Title: Spironolactone for Adult Female Acne (SAFA): pragmatic multicentre double-blind randomised superiority trial to investigate the clinical and cost-effectiveness of spironolactone for moderate or severe persistent acne in women
Funder: Department of Health and Social Care

Abstract: DESIGN Pragmatic multicentre double-blind randomised superiority trial SETTING Primary care, secondary care and community POPULATION Women aged 18 years and over with persistent acne of sufficient severity to warrant oral antibiotics. HEALTH TECHNOLOGIES Oral spironolactone 50mg/100mg will be compared with placebo for 24 weeks. Spironolactone is usually started at a lower dose to minimise side effects. Therefore, the spironolactone group will start on 50mg once daily, increasing to 100 mg (2*50mg) once daily if there is insufficient treatment response at 6 weeks. To maintain blinding, the placebo group will increase to two tablets once daily if there is insufficient treatment response at 6 weeks. The trial will be blinded for 24 weeks followed by un-blinded follow-up to 52 weeks. Participants in either group may use the following additional treatments during the trial: • Participants in either group may use any topical treatment throughout the trial. • Participants in either group may use oral antibiotics from 12 weeks. • Participants in either group may use isotretinoin from 24 weeks. • After 24 weeks, participants in the spironolactone arm may seek to continue this treatment. The control group will receive treatment as required and as per current recommended UK (NICE CKS) guidelines. Potential participants already using hormonal contraception or co-cyprindiol will be included if they have been using this for 3 months or more prior to the baseline appointment. If they have recently changed to or from hormonal treatments, they will be asked to wait for 3 months ‘stabilisation’ prior to baseline appointment. PRIMARY OUTCOME The primary outcome will look at impact on quality of life, comparing mean Acne-QoL symptom subscale score between groups at 12 weeks, adjusted for baseline variables. Acne-QoL is the most extensively validated patient-reported outcome for acne. The Acne-QoL contains 19 questions with seven response categories referring to the past week, organised into four domains (self-perception, role-social, role-emotional, acne symptoms). SECONDARY OUTCOMES • Comparison of mean Acne-QoL symptom subscale score between groups at 24 weeks and 52 weeks, adjusted for baseline variables • Comparison of mean Acne-QoL other subscales (self-perception, role-emotional and role-social) between groups at 12 weeks, 24 weeks and 52 weeks, adjusted for baseline variables • Appearance will be judged using participant self-assessed improvement at 12 weeks recorded on a 6-point Likert scale (with baseline photograph to assist recall) • Investigators’ Global Assessment change from baseline to 12 weeks • Generic quality of life change at 12 weeks, 24 weeks and 52 weeks (EQ-5D-5L) • Satisfaction with treatment will be asked prior to unblinding. • Adverse reactions • Use of other oral treatments for acne during follow-up • Resource use HEALTH ECONOMICS Within-trial cost-effectiveness analysis will assess value for money of spironolactone versus usual care for women aged 18 years and over with persistent acne of sufficient severity to warrant oral antibiotics, from the perspective of the NHS and personal social services. QALYs for the trial period will be estimated using linear interpolation and area under the curve with and without baseline adjustment. Incremental cost utility analysis will be conducted. SAMPLE SIZE Based on comparison of Acne-QoL symptom subscale scores between groups at 12 weeks, power 90%, alpha 0.05 and seeking effect size 0.35, 346 participants are needed. Allowing for 20% loss to follow up gives total 434 participants (217 per arm). TIMETABLE • 1-6 months: approvals, prepare study materials, database, randomisation. • 7-23 months: recruitment. • 10-36 months: follow-up. • 35-42 months: data preparation, analysis, reports, dissemination. • 18 month recruitment period includes 6 month internal pilot with stop-go criteria based on recruitment and retention rates. The detailed project description includes details of our estimate of recruiting six patients per month from each of five centres. EXPERTISE This is an experienced multidisciplinary team with established working relationships.

Lay abstract: BACKGROUND Acne is very common and, although thought of as a teenage condition, often continues into adulthood where impact on quality of life can be significant. Creams and lotions (topical treatments) can be effective but these may not be helpful and oral treatment (treatment taken by mouth) using antibiotics, the contraceptive pill or a hormonal treatment called co-cyprindiol may be required. These are slow to work and not recommended for use over long periods of time. This can be frustrating to people who are unable to take hormones due to conditions such as migraine and /or those that require treatments for longer periods to contain their acne. The most commonly used treatment for acne is long courses of antibiotics but concerns about antibiotic resistance mean we need to find alternatives. Spironolactone is widely used to treat conditions such as high blood pressure. Spironolactone reduces hormones called androgens that are implicated in acne as these increase grease production and cause changes in follicles in the skin making them prone to acne. AIM This study will measure whether spironolactone helps adult women with persistent acne that would normally be treated with oral antibiotics. METHODS Women aged 18 years and over will be randomly allocated to one of two groups, in addition to standard care: spironolactone tablets or placebo (dummy pill) will be taken once a day for 24 weeks in each of the groups. We will ask women to come back to clinic after 6 and 12 weeks to assess the effect of the treatment they are using. During the first 12 weeks of the study, participants may continue using topical treatments as usual but we will ask them to avoid using oral treatments for acne (with the exception of the contraceptive pill if they are already using it and have been on it for 3 months or more). Participants will be followed up for a total of 52 weeks, but will be able to use all other treatments as usual after the first 24 weeks (apart from oral antibiotics, which may be used from 12 weeks onwards). After 24 weeks all participants will be informed which tablets they have been allocated to in the study. If a participant who received spironolactone is happy with it, they may ask their GP or dermatologist to continue prescribing it. Participants that received the placebo will receive treatment as required and as per current recommended UK (NICE CKS) guidelines until the end of the study. We will assess the result of the study by asking participants to complete a standardised questionnaire about acne that has been used in other studies. We will also compare ‘before and after’ photographs, ask about quality of life and side effects of the treatment. We will monitor safety and the need for additional treatments. Most acne is treated by GPs so this study will invite participants through general practices as well as hospitals. We will invite women by post, by community advertising and directly in GP and hospital clinics. PATIENT AND PUBLIC INVOLVEMENT We have received feedback from a patient survey sent to patient groups including participants of the James Lind Alliance Priority Setting Partnership for acne. We recruited a patient panel for acne from a study on acne questionnaires that started in April 2017. SAFA includes one PPI co-applicant and we have a second PPI member for the Trial Management Group. Input from a broader range of patients and training for PPI members will be provided through the Centre of Evidence Based Dermatology’s Patient Panel. DISSEMINATION A user-friendly website will publicise progress and participants’ stories to generate interest. Once analyses are complete, we will discuss results with key stakeholders, to ensure we include their perspectives in disseminating results. The findings will be published in peer-reviewed journals, funders’ report and updates to participants and through contacts with patient groups. We will publicise through existing networks (email lists and social media) to maximise impact.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: SKIN