Randomized Double-blind Study on the Benefit of Spironolactone for Treating Acne of Adult Woman.

Study Overview
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Brief Summary
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Acne vulgaris of adult woman has increased over the past 10 years; it affects currently 20% to 30% of adult women. The physiopathology of adult woman acne is distinguished from the teenager one by essentially 2 factors: hormonal factor with a peripheral hyperandrogenism coupled with an hypersensibility of cutaneous androgens receptors of these women. But this point is still at the stage of hypothesis. inflammatory factor linked with Propionibacterium Aces ; indeed these women received most of the time many cures of local and systematic antibiotics at the origin of resistant Propionibacterium Aces strains which lead to a chronical activation of cutaneous innate immunity. On a therapeutic plan, four types of systemic treatment, approved in this indication are: Tetracyclines which are problematic for the bacterial resistance and consequently constant relapse when they are stopped. Zinc salts which target only the inflammatory lesions and were shown less effective than cycline Antiandrogens, with acetate of cyproterone associated with risks of phlebitis and pulmonary embolism, and increase risk of triglycerides, cholesterol and hepatic balance. The last alternative is represented by isotretinoin but the use in women of childbearing potential is binding because of the teratogen risks and the hyperandrogenism represents an identified risk of relapse. In this context, the spironolactone could represent an interesting alternative. It blocks the 5-alpha-reductase receptors at sebaceous gland and inhibits Luteinizing hormone (LH) production at the pituitary level. It is not submitted to isotretinoin constraints, does not lead to bacterial resistance and targets the peripheral hyperandrogenism. Currently, very few studies have been performed and on a weak number of patients but they showed that at low doses (lower than 200mg/day), spironolactone can be effective against acne. In that context, it seemed clearly interesting to perform the first double-blind randomized study spironolactone vs cyclines which remains the moderate acne reference treatment and to demonstrate the superiority of spironolactone's efficacy in order to establish it as alternative way to cycline.

Official Title
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Randomized Double-blind Study on the Benefit of Spironolactone for Treating Acne of Adult Woman.

Conditions
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Acne Vulgaris

Intervention / Treatment
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* Drug: spironolactone
* Drug: Doxycycline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with acne, with at least 10 inflammatory lesions and no more than 3 nodules Patient who already had one cycline course for her acne treatment with a 3 months* wash out or who never had any cycline Patient having signed an informed consent Absence of use of oral antibiotics and Zinc salts in the last 30 days Absence of use of systemic isotretinoin and antiandrogens in the last 6 months Absence of microphysiotherapy in the last 15 da Women of child-bearing age under contraception since 3 months (oral contraception, implant or IUD). Patients with social security Exclusion Criteria: Patient affected by active /progressive diseases, as infections including Hidradenitis suppurativa, cancers, or endocrine syndrome (eg polycystic ovary syndrome), Addison's disease) Patient affected by Rosacea Patient with contra-indication to the use of one of the investigational products or auxiliary : Patient with intolerance or hypersensitivity to cyclin's, spironolactone or to any ingredient present in associated benzoyl peroxide gel Patient with significant impairment of renal excretory function, acute or chronic renal failure, anuria. Patient with life-threatening or very severe hepatic impairment.(grade III or IV) Patient with hyperkalaemia or strongly requiring potassium-sparing diuretics (eg amiloride, canrenoate, eplerenone, triamterene), or treated continuously with Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II antagonist, NSAIDs, heparin and molecular weight heparin, ciclosporin and tacrolimus. Patient requiring topical isotretinoin or who stopped this drug since less than 2 weeks Patient previously treated with spironolactone Pregnant woman or likely to become pregnant or nursing and refusing to use an effective contraceptive method Patient participating in another interventional clinical trial Patient under guardianship or trusteeship

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: spironolactone<br>Spironolactone ARROW ® 75 mg, 150mg, orally, once a day during all the trial (12 months: 6 months on double-blinded spironolactone then 6 months on open-label spironolactone), + topical therapy during all the trial (benzoyl peroxide 5%) | Drug: spironolactone<br>* Dispensation of spironolactone at each visit according to the arm description described above.<br>|
| Active Comparator: doxycycline<br>(Doxycycline Sandoz 100 mg), 100mg/day during 3 months followed by placebo during 3 months, on double-blinded + topical therapy during all the trial (benzoyl peroxide 5% | Drug: Doxycycline<br>* Dispensation of doxycycline then placebo, at each visit according to the arm description described above.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy | The treatment's efficacy will be determined by the rate of success in each arm. The best rate of success between Month 4 and Month 6 will be chosen for the final result. Rate of success, defined by a decrease of both Adult Female Acne Scoring Tool (AFAST) scores 1 and 2: AFAST score 1: decrease of at least 2 grades compared to baseline or to grade 0 if the baseline was at 1 and AFAST score 2: decrease to grade 1 if baseline was > 1 or to grade 0 if the baseline was at 1 AFAST 1 (also called GEA) assesses the comedones (open and closed), the non-inflammatory lesions, the papules and pustules and the nodules. The stage is defined according to a global evaluation of severity of acne and ranges from Grade 0 (no acne) to Grade 5 (the worse situation). AFAST 2 assesses acne on an area from the left and right mandibular zone to the upper edge of the trunk and ranges from Grade 0 (no acne) to Grade 3 (the worse situation). | Month 4 and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical adverse events | Number and type of Adverse Events (AE) and Serious Adverse Events (SAE) occurring from the beginning of the treatment until end of the follow-up | Within 12 months after randomization | 
| Sodium abnormal values (biological adverse events) | Sodium measurement (mmol/L) | From 30 days to 7 days before randomization visit, Month 2, Month 4, Month 9 | 
| Potassium abnormal values (biological adverse events) | potassium measurement (mmol/L) | From 30 days to 7 days before randomization visit, Month 2, Month 4, Month 9 | 
| Chlore abnormal values (biological adverse events) | Chlore measurement (mmol/L) | From 30 days to 7 days before randomization visit, Month 2, Month 4, Month 9 | 
| Calcium abnormal values (biological adverse events) | Calcium measurement (mmol/L) | From 30 days to 7 days before randomization visit, Month 2, Month 4, Month 9 | 
| AFAST score 1 (GEA) at 0 or 1 | Number of patients with AFAST score 1 (GEA) at 0 or 1. | Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| AFAST score 2 (Mandibular) at 0 or 1 | Number of patients with AFAST score 2 (Mandibular) at 0 or 1. | Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| AFAST score 1 associated with AFAST score 2 at 0 or 1 | Number of patients with both AFAST score 1 and AFAST score 2 at 0 or 1. | M2, M4, M6, M9 and M12 | 
| Quality of life (cost-utility assessment and general quality of life assessment) | EQ-5D (EuroQol 5 dimensions) questionnaire: The questionnaire focuses on five dimensions: mobility, personal autonomy, current activities, pain/discomfort, and anxiety/depression. For each of these dimensions, three answers are possible. | Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| Quality of life (specific to acne) | Cardiff Acne disability Index (CADI) is a disease-specific questionnaire measuring disability induced by acne. | Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| Bacterial and parasital evaluations | Presence of P acnes, M Furfur and S epidermidis, aureus | Day 0 (baseline) and Month 4 | 
| Inflammatory lesions of the face | Number of inflammatory lesions of the face | Day 0 (baseline), Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| retentional lesions of the face | Number of retentional lesions of the face | Day 0 (baseline), Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| Face lesions | Total number of face lesions | Day 0 (baseline), Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| Trunk lesions | Factor F2 of ECLA scale ECLA (Echelle de Cotation des Lésions d'Acné) is a scale for acne proposed by the dermatology research team of Nantes University Hospital. It is composed of 3 factors: Factor 1 (F1) counts the acne lesions on the face; Factor 2 (F2) counts the lesions acne on the trunk and Factor 3 (F3) counts the scars. In this study, the factor F2 will be used. The factor F2 assesses the extensive character of acne lesions on 5 defined areas: cervical areas (F2N); chest areas (F2C); back area (F2B) and arm area (F2A) according to a qualitative scale 0=absent, 1=poor 2=medium 3=significant. It is completed by the count of the present nodules in each area. | Day 0 (baseline), Month 2, Month 4, Month 6, Month 9 and Month 12 | 
| Relapse | number of patients with relapse, defined as follows : AFAST score 1 (GEA score): increase of 2 points versus score of previous visit, in case of success Or AFAST score 2 (mandibular score): increase of 1 point versus score of previous visit, in case of success | Month 4 and Month 6 | 
| Reappearance of 10% and more of inflammatory lesions. | Number of patients with a reappearance of 10% and more of inflammatory lesions. | Month 6 | 
| Incremental cost-effectiveness ratio (cost per Quality-Adjusted Life-Year, QALY) of the comparison between the spironolactone and cycline. | costs: resources consumed, QALY: EQ-5D | Month 6 |