Parts of this report are based on Williams et al.24 This article is published open access under the terms of the Creative Commons Attribution 4.0 licence (CC-BY) (https://creativecommons.org/licenses/by/4.0).
Trial design
The Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial was a two-arm, parallel-group, multicentre, multinational randomised controlled trial of 52 weeks’ duration. The design was towards the pragmatic end of the explanatory–pragmatic spectrum.25 We recruited patients with BP from the UK and Germany who had not started systemic treatment. Participants were randomised to receive either doxycycline or prednisolone as initial treatment and were followed up at weeks 3, 6, 13, 26, 39 and 52, with unscheduled visits as required to reflect normal clinical care.
The two primary outcomes in this trial reflect the need for patients and clinicians to balance the likely differences in effectiveness and safety for oral prednisolone and doxycycline when making a shared decision on treatment. Although topical corticosteroids have been shown to be effective for BP, it is not always practical or cost-effective to admit elderly people into hospital for whole body application15 and therefore oral treatment alternatives are needed. Although oral prednisolone is thought to be effective at reducing the blisters in BP, it has many side effects as indicated in previous trials comparing topical corticosteroids with oral corticosteroids.18,19,26 Doxycycline, on the other hand, is perceived to be less effective by clinicians but probably has fewer side effects. Therefore, a non-inferiority comparison was used to assess effectiveness, the results of which could be considered alongside the superiority comparison of safety in clinical decision-making.
The trial protocol was published prior to the analysis.27
Choice of intervention
At baseline, patients were randomised to receive either 0.5 mg/kg/day of prednisolone or 200 mg/day of doxycycline, both taken as a single, daily dose (brand not specified). We chose a starting dose of 0.5 mg/kg/day for prednisolone based on safety concerns over higher doses such as 0.75–1 mg/kg/day highlighted in the Cochrane systematic review.22 The study protocol encouraged investigators to stick to the allocated treatment and dose for the first 6 weeks unless it was medically necessary to change, but after the 6-week effectiveness assessment investigators were free to modify the dose as needed, switch to the other treatment arm or administer an alternative treatment if appropriate, to reflect normal clinical practice. Participants were followed up for the full 52 weeks when possible, regardless of any changes to treatment. Participants recorded study medication use in their diary.
Rescue medication
Up to 30 g/week of topical corticosteroids in the potent class [preferably mometasone furoate (Elocon®, Merck Sharp & Dohme Ltd)] was permitted throughout the study, except between weeks 3 and 6. The cessation of topical corticosteroids from week 3 to week 6 provided a washout period to minimise the potential effect of systemic absorption of topical corticosteroids on the primary effectiveness outcome at 6 weeks. To minimise potential systemic effects, topical corticosteroids were applied only to blisters and erosions. Participants were permitted to apply a moisturiser to blisters and erosions at any time.
Choice of tetracycline
Doxycycline was chosen for this trial because (1) it is associated with a lower incidence of gastrointestinal side effects than other tetracyclines and (2) the alternative option of oxytetracycline would have required participants to swallow approximately eight large tablets a day.
Although the only published randomised controlled trial investigating tetracycline antibiotics for the treatment of BP used a combination therapy of tetracycline plus nicotinamide,21 a single therapy of doxycycline was chosen for this trial to allow the effects of the tetracycline to be clearly defined.
Trial outcomes
We did not identify any core outcome sets for BP when this study was designed, although some consensus criteria have subsequently been suggested by an international group.28
Primary outcomes
The primary outcomes were the absolute difference between the two treatment arms in the:
For the primary outcome, treatment success was defined as three or fewer significant blisters, regardless of whether or not treatment had been modified because of a poor response (either by changing the dose or by changing the treatment) during the first 6 weeks. However, for all secondary and tertiary end points, participants were classed as a treatment success at each visit only if (1) they had three or fewer significant blisters present on examination and (2) their treatment had not been altered because of a poor response prior to that visit.
Secondary outcomes
The secondary outcomes were the absolute difference between the two treatment arms in the following:
Tertiary outcomes
The tertiary outcomes were the absolute difference between the two treatment arms in the following:
Participants
Adults (aged ≥ 18 years) who were capable of giving written informed consent and who had a clinical diagnosis of BP were eligible. To ensure that active disease was present, at least three significant blisters (defined as intact, fluid-filled blisters measuring ≥ 5 mm) must have appeared within the week prior to screening and must have been present across at least two body sites. Recent erosions could be included provided that they had a flexible (not dry) roof over a moist base. Positive direct (skin biopsy) or indirect (serum) immunofluorescence [immunoglobulin G (IgG) and/or complement component 3 (C3) at the epidermal basement membrane zone) was required to confirm diagnosis. Anonymised samples were tested at the Immunofluorescence Laboratory at the Department of Dermatology, John Radcliffe Hospital, Oxford, and the Institute of Dermatology Immunodermatology Laboratory at St John’s Institute of Dermatology, St Thomas’s Hospital, London. Samples with appropriately obtained consent were sent to the Clinical Immunological Laboratory, University of Lübeck, Germany, for additional immunology substudies, which will be published separately.
Patients must have been free of blisters and have not received treatment for previous episodes of BP in the preceding year. Patients were excluded if they had predominantly mucosal pemphigoid, had received any systemic medication for the current episode of BP or had received oral prednisolone or doxycycline for any other conditions in the preceding 12 weeks. Women of childbearing potential who were not taking adequate contraception, as well as those who were pregnant or who planned to become pregnant during the study or who were currently lactating, were excluded. Additional exclusions for safety reasons were live virus vaccine administration within the previous 3 months, allergy to any member of the tetracycline family or a pre-existing condition or use of a medication that precluded the use of either study drug or that made the patient unsuitable for this trial, as assessed by the investigator.
Retention of participants
To help retain participants in the study, in addition to being able to speak to the investigator, participants were able to telephone the trial manager if they wished to discuss any aspect of the study. For medical queries, participants were directed to a medical member of staff. In addition, the trial administrator made telephone calls to participants to support them throughout the duration of the study. Participants were sent birthday and Christmas cards while they were participating in the study.
Withdrawal of participants
Patients whose immunofluorescence test results were not available until after randomisation and which were subsequently both negative, indicating that they did not have BP, were withdrawn from the trial, replaced and not included in the analysis. This approach reflects normal practice: if there is a clinical picture of BP, treatment is commenced and this is changed later if the laboratory tests are subsequently negative.
Participants who withdrew from study treatment were followed up for the remainder of the year unless they had withdrawn their consent.
Informed consent
Patients presenting with suspected BP were assessed by the recruiting investigator as per normal clinical practice. If a diagnosis of BP was suspected, the patient was given details of the study verbally. If the patient was interested in taking part he or she was given time to read the full participant information leaflet and the investigator answered any questions. A consent form was signed before any study procedures were carried out.
If the disease severity was such that immediate oral treatment was required or the patient did not wish to delay the start of treatment, he or she was able to give consent and be randomised to the study during the first visit to the dermatologist. Otherwise, the patient was given a second appointment for consent and randomisation.
Recruitment
To meet the target for this rare disease, recruitment took place at a large number of hospitals, mainly in dermatology clinics (54 in the UK and seven in Germany).
Randomisation
Randomisation was based on a computer-generated pseudorandom code using random permuted blocks of randomly varying size, created by the Nottingham Clinical Trials Unit (NCTU) in accordance with its standard operating procedure and held on a secure server. Access to the sequence during the trial was confined to the NCTU data manager.
Participants were allocated in a 1 : 1 ratio to the doxycycline and prednisolone treatment arms. Randomisation was stratified by disease severity, which was defined as the number of blisters present at baseline (mild: 1–9; moderate: 10–30; severe: > 30).
The investigator or research nurse randomised participants using the web-based NCTU randomisation system. The treatment allocation was sent directly to the pharmacist who dispensed the appropriate medication directly, which allowed the investigator to remain blinded.
Blinding
Investigators (outcome assessors) were unaware of treatment allocation and remained blinded to treatment allocation for the first 6 weeks of the trial. At the week 6 visit, the investigators carried out the blister count (primary effectiveness outcome) while blinded to treatment allocation. The investigators were unblinded for the remaining assessments: that is, for the primary safety outcome (adverse events over the full 52 weeks) and the long-term effectiveness outcomes. Unblinding before the 6-week point was permitted if required for treatment decisions that affected patient safety. Investigators were asked at week 6 if they were aware of the treatment allocation prior to carrying out the blister count for the primary effectiveness outcome to capture the rate of unblinding. A subgroup analysis to assess any potential bias of unblinding on the blister count at 6 weeks was performed. The patients and pharmacists were not blinded to treatment allocation.
Sample size
In total, 256 participants were needed to detect a clinically important absolute difference of 20% in grade 3, 4 and 5 (mortality) side effects within 1 year of randomisation (primary safety outcome). This was based on an expected 60% incidence with prednisolone compared with 40% with doxycycline29 with 80% power at the 5% significance level allowing for a 20% loss to follow-up by 1 year using a 1 : 1 allocation ratio. A survey of UK dermatologists showed that a 20% absolute reduction in side effects was considered to be an acceptable and worthwhile clinical difference. More detailed results can be found in Appendix 1.
The effectiveness outcome at 6 weeks was expressed as a two-sided 90% confidence interval (CI) for the absolute difference in success rates (based on blister count) between the prednisolone (control) arm and the doxycycline (intervention) arm. It was assumed that the point estimate for this difference would be 25%, based on an expected response rate of 95% in the control (prednisolone) arm and 70% in the intervention (doxycycline) arm. The acceptable non-inferiority margin was set at 37% based on the upper bound of the 90% CI for an expected 25% difference. Because the non-inferiority margin is inversely proportional to the sample size, the number of patients who we could realistically expect to recruit in a rare disease of the elderly was factored in when setting the non-inferiority margin. The closer to the expected difference of 25% we set the non-inferiority margin, the larger the sample size that would be required. With 80% power, a total of 111 evaluable participants per group was required. The attrition rate in the initial 6 weeks was expected to be low (5%) and so a total of 234 participants was required, that is, within the 256 required for the primary safety outcome.
Analysis
All superiority analyses were conducted on a modified intention-to-treat (mITT) basis and all non-inferiority analyses were performed on both the mITT and the per-protocol (PP) population according to recommended practice.30
The mITT population consisted of those participants who fulfilled the eligibility criteria, who were randomised to receive either study drug and who had data on the outcome of interest.
For each non-inferiority outcome, the doxycycline arm was considered to be non-inferior to the prednisolone arm if the upper bound of the CI for the difference in proportions was less than the agreed non-inferiority margin of an absolute difference of 37% in both the mITT and the PP analyses.
All analyses were adjusted for baseline disease severity to optimise power and reduce possible imbalances in possible response predictors. Age and Karnofsky score31 were also adjusted for in analyses as continuous variables when possible using a binomial regression with identity links. Methods for dealing with missing data can be found in the statistical analysis plan [see www.nottingham.ac.uk/research/groups/cebd/projects/5rareandother/index.aspx (accessed 19 May 2015)]. Multiple imputation was used to handle missing data because of missed visits for the primary safety analysis.
Patients were excluded from the PP analysis of the primary outcome if, before their 6-week visit, for reasons other than treatment success or failure, they had:
increased the dose of their allocated treatment
changed treatment or added a new treatment to their allocated treatment (for a reason other than for treatment failure or success)
used topical steroids between visit weeks 3 and 6
missed more than 3 consecutive days of treatment.
For non-inferiority outcomes after week 6, the PP populations consisted of those participants who were included in the PP analysis of the 6-week primary effectiveness outcome and who had:
not missed more than 3 consecutive weeks of allocated treatment between 6 and 52 weeks (regardless of whether the dose had been increased or decreased) unless they had stopped for good clinical response
used no more than 30 g of topical steroids per week after week 6
not added systemic steroids to doxycycline (if allocated) or doxycycline or an immunosuppressant to prednisolone (if allocated) unless for poor clinical response.
For the non-inferiority outcomes, 90% CIs are presented. For the study treatment doxycycline to be considered non-inferior to the control treatment, the upper bound of the 90% CI should fall below 37%. For the superiority outcomes, 95% CIs are presented. A difference between treatment arms was considered statistically significant at the 5% level, that is, the 95% CIs do not contain zero (no difference between arms).
The primary analysis had a dual outcome, one primary outcome for effectiveness and one for safety. For the study treatment doxycycline to be considered acceptable as an alternative to prednisolone, non-inferiority had to be demonstrated (as defined above) with regard to effectiveness, as well as the superiority of doxycycline over prednisolone for safety.
Subgroup analyses
For some patients the blister count at 6 weeks may have been performed by an investigator who knew what treatment the patient was on. To determine whether or not this introduced bias into the results of the 6-week effectiveness outcome, an interaction test was performed to compare the treatment effects in patients who were and patients who were not assessed by an investigator who knew the treatment allocation. This interaction analysis was performed on both the primary and the secondary definition of treatment success at 6 weeks.
Subgroup analyses of treatment success (using both definitions) at 6 weeks by the three categories of baseline disease severity (mild, moderate and severe) were also performed. A global test for a treatment interaction was used to determine whether or not treatment effects were different in the three categories of disease severity.
Cost-effectiveness
The EuroQoL tool
The EuroQol tool is a two-page questionnaire consisting of the EQ-5D descriptive system and the EuroQol visual analogue scale (EQ VAS).32 The tool is a standardised measure of current health status developed by the EuroQol group for clinical and economic studies. The EQ-5D three-level version (EQ-5D-3L) was used, consisting of five questions addressing the health dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is assessed at three levels: no problems, some problems and extreme problems. EQ-5D and EQ VAS data were collected using patient-completed questionnaires at baseline and 6, 13, 26, 39 and 52 weeks. Scores were converted to a single health-related index ranging from 0 (death) to 1 (perfect health), with negative scores possible for some health states. Patients who died during the study were subsequently scored 0 at later scheduled follow-up visits.
Resource use
Resource use assessments were carried out at 3, 6, 13, 26, 39 and 52 weeks during mandatory clinical visits and were augmented by telephone calls. Recall was assisted by the use of patient diaries. Patients’ use of study and non-study drugs was recorded and costed using weighted average prices determined from Prescription Cost Analysis (PCA) data.33 Health service contacts were recorded by asking patients to recall general practitioner (GP) clinic and home visits, practice and district nurse visits, outpatient visits and inpatient stays. Health-care resource use was costed using published national reference costs.34–36 Patient-level resource costs were estimated as the sum of resources used weighted by their national reference costs.
Economic analysis
The economic analysis followed intention-to-treat (ITT) principles and a prospectively agreed analysis plan (see Appendix 2). No discounting was applied to economic data reflecting the follow-up period of 1 year. Costs were estimated in UK pounds sterling using patient resource use and 2013 reference costs.35 The analysis took an English NHS perspective, reporting generic (EQ-5D, EQ VAS)32 and disease-specific (DLQI)37 health outcomes. Repeated scores over time were used to construct area under the curve (AUC) estimates for each patient, using the trapezoidal method. Missing values at individual follow-up points were managed using two scenarios: multiple imputation (the base-case analysis38) and analysis of complete cases (in which patients with any missing data were excluded).
Patient estimates of costs and quality-adjusted life-years (QALYs) at 1 year were used to derive an estimate of the cost-effectiveness of doxycycline-initiated therapy compared with prednisolone-initiated therapy for patients with BP. Estimates using imputed missing data provided the base-case analysis and estimates using complete data provided supportive sensitivity analysis. Analysis and modelling were undertaken in Stata 13 (StataCorp, College Station, TX, USA). The base-case analysis included the imputed within-trial incremental cost/QALYs gained, adjusted for trial covariates (age, sex, baseline blister severity and baseline Karnofsky score). QALY estimates were also adjusted for baseline EQ-5D score.
