reported in the results (i.e., the study group treated most bothersome symptom as continuous, not ordinal data when reporting results). Considering that the study group performed logistic regression to confirm the results, it seems appropriate to treat data as continuous. However, the primary approach makes inappropriate assumption about the data from a relatively small sample size.
The study was conducted for a period of 12 weeks. The 12-week duration may not be ideal for capturing the efficacy and safety and treatment with DHEA among post-menopausal women with history of breast and gynecological cancers. Treatment with DHEA may occur for longer periods of time, and longer-term data would be necessary to understand the long-term impact of treatment in this patient population with history of hormone-dependent cancers.
One could assume that based on the inclusion criteria requiring a history of breast cancer or gynecological cancer (and protocol adherence), most patients would have a history of breast cancer. However, with data missing in the percentage of patients with a history of breast cancer in the intravaginal DHEA group, it is difficult to generalize the finding to a broad population composed of post-menopausal breast cancer survivors. Also, since there is no protocol available, there is a potential for selective outcome reporting.
Even though the FSFI is widely used and assessed in cancer survivors, the MID has not been established. Therefore, determining meaningful improvement or deterioration of sexual function based on changes in the FSFI total or subscale scores remains unclear.
This study specified that patients administer compounded intravaginal DHEA in a gel formulation using a syringe (without a needle) whereas the Health Canada product monograph specifies that prasterone be administered as an ovule and inserted using an applicator. According to the clinical expert consulted by CADTH for this review, the difference between gel, which is similar to creams, and ovule formulations is significant enough to affect adherence and satisfaction rates in patients. Therefore, comparability across other studies which assess DHEA as an ovule versus the gel is limited.
Two multi-centre, randomized, DB, placebo-controlled trials (the ERC-238 and ERC-231 trials), 1 multi-centre single-group, open-label study (the ERC-230 trial), 1 published ITC, and 3 studies providing supplemental information (the ERC-210 trial15 [N = 217], the Estip-Es study16 [N = 184, and another study by Barton et al.12 [N = 464]) contributed evidence to this report. Patients assessed included post-menopausal women with VVA. The ERC-210 trial also enrolled patients whose most bothersome symptom was not necessarily dyspareunia, the Estip-Es study evaluated the efficacy and safety of prasterone in a real-world clinical setting, and the study by Barton et al.12 included post-menopausal women who had a history of breast or gynecological cancer while having VVA symptoms. The coprimary end points of the ERC-238 and ERC-231 trials included change in percentage of parabasal cells, change in the percentage of superficial cells, change in vaginal pH, and change in the severity score of dyspareunia as the most bothersome self-reported VVA symptom. The primary objective of the ERC-230 trial was to assess the long-term safety of treatment with DHEA.
Patients included in the ERC-238, ERC-231, and ERC-230 trials were of mostly White or non-Hispanic or Latino ethnicity and had a mean of 13 years since their last menses. Patients enrolled also self-identified with moderate to severe dyspareunia (or, in the ERC-230 trial, self-identified at least 1 of dyspareunia, vaginal dryness, or vaginal and/or vulvar irritation or itching as moderate to severe) as their most bothersome VVA symptom at baseline. The major limitation of the trials included a lack of an appropriate comparator, as the ERC-238 and ERC-231 trials included comparison to placebo and the ERC-230 trial did not include a comparator group at all. A published ITC by Li et al.11 was identified which compared prasterone to vaginal estrogen. However, the overall quality of the ITC was considered poor and had statistical limitations which are likely to introduce uncertainty in the treatment comparisons. Additional statistical limitations of the ERC-238, ERC-231, and ERC-230 trials should be considered, including a lack of adjustment of multiplicity and end points which were not included in statistical hierarchies and the results of which should be considered descriptive.
The ERC-238 and ERC-231 trials demonstrated a statistically significant improvement with DHEA over placebo in the 4 coprimary end points after 12 weeks of treatment including a: decrease in percentage of parabasal cells, increase in the percentage of superficial cells, decrease in vaginal pH, and improvement in the severity score of dyspareunia as the most bothersome self-reported VVA symptom. These end points were considered clinically meaningful for patients, and the clinical expert consulted by CADTH for this review confirmed that the magnitude of benefits observed were clinically meaningful. However, it should be noted that no formal values (e.g., MIDs) have been validated to confirm efficacy of end points assessed in this CADTH report beyond clinical expert opinion. In addition, efficacy end points assessing cytology (change in parabasal and superficial cells) and vaginal pH are not outcomes which are used to guide treatment practices or assess patient’s responses to treatment in clinical settings; such end points may be more useful in settings of clinical trials. Rather, treatment of patients is more likely to rely on assessment of symptoms and physical examination for colour, size, and integrity of the anatomy of the vagina. Further, it is likely that only symptomatic patients are likely to be considered for treatment; these patients may have initially started with over-the-counter therapies before seeking intervention from a health care practitioner as their symptoms worsened.
The clinical expert consulted by CADTH indicated that in clinical practice, patients would be expected to use prasterone for longer than 12 weeks. Comparative evidence was unavailable to understand the potential beneficial effects of longer-term treatment with confidence. Longer-term data were available from the single-arm ERC-230 trial which was conducted over a 52-week period. Efficacy end points were secondary in the ERC-230 trial and the lack of comparison group or control for confounding variables, in addition to the absence of consideration for multiple testing, limits the conclusions that can be drawn from this study. The treatment group showed improvements at 52 weeks that seemed to align with the treatment groups in the ERC-238 and ERC-231 trials, which may provide some support to the idea that the benefits of prasterone would be sustained over longer periods of time with consistent administration.
Sexual function results were summarized for the ERC-238 and ERC-230 trials, based on the FSFI. The FSFI is a commonly used and validated tool for measurement of women’s overall sexual function. Results for the ERC-238 trial suggested improvement in sexual function domains, including desire, arousal, lubrication, orgasm, satisfaction, and pain. Longer-term data from the ERC-230 trial suggested that improvements in sexual function may continue to be experienced by patients with continued use of prasterone. Although, it should be noted that the week 12 score for the total score of the FSFI was 23.14 in the prasterone group in the ERC-238 trial, and the week 52 total score was 21.50 in the ERC-230 trial. While these scores are improvements compared to baseline scores, which were 14.29 in the ERC-238 trial and 13.43 in the ERC-230 trial, they are both below the score of 26.55; a value of less than 26.55 is considered to indicate sexual dysfunction in women who complete the questionnaire. Therefore, women may continue to experience symptoms related to VVA even while being treated with prasterone. However, the clinical expert consulted by CADTH for this review agreed that improvements were observed compared to baseline which suggest that treatment with prasterone is likely beneficial in helping to ease symptoms related to VVA and treating the underlying condition to slow its progression. However, statistical considerations should be made when interpreting data pertaining to the FSFI, as assessment of sexual function was a secondary end point in all trials and was not adjusted for multiplicity. In addition, long-term data from the ERC-230 trial was likely underpowered as only data from patients who enrolled after an amendment to the protocol were included. Data pertaining to the FSFI and the impact of prasterone on sexual function should be interpreted with caution.
The comparator group in the ERC-238 and ERC-231 trials included placebo. However, a number of therapies are available to patients, including estrogen therapies. In particular, Vagifem was identified as being available to Canadian patients and is covered under most public insurance plans. The lack of head-to-head comparative evidence is a key limitation of the evidence available for prasterone. No indirect comparisons were submitted by the sponsor. One published ITC was identified in the CADTH literature search that compared DHEA to laser therapy, vaginal estrogen, ospemifene, and moisturizers and lubricants. Efficacy end points included changes in vaginal dryness, dyspareunia, health-related quality of life (assessed through the FSFI), vaginal pH, and proportion of parabasal cells. The results did not clearly favour DHEA over other therapies other than placebo. In particular, neither DHEA nor estrogen therapies, which may be more commonly used among Canadian patients, were favoured between each other. In general, CrIs were wide which may suggest considerable uncertainty between treatment comparison estimates. A number of methodological concerns were identified for the NMA presented, including in some cases violations to the underlying assumptions of transitivity and coherence. It is difficult to interpret the results of the NMA because of important limitations related to reporting of methods and other information needed to appraise the NMA, and unaccounted for heterogeneity across the 29 trials included in the analyses. The limitations of the currently available comparative evidence make it unclear how DHEA may compare to other therapies post-menopausal patients may use for treatment of VVA.
The purpose of the ERC-230 trial was to inform on the long-term harms of treatment with prasterone, as the trial was conducted for a period of 12 months versus the ERC-238 and ERC-231 trials which were conducted for a period of 12 weeks. The clinical expert consulted by CADTH for this review expected that the benefit of treatment with prasterone would continue to be observed over time, and that the results of the ERC-230 trial were supportive of this. While results of the ERC-230 trial appear to support improved symptoms related to VVA for post-menopausal women, the lack of a control group and the statistical considerations of efficacy end points should be considered.
Additional evidence was also summarized in the CADTH report related to the ERC-210 trial, the Estip-Es study, and the study by Barton et al. Although the results of the ERC-210 trial, the observational Estip-Es study, and the trial by Barton et al. were supportive of treatment with prasterone (or DHEA), and aligned with results from the ERC-238, ERC-231, and ERC-230 trials, limitations of the design and analyses of the studies precluded drawing concrete conclusions regarding the efficacy or effectiveness of prasterone.
AEs were reported in approximately half of patients in the ERC-238 and ERC-231 trials and did not suggest major differences between the prasterone or placebo groups. Application site discharge was 1 of the most commonly reported AEs in the ERC-238, ERC-231, and ERC-230 trials. This AE was stated to be an expected outcome of treatment with the ovule containing prasterone, as the intravaginal administration of the therapy is expected to result in some discharge at the application site. The clinical expert consulted by CADTH confirmed that this AE is likely not due to the prasterone itself and is most likely related to the hard fat composition of the vehicle which is expected to cause discharge when administered intravaginally. Other commonly reported AEs included urinary tract infections, hot flush, and nasopharyngitis; the clinical expert consulted by CADTH confirmed that the frequency of these AEs was as expected and are likely to be manageable by patients and clinicians. The reporting of AEs was greater in the ERC-230 trial compared to the ERC-238 and ERC-231 trials. However, the trial duration of the ERC-238 and ERC-231 trials was 12 weeks, while the ERC-230 trial was conducted over a 52-week period. It was expected that reporting of AEs would be greater for the ERC-230 trial as the trial duration is longer, and patients would have an overall greater exposure to prasterone. In particular, the proportion of urinary tract infections reported in the ERC-230 trial was almost double what was reported for patients who also received prasterone in the ERC-238 and ERC-231 trials (10.2% versus 4.5% and 5.7%, respectively). As the ERC-230 trial did not have a comparison group, it is unclear whether this increase in urinary tract infections was related to treatment with prasterone.
Notable harms pre-specified in the CADTH systematic review protocol included vaginal hemorrhage, endometrial dysplasia, cervical dysplasia, and breast mass. In general, the proportion of patients with these harms as AEs was low (< 4%); for the ERC-238 and ERC-231 trials, the proportions of patients with these harms were similar between the prasterone and placebo groups. The ERC-230 trial also reported on additional breast, cervical, and endometrial safety data which were obtained from patients who underwent mammograms, Pap smears, and endometrial biopsies, respectively, at baseline and at the end of the study. Breast safety data showed that almost all (99%) patients who underwent a mammogram had normal or no significant findings. Pap smear safety data revealed that of the 430 patients who underwent a Pap smear, only 13 patients revealed atypical results of ASCUS, low-grade squamous epithelial lesion, or high-grade squamous epithelial lesion; of these 13 patients, 7 had a negative HPV test. Regarding endometrial safety, the endometrium of most patients who were able to undergo an endometrial biopsy (86%) was considered atrophic with no clinically significant histological findings; the 43 patients who instead underwent a transvaginal ultrasound had an average endometrial thickness of 2.2 mm (SD = 1.4). Additional endometrial safety data were reported for non-hysterectomized patients enrolled in the ERC-231 trial, which reported similar results as the ERC-230 trial where all patients were found to have an atrophic endometrium after biopsy. In general, while no evidence suggested an increased risk of breast, cervical, or endometrial dysplasia, the short trial duration of the ERC-231 trial and the lack of a comparator in the ERC-230 trial should be taken into consideration when interpreting these safety data.
Additional safety data were identified for post-menopausal patients with history of breast and gynecological cancers in a study by Barton et al.12; this was identified as a population of interest as many therapies for VVA rely on estrogen-based therapies which are contraindicated for patients with history of breast and gynecological cancers. The most commonly reported AEs (> 5) in the study by Barton et al.12 included headache and breast pain; there were no differences in the proportions of these AEs between patients who were treated with prasterone and plain moisturizers. While there were no indications of serious harms with treatment of prasterone in this patient population, the study was limited by a short follow-up time of 12 weeks. Longer-term data would be valuable for understanding the effects of prasterone treatment in this population of patients who are sensitive to hormonal therapies and are having VVA.
AEs were assessed in the NMA published by Li et al.11 and no evidence was found for a difference in the odds of AEs occurring with treatment between prasterone and vaginal estrogen therapy. As mentioned previously, the NMA had some limitations which may have introduced uncertainty into estimates and results should be interpreted with caution.
Three trials, including 2 multi-centre, randomized, DB, placebo-controlled trials (the ERC-238 and ERC-231 TRIALS), and 1 multi-centre, single-group, open-label study (the ERC-230 study) provided evidence on the safety and efficacy of prasterone for post-menopausal patients with VVA. Compared to placebo, prasterone 6.5 mg showed greater improvements after 12 weeks of treatment in percentage of parabasal cells, percentage of superficial cells, vaginal pH, dyspareunia, and vaginal dryness that were clinically meaningful according to the clinical expert consulted by CADTH. The ERC-230 trial provided long-term data on the use of prasterone; however, the lack of a comparator precluded the ascertainment of causal relationships, and the study did not adjust for multiple comparisons. The findings over a treatment period of 52 weeks, however, seemed similar to the findings of the 2 shorter-term trials, suggesting that it is possible that the benefits would be sustained with continued treatment. While the results for sexual function measured using the FSFI in the ERC-238 trial also favoured the prasterone group compared to the placebo group, these results were unadjusted for multiplicity and should be considered exploratory. Safety data from the ERC-238 and ERC-231 trials showed similar proportions of patients with AEs between the prasterone and placebo groups; the ERC-230 trial reported higher proportions of patients with AEs compared to the ERC-238 and ERC-231 trials, which may be expected due to the longer exposure to prasterone. However, due to the lack of a control group, it is unclear whether AEs may be associated with prasterone itself. AEs identified in the ERC-230 trial were mostly similar to those identified in the ERC-238 and ERC-231 trials; all trials reported application site discharge and urinary tract infections as the most commonly reported AEs. Comparison of prasterone to other therapies was assessed through a published ITC. In general, the ITC did not provide evidence for a difference in efficacy between prasterone and vaginal estrogen therapies (grouped as a single comparator), though there was considerable uncertainty in the treatment effect estimates. Limitations related to reporting of the NMA and heterogeneity across the included studies that could not be resolved precluded drawing strong conclusions about the comparative effectiveness and safety of prasterone versus other treatments for VVA. Additional evidence was identified to inform on the safety and efficacy of prasterone: the ERC-210 trial, the Estip-Es study, and a study by Barton et al. While the results of the ERC-210 trial were supportive of those from the 3 pivotal trials mentioned above, limitations of the design and analyses of the Estip-Es and Barton et al. studies precluded drawing concrete conclusions regarding the efficacy or safety of prasterone versus vaginal estrogen therapies or moisturizers and lubricants. The study by Barton et al. enrolled patients with history of breast and gynecological cancers but did not find a difference between DHEA 6.5 mg daily and placebo for the most bothersome symptom (dyspareunia or vaginal dryness) and did not assess the notable harms identified for this review outside of AE reporting over the 12-week treatment period.
adverse event
confidence interval
credible interval
Common Terminology Criteria for Adverse Events
double blind
dehydroepiandrosterone
Female Sexual Function Index
genitourinary syndrome of menopause
indirect treatment comparison
intention to treat
last observation carried forward
mean difference
Menopause-Specific Quality of Life questionnaire
minimal important difference
network meta-analysis
Papanicolaou
per protocol
randomized controlled trial
serious adverse event
standard deviation
Society of Obstetricians and Gynaecologists of Canada
visual analogue scale
Vaginal Atrophy Symptom Questionnaire
Vaginal Health Index
vulvovaginal atrophy
Women’s Health Coalition of Alberta
Note that this appendix has not been copy-edited.
Interface: Ovid
Databases:
Date of search: October 27, 2021
Alerts: Bi-weekly search updates until project completion
Search filters applied: No filters were applied to limit retrieval by study type
Limits:
Syntax Guide.
Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.
[Search -- Studies with results | Intrarosa*, prasterone, menopaus*, DHEA, dehydroepiandrosterone]
International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.
[Search terms -- Intrarosa*, prasterone, menopaus*, DHEA, dehydroepiandrosterone]
Produced by Health Canada. Targeted search used to capture registered clinical trials.
[Search terms -- Intrarosa*, prasterone, menopaus*, DHEA, dehydroepiandrosterone]
European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.
[Search terms -- Intrarosa*, prasterone, menopaus*, DHEA, dehydroepiandrosterone]
Search dates: October 21, 2021 – October 25, 2021
Keywords: Intrarosa*, prasterone, menopaus*, DHEA, dehydroepiandrosterone
Limits: No limits were applied
Updated: Search updated prior to the completion of stakeholder feedback period
Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:
Note that this appendix has not been copy-edited.
Excluded Studies.
Note that this appendix has not been copy-edited.
To describe the following outcome measures and review their measurement properties (validity, reliability, responsiveness to change, and MID):
Summary of outcome Measures and Their Measurement Properties.
The FSFI is a self-reported, multidimensional, 19-item measure of female sexual function consisting of 6 domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. Following initial usability testing among 30 female volunteers, the FSFI was tested for validity and reliability with a sample of 259 control females from the general population (age 21–68 years) and an age-matched clinical sample of patients who met DSM-IV-TR criteria for Female Sexual Arousal Disorder (FSAD).31 Later, the instrument was tested among females with other sexual dysfunction diagnoses, e.g., Female Sexual Orgasm Disorder (FSOD), Hypoactive Sexual Desire Disorder (HSDD), dyspareunia / vaginismus (pain), and multiple sexual dysfunctions.37,38 The questionnaire was designed to be used to assess female sexual function and QoL in clinical trials or epidemiological studies.31
FSFI provides an overall sexual function score on a Likert-type scale. Specifically, each item is scored from 0 to 5 except for questions 1 and 2 (for desire domain), 15-16 (in satisfaction domain), which are scored from 1 to 5. The individual domain scores and full-scale (overall) score of the FSFI can be derived from the computational formula. For individual domain scores, scores of the individual items that comprise the domain are added and multiplied by the corresponding domain factor. Full-scale score is obtained by adding 6 domain scores together. Score ranges for the arousal, lubrication, orgasm, and pain domains are from 0 to 6.0; for desire and satisfaction domains ranges are from 1.2 to 6.0 and from 0.8 to 6.0, respectively. The total FSFI score ranges from 2.0 to 36.0. Higher scores indicate a greater level of sexual function. The recall period is the past 4 weeks. A domain score of zero indicates that the subject reported having no sexual activity during the past month.39 An FSFI total score of 26.55 is taken to be the cut score for differentiating women with and without sexual dysfunction.38
The FSFI has been translated into more than 20 languages and has been adapted in more than 30 countries.40,41 Also, it has been studied for use with multiple populations, including women from different age groups, with diverse medical conditions, and with various sexual dysfunctions.40,41
Rosen et al.31 assessed test-retest reliability at 2 separate visits 2 to 4 weeks apart, with 131 general population controls and 128 age-matched patients diagnosed with FSAD at 5 research centres in the US. It is unclear if the post-menopausal patients included in the study had symptoms attributable to VVA. Overall test-retest reliability was acceptable (r ≥ 0.70)42 for all of the domains (Pearson’s product-moment correlation [r] = 0.79 – 0.86) and for the total scale (r = 0.88) among the full sample. In general, higher test-retest reliability of domain scores was obtained for the control group than for the FSAD group. For the FSAD group, the domain of desire showed the highest test-retest reliability (r = 0.80), with the other domains showing moderate to high correlations (r = 0.62 to 0.71).
In addition, Rosen et al.31 demonstrated acceptable internal consistency (Cronbach alpha ≥ 0.70)42 for all 6 domains (Cronbach alpha ≥ 0.82 for all 6 domains). Meston37 conducted further internal consistency testing among women with FSOD (n = 71) or HSDD (n= 44), as well as control patients (n = 71) who were age-matched to FSOD patients. Meston found that inter-item correlations remained high for all the domain scores among women with FSOD (Cronbach alpha ≥ 0.84), control women (alpha ≥ 0.83), and women with HSDD (alpha ≥ 0.74), except for the desire domain in patients with HSSD (alpha = 0.58). The moderate Cronbach alpha value of 0.58 suggests that the 2-item FSFI desire composite may not be a reliable indicator of sexual desire among this population.
Lastly, Wiegel et al.38 combined data from Rosen et al. (n = 255) and Meston (n = 138) with an additional sample population (n = 134) to assess internal consistency in women with or without sexual dysfunction. Internal consistency for subscales and total score was acceptable (alpha ≥ 0.7)42 for all sample populations and all domains regardless of sexual dysfunction status indicating that questionnaire items remained highly related within each domain or all scale in women with or without sexual dysfunction.
Validity reflects the degree to which the instrument measures what it aims to measure.
Content validity has been ensured by Rosen et al.31 in the population as described in the reliability section above. Briefly, the FSFI was developed in a series of stages, including panel selection of the initial items, pre-testing with 30 healthy, female volunteers at 3 investigational sites, followed by linguistic and conceptual validation with a panel of expert consultants.
Discriminant validity was assessed by Rosen et al.31 by comparing the mean responses of patients with FSAD (n = 126-128) with those of the controls without FSAD (n = 129-131). Significant differences (for all P ≤ 0.001) between the groups were observed for all 6 domains (not included in this report) and the full-scale score (19.2 ± SD 6.63 in 126 patients with FSAD vs. 30.5 ± SD 5.29 in 129 control patients). Moreover, Meston37 assessed the discriminant validity in additional clinical samples by comparing the mean responses of women with FSOD (n = 71) and HSDD (n = 44) to those of the age-matched control women (n = 71 and 44, respectively). The results from between groups analyses of variance revealed significant differences between women with sexual dysfunction (FSOD or HSDD) and their controls on each of the FSFI domain and total scores (for all P ≤ 0.001). As expected, the largest differences between women with FSOD and controls were noted for orgasm and arousal domains (effect size estimated using Cohen D = 1.69, 1.58, respectively), and the largest differences between women with HSDD and controls were seen for the arousal and desire domains (ES estimated using Cohen D = 1.85, 1.69, respectively). Lastly, discriminant validity has been confirmed by Wiegel et al.38 with the sample populations described above in reliability section. Evidence for discriminant validity was observed for the total score (MANOVA and univariate tests, p < 0.001) and individual domain scores (univariate tests, P < 0.001) between patients with and without sexual dysfunction diagnoses.
Divergent validity was tested by Rosen et al.31 by specifically measuring the construct under study (i.e., sexual function) compared to an instrument that assesses a different, albeit partially related, construct (e.g., marital satisfaction). The Pearson product-moment correlation between the Locke-Wallace Marital Adjustment Test and the total FSFI score was moderate for the control group (r = 0.53) and low for the FSAD group (r = 0.22). This result indicates that for subjects with sexual dysfunction, FSFI scores appeared to have a greater degree of independence with the marital adjustment effect compared to control group. To extend divergent validity testing in other clinical samples, Meston37 calculated Pearson correlations between the FSFI scores and the Locke-Wallace Marital Adjustment Test score in patients with FSOD or HSDD. Correlations between the Locke-Wallace Marital Adjustment Test and total FSFI scores were low for women with FSOD (r = 0.22) or HSDD (r = 0.16), and moderate for controls (r = 0.52). Of note, the satisfaction domain showed moderate to high level of correlation (r = 0.40 – 0.72) between FSFI and Locke-Wallace across all the samples.
There was no evidence located to support the FSFI’s responsiveness to clinical or health status changes among post-menopausal patients over time.
MID for FSFI has not been estimated in post-menopausal patients with VVA-associated symptoms.
The 3 studies, i.e., Rosen et al., Meston, Wiegel et al., assessed validity in control and sexually dysfunctional populations that contain various numbers of post-menopausal women. Based on the age of populations included in these studies, the number of post-menopausal women seems small, For example, Rosen et al.31 study population had mean age ± SD ages of the FSAD group (n = 128) and control group (n = 131) 40.5 ± 12.98 years and 39.7 ± 13.15 years, respectively. Meston study37 included women between 18 and 53 years of age with mean ± SD for patients with FSOD (n = 71) 29.4 ± 8.76 years, HSDD (n = 44) 33.0 ± 10.42 years, and controls (n = 71) 29.2 ± 7.9 years, respectively. Lastly, in Wiegel et al., the mean age of the combined sample was 36.2 ±13.2 years and ranged from 18-72 years. Only 3.6% (n = 20) patients in Wiegel et al. study were peri-or post-menopausal. Taken together, no study is specifically designed to test psychometric properties of FSFI in post-menopausal women.
Also, these studies were conducted with patients diagnosed with sexual dysfunctions rather than those with symptoms of post-menopausal VVA. Some manifestations of sexual dysfunctions and post-menopausal VVA may overlap, for example, dyspareunia. However, the extent of overlap is unclear. It makes it difficult to apply the validity results to population other than those with sexual dysfunction diagnoses.
The sponsor used their own term, VASQ, to refer to the atrophy symptom questionnaire, which was modified from previous reported form, Vaginal Atrophy Index (VAI).43
The VASQ that was to be completed by patients in the sponsor’s trials consists of 5 items: dryness, soreness, irritation, dyspareunia, and vaginal discharge. The dyspareunia item is only to be completed if patients are sexually active. Each item can be answered among 4 choices, i.e., none, mild, moderate, and severe, according to the symptom severity the patients are experiencing. No information regarding recall period was available.
The presence and/or severity of each recorded symptom on the patient form was assigned a score from 0 (none/no atrophy) to 3 (severe). The total atrophy symptoms (or VASQ) score is calculated as the sum of individual symptom scores divided by 5, for the sexually active patients who completed the question regarding dyspareunia. For those respondents who were not sexually active and who answered “N/A” to the dyspareunia question, the sum of individual symptom scores is divided by 4. Higher scores represent more severe atrophic symptom burden.
There was no evidence located to support the reliability of the VASQ.
Davila et al.30 assessed construct validity of the VASQ in 135 female volunteers who were patients being seen for gynecologic care (mean age = 68.55 years, range 23-89 years). Results showed that women who were receiving systemic estrogen therapy had significantly higher atrophy symptoms scores (mean =0.53; SD = not reported) than women who were not on systemic estrogen treatment (mean = 0.27; SD = not reported; P = 0.0007).
In addition, Davila et al.30 assessed the strength of relationships between several variables and atrophy symptom score. Vaginal atrophy symptom scores had little-to-no correlation with maturation value (r = 0.061), age (r = -0.004), or vaginal pH (r = 0.031).
There was no evidence located to support the responsiveness of the VASQ to changes in vaginal symptom in post-menopausal patients during treatments over time.
MIDs for the VASQ has not been estimated in post-menopausal patients with VVA-associated symptoms.
Even though VAI has been used in previous urogenital atrophy study,43 it has not been rigorously tested for psychometric properties.
Even though Davila et al. study provides some validity evidence for the VASQ, the population chosen did not select for patients who were post-menopausal or who had symptoms of VVA.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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