- The collection period for sanitary products was extended to cover the entire study. The rationale for this change was based on the fact that the AH method was the only validated method to collect information on menstrual blood loss volume accepted by the FDA. - The statistical sections of the protocol were updated. In order to consider feedback from Authorities and to support label claims on the efficacy endpoints HMB response, time to onset of amenorrhea, and time to onset of controlled bleeding. Time to onset of amenorrhea was elevated to a secondary endpoint and all of these above-mentioned endpoints were included in the hierarchical testing strategy. Description of analyses and missing data considerations were added for these endpoints and the rationale for the study sample size was modified with respect to these changes in the testing strategy. Furthermore, the calculation of the primary efficacy variable was adapted and further efficacy variables were added to ‘other’ efficacy variables.

- Text added describing hepatic safety signal with Esmya (ulipristal acetate), a compound that belongs to the compound group of selective PRMs, and the result of the respective PRAC review procedure including risk minimization measures. - Provided rationale that vilaprisan is structurally different from other selective PRMs. - Description of increased frequency of liver monitoring and its background in subsection “safety monitoring” added. The criterion about abnormal liver parameters was revised. The diagnosis of chronic hepatitis B / C infection was added to exclusion criteria. A description for liver symptom inquiry was included and added to all visits. More detailed instructions for the monitoring of liver parameters and liver disorders and for close observation in cases with increased liver parameters and liver disorders were added.

- Introduction of measures for the temporary pause of the study: due to preliminary findings from 2-year animal carcinogenicity studies, the sponsor decided on 3 DEC 2018 that patients must not start treatment/not start a new treatment course while the preliminary findings from the carcinogenicity studies and their relevance to humans were further investigated.

- Introduction of measures and processes to prepare the study for an orderly closure to allow for thorough evaluation of preclinical and clinical data prior to further decisions on the development of vilaprisan. - Information on carcinogenicity studies with vilaprisan in rodents as well as details regarding the additional safety measures were added, including adrenal monitoring, endometrial monitoring and skin monitoring. - Primary efficacy analysis limited to Treatment Period 1.

- The amendment addresses comments from the FDA regarding details of the safety-follow-up measures introduced in protocol amendment 5, Version 5.0. - Described how subjects were counseled when test results (e.g., hormone, liver, physical examination) were abnormal but still below the thresholds to trigger outside evaluation in the context of the study. In such cases subjects were at least to be counseled about medical follow up according to local practice. - Revised the interval for blood sampling after intake of high doses of biotin from 8 to 72 hours. - Added glycosylated hemoglobin (HbA1c) to the parameters measured for adrenal monitoring also in subjects who had completed or discontinued the study before or during the temporary pause. - Added clarification that all randomized subjects belong to the FAS, excluding randomized subjects who did not start Treatment Period 1 due to the premature closure of the study.