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

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 an un-blinded follow-up period of up to 6 months (up to 52 weeks after baseline). 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). Allowing for a correlation with baseline of 0.293 and a deflation factor of 1-?215, gives a total sample size (including allowing for 20% loss to follow up) of 398 participants. A difference of 2 points on the symptom subscale and a standard deviation of 5.8 (equivalent to an effect size 0.35) is in line with that reported in trials in a similar patient group and with the MCID reported for Acne-QoL. TIMETABLE • 1-14 months: approvals, prepare study materials, database, randomisation. • 15-41 months: recruitment. • 18-48 months: follow-up. • 49-53 months: data preparation, analysis, reports, dissemination. • recruitment period includes 6 month internal pilot with stop-go criteria based on recruitment and retention rates. EXPERTISE This is an experienced multidisciplinary team with established working relationships.