Study setting {9}
Patients will be recruited by the dermatology departments of several French reference centres, including study centres in western France belonging to IDGO – Dermatological Institute of the Western Region, supported by GIRCI GO. The investigation centres are the dermatological departments of the university hospitals of Nantes, Brest, Le Mans, Grenoble and Tours, the regional hospital of La Rochelle and a private dermatologist of Tours.
Eligibility criteria {10}
It is commonly admitted that acne affecting female patients under 20 is considered to be "adolescent female acne". Since this protocol concerns adult female acne, the recruited patients will be women aged at least 20 years. These patients will have acne vulgaris with at least ten inflammatory lesions and no more than three nodules. The eligibility criteria are shown in Table 1
Who will take informed consent {26a}
Before proceeding with any examination related to the research, the investigator will obtain the patient’s freely given FASCE informed consent, in writing.
Model consent form and other related documentation given to participants and authorized surrogates {32}
The Supplementary Material file contains the French informed consent form that the patient signs prior to their inclusion in the trial (version 2, updated 1 July, 2017)
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Biological samples for bacterial strain identification will be collected and stored if the patient has signed the biocollection informed consent. In this informed consent form it is noted that the samples may be used for other scientific research. This biocollection and consent procedure has been registered under number DC-2011-1399 by the French Ethics Committee: CPP Ouest IV.
Interventions
Explanation for the choice of comparators {6b}
As already stated, although acne is not an infectious disease, oral antibiotics have remained a mainstay of treatment over the last 40 years. The anti-inflammatory properties of oral antibiotics, particularly cyclines, are effective in treating inflammatory acne [39,40]
All the guidelines – French[41], European[42] and American[43] – recommend cycline for first treatment but limited to a treatment period of three months to minimize the development of bacterial resistance. This is why the treatment duration of the comparator arm we chose is doxycycline 100 mg/day for three months. The guidelines specify also that monotherapy with a systemic antibiotic is not recommended. Concomitant topical therapy with, for example, benzoyl peroxide should be used with systemic antibiotics and for maintenance after completion of systemic antibiotic therapy. In the two arms, patients will receive this topical therapy.
The primary objective is efficacy of doxycycline or spironolactone seen at M4 and/or M6. To avoid results bias and because our experience shows that maximum efficacy is seen for cycline between M4 and M6, the best clinical response between M4 and M6 will be chosen for the primary endpoint.
After only three months of treatment, the response of acne to spironolactone may not be optimal [22]. A retrospective trial made by Burcke and Cunliffe observed an average reduction of acne that was optimal at month 6 [24].
In conclusion, in order not to bias the study in either direction, regarding the primary objective, the efficacy of the two treatments will be measured at four and six months in each arm and the best results of the two arms will be compared (Figure 1). At the end of the M6 visit, after the clinical evaluation, the unblinding data will be broken down. Patients with complete or partial remission will continue the trial. Other patients will drop out of the trial and be treated by the investigators according to their usual practice. The same will be done at M9 visit: avoided patients will drop out of the trial and will be treated by the investigators according to their usual practice.
Intervention description {11a}
Being double-blind the study’s treatment, the comparator and its placebo will be managed by the pharmacist of the coordinating centre, CHU Nantes. The oral dose of 150 mg of spironolactone, once a day during the complete trial period has been chosen as a result of the literature and our experience. Pills will be dispensed at each protocol visit (i.e. every two months for twelve months). The efficacy of spironolactone has been established by several studies which showed improvement, with lesion reductions ranging from 50 to 100 percent in women treated for acne [44]. In most of these studies, the dosage range used was 100 to 200 mg daily, with response noted over approximately three months [44].
For the comparator, as recommended by the French Guidelines for acne treatment [41], the doxycycline treatment for acne vulgaris will be 100 mg for three months, administered once a day. From M4 to M6, a placebo will be administered to the patient Pills will be dispensed at each protocol visit (i.e. every two months for six months). The two treatments will be taken orally. As the antibiotics must be taken during a meal, and to retain the double-blind effect of our trial, the patients of the two arms should take their treatment during a meal. The treatment should be taken with a full glass of water and the patient should remain in the upright position for at least one hour.
Monotherapy with a systemic antibiotic is not recommended [43]. Concomitant topical therapy with, for example, benzoyl peroxide 5% should be used with systemic antibiotics and for maintenance after completion of systemic antibiotic therapy. In the two arms, patients will have this topical therapy.
The treatment continues after M6, which is the main objective to meet the secondary objectives. However, from Visit M6, in case of failure, the treatment will be stopped, the patient will be withdrawn from the study and the investigator will prescribe another treatment according to usual practice. In case of success, the patient in the spironolactone arm will continue with this treatment "open", and the patient in the doxycycline arm will continue to participate only with the topical therapy. The schedule of the complete trial is shown in Figure 2.
Criteria for discontinuing or modifying allocated interventions {11b}
No dosage adjustment is required by the protocol. However, in case of hyperkalemia, the treatment by spironolactone will be adjusted. The patient must stop using the product and seek emergency medical attention immediately if she develops signs and symptoms of a serious hypersensitivity reaction such as throat tightness, difficulty breathing, feeling faint, or swelling of the eyes, face, lips, or tongue. Also she must stop using the product if she develops hives or itching of the face or body.
Strategies to improve adherence to interventions {11c}
FASCE will assess compliance using the return tablet count. At M2, M4, M6, M9 and M12 visits, the patient will return the empty study drug packages and the investigator or a member of their team will count them.
Relevant concomitant care permitted or prohibited during the trial {11d}
Due to spironolactone, anything that can induce hyperkalemia is forbidden: potassium-sparing diuretics, potassium supplements and drugs such as ACE inhibitors, angiotensin II antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparin and low molecular weight heparin, ciclosporin, tacrolimus and trimethoprim. Lithium is also not recommended in this trial. Concurrent use of lithium and spironolactone may result in increased lithium concentrations and lithium toxicity due to decreased lithium excretion. So, the monitoring of lithium plasmatic concentration will be reinforced.
Provisions for post-trial care {30}
At the end of the clinical research, the patient will be followed by her dermatologist and will benefit from the usual care of her disease. The sponsor will take out an insurance policy covering the financial consequences of its civil liability in compliance with the regulations.
Outcomes {12}
The primary endpoint corresponding to the treatment’s efficacy is determined by the probability of success in each arm. In order to reduce the variability related to the fluctuation over time of the therapeutic response, we took the maximum value of this response. This maximum value appears between the 4th and 6th month of treatment. We could also have taken the average measured over two months, but clinically this is not interesting because the optimal time of efficacy is different between the two treatments This probability of success (or relapse) is defined by a decrease of both AFAST scores: 1) AFAST score 1 (corresponding to GEA score): decrease of at least two grades compared to baseline or to grade 0 if the baseline was at 1, and 2) AFAST score 2 (mandibular score): decrease to grade 1 if baseline was > 1 or to grade 0 if the baseline was at 1.
AFAST score 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 worst situation). AFAST score 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 worst situation).
For the secondary endpoints:
- Safety/tolerance: Reporting of the number and type of Adverse Events (AE) and Serious Adverse Events (SAE) up to month 12 of follow-up and abnormal values of ionogram (sodium, potassium, Chlorine and calcium) at 0, 2, 4 and 9 months. First the percentage of AEs and SAEs will be calculated then classified according to the organ affected.
- Efficacy: These outcomes correspond to the reporting of the:
- Number of patients with AFAST score 1 (GEA) at 0 or 1, at M2, M4, M6, M9 and M12
- Number of patients with AFAST score 2 (Mandibular) at 0 or 1, at M2, M4, M6, M9 and M12
- Number of patients with both AFAST scores 1 and 2 at 0 or 1, at M2, M4, M6, M9 and M12
- Number of inflammatory lesions of the face at D0 (baseline), M2, M4, M6, M9 and M12
- Number of retentional lesions of the face at D0 (baseline), M2, M4, M6, M9 and M12
- Number of face lesions at D0 (baseline), M2, M4, M6, M9 and M12
- Number of trunk lesions (Factor F2 of ECLA) at D0 (baseline), M2, M4, M6, M9 and M12
- Number of patients with relapses at M4 and M6.
The definition of relapse is the same as the primary endpoint:
1°) AFAST score 1 (GEA score): increase of 2 points over score of previous visit, in case of success
Or 2°) AFAST score 2 (mandibular score): increase of 1 point over score of previous visit, in case of success
- Number of patients with a reappearance of 10% and more of inflammatory lesions at M6
For these nine outcomes, percentages will be calculated at each time point.
- Quality of life: Reporting of the scores of 2 QoL questionnaires: EQ-5D and the CADI index of quality of life in acne at M2, M4, M6, M9 and M12. This outcome will be measured by the percentage of patients whose quality of life has improved relative to baseline.
- Microflora: Bacterial and parasitic sampling at D0 and M4. The presence of P. acnes, M. Furfur and epidermidis/ aureus will be sought and a change in these populations from baseline will be measured at M4. A percentage of decrease will be given.
- Medico-economy: Incremental cost-effectiveness ratio (cost per Quality-Adjusted Life Year, QALY) of the comparison between spironolactone and cycline at 6 months. Criteria for the calculation of the cost-effectiveness ratio are detailed in the Methods for Additional Analyses paragraph.
Participant timeline {13}
The maximum duration of treatment per patient is 12 months, and the recruitment period is 41 months.
Sample size {14}
For sample size estimation purposes, the targeted difference in the percentage of success is 70% in the experimental arm compared with 50% success in the control arm, indicating a relative increase of success equal to 40%. Assuming a Type I error rate of 5% and at least 80% statistical power, the sample size required is at least 91 subjects per group. To take into account the possibility of those lost to follow-up, 10% (9 subjects) will be added to each group. Finally, approximately 200 subjects will be randomized to the two arms in a 1:1 ratio.
Recruitment {15}
Acne vulgaris is a common pathology. However, it is a pathology that is more common in the private sector than in public hospitals. Some centres such as Nantes have a one-day consultation devoted to acne. A feasibility study performed in each centre showed that between 8 and 15 patients per centre could be included per year, making these recruitment targets achievable.
Assignment of interventions: allocation
Sequence generation {16a} and Concealment mechanisms {16b}
This balanced block randomization is computer-generated. Subjects are randomized into blocks as the allocation progresses, a block being a subgroup of predetermined size within which there is a random allocation of patients. The software used for the randomization is SAS version 9.4. The randomization will be centralized and stratified based on the following four groups of contraception:
Strata 1: Implant, generation I and II OCs, progesterone intrauterine device or other kind of hormonal contraception (vaginal ring, patch, injection…)
Strata 2: Copper intrauterine device (IUD) (hormone-free contraception)
Strata 3: Generation III and IV OCs
Strata 4: No contraception (sterilization surgery or menopause)
Implementation {16c}
The randomization key is known only to the biostatistician and data managers, to make it impossible for the investigator to assign a specific treatment. At the randomization visit (Day0) the investigator, after checking the inclusion and non-inclusion criteria, will validate the randomization on the eCRF. Drug prescriptions for two months will be made out (blindspironolactone/doxycycline). In addition, a concomitant topical therapy, benzoyl peroxide 5%, will be given.
Assignment of interventions in a double-blind method
Who will be blinded {17a}
Our study is a randomized double-blind trial during the first six months (timeline for the primary objective), and open during the last six months of follow-up. The female patients will be randomized either in the acne routine care arm, i.e. cycline (Doxycycline 100 mg/day for three months followed by a placebo for three months) or in the experimental drug arm (Spironolactone 150 mg/day for twelve months).
Only the patients and the investigators and their teams will be blind and will not know the treatment assigned during the first six months. As Karanicolas et al. pointed out in their article from 2010, their study should have been masked to the biostatisticians until analyses had been performed, to reduce the study bias [45]
Blinding will be removed for all patients after 6 months’ evaluation – once the primary endpoint has been measured – whatever the result, to limit the constraints for the patients in the doxycycline arm. If blinding were maintained, patients in the doxycycline arm would have to take a placebo for up to six months in addition to the three months already taken. The objective of the last six months’ follow-up is to assess the maintenance of each treatment's efficacy during this time.
Procedure for unblinding if needed {17b}
If unblinding, due to emergencies, is deemed to be necessary, the investigator should inform the sponsor. The unblinding will be done via the eCRF thanks to a detailed procedure which will be given to each site. Each decoding will be tracked and classified in the investigator’s management file and the trial management file.
Data collection and management
Plans for the assessment and collection of outcomes – description of the parameters for evaluating efficacy {18a}
The first endpoint is the new validated score for adult female acne: AFAST [36]. AFAST (for Adult Female Acne Scoring Tool) uses two independent scores: Score 1 corresponding to GEA grading for acne on the face [34] and Score 2 corresponding to the evaluation of the mandibular region. Scores are not added together. For each patient, AFAST score 1 (GEA) and AFAST score 2 should be assessed by the same evaluator at each visit.
The other score we will use is ECLA. The ECLA evaluation chart of acne has been identified by six dermatologists (in private and hospital practice) [35]. It is composed of three factors: Factor 1 (F1) counts the acne lesions on the face; Factor 2 (F2) counts the acne lesions on the trunk and Factor 3 (F3) counts the scars. In this study, only factor F2 will be used. Factor F2 assesses the extensive character of acne lesions in five defined areas: cervical area (F2N), chest area (F2C), back area (F2B) and arm area (F2A) according to a qualitative scale where 0=absent, 1=poor 2=medium, 3=significant. It is completed by counting the nodules present in each area.
With regard to the study questionnaires, we will use EQ-5D and the Cardiff Acne Disability Index (CADI). The EQ-5D questionnaire, validated in France [46], will be given to the patient at each visit to measure their quality of life. The EQ-5D consists of a questionnaire and a visual analogue scale. 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 (EQ-5D-3L), thus allowing for 243 health states. The Cardiff Acne disability Index (CADI) is a disease-specific questionnaire measuring disability induced by acne[47]. It is a well-known acne disability measure and has been used in some studies to assess the burden of living with acne on a patient’s experience of disability [48,49]. The questionnaire was developed as a multidimensional measure related to the impact of acne [50]. It is a 5-item scale: questions 1 and 2 address the psychological and social consequences of acne in general; question 3 is targeted at those with acne of the chest or back; question 4 enquires about the patient’s psychological state; and question 5 asks for the patient’s (subjective) assessment of their current acne severity. The response to each question is scored from 0 to 3. CADI is validated by our team in French [51].
Bacterial and parasitic samples will be collected from the nodulocystic and pustular skin of the included patients at D0 and M4, using an Eswab to be delivered in an AMIES transport environment (1 ml). The analysis will be centralized at Nantes University hospital and performed by Dr Stéphane Corvec.
Plan to promote participant retention and complete {18b}
At the randomization visit, the patient will be given a diary to note their health resource consumption, medical compliance, concomitant treatments and AEs. The visits will be arranged every two months up to M6, where the main objective is set. At each visit, empty blisters will be collected and counted. At each visit, the drugs prescribed will be for two months (blind spironolactone/doxycycline and a placebo plus concomitant topical therapy). At visit M2 (two months after randomization), the physician or a member of their team will have to be vigilant and tell the patient to carefully follow the chronological order of treatments. Two envelopes will be given to the patient, one for M3 (blind spironolactone or doxycycline) and one for M4 (blind spironolactone or a placebo in place of doxycycline). As already mentioned above, the guidelines stipulate that the treatment with doxycycline should not exceed three months. For this reason, the doxycycline arm patients will be given a placebo during month 4 and the following months [41–43].
Data management {19}
An electronic Case Report Form (eCRF) will be drawn up for each subject. The identification of the subject will be performed using the first letter of the family name, the first letter of the first name, the centre number and the inclusion number, supplemented by the month and year of birth. This code should be the only information featuring in the eCRF, enabling a retrospective link with the patient.
The investigator will also encode the patient data on any documents that may be in their possession (imaging, biology test reports, etc.) and attached to the eCRF. At the end of the study, database reconciliation will be carried out between the CRF database and safety database. This reconciliation will be performed before database locking. Similarly, an annual reconciliation will be carried out when updating the Annual Safety Report (ASR).
Confidentiality {27}
Each patient's medical data will only be provided to the sponsor or any person duly authorized by the sponsor and, where applicable, to authorized health authorities, under conditions of confidentiality. The sponsor and the supervisory authorities may request direct access to medical records for the purposes of verification of the procedures and/or data in respect of the clinical trial, within the limits authorized by legislation and regulations. The data compiled during the trial may be processed electronically in compliance with CNIL (the French Data Protection Agency) requirements. CNIL is an independent French administrative regulatory body whose mission is to ensure that data privacy legislation is applied to the collection, storage, and use of personal data.
Plans for the collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
At the end of the study, biological samples resulting from sampling (bacterial strains) will be kept in anticipation of further scientific benefit, but naturally the subject's written consent should be collected. The samples will be stored in the biocollection under the responsibility of Pr. Dréno. This biocollection and its consent procedure have been registered under number DC-2011-1399 by the French Ethics Committee: CPP Ouest IV.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The primary efficacy variable is the percentage of success defined in paragraph 2.1.2. The comparison between the two arms will be done using a Cochran–Mantel–Haenszel test checking for class of contraception (four strata). The modified ITT will be applied. That implies that to maintain the initial statistical power of the ITTm analysis, all randomized patients will be included in the final analysis, minus those who did not reach the inclusion criteria after randomization and those who never began their treatment.
All secondary objectives are expressed as a percentage or a status at a fixed time of follow-up. General Linear Mixed models will be planned to take into account the repeated measurements collected on the same subject during their follow-up. The Cox model with time dependent covariates can also be used for secondary objectives for which a status is considered. Significance will be set at 5% in a bilateral situation.
For the cost-effectiveness analysis, 95% confidence intervals for differential (between arms) costs and QALYs and for the incremental cost-effectiveness ratio will be estimated using the non-parametric bootstrap estimation procedure.
Interim analyses {21b}
No interim analysis will be performed and no early stopping rule for futility will be proposed.
Methods for additional analyses (e.g. subgroup analyses) {20b}
An economic evaluation taking the form of a cost-effectiveness analysis (CEA) will be conducted to compare the efficiency of spironolactone with cycline treatment. The analysis will be conducted from the societal perspective, which means that costs to hospitals, to the National Health Insurance System and to patients will be considered, over a six-month time horizon, to be consistent with the primary endpoint. The main judgement criterion will be the Incremental Cost-Effectiveness Ratio defined as a Cost per Quality-Adjusted Life Year (QALY) gained. To estimate QALYs, patients will be asked to fill in the EuroQol EQ-5D health-related quality of life questionnaire.
For the estimation of costs, resources consumed will be recorded prospectively in the patient’s diary for a period of six months following the start of the treatment. The main resources to be collected are presented in the following table.
Ambulatory care
|
- Medication
- Ambulatory physician visits
- Dermocosmetic care
|
Unit costs will be estimated using conventional tariffs from the French National Health Insurance System to value ambulatory care consumption. Costs in each arm will be estimated by multiplying the amount of each type of resources consumed by their corresponding unit monetary value. In CEA, the outcomes of an intervention are evaluated in terms of Quality-Adjusted Life Years (QALYs). QALYs are a numerical composite measure that encompasses information about the length of life and the health-related quality of life. They are computed by weighting each year by a corresponding quality of life factor, usually ranging from 0 (death) to 1 (perfect health). Quality of life weights will be obtained by asking patients to answer the EuroQol EQ-5D quality of life questionnaire at the baseline and at two, four, and six months from the baseline. The difference in QALYs between the two arms of the study will be calculated by using an area under the curve analysis, with linear interpolation of utility scores between measurement time points.
EQ-5D will be submitted also at nine and twelve months to evaluate the quality of life up to M12, as a secondary objective, independently from the cost-effective analysis.
The Incremental Cost-Effectiveness Ratio (ICER, see below) comparing the spironolactone and cycline arms will be analyzed via a non-parametric bootstrap approach to produce estimated confidence intervals at 95% over the mean ICER.
ICER = [CostsSpironolactone – CostsCycline] / [QALYsSpironolactone – QALYsCycline]
The cost-effectiveness of spironolactone will be assessed according to a willingness to pay of 50,000 euros. The probability of cost-effectiveness will also be assessed with several willingness to pay thresholds and will be represented in an acceptability curve. A sensitivity analysis will be performed in order to assess the robustness of the ICER result.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
All subjects will receive the assigned study treatment until unacceptable toxicity, death, loss to follow-up, withdrawal of consent, or termination of the study by the sponsor, in accordance with local standards of care. Unacceptable toxicity and death will be considered as failure for the primary criteria analysis. Loss to follow-up, missing data for the primary criteria and early termination of the study by the sponsor will be also considered as failures by the ITTm and not replaced.
Patients who did not reach the inclusion criteria after randomization and those who never began their treatment will be replaced. For the clinical secondary criteria analysis, patients with missing data will be withdrawn. Missing data in cost-effectiveness analysis will be handled according to a multiple imputation method on the ITTm sample. If a patient is released from the study (e.g. in the event of Adverse Reactions (AR) preventing the continuation of the study), her data will not be collected, except for safety data (follow-up of AR or onset of AR associated with the experimental treatment, based on pharmacokinetic data).
Plans to give access to the full protocol, participant-level data and statistical code {31c}
According to French law, the results of the study will be published on the website of the regulatory authority. Data sharing will be between the investigators only. However, the datasets analyzed during the current study will be available from the corresponding author on reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
It has been possible to carry out the protocol and the trial thanks to an Executive Committee which includes a Scientific Committee and a Steering Committee. The Scientific Committee was created and coordinated by Prof. B. Dreno. Its membership comprises a biostatistician and methodologist, the study coordinator, the health economist and the project manager of the clinical investigation centre (CIC1413). The Steering Committee is composed of the members of the Scientific Committee with the addition of the data management team, the study’s nurse who coordinates assistance for patient inclusion in the other centres, and the monitoring Clinical Research Assistant (CRA). The sponsor project manager coordinates this committee and drafts the “FASCE newsletter” which provides, among other things, the latest news on patient inclusion and amendments to the protocol.
Composition of the data monitoring committee, its role and reporting structure {21a}
The Data and Safety Monitoring Committee “DSMC” is an advisory committee responsible for reviewing the safety of a clinical trial for the sponsor and the coordinator of the study. Its members, well-versed in the field of clinical trials (pathology and methodology), are not involved in the study. They are appointed for the duration of the study and undertake to take part in and observe data confidentiality. The members of the DSMC are selected collectively by the coordinator, Prof. B. Dreno and the sponsor. The DSMC is convened at least once a year for safety analysis: the members receive the annual safety report and may be additionally consulted if a SUSAR or SAR involves a specific analytical problem or in the event of any unresolved risk/benefit question arising during the course of the study.
Adverse event reporting and harms {22}
Side effects reported in clinical trials and case series with spironolactone and the management of acne in adult females [22]: (i) The most common side effect in both the clinical trials and case series was menstrual irregularities: 38/264 (14.4%) in the clinical trials and 216/543 (39.8%) in the case series. No side effect apart from menstrual disturbances had an incidence above 5% in the Randomized Clinical Trials or case series. (ii) Uncommon side effects (0.1–1.0%) were postural hypotension, depression, diarrhea, muscle pain, increased appetite, drowsiness, rashes/drug eruptions, chloasma-like skin pigmentation, polydipsia, weakness, edema of the legs, change in libido, and palpitations. No women were reported to have elevated levels of potassium, and a recent multicentre study of 974 women [52] concluded that routine monitoring of serum potassium in healthy women taking spironolactone for acne is not necessary. Some investigators mentioned that certain side effects were considered beneficial: breast enlargement, reduced symptoms of premenstrual syndrome, and less greasy skin and hair. The most frequent adverse reactions to cyclines are photosensitization, gastrointestinal disorders including gastric or esophageal pain, and nausea/vomiting.
Any adverse event, whether expected or unexpected, serious or not, must be collected real-time in the study eCRF. All SAEs, whether expected or unexpected, must be reported immediately (on the day of the investigator becoming aware of the event) to the sponsor through the eCRF. The information mentioned on this form and on attached documents must be complete, accurate, clear (no abbreviations…) and coded. Pregnancy, overdose, misuse, medication errors or potential medication errors, and quality defects should be notified by the investigator to the sponsor even if there is no associated adverse reaction.
Frequency of and plans for trial conduct auditing {23}
An inspection or audit may take place as part of this study, performed by the sponsor and/or by the regulatory authorities. Inspectors will check the documents, logistics, records and any other resources that the authorities consider to be associated with the clinical trial and that may be located at the trial site itself.
Plans for seeking research ethics committee/institutional review board (REC/IRB) approval {24}
This clinical study was submitted to and approved by the southwest Ethical Review Board (Comité de Protection des Personnes Sud-Ouest et Outre-mer III) on 3 October, 2017.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
The amended protocol should be a dated, updated version. If necessary, the information form and consent form should be amended. The updated protocol is at version 8 on 26 November, 2019. All the submissions/declarations were made by the Sponsor Department at CHU Nantes to the French Regulatory Authority (ANSM) and the southwest Ethical Review Board (Comité de Protection des Personnes Sud-Ouest et Outre-mer III).
Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators {29}
The investigators will share the entirety of the final trial dataset.
Disseminations plans {31a}
The trial results will be published in international dermatological, medical and scientific journals and presented at national and international conferences.
Authorship eligibility guidelines and any intended use of professional writers {31b}
The investigators will follow the rules and guidelines of the International Committee for Medical Journal Editors (ICMJE) [53]. In practice, the Scientific Committee will be among the authors of the publication, as will the investigators who have included the most patients in the trial. The trial sponsor and the French Ministry of Health, which provided the grant, must be cited in the publication.