Clinical Trial Results:
Spironolactone for Adult Female Acne: A pragmatic multicentre double-blind randomised superiority trial to investigate the clinical and cost-effectiveness of spironolactone for moderate or severe persistent acne in women
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Summary
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EudraCT number |
2018-003630-33 |
Trial protocol |
GB |
Global end of trial date |
31 Aug 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Apr 2024
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First version publication date |
11 Apr 2024
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Other versions |
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Summary report(s) |
Adverse event |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SAFA study
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Additional study identifiers
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ISRCTN number |
ISRCTN12892056 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Hospital Southampton
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Sponsor organisation address |
University Rd, Southampton, United Kingdom, SO17 1BJ
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Public contact |
Southampton Clinical Trials Unit, University of Southampton, 44 02381205596, safa@soton.ac.uk
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Scientific contact |
Southampton Clinical Trials Unit, University of Southampton, 44 02381205596, safa@soton.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Aug 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Aug 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This study will measure whether spironolactone plus standard care is better than placebo plus standard care for adult women (18 years or older) with persistent acne that would normally be treated with oral antibiotics.
This will be measured using a participant-reported acne-specific Quality of Life questionnaire (Acne-QoL) at 12 weeks.
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Protection of trial subjects |
None
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Background therapy |
Participants in both groups could continue to use their usual topical treatments throughout the trial but adherence to topical treatment was not promoted beyond usual care. Participants were asked not to change topical treatments between baseline and 12 weeks or take oral treatments for acne other than study medication; although, women who had been on oral contraception for more than three months could continue this medication. After 12 weeks, participants in both groups could receive usual care, such as oral antibiotics, hormonal treatments, or isotretinoin, if judged necessary by their usual clinical team. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Feb 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 410
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Worldwide total number of subjects |
410
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
410
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were recruited through primary care (search and mail-out or opportunistic recruitment), secondary care (opportunistic recruitment), and by advertising in the community and on social media. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Baseline assessments were conducted in secondary care clinics to ensure standard clinical assessments because the IGA for acne was an inclusion criterion and an important secondary outcome. Baseline appointments also included a pregnancy test, blood test (to exclude renal impairment or raised serum potassium), participant photo. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | ||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Participants, recruiting staff, and investigators were masked to treatment allocation until participants were unmasked at 24 weeks.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Spironolactone | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Intervention arm - 50 mg spironolactone one tablet daily for the first six weeks and then two tablets daily (totalling 100 mg at (or after) six weeks, providing the participant was tolerating side effects. Treatment continued for 24 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Spironolactone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
50 mg spironolactone (one tablet daily) for the first six weeks and then two tablets daily (totalling 100 mg) at (or after) six weeks, providing
the participant was tolerating side effects. Treatment continued for 24 weeks
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Matched placebo (one tablet daily) for the first six weeks and then two tablets daily. Treatment continued for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
One tablet daily for the first six weeks and then two tablets daily. Treatment continued for 24 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Intervention arm - 50 mg spironolactone one tablet daily for the first six weeks and then two tablets daily (totalling 100 mg at (or after) six weeks, providing the participant was tolerating side effects. Treatment continued for 24 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matched placebo (one tablet daily) for the first six weeks and then two tablets daily. Treatment continued for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Spironolactone
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Reporting group description |
Intervention arm - 50 mg spironolactone one tablet daily for the first six weeks and then two tablets daily (totalling 100 mg at (or after) six weeks, providing the participant was tolerating side effects. Treatment continued for 24 weeks | ||
Reporting group title |
Placebo
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Reporting group description |
Matched placebo (one tablet daily) for the first six weeks and then two tablets daily. Treatment continued for 24 weeks. | ||
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End point title |
Acne-QoL symptom subscale score at 6 weeks [1] | ||||||||||||
End point description |
The primary outcome was comparison of the mean Acne-QoL symptom subscale score between groups, adjusted for baseline variables. The Acne-QoL contains 19 questions with seven response categories, each referring to the past week, reported
in four domains (self-perception, role-social, role-emotional, and acne symptoms): each subscale has a range of 0-30, in which higher scores reflect improved quality of life.
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End point type |
Primary
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End point timeframe |
6 weeks
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Week 6 data are not presented as participants were not yet on full dose of spironolactone. |
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| Notes [2] - Participants who did not finish the treatment or had a missing data excluded from the analyses [3] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Acne-QoL symptom subscale score at 12 weeks | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
12 weeks
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| Notes [4] - Participants who did not finish the treatment or had a missing data excluded from the analyses [5] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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Statistical analysis title |
Mean differences Adjusted | ||||||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
342
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Adjusted Mean differences | ||||||||||||
Point estimate |
1.27
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.07 | ||||||||||||
upper limit |
2.46 | ||||||||||||
Statistical analysis title |
Mean differences Unadjusted | ||||||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
342
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Unadjusted mean difference | ||||||||||||
Point estimate |
1.48
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.3 | ||||||||||||
upper limit |
2.67 | ||||||||||||
Statistical analysis title |
Mean differences Adjusted (100 imputations) | ||||||||||||
Statistical analysis description |
100 imputations - Adjusted for stratification factors (site and baseline severity (IGA <3 versus 3 or more)), baseline Acne-QoL symptom subscale score, topical treatment use (yes/no to using any topical treatment), hormonal treatment, age, and polycystic ovary syndrome status.
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
342
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
1.26
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.04 | ||||||||||||
upper limit |
2.48 | ||||||||||||
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End point title |
Acne-QoL symptom subscale score at 24 weeks | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
24 weeks
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| Notes [6] - Participants who did not finish the treatment or had a missing data excluded from the analyses [7] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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Statistical analysis title |
Mean differences Adjusted | ||||||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
299
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Adjusted mean differences | ||||||||||||
Point estimate |
3.45
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.16 | ||||||||||||
upper limit |
4.75 | ||||||||||||
Statistical analysis title |
Mean differences Unadjusted | ||||||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
299
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Unadjusted mean difference | ||||||||||||
Point estimate |
3.77
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.5 | ||||||||||||
upper limit |
5.03 | ||||||||||||
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End point title |
Acne-QoL symptom subscale score at 52 weeks [8] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
52 weeks
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Week 52 data not presented as participants were unmasked at 24 weeks and both groups could seek any treatments after that point, including spironolactone. |
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| Notes [9] - Participants who did not finish the treatment or had a missing data excluded from the analyses [10] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Self-assessed overall improvement score of 3-6 at 12 weeeks | |||||||||
End point description |
Data are number of participants/total number (percentage)
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End point type |
Secondary
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End point timeframe |
12 weeks
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| Notes [11] - Participants who did not finish the treatment or had a missing data excluded from the analyses [12] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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Statistical analysis title |
Unadjusted odds ratio at 12 weeks | |||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
328
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.23
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.76 | |||||||||
upper limit |
1.96 | |||||||||
Statistical analysis title |
Adjusted* odds ratio at 12 weeks | |||||||||
Statistical analysis description |
*Adjusted for stratification factors (site and baseline severity (IGA <3 versus 3 or more)), baseline Acne-QoL symptom subscale score, topical treatment use (yes/no to using any topical treatment), hormonal treatment, age, and polycystic ovary syndrome status.
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
328
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.16
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.7 | |||||||||
upper limit |
1.91 | |||||||||
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End point title |
Self-assessed overall improvement score of 3-6 at 24 weeks | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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| Notes [13] - Participants who did not finish the treatment or had a missing data excluded from the analyses [14] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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Statistical analysis title |
Unadjusted odds ratio at 24 weeks | |||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
288
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
2.62
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.53 | |||||||||
upper limit |
4.5 | |||||||||
Statistical analysis title |
Adjusted* odds ratio at 24 weeks | |||||||||
Statistical analysis description |
*Adjusted for stratification factors (site and baseline severity (IGA <3 versus 3 or more)), baseline Acne-QoL symptom subscale score, topical treatment use (yes/no to using any topical treatment), hormonal treatment, age, and polycystic ovary syndrome status
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
288
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
2.72
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.5 | |||||||||
upper limit |
4.93 | |||||||||
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End point title |
Satisfaction with trial treatment, score 3-5 at 24 weeks | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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| Notes [15] - Participants who did not finish the treatment or had a missing data excluded from the analyses [16] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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Statistical analysis title |
Unadjusted odds ratio at 24 weeks | |||||||||
Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
266
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
3.18
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.91 | |||||||||
upper limit |
5.27 | |||||||||
Statistical analysis title |
Adjusted odds ratio at 24 weeks | |||||||||
Statistical analysis description |
*Adjusted for stratification factors (site and baseline severity (IGA <3 versus 3 or more)), baseline Acne-QoL symptom subscale score, topical treatment use (yes/no to using any topical treatment), hormonal treatment, age, and polycystic ovary syndrome status.
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Comparison groups |
Spironolactone v Placebo
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Number of subjects included in analysis |
266
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
3.12
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.8 | |||||||||
upper limit |
5.41 | |||||||||
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End point title |
PGA success core at 24 weeks | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 weeks
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| Notes [17] - Participants who did not finish the treatment or had a missing data excluded from the analyses [18] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
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Statistical analysis title |
Unadjusted odds ratio at 24 weeks | |||||||||
Comparison groups |
Spironolactone v Placebo
|
|||||||||
Number of subjects included in analysis |
300
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
||||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
3.93
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
2.09 | |||||||||
upper limit |
7.37 | |||||||||
Statistical analysis title |
Adjusted odds ratio at 24 weeks | |||||||||
Statistical analysis description |
Adjusted for stratification factors (site and baseline severity (IGA <3 versus 3 or more)), baseline Acne-QoL symptom subscale score, topical treatment use (yes/no to using any topical treatment), hormonal treatment, age, and polycystic ovary syndrome status.
|
|||||||||
Comparison groups |
Spironolactone v Placebo
|
|||||||||
Number of subjects included in analysis |
300
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
||||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
3.76
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
1.95 | |||||||||
upper limit |
7.28 | |||||||||
|
||||||||||
End point title |
IGA success score at 12 weeks | |||||||||
End point description |
||||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
12 weeks
|
|||||||||
|
||||||||||
| Notes [19] - Participants who did not finish the treatment or had a missing data excluded from the analyses [20] - Participants who did not finish the treatment or had a missing data excluded from the analyses |
||||||||||
Statistical analysis title |
Unadjusted odds ratio at 12 weeks | |||||||||
Comparison groups |
Spironolactone v Placebo
|
|||||||||
Number of subjects included in analysis |
328
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
||||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
3.78
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
1.73 | |||||||||
upper limit |
8.27 | |||||||||
Statistical analysis title |
Adjusted odds ratio at 12 weeks | |||||||||
Comparison groups |
Placebo v Spironolactone
|
|||||||||
Number of subjects included in analysis |
328
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
||||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
5.18
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
2.18 | |||||||||
upper limit |
12.28 | |||||||||
|
||||||||||
End point title |
PGA success core at 12 weeks | |||||||||
End point description |
||||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
12 weeks
|
|||||||||
|
||||||||||
Statistical analysis title |
Unadjusted odds ratio at 12 weeks | |||||||||
Comparison groups |
Spironolactone v Placebo
|
|||||||||
Number of subjects included in analysis |
342
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
||||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.91
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
1.05 | |||||||||
upper limit |
3.45 | |||||||||
Statistical analysis title |
Adjusted odds ratio at 12 weeks | |||||||||
Comparison groups |
Placebo v Spironolactone
|
|||||||||
Number of subjects included in analysis |
342
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
Method |
||||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.69
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.89 | |||||||||
upper limit |
3.19 | |||||||||
|
|||
|
Adverse events information [1]
|
|||
Timeframe for reporting adverse events |
52 weeks
|
||
Assessment type |
Non-systematic | ||
|
Dictionary used for adverse event reporting
|
|||
Dictionary name |
Acne-QoL symptom sub | ||
Dictionary version |
1
|
||
| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: The adverse reaction does not have SOC terms or seriousness, just symptom and severity information. |
|||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
12 Apr 2019 |
Exclusion of women who have ‘ever taken spironolactone’ due to unknown effect duration of spironolactone
Use of social media advertising campaign as recruitment avenue
|
||
03 Dec 2019 |
Updated social media advertising campaign process
Blood test results clarified as stopping criteria rather than eligibility criteria
Clarification of oral antibiotic use to treat infections unrelated to acne
Addition of two more CRNs as Participant Identification Centres
|
||
15 Jun 2020 |
Addition of hospital Trusts as trial sites and CRNs local to new hospital Trusts
Addition of hospital Trusts as secondary care Participant Identification Centres
GP Invite Card • Summary sheet for mail-out pack
Revised 52-week follow-up documents: protocol, unblinding letter, PIS, ICF, Follow-up questionnaire
|
||
06 Apr 2021 |
Reduction of sample size to 398 participants
Update to pregnancy reporting process wording in protocol
Option of patients to send photos their acne to site team for assessment at follow-up appointments
Updated process in protocol on sharing consent forms and follow-up questionnaires with Southampton CTU to facilitate follow-up during pandemic
|
||
02 Aug 2021 |
Addition of optional qualitative interviews participants taking part in the main trial
Updated existing trial documents with qualitative interview sub-trial information
New trial documents for qualitative interview sub-trial: Qualitative interview PIS, Qualitative interview ICF, Qualitative interview guide and invitation letter. Collection of ethnicity in retrospect using ethnicity group reply slip
|
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/37192767 |
|||
