Clinical Study Protocol Version 2.0 made the following changes: -Corrected discrepancies regarding what procedures could be performed either at day -1 or day 1 (this was correctly assigned in the appendix E Schedule of Study Procedures, but erroneously described in the protocol text sections 7.2 and 7.7). This was for clarification. -Corrected an error in sections 7.1 and 7.2 that erroneously put the hematology and serum chemistry at the baseline visit, rather than at the screening visit. The same error was also in sections 7.7.1 and 7.7.2 for the PK Sub-study. -Simplified Appendix B re. microbiological sampling to not include a description of the processing of the samples. Discussion with the local laboratories, who will perform the sampling revealed that procedures and preferred materials varied slightly from country to country. It was deemed to be preferable to capture these procedures in the laboratory protocols instead of the study protocol, to allow for local variations and thus allow laboratories to use their current standard operating procedures and supplies that they are already trained in using and that have been validated on site.

Clinical Study Protocol Version 3.0 made the following changes: -Changed the process for weighing of returned kits (Sections 6.5 and 7.3-7.7), so weighing to happens at each visit as opposed to all returned kits from one subject being weighed of at the end of study (for that subject). Monitoring the actual dosing of subjects continuously during the study allows the investigators to intervene in cases where subjects are dosing much higher or lower than expected and by doing so hopefully adjust the dosing in order for the study results to reflect ‘normal’ dosing of an ointment. -Added a triplicate set of ECGs to be taken 1 hour after application of IMP at the Day 1 (Section 7.7.2) and Week 2 (Section 7.7.4) visits in addition to the ECGs already planned at those Visits 2, 4, and 12 hours after application. (This change only impacted the PK substudy.) Adding an additional set of ECGs will strengthen the data collected on cardiac safety. Adding a set of ECGs 1 hour after application ensures that in the case that maximum systemic exposure (Cmax) occurs before 2 hours after application, the study will still produce the desired data on cardiac safety at Cmax. -Added a list of Adverse Events of Special Interest (AESIs) in Section 8.1 to require additional and prompt reporting if such AEs arose.

Clinical Study Protocol Version 4.0 made the following changes: -Allowed the use of emollient in lesional areas, if subjects develop dry skin in the areas treated by IMP and if so authorized on a case-by-case basis based on the medical judgment of the investigator (Previously the use of emollient was only allowed in areas around, but not overlapping, the treatable areas.) Feedback has been received from investigators in the study that some patients, while showing improvement of redness, developed skin dryness. Following discussion with the investigators, it was concluded that the use of an emollient on such areas would be beneficial for subject comfort and compliance with study procedures. -Removed collection of full body photo documentation at the Week 2 and 4 visits (was still collected at Day -1/1 [baseline] and Week 6 [end-of-treatment] visits). The image procedure is challenging and takes a lot of time for both subjects and study staff. Therefore it was decided to limit the photo requirements to the 2 timepoints most important for efficacy assessment, baseline and end-of-treatment. -Clarification added that IP application is not performed during Week 6 visit.

Clinical Study Protocol Version 5.0 made the following changes: -Changed the estimated date for the completion of the last subject from June 2020 to November 2020. Recruitment of new subjects was not possible during the months where societies have been closed down due to COVID-19. -Added interim analysis based on the 89/210 subjects that have been randomized and completed or dropped-out of the study by end-of-May. Due to COVID-19 restrictions making recruitment and visit attendance difficult, it was decided to assess an early stop of the study, either for futility or efficacy. -Removed an erroneous statement specifying that the trough level PK sample at the Week 6 visit should be collected “prior to morning or evening application.” -Clarification added to Appendix C Assessment Measurements (Local Tolerability Score) that Severe Irritation should also be reported as adverse event. By mistake severe irritation was not marked as requiring reporting as adverse event.