LIVERPOOL – Spironolactone, a synthetic steroid with anti-androgenic properties, significantly improves persistent acne in adult women, with possible greater effectiveness in women over 25 years of age, according to the findings from a phase 3, double-blind, randomised, placebo-controlled pragmatic clinical trial.
Participants were selected at the point of their condition where oral antibiotics would usually be given, however spironolactone was trialled as an alternative to antibiotics, which carry the global threat of antibiotic resistance.
Eva Lau, MD, a dermatologist from Harrogate and District NHS Foundation Trust, North Yorkshire, presented results of the multi-centre trial at this year's British Association of Dermatologists (BAD) 103rd annual meeting.
For Adult Women Only
At both 12 and 24 weeks, patients taking spironolactone had significantly improved acne-specific symptom scores on the patient reported quality of life scale (Acne QoL), when compared to placebo. Spironolactone was also well-tolerated, and no serious adverse effects were noted.
"Based on these findings, spironolactone may be a potential alternative treatment to oral antibiotics for adult women with moderate to severe acne, and should be considered in this context given the rates of antimicrobial resistance which are increasing globally," said Dr Lau, who was speaking on behalf of the SAFA [spironolactone for adult female acne] trial investigators who published the results in the BMJ a few weeks before the conference.
"We only hope we will identify an alternative for our male patients in the future as spironolactone is not considered a suitable treatment for men," she added.
Alison Layton, FRCP, professor and consultant dermatologist from the Skin Research Centre, University of York and Harrogate and District NHS Foundation Trust was co-clinical lead for the study with Miriam Santer, MRCGP, and the Clinical Trials Unit, University of Southampton. Professor Layton, who spoke from the audience added that: "From a clinical perspective, patients reported good outcomes at 24 weeks and many patients wanted to remain on spironolactone at the end of the study.
"Most patients had significant improvement at 6 months and, interestingly, response time was similar to oral contraceptives which also take about 6 months to deliver a good response," she pointed out. "I feel confident that this study has demonstrated a novel approach demonstrating good efficacy of spironolactone for acne in adult women. This is very positive for women's health."
Dr Lau emphasised the importance of finding an alternative to antibiotics in these patients. "One in three people are prescribed antibiotics frequently for longer than the recent NICE [National Institute of Health and Care Excellence] guidance," she said. "The combined oral contraceptive pill is unsuitable for many women and non-adherence to topical treatments is common."
Used Off Licence for 30 Years
Dr Lau explained that spironolactone has been used off-licence for acne for 30 years. Yet, due to a lack of robust evidence from randomised controlled trials, there was no mention of it in the recently published NICE guidance for acne management.
As such, the SAFA team developed a pragmatic clinical study which aimed to assess the effectiveness of oral spironolactone for acne vulgaris in adult women of at least 6 months standing, that warranted oral antibiotic treatment. Out of the 410 women randomised into the trial, 342 were included in the primary analysis with 176 on 50 mg/day (one tablet) spironolactone to week six, then dose was escalated to 100 mg/day (two tablets) until week 24, and 166 on placebo (matched by the number of tablets). Use of topical treatments was allowed throughout. At 12 weeks, usual acne management was permitted if a change was required.
"At week 24, the patients were unblinded and could choose to switch to spironolactone if they had been on placebo, or continue on spironolactone at 50 mg or 100 mg. They were then followed up at week 52 with a questionnaire," explained Dr Lau.
The primary endpoint was initial treatment response measured by the AcneQoL symptom subscale at week 12, while 24-week Acne-QoL score, safety, and cost effectiveness were secondary endpoints. The Acne QoL captures self-perception, social role, emotional role, and acne symptoms, and applies to people aged 13-35 years.
Patients recruited had a mean age of 29 years, were mainly white, with 46% having mild, 40% moderate, and 13% severe acne. Body mass index (BMI) was similar across the groups, but average BMI was at the higher end of the scale, Dr Lau reported.
"The acne symptoms improved over time for both groups, with highest scores in the spironolactone group. After 12 weeks the spironolactone still saw increasing positive results, but the placebo flattened off," said Dr Lau describing the graph. "The biggest difference between the groups was seen at week 24."
At week 12, the mean Acne QoL-symptom scores were 19.2 and 17.8 in the spironolactone and placebo groups, respectively, and the difference in mean Acne QoL-symptom scores between spironolactone and placebo, adjusted for site, baseline severity, baseline QoL score, topical treatment, hormonal contraception, and polycystic ovary syndrome, was 1.27 (95%CI: 0.07 to 2.46).
At week 24, this increased to 3.45 (95% CI 2.16 to 4.75). "This is well above the two-point difference we were looking for, and because the confidence interval is above two, it shows the drug is clearly having an effect. We see a statistically significant greater improvement in the spironolactone group at both week 12 and week 24."
Particularly Effective for Women Over 25
Other secondary outcomes at 24 weeks included further symptom subscales of the Acne-QoL, participant self-assessed improvement; investigator's global assessment (IGA) for treatment success; and adverse reactions.
"There were quite big differences in the secondary endpoints related to self-perception and emotion showing there's a positive therapeutic effect on patient well-being," remarked Dr Lau.
More participants in the spironolactone group reported acne improvement than in the placebo group, but there was no statistically significant difference at week 12 at 72% versus 68% respectively with an odds ratio 1.16 (95% CI 0.70 to 1.91). At week 24 this increased to 82% versus 63% with an odds ratio of 2.72 (95% CI 1.50 to 4.93).
"Women over 25 years of age seemed to do better than younger ones," said Dr Lau. The 12-week Acne QoL symptom subscale difference between spironolactone and placebo was 2.42 (95% CI 1.04 to 3.84), while a similar measure for the under-25 year-olds was -0.87 (95% CI -3.67 to 1.92). "The population below 25 years was small at 90 people, so it is difficult to say how well the treatment worked in this group."
Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% versus 12%; P=0.02). Irregular menstrual bleeding was similar between groups (around 33%), but there was slightly more dizziness and polyuria in the spironolactone group. No serious adverse reactions were reported.
Julia Schofield, MB ChB, FRCP, MBE, consultant dermatologist for United Lincolnshire NHS Trust commented on the study. "I think not only is it an excellent study, but it's pivotal and will change the way we manage women with acne. This is particularly true in the group who are older and in whom it has always been challenging because the only alternative is to use long-term, low-dose oral antibiotics, which are not to be recommended now because of the challenges of antibiotic resistance," she said, adding that, "It's definitely going to change my clinical practice. I think it's a great piece of work."
Presented on June 29, 2023 at British Association of Dermatologists 103rd annual meeting in Liverpool. The study was also published in the May 16, 2023 issue of the BMJ. Abstract RF04.
The study was supported by an independent National Institute of Health research Health Technology Assessment grant and delivered by NHS sites across the UK to provide equity and diversity. Dr Lau has declared no financial disclosures. Co-author Professor Layton declares the following: AML has served as advisor, consultant, and/or investigator for research (funded to institution) and/or received honoraria for unrestricted educational events from Almirall, Eucerin, Galderma, GSK, La Roche-Posay, LEO Pharma, L’Oréal, Mylan, Origimm, and Proctor and Gamble. Dr Schofield has made no relevant disclosures.