The main purpose of this amendment was to define study population used for primary, secondary and exploratory statistical analyses.

The main purpose of this amendment was to align the clinical outcome assessments (COAs) with the comments from the Dutch Ethics Committee (Beoordeling Ethiek Biomedisch Onderzoek) following the review of the initial Clinical Trial Application. Acne-QoL was removed from the COAs. The preliminary assessment for futility at the planned IA1 was removed, and only preliminary safety and efficacy assessment for potential sample size revision was proposed. This amendment clarified the data privacy rights related to the European Economic Area General Data Protection Regulation (EEA GDPR) in force since 25 May 2018. The withdrawal of informed consent section was aligned with the EEA GDPR, in order to correctly inform the EEA based subjects on their data privacy rights when recruitment started.

The main purpose of this amendment was to integrate FDA comments received after initiation of the study, mainly pertaining to the eligibility criteria and endpoints. In particular, a minimal threshold for facial non-inflammatory lesions (>10 at baseline) was implemented in the inclusion criteria to comply with FDA recommendations.

The main purpose of this amendment was to reduce the sample size of the study in order to limit exposure to the 2 mg BID arm (low dose), while keeping the power to detect efficacy of the 20 mg BID arm (high dose). The planned number of subjects to be enrolled was decreased from 75 to 56 subjects. The randomization ratio 3:1:3 for first 35 patients was extended to 56 patients. In addition, the assessment schedule was revised in order to simplify further the protocol. Visit 102 (Week 1) was removed and the time window for Visit 103 (Week 2) was extended. The number and timing of interim analysis was updated. The wash-out period for systemic retinoids was reduced from 6 months to 3 months prior to baseline. This amendment also included country specific request from Health Authorities in Czech Republic to use highly effective or double barrier methods of contraception in the Czech investigation sites.

The main purpose of this amendment was to implement learnings from an interim analysis (IA) conducted on 32 randomized and treated subject’s data. A higher-than-expected drop-out rate was observed (approximately 28% instead of 20% assumed). Thus, a replacement policy was set up for subjects who discontinued from the study treatment before completion of Week 12 assessments in order to ensure a sufficient number of evaluable subjects at Week 12 at time of final analysis. The results from IA were encouraging, therefore, the sponsor proposed to drop the central reader as one of the requirements for inclusion as central reader is not a common practice in clinical trials. The central reader would continue to assess pictures collected during the trials but would not constitute a criterion for eligibility anymore. A few additional changes and corrections were done, such as clarification of exclusion criteria, biomarkers and analysis of the primary endpoint. The exclusion criteria #16 was slightly updated, as the data on safety in subjects from interim analysis did not indicate an increased risk in particular for urinary crystals, which could be seen in healthy volunteers due to specific food consumptions. Due to the closure of one site, interested in imaging [and in particular in reflectance confocal microscopy (RCM)], this endpoint was no more conducted. Based on a request from HA, double barrier method of contraception was withdrawn.