Conditions: Uterine Fibroids
Keywords: Uterine Fibroid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1272
Healthy volunteers: no

Brief summary:
The study was performed to assess the efficacy and safety of Vilaprisan in subjects with uterine fibroids compared to standard of care

Detailed description:

Arms:
arm 1: 2.0 mg treatment of 12 weeks, each separated by 1 bleeding break arm 2: 2.0 mg treatment period of 24 weeks, each separated by 2 bleeding break arm 3: 2.0 mg treatment period of 12 weeks, each separated by 2 bleeding break arm 4: Standard of care as determined by the investigators, this could be watch \& wait or non-hormonal medical treatment

Interventions: intervention 1: Vilaprisan (BAY1002670) intervention 2: Vilaprisan (BAY1002670) intervention 3: Vilaprisan (BAY1002670) intervention 4: Standard of care intervention 5: Vilaprisan (BAY1002670) intervention 6: Vilaprisan (BAY1002670) intervention 7: Vilaprisan (BAY1002670)
Intervention descriptions: intervention 1: 2 mg of Vilaprisan once daily for 12 weeks, 4 treatment periods of 12 weeks, each separated by 1 bleeding episode (3/1 regimen). intervention 2: 2 mg of Vilaprisan once daily for 24 weeks, 2 treatment periods of 24 weeks, each separated by 2 bleeding episodes (6/2 regimen). intervention 3: 2 mg of Vilaprisan once daily for 12 weeks, 4 treatment periods of 12 weeks, each separated by 2 bleeding episodes (3/2 regimen). intervention 4: Standard of care as determined by the investigators (including watch and wait, symptomatic nonhormonal) intervention 5: 2 mg of Vilaprisan once daily for 12 weeks, 8 treatment periods of 12 weeks, each separated by 1 bleeding episode (3/1 regimen) intervention 6: 2 mg of Vilaprisan once daily for 24 weeks, 4 treatment periods of 24 weeks, each separated by 2 bleeding episodes (6/2 regimen) intervention 7: 2 mg of Vilaprisan once daily for 12 weeks, 6 treatment periods of 12 weeks, each separated by 2 bleeding episodes (3/2 regimen)

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
An open-label, parallel-group, randomized, multicenter study to 
assess the safety and efficacy of vilaprisan in subjects with uterine 
fibroids versus standard of care 
NCT Number: 
NCT03194646 
Document Date: 
17 FEB 2020 
 


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Cover page of the integrated protocol
An open-label, parallel-group, randomized, multicenter study to assess the safety and 
efficacy of vilaprisan in subjects with uterine fibroids versus standard of care
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 17 MAR 2017

Amendment 03 (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 13 JUN 2017

Amendment 04 (global amendment described in Section 15.2)
forming integrated protocol Version 3.0, dated 13 SEP 2017

Amendment 06 (global amendment described in Section 15.3)
forming integrated protocol Version 4.0, dated 04 JUL 2018

Amendment 07 (global amendment described in Section 15.4)
forming integrated protocol Version 5.0, dated 20 AUG 2018

Amendment 09 (global amendment described in Section 15.5)
forming global protocol Version 6.0, dated 11 DEC 2018

Amendment 10 (global amendment described in Section 15.6)
forming integrated protocol Version 7.0, dated 21 NOV 2019

Amendment 11 (global amendment described in Section 15.7)
forming integrated protocol Version 8.0, dated 17 FEB 2020
Local amendments not forming part of this integrated global protocol:

Amendment 01 (dated 18 APR 2017)
(local amendment, valid for Japan only)

Amendment 02 (dated 16 MAY 2017)
(local amendment, valid for the United States only)

Amendment 05 (dated 13 SEP 2017)
(local amendment, valid for the South Africa only)

Amendment 08 (dated 30 AUG 2018)
(local amendment, valid for Japan only)


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1.
Title page
An open-label, parallel-group, randomized, multicenter study to assess the safety and 
efficacy of vilaprisan in subjects with uterine fibroids versus standard of care
Short title:  Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids
Acronym:   ASTEROID 6
Test drug:
Vilaprisan (BAY 1002670)
Clinical study phase:
3
Date:
17 FEB 2020
Registration:
EudraCT:  2016-004822-41
Version no.:
8.0
Sponsor’s study no.:
16953
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory:  Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981-0915, 
United States
Sponsor’s medical expert:
Bayer U.S. LLC
100 Bayer Boulevard
Whippany NJ  07981-0915
United States 
Phone no. 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD


PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final integrated clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.
In the protocol document, this page may remain unsigned.


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2.
Synopsis
This section was changed in Amendment 4, see Section 15.2.1
Title
An open-label, parallel-group, randomized, multicenter study to assess the 
safety and efficacy of vilaprisan in subjects with uterine fibroids versus 
standard of care
Short title
Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids
Acronym
ASTEROID 6
Clinical study phase
3
Study objectives
The primary objective of this study is to evaluate the safety of vilaprisan in 
subjects with uterine fibroids in comparison to nonhormonal medical 
treatment in accordance with local standard of care.
The secondary objective of this study is to evaluate the efficacy of 
vilaprisan in subjects with uterine fibroids in comparison to nonhormonal
medical treatment in accordance with local standard of care.
Other objectives of this study are to evaluate the variability in exposure in 
relation to the efficacy and safety for vilaprisan and to collect patient-
reported outcome (PRO) and clinician-reported outcome (ClinRO) data.
Test drug
Not any longer applicable due to the closing of the clinical study. With 
the implementation of Protocol Amendment 10 (version 7.0) and 
aligned with the previous temporary pause measures, no new subjects 
will be recruited and no study medication or standard of care 
symptomatic nonhormonal will be given to the subjects who have been 
enrolled in the study. Originally, the information and instructions 
related to the test drug were the following:
Vilaprisan (BAY 1002670)
Name of active ingredient Vilaprisan (BAY 1002670)
Dose 2 mg, once daily
Route of administration Oral
Duration of treatment
Subgroup 1
About 1 year of treatment:
Treatment Group A1: 4 treatment periods of 12 weeks, each separated by 
1 bleeding episode (3/1 regimen)
Treatment Group A2: 2 treatment periods of 24 weeks, separated by 
2 bleeding episodes (6/2 regimen)
Treatment Group A3: 3 treatment periods of 12 weeks, each separated by 
2 bleeding episodes (3/2 regimen)
Duration of treatment
Subgroup 2
About 2 years of treatment:
Treatment Group A1: 8 treatment periods of 12 weeks, each separated by 
1 bleeding episode (3/1 regimen)
Treatment Group A2: 4 treatment periods of 24 weeks, each separated by 
2 bleeding episodes (6/2 regimen)
Treatment Group A3: 6 treatment periods of 12 weeks, each separated by 
2 bleeding episodes (3/2 regimen)


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Reference treatment
Not any longer applicable due to the closing of the clinical study. With 
the implementation of Protocol Amendment 10 (version 7.0) and 
aligned with the previous temporary pause measures, no new subjects 
will be recruited and no study medication or standard of care 
symptomatic nonhormonal will be given to the subjects who have been 
enrolled in the study. Originally, the information and instructions 
related to the reference drug were the following:
Standard of care symptomatic nonhormonal medical treatment as
determined by the investigators and/or watch and wait (Subgroup 1: 52
weeks, Subgroup 2: 104 weeks)
Name of active ingredient Not applicable
Doses Not applicable
Route of administration Not applicable
Duration of treatment Not applicable
Indication
Uterine fibroids
Diagnosis and main criteria for 
inclusion/exclusion
With the implementation of Protocol Amendment 10 (version 7.0) no 
new subjects will be enrolled in the study.
Originally, the study population had to fulfill the following criteria:
Women, 18 years or older, with symptomatic uterine fibroids or at high risk 
for recurrence after surgery will be eligible for enrollment in the study. 
Women who are pregnant, lactating, or have any condition requiring 
immediate blood transfusion are not eligible.
Study design
This is an open-label, parallel-group, randomized, multicenter study.
Methodology
With the implementation of Protocol Amendment 10 (version 7.0) no 
new subjects will be recruited and no study medication will be given to 
the subjects who have been enrolled in the study.
Subjects are not any longer required to document any data in the 
electronic diary (eDiary). 
Any subjects who have taken at least one dose of study medication 
(including the subjects who completed the study or were prematurely 
terminated) and SoC subjects who are still in the study will be asked to 
undergo a DEXA scan and the safety evaluation procedures described 
in this document.
Prior to the temporary pause, approximately 60% of eligible subjects were
randomized to one of three vilaprisan treatment groups (Groups A1, A2, or 
A3) or to the standard of care group (Group B) for about one year of 
treatment (Subgroup 1).
The remaining eligible subjects (about 40%) were randomized to one of 
three vilaprisan treatment groups (Groups A1, A2, or A3) or to the standard 
of care group (Group B) for about 2 years of treatment (Subgroup 2).
After the end of treatment (EoT), subjects were followed up for 24 weeks
(Subgroup 1) or for 12 weeks (Subgroup 2). 
Bone mineral density (BMD) of the lumbar spine, hip, and femoral neck
are assessed by DEXA


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
at baseline, after about 1 year of treatment, and follow-up 2
(FUP2) (Subgroup 1)

at baseline, after about 1 year of treatment, and at the EoT visit
(Subgroup 2)
Subjects documented the intensity of their menstrual bleeding in the 
Uterine Fibroid Daily Bleeding Diary (UF-DBD) and assessed the intensity 
of their menstrual blood loss daily using a visual scoring system (Menstrual 
Pictogram [MP]) in an electronic diary (eDiary). 
Uterine fibroids were assessed during the study by ultrasound.
Patient-reported outcome (PRO) data were also collected using the Uterine 
Fibroid Daily Symptom Diary (UF-DSD) and the Uterine Fibroid 
Symptom and Quality of Life questionnaire (UFS-QoL). Clinician-reported 
outcome (ClinRO) data were collected using the Clinical Global 
Impression - Investigator (CGI_I).
Safety is also assessed by the evaluation of adverse events (AEs), 
laboratory parameters, endometrial biopsies, cervical smears, physical and 
gynecological examinations, and vital signs. In addition, liver parameters 
were monitored on a monthly basis during treatment.
The (population) PK and the effect of intrinsic and extrinsic factors on the 
variability in exposure were assessed by population PK analysis using 
sparse vilaprisan concentration samples.
Leftover material from the endometrial biopsies scheduled for histological 
examinations were used to investigate biomarkers from subjects who have 
consented to this research. 
Type of control
Not any longer applicable as with the implementation of Protocol 
Amendment 10 (version 7.0), no new subjects will be recruited and no 
study medication or standard of care symptomatic nonhormonal will 
be given to the subjects who have been enrolled in the study
Standard of care symptomatic nonhormonal medical treatment as 
determined by the investigator and/or watch and wait 
Number of subjects
With the implementation of Protocol Amendment 10 (version 7.0) no 
new subjects will be enrolled in the study and no subjects will be 
treated.
Any subjects who have taken at least one dose of study medication 
(including the subjects who completed the study or were prematurely 
terminated) and SoC subjects who are still in the study will be asked to 
undergo a DEXA scan and the safety evaluation procedures described 
in this document.
About 2170 subjects were planned to be enrolled in order to achieve the 
planned number of randomized subjects.
A total of 1302 subjects were planned to be randomized as follows: 
372 subjects each in Treatment Groups A1, A2, and B; 186 subjects in 
Treatment Group A3
The sample size was chosen to fulfill the regulatory requirements for safety
data.
Primary variable
Percentage change in BMD of lumbar spine from baseline to about one 
year after start of treatment (SoT)


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Time point/frame of 
measurement for primary 
variable
About one year after SoT
Plan for statistical analysis
The primary analysis comprises the display of the percentage change in 
BMD of lumbar spine from baseline to about one year after SoT in all 
randomized and treated subjects with measurements at those 2 time points
in each treatment group. The mean and the two-sided 95% confidence 
interval (CI) for the mean difference of the percentage change in BMD of 
lumbar spine from baseline to about one year after SoT will be calculated 
for each vilaprisan treatment group as compared to standard of care. 
No statistical hypothesis is planned to be tested. 


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Protocol amendment summary of changes table
Amendment 11 (17 FEB 2020) 
Overall Rationale for the Amendment
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018 (refer to Protocol Amendment 9 [version 6.0]) while pre-clinical 
toxicology findings and their relevance to humans were being further investigated. Although 
the outcome of Bayer’s investigation revealed that the observed pre-clinical findings are 
regarded to be of limited relevance to the human situation (refer to vilaprisan Investigator’s 
Brochure [IB] version 11.0 including the associated amendment and Introduction Section 3), a 
comprehensive safety follow up will be conducted to provide additional confirmatory 
evidence. The protocol amendment 10 (version 7.0) introduced measures and processes to 
prepare this study for an orderly closure, including safety follow up measures in all study 
subjects who received at least one dose of study drug. Also subjects randomized to SoC who 
are still in the study will be asked to undergo these procedures.
Recently Bayer received comments from FDA regarding details of the safety follow-up 
measures introduced in the protocol amendment 10 (version 7.0). The current amendment 
(protocol amendment 11, version 8.0) implements these FDA recommendations.    
Section # and 
Name
Description of Major Changes
Brief Rationale
Short summary 
for sites
Described how subjects will be counseled 
when test results (e.g., hormone, liver, 
physical examination) are abnormal but still 
below the thresholds to trigger outside 
evaluation in the context of the study. In 
such cases subjects should at least be 
counseled about medical follow up 
according to local practice.  
To address FDA requests
9.1 and 9.6.3.4
Procedures and 
variables
Text adjusted and footnote "Physical 
examination" deleted, as physical 
examination needs to be performed to all 
subjects.
To address FDA requests
9.6.3.1
Laboratory 
evaluations
Revised the interval for blood sampling after 
intake of high doses of biotin from 8 to 72 
hours.
To address FDA requests
Added glycosylated hemoglobin (HbA1c) to 
the parameters measured for adrenal 
monitoring also in subjects who have 
completed or discontinued the study before 
or during the temporary pause.
To address FDA requests


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9.6.3.2.7 Heavy 
menstrual 
bleeding / 
suspicious 
bleeding pattern
Described that, for comparison of subject’s 
subjective report with documented bleeding 
pattern and amount of blood loss, bleeding 
data of UF-DBD, MP, and/or AH method, if 
available, from the months preceding the 
safety closeout visit will be used.
To address FDA requests
9.6.3.9.3 
Laboratory 
testing
Footnote was adjusted to trigger an 
assessment by one of the external adrenal 
panel experts in case tT level >150 ng/dL.
To address FDA request
Short summary for sites:
With the implementation of Protocol Amendment 10 (version 7.0) no new subjects will be 
enrolled in the study and no subjects will re-start treatment. All subjects who were 
randomized and started treatment before the temporary pause will be asked to have the 
comprehensive safety evaluation (with particular focus on endometrial, adrenal and skin
safety) performed which is implemented. This also applies to subjects who have completed or 
discontinued the study before or during the temporary pause, provided they have taken at least 
one dose of study medication. Likewise, subjects randomized to SoC who are still in the study 
will be asked to undergo these procedures.
All these subjects are asked to come to the site for the “Safety closeout visit” which is 
implemented with the protocol amendment 10 (Version 7.0). In most cases the procedures 
scheduled for this safety closeout visit will not take place on the same day. The second 
scheduled visit, the “Safety result reporting visit” can be done as a telephone visit.
The following procedures are to be performed in the context of the Safety closeout visit; for 
details please refer to Sections 9.1 and 9.2 and Table 9–1:

Reconsenting the subject 

Documentation of concomitant medication and AEs

Check for adrenal disorder signs and symptoms, incl. vital signs and body weight

MRI of adrenal glands

Dispensation and collection of saliva test tubes

Referral to dermatology expert

Physical examination

Gynecological/breast exam

Cervical smear

Urine pregnancy test

Ultrasound examination 

Endometrial biopsy

Laboratory (blood sampling)


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
Bone mineral density

Collection of unused study drug and empty drug packs/drug accountability (if 
applicable)

Collection of eDiary devices and review of bleeding data for unusual bleeding pattern 
(see Section 9.6.3.2.7)

Deactivation of the subject on the tablet computer without selecting a particular visit
At the second scheduled visit (“Safety result reporting visit”), the investigator is asked to 
communicate the results from the safety evaluations to the subject. This can be done as a 
telephone visit.
Details regarding the safety evaluation procedures and algorithms for identified abnormalities 
can be found in the respective sections of the protocol amendment 10 (Version 7.0). Test 
results (e.g., hormone, liver, physical examination) may be abnormal but still below the 
thresholds to trigger outside evaluation in the context of the study. In these cases subjects 
should at least be counselled about medical follow up according to local practice.
Before a subject is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject’s source document.


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Table of contents
Cover page of the integrated protocol .................................................................................... 1
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person ..................................................... 3
Signature of principal investigator ......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Protocol amendment summary of changes table................................................................... 9
Table of contents..................................................................................................................... 12
Table of tables......................................................................................................................... 17
Table of figures....................................................................................................................... 17
List of abbreviations............................................................................................................... 17
Definition of terms.................................................................................................................. 19
3.
Introduction ..................................................................................................................... 21
4.
Study objectives............................................................................................................... 24
5.
Study design..................................................................................................................... 24
6.
Study population ............................................................................................................. 29
6.1
Inclusion criteria ............................................................................................................ 29
6.2
Exclusion criteria ........................................................................................................... 30
6.3
Justification of selection criteria .................................................................................... 33
6.4
Withdrawal of subjects from study................................................................................ 33
6.4.1
Withdrawal ................................................................................................................. 33
6.4.2
Replacement ............................................................................................................... 35
6.5
Subject identification ..................................................................................................... 35
7.
Treatments ....................................................................................................................... 35
7.1
Treatments to be administered....................................................................................... 35
7.2
Identity of study treatment............................................................................................. 37
7.3
Treatment assignment .................................................................................................... 38
7.4
Dosage and administration............................................................................................. 38
7.5
Blinding.......................................................................................................................... 38
7.6
Drug logistics and accountability................................................................................... 38
7.7
Treatment compliance.................................................................................................... 38
8.
Non-study therapy........................................................................................................... 39
8.1
Prior and concomitant therapy....................................................................................... 39
8.1.1
Iron supplementation .................................................................................................. 39
8.1.2
Progestin therapy for induction of bleeding ............................................................... 39
8.2
Post-study therapy.......................................................................................................... 39
9.
Procedures and variables................................................................................................ 40
9.1
Tabular schedule of evaluations..................................................................................... 40
9.2
Visit description............................................................................................................. 43
9.2.1
Optional pre-screening phone contact ........................................................................ 43


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9.2.2
Scheduled visits .......................................................................................................... 43
9.2.3
Unscheduled visits...................................................................................................... 43
9.3
Population characteristics .............................................................................................. 43
9.3.1
Demographic............................................................................................................... 43
9.3.2
Medical history........................................................................................................... 43
9.3.3
Reproductive, menstrual, and fibroids history............................................................ 44
9.3.4
Heavy menstrual bleeding questions .......................................................................... 44
9.4
Efficacy.......................................................................................................................... 44
9.4.1
Ultrasound (efficacy) to assess uterine fibroids.......................................................... 44
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 45
9.5.1
Drug measurements .................................................................................................... 45
9.5.2
Population pharmacokinetic analysis of vilaprisan .................................................... 46
9.5.3
Pharmacokinetic/pharmacodynamic relationship of vilaprisan.................................. 46
9.6
Safety ............................................................................................................................. 46
9.6.1
Adverse events............................................................................................................ 46
9.6.1.1
Definitions............................................................................................................... 46
9.6.1.2
Classifications for adverse event assessment .......................................................... 49
9.6.1.2.1
Seriousness........................................................................................................... 49
9.6.1.2.2
Intensity................................................................................................................ 49
9.6.1.2.3
Causal relationship............................................................................................... 49
9.6.1.2.4
Action taken with study treatment ....................................................................... 50
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 50
9.6.1.2.6
Outcome............................................................................................................... 50
9.6.1.3
Assessments and documentation of adverse events ................................................ 50
9.6.1.4
Reporting of serious adverse events........................................................................ 51
9.6.1.5
Expected adverse events.......................................................................................... 52
9.6.1.6
Adverse events of special safety interest................................................................. 52
9.6.2
Pregnancies................................................................................................................. 53
9.6.3
Further safety.............................................................................................................. 55
9.6.3.1
Laboratory evaluations............................................................................................ 55
9.6.3.2
Endometrial biopsies............................................................................................... 57
9.6.3.2.1
Algorithm for evaluation of endometrial safety................................................... 57
9.6.3.2.2
Timing of last endometrial biopsy ....................................................................... 58
9.6.3.2.3
Sampling of endometrial biopsies........................................................................ 58
9.6.3.2.4
Assessment of endometrial biopsies .................................................................... 59
9.6.3.2.5
Follow-up of endometrial biopsies with abnormalities........................................ 60
9.6.3.2.6
Follow-up of PAEC ............................................................................................. 60
9.6.3.2.7
Heavy menstrual bleeding / suspicious bleeding pattern..................................... 61
9.6.3.2.8
Unscheduled endometrial biopsy......................................................................... 62
9.6.3.3
Cervical smear......................................................................................................... 63
9.6.3.4
Physical and gynecological examinations............................................................... 63
9.6.3.5
Vital signs, weight, and height ................................................................................ 63
9.6.3.6
Ultrasound (safety).................................................................................................. 63
9.6.3.7
Contraception and pregnancy test ........................................................................... 64
9.6.3.8
Bone mineral density............................................................................................... 64
9.6.3.9
Adrenal monitoring ................................................................................................. 66
9.6.3.9.1
Timing of adrenal monitoring.............................................................................. 67
9.6.3.9.2
Adrenal MRI ........................................................................................................ 68


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9.6.3.9.3
Laboratory testing ................................................................................................ 68
9.6.3.9.4
Adrenal signs and symptom inquiry .................................................................... 69
9.6.3.10
Liver monitoring...................................................................................................... 69
9.6.3.11
Liver symptom inquiry............................................................................................ 70
9.6.3.12
Skin monitoring....................................................................................................... 70
9.6.3.13
Reporting of medical device failures (Japan only).................................................. 71
9.6.4
Hemoglobin ................................................................................................................ 71
9.7
Other procedures and variables...................................................................................... 71
9.7.1
Iron supplementation .................................................................................................. 71
9.7.2
Algorithm for monitoring of endometrial safety........................................................ 71
9.7.3
Heavy menstrual bleeding / suspicious bleeding pattern............................................ 71
9.7.4
Unscheduled endometrial biopsy................................................................................ 71
9.7.5
Monitoring of ovarian cysts........................................................................................ 71
9.7.6
Exploratory biomarker analysis.................................................................................. 72
9.8
Appropriateness of procedures / measurements............................................................. 72
10. Statistical methods and determination of sample size ................................................. 72
10.1
General considerations................................................................................................... 72
10.2
Analysis sets................................................................................................................... 73
10.3
Variables and planned statistical analyses ..................................................................... 73
10.3.1
Variables..................................................................................................................... 73
10.3.1.1
Primary safety variable............................................................................................ 73
10.3.1.2
Secondary efficacy variable .................................................................................... 73
10.3.1.3
Other efficacy variables........................................................................................... 73
10.3.1.4
Secondary safety variables...................................................................................... 74
10.3.1.5
Other safety variables.............................................................................................. 74
10.3.2
Statistical and analytical plans.................................................................................... 75
10.3.2.1
Demographic and other baseline characteristics ..................................................... 75
10.3.2.2
Primary safety analysis............................................................................................ 75
10.3.2.3
Secondary efficacy analysis .................................................................................... 75
10.3.2.4
Other efficacy.......................................................................................................... 75
10.3.2.5
Secondary safety analysis........................................................................................ 76
10.3.2.6
Other safety analysis ............................................................................................... 76
10.3.2.7
Subgroup analysis.................................................................................................... 76
10.3.3
Missing data/drop outs................................................................................................ 76
10.4
Determination of sample size......................................................................................... 76
10.5
Planned interim analyses................................................................................................ 78
11. Data handling and quality assurance ............................................................................ 78
11.1
Data recording................................................................................................................ 78
11.2
Monitoring ..................................................................................................................... 80
11.3
Data processing.............................................................................................................. 80
11.4
Missing data................................................................................................................... 80
11.5
Audit and inspection ...................................................................................................... 80
11.6
Archiving ....................................................................................................................... 81
12. Premature termination of the study .............................................................................. 81
13. Ethical and legal aspects................................................................................................. 82
13.1
Investigators and other study personnel......................................................................... 82
13.2
Funding and financial disclosure ................................................................................... 82


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13.3
Ethical and legal conduct of the study........................................................................... 82
13.4
Subject information and consent.................................................................................... 83
13.5
Publication policy and use of data ................................................................................. 84
13.6
Compensation for health damage of subjects / insurance.............................................. 85
13.7
Confidentiality ............................................................................................................... 85
14. Reference list.................................................................................................................... 86
15. Protocol amendments...................................................................................................... 86
15.1
Amendment 3 – dated 13 JUN 2017.............................................................................. 86
15.1.1
Overview of the changes to the study......................................................................... 86
15.1.2
Changes to the protocol text ....................................................................................... 86
15.1.2.1
Section 6.2 Exclusion criteria.................................................................................. 87
15.1.2.2
Section 8.1 Prior and concomitant therapy ............................................................. 88
15.1.2.3
Section 16.2 Strong CYP3A4 inducers ................................................................... 88
15.2
Amendment 4 – dated 13 SEP 2017 .............................................................................. 88
15.2.1
Overview of the changes to the study......................................................................... 88
15.2.1.1
Change 1: Changes requested by health authorities................................................ 88
15.2.1.2
Change 2: Removal of Rifabutin from the examples of strong CYP3A4 
inducers ................................................................................................................... 89
15.2.1.3
Change 3: Revision of prior and concomitant therapy............................................ 89
15.2.1.4
Change 4: Modifications on the tabular schedule of evaluations............................ 89
15.2.1.5
Change 5: Gynecological examination was added to the premature 
discontinuation visit ................................................................................................ 89
15.2.1.6
Change 6: Ultrasound personnel ............................................................................. 90
15.2.1.7
Change 7: Section on Hemoglobin was moved....................................................... 90
15.2.1.8
Change 8: Rewording sampling of endometrial biopsies........................................ 90
15.2.1.9
Change 9: Correction of the number of enrolled subjects....................................... 90
15.2.1.10 Change 10: Minor clarifications for consistency .................................................... 90
15.2.2
Changes to the protocol text ....................................................................................... 91
15.2.2.1
Section 2 Synopsis................................................................................................... 91
15.2.2.2
Section 3 Introduction ............................................................................................. 92
15.2.2.3
Section 5 Study design ............................................................................................ 93
15.2.2.4
Section 6.1 Inclusion criteria................................................................................... 95
15.2.2.5
Section 6.2 Exclusion criteria.................................................................................. 95
15.2.2.6
Section 6.4.1 Withdrawal ........................................................................................ 96
15.2.2.7
Section 7.1 Treatments to be administered ............................................................. 97
15.2.2.8
Section 8.1 Prior and concomitant therapy ............................................................. 98
15.2.2.9
Section 8.2 Post-study therapy................................................................................ 99
15.2.2.10 Section 9.1 Tabular schedule of evaluations........................................................... 99
15.2.2.11 Sections 9.2.2.1-9.2.2.12 Visit descriptions for visits 1-10, EoT Visit and 
FUP 1..................................................................................................................... 102
15.2.2.12 Section 9.2.2.5 BMD Visit – Subgroups 1 and 2 .................................................. 103
15.2.2.13 Section 9.2.4 Premature discontinuation visit....................................................... 103
15.2.2.14 Section 9.3.4 Heavy menstrual bleeding questions............................................... 103
15.2.2.15 Section 9.4.2 Ultrasound (efficacy) to assess uterine fibroids .............................. 104
15.2.2.16 Section 9.4.3 Hemoglobin..................................................................................... 104
15.2.2.17 Section 9.6.1.6 Adverse events of special interest ................................................ 104
15.2.2.18 Section 9.6.2 Pregnancies...................................................................................... 105
15.2.2.19 Section 9.6.3.1 Laboratory evaluations................................................................. 105


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15.2.2.20 Section 9.6.3.2.2 Sampling of endometrial biopsies ............................................. 105
15.2.2.21 Section 9.6.3.2.3 Assessment of endometrial biopsies.......................................... 106
15.2.2.22 Section 9.6.3.3 Cervical smear.............................................................................. 106
15.2.2.23 Section 9.6.3.4 Physical and gynecological evaluations....................................... 106
15.2.2.24 Section 9.6.3.6 Ultrasound (safety)....................................................................... 107
15.2.2.25 Section 9.6.3.7 Contraception and pregnancy test ................................................ 107
15.2.2.26 Section 9.6.3.8 Bone mineral density.................................................................... 107
15.2.2.27 Section 9.6.4 Hemoglobin..................................................................................... 108
15.2.2.28 Section 9.7.1 Iron Supplementation ...................................................................... 108
15.2.2.29 Section 9.7.5 Induction of bleeding....................................................................... 109
15.2.2.30 Section 9.7.7 Exploratory biomarker analysis....................................................... 110
15.2.2.31 Section 10.2 Analysis sets..................................................................................... 110
15.2.2.32 Section 10.3.1.2 Secondary efficacy variable ....................................................... 111
15.2.2.33 Section 10.3.1.3 Other efficacy variables.............................................................. 111
15.2.2.34 Section 13.4 Subject information and consent ...................................................... 111
15.3
Amendment 6 – dated 04 JUL 2018 ............................................................................ 112
15.4
Amendment 7 – dated 20 AUG 2018 .......................................................................... 115
15.5
Amendment 9 – dated 11 DEC 2018 ........................................................................... 116
15.5.1
Overview of Changes ............................................................................................... 116
15.5.2
Changes to the protocol text ..................................................................................... 116
15.5.2.1
Background and justification of changes .............................................................. 116
15.5.2.2
Description of temporary measures....................................................................... 116
15.6
Amendment 10 – dated 21 NOV 2019 ........................................................................ 117
15.6.1
Overview of Changes ............................................................................................... 117
15.7
Amendment 11 - dated 17 FEB 2020........................................................................... 121
16. Appendices ..................................................................................................................... 122
16.1
Strong CYP3A4 inhibitors........................................................................................... 122
16.2
Strong CYP3A4 inducers............................................................................................. 122


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Table of tables
Table 7–1: Identity of test drug/vilaprisan tablets ................................................................... 37
Table 9–1: Schedule of procedures .......................................................................................... 41
Table 10–1: Percentage change in BMD of lumbar spine from baseline to about one year after 
SoT relative to Treatment Group B can be ruled out with planned sample size and 
corresponding power ............................................................................................. 77
Table 10–2: Power to rule out -2.2% (the clinical meaningful percent change in BMD of 
lumbar spine from baseline to about one year after SoT relative to Treatment 
Group B) with planned sample size....................................................................... 78
Table 16–1: Strong CYP3A4 inhibitors................................................................................. 122
Table 16–2: Strong CYP3A4 inducers................................................................................... 122
Table of figures
Figure 5–1:Design overview.................................................................................................... 25
Figure 9–1: Overview of the endometrial safety monitoring algorithm .................................. 57
Figure 9–2: Adrenal monitoring algorithm .............................................................................. 67
List of abbreviations
ACTH
adrenocorticotropic hormone
AE(s)
adverse event(s)
AESI
adverse event of special safety interest
AG
Aktiengesellschaft, incorporated company
ALT
alanine aminotransferase (also known as GPT)
ANA/ANCA
antinuclear antibody/antineutrophil cytoplasmic antibody
AP
alkaline phosphatase 
aPTT
activated partial thromboplastin time
ASCUS
atypical squamous cells of undetermined significance
AST
aspartate aminotransferase (also known as GOT)
ATC
Anatomical Therapeutic Chemical
B
bleeding episode
-HCG
beta human chorionic gonadotropin
BMD
bone mineral density
CD
compact disc
CGI_I
Clinical Global Impression - Investigator
CI
confidence interval
ClinRO
clinician-reported outcome
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSP
clinical study protocol
CTX
collagen type 1 cross-linked C-telopeptide
CYP3A4
cytochrome P450 isoenzyme 3A4
DEXA
dual-energy X-ray absorptiometry 
DHEA-s
dehydroepiandrosterone sulfate
dL
deciliter


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EA
endometrial ablation
eConsent
electronic informed consent
eCRF
electronic Case Report Form
EDC
electronic data capture
eDiary
electronic diary
eg
exempli gratia, for example
EIN
endometrial intraepithelial neoplasia
EMA
European Medicines Agency
EoT
end of treatment 
ePRO
electronic patient-reported outcome
ESP
European Spine Phantoms
EU
European Union
EudraCT
European Union data repository for clinical trials
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FUP
follow-up 
g
gram
GCIS
general clinical imaging services
GCP
Good Clinical Practice
GT
gamma-glutamyl transpeptidase
GMP
Good Manufacturing Practice
GnRH
gonadotropin-releasing hormone
GnRHa
gonadotropin-releasing hormone agonist
GOT
glutamic oxaloacetic transaminase (also known as AST)
GPT
glutamic pyruvic transaminase (also known as ALT)
HA
health authority
HbA1c
glycosylated hemoglobin
HDL
high density lipoprotein
HMB
heavy menstrual bleeding
HPV
human papilloma virus
HRQoL
health-related quality of life
IB
investigator’s brochure
ICH
International Council for Harmonisation
ie
id est, that is
IEC
Independent Ethics Committee
INN
international nonproprietary name
INR
international normalized ratio
IRB
Institutional Review Board
ISO
International Organization for Standardization
IVRS/IWRS
interactive voice/web response system
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LDL
low density lipoprotein
LH
luteinizing hormone
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MD
doctor of medicine
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mL
milliliter
mo
month
MP
menstrual pictogram
MRI
magnetic resonance imaging


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mRNA
messenger ribonucleic acid
M&S
Modeling and Simulation
mSV
milisievert
NA
not applicable
P
progesterone
PAEC
progesterone receptor modulator-associated endometrial changes
PD
pharmacodynamic(s)
pH
negative logarithm of proton concentration
PK
pharmacokinetic(s)
PM
post meridiem
PRM
progesterone receptor modulator
PRO
patient-reported outcome
QC
quality control
RAVE
electronic data capturing system
RND
randomization 
SAE
serious adverse event
SAF
safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SCR
screening
SD
standard deviation
SERM
selective estrogen receptor modulators
SESAC
site electronic source assessment checklist
SID
subject identification
SoC
standard of care
SoT
start of treatment
SUSAR
suspected, unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
THIN
The Health Improvement Network
TOSCA
Tools for Statistical Analysis
TP
Treatment Period
trt
treatment
TSH
thyroid-stimulating hormone
tT
total testosterone
TVU
transvaginal ultrasound
UAE
uterine artery embolization
UF-DBD
Uterine Fibroid Daily Bleeding Diary
UF-DSD
Uterine Fibroid Daily Symptom Diary
UFS-QoL
Uterine Fibroid Symptom and Quality of Life questionnaire
ULN
upper limit of normal
UPA
ulipristal acetate
UPP
uterine preserving procedure
US
United States
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
wk
week
Definition of terms
3/1 regimen
3 months (ie, 3 x 28 days) of treatment with 1 bleeding episode between 
treatment periods
3/2 regimen
3 months(ie, 3 x 28 days) of treatment with 2 bleeding episodes between 
treatment periods


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6/2 regimen
6 months (ie, 6 x 28 days) of treatment with 2 bleeding episodes between 
treatment periods
month
equals 28 days when referring to treatment (ie, 28 tablets per drug pack); 
equals 30 days when referring to the number of days in a month


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3.
Introduction
With the implementation of Protocol Amendment 10 (version 7.0) no new subjects will be 
enrolled in the study and no subjects will receive any further study drug treatment. Any 
subjects who have taken at least one dose of study medication (including the subjects who 
completed the study or were prematurely terminated) and SoC subjects who are still in the 
study will be asked to undergo a DEXA scan and the safety monitoring procedures described 
in this document.
Based on findings in preclinical carcinogenicity studies in rats and mice all vilaprisan clinical 
studies were temporarily paused since December 2018. In those carcinogenicity studies, 
adenocarcinomas of the endometrium and tumors of the adrenal cortex (benign and 
malignant) were seen in female rats and mice. Furthermore, skin sarcomas were found in 
female mice at a high exposure, representing 100 times the human therapeutic dose of 2 mg. 
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018 (refer to Protocol Amendment 9 [version 6.0]) while pre-clinical 
toxicology findings and their relevance to humans were being further investigated. Although 
the outcome of this investigation revealed that the observed pre-clinical findings are regarded 
to be of limited relevance to the human situation (refer to IB version 11.0 including the 
associated amendment and Introduction Section 3) Bayer will conduct a comprehensive safety 
follow up to confirm this. The protocol amendment 10 (Version 7.0) introduced measures and 
processes to prepare this study for an orderly closure, including safety follow up measures in 
all study subjects who received at least one dose of study drug.
The protocol amendment 10 (Version 7.0) introduced endometrial, adrenal, and skin safety 
evaluations with the aim to confirm that the carcinogenicity study findings did not translate 
into an increased risk for subjects when treated with the regimens and doses tested in the 
current studies.
In conclusion, all ongoing clinical studies with vilaprisan will be closed after implementation 
of a structured safety follow-up in all exposed subjects which aims to: 

provide certainty to subjects that they leave the study without any concerning finding,

generate clinical data that will support a thorough analysis of human safety data to 
confirm the hypothesis that the animal findings are of limited relevance to humans.
While closing the current clinical studies for the reasons explained above, the newly collected 
safety data will be thoroughly evaluated.
Further detailed information and assessment of the carcinogenicity study findings are 
described below and also in the current version (V 11.0) of the vilaprisan Investigator’s 
Brochure.
Results from chronic carcinogenicity studies with vilaprisan in rodents (rat and mice)
In preclinical chronic carcinogenicity studies in rats and mice, adenocarcinomas of the 
endometrium were found. Furthermore, in female rats, benign and malignant tumors of the 
adrenal cortex were seen. Such tumors were not seen in male rats or in mice. In addition, skin 
sarcoma (not otherwise specified) were found with increased incidence of statistical 
significance at the high dose of 60 mg/kg in female mice only. This corresponds to about 100 
fold of the daily dose of 2 mg administered in this study). The tumors were derived from 
various cell lineages and were seen at various anatomical locations. The cause and the 


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relevance of these skin tumors in mice is unclear but based on the high margin of exposure at 
which these tumors were found, the relevance for humans treated at the intended therapeutic 
dose is regarded as limited.
Bayer assessment of human relevance of the observed rodent tumors: 
The etiology of the observed endometrial and adrenal tumors is regarded as related to 
vilaprisan’s mode-of-action with species-specific consequences. There was no indication of 
any direct carcinogenic or direct tumor-promoting effect of vilaprisan, which is non-
genotoxic. Male animals did not show any findings and in female animals, effects were 
limited to reproductive and endocrine organs, with the exemption of the skin sarcomas, where 
the high margin of exposure suggested limited human relevance. Reasons why the 
endometrial and adrenal tumors are regarded as of limited relevance in the human setting are 
described in more detail below: 
In the course of these carcinogenicity studies, rats and mice were treated with life-long and 
uninterrupted doses of vilaprisan leading to much higher unbound exposures compared to the 
human dose of 2 mg/day. As a consequence, progesterone action was blocked in these animals 
during their whole life-span. Compatible with this are signs of estrogen dominance that were 
observed in the aging female rats and mice. Such signs have not been found in clinical trials 
of vilaprisan in humans. In the carcinogenicity study rodents entered into reproductive 
senescence during the treatment phase leading to rodent specific endocrine changes resulting 
under continuous blockade of the progesterone receptor in the formation of tumors in the 
endometrium and adrenal cortex. The rodent specific endocrinology does not resemble the 
situation in humans. 
Relevant differences between the treatment of humans with vilaprisan and the setting of the 
carcinogenicity studies in rodents are:

Female rodents undergo specific endocrine changes during reproductive senescence 
that do not resemble human menopause, human premenopausal endocrine status or the 
endocrine situation during vilaprisan treatment. 

Prolonged estrous periods with high estradiol levels occur in rodent reproductive 
senescence, or a pseudopregnancy state with moderately high estradiol levels. This 
process takes place due to neurodegeneration on the hypothalamus-pituitary gland and 
in the presence of follicles in the ovaries which are capable of producing hormones. In 
the presence of vilaprisan with its strong antagonistic effect on the progesterone 
receptor this leads to a prolonged, fully unopposed estradiol exposure in the animals. 
Specifically, in rats, life-long vilaprisan treatment seems to promote prolonged estrous 
periods with follicular cysts and reduce states of pseudopregnancy, thus further
enhancing estrogen dominance.

Regarding the development of endometrial adenocarcinomas, prolonged phases of 
unopposed estrogen are a recognized risk factor for development of endometrial 
adenocarcinoma in rodents as well as in humans. However, in contrast to the rodents 
in the pre-clinical carcinogenicity studies, available clinical data for vilaprisan do not 
indicate the occurrence of an unopposed estrogen effect on human endometrium. This 
is supported by the estrogen-lowering effect of vilaprisan shown in the Phase 1 and 
Phase 2 studies as well as by the morphological features of endometrial histology in 
humans under vilaprisan treatment which do not seem to indicate a relevant 
proliferative effect. There was no increased incidence of relevant endometrial 


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pathology (hyperplasias, neoplasms) seen in biopsies taken after up to 12 months of 
treatment with vilaprisan. 

Furthermore, vilaprisan is administered in treatment regimens with regular breaks for 
one or two menstrual bleeds, to allow for ovulation, endogenous progesterone 
production, menstruation, and endometrial shedding (versus life-long continuous 
treatment in the rodent carcinogenicity study).
With regards to the development of adrenal tumors, a role of estrogen dominance in adrenal 
stimulation (e.g. hormonal imbalance) is recognized in rodents, whereas in humans adrenal 
functional disorders and adrenal tumors have a different etiology and are not known to be 
influenced in a relevant way by unopposed estrogen. In addition, adrenal tumors under 
vilaprisan treatment occurred only in female rats, but not in mice. Vilaprisan treatment in the 
chronic monkey study also did not result in any hypertrophic or hyperplastic adrenal changes. 
In rats there were likely further species-specific contributing factors like pituitary 
dysregulation and activation of the hypothalamic-pituitary-adrenal (HPA) axis, which was not 
found in the other tested species.
In conclusion, the combination of a hyperestrogenic background status in reproductive 
senescence of female rodents (unopposed estrogen effect) with a continuous blockade of 
progesterone action by vilaprisan is a conclusive mechanistic hypothesis to explain the 
endometrial and adrenal tumors observed in the rodent carcinogenicity studies. Based on these 
major differences between rats and humans, the observed findings are most likely to be rodent 
specific with limited relevance to the human situation. 
However, in order to demonstrate endometrial and adrenal safety of repeated intermittent 
treatment with vilaprisan, study subjects will be carefully monitored.

A thorough endometrial monitoring program has been part of the vilaprisan studies 
from the start. 

With the current protocol amendment, a robust adrenal safety monitoring program is 
being implemented in this study as well as in all ongoing vilaprisan studies, to 
adequately address this new topic in the clinical program. 
The cause and the relevance of the skin sarcomas observed in the mouse carcinogenicity study 
is unclear but based on the high exposure at which these tumors were found, the relevance for 
humans treated at the intended therapeutic dose is regarded as limited. 
Nevertheless, all study subjects who took at least one dose of vilaprisan in any of the currently 
paused clinical studies will be asked to undergo careful evaluation in order to demonstrate 
skin safety of repeated intermittent treatment with vilaprisan via a thorough skin examination
by a dermatology expert.
Benefit risk assessment 
The parameters measured in the context of the endometrial, adrenal and skin safety 
monitoring have been aligned with clinical experts and represent a positive benefit risk 
balance between their ability to detect relevant pathologies and the low procedure related risks 
associated with them.
These safety measures for subjects participating in the vilaprisan studies intend to ensure that 
potential tumors or diseases of the uterus, the skin or the adrenal glands are detected. If 
detected, it is important to understand that these tumors or diseases are not automatically 
related to the study drug as they can occur in a certain number of women independently of 


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participation in a clinical study and independently of whether vilaprisan was taken as a study 
drug or not (“background incidence”). These measures can help to detect such findings, 
probably even at an earlier stage than it would have become apparent otherwise. Furthermore, 
the safety measures will generate important data allowing to examine whether vilaprisan has a 
role in the development of such tumors and diseases.
The safety measures newly introduced with the protocol amendment 10 (Version 7.0) were
applicable also to subjects in the SoC group since a background incidence of adrenal and skin 
abnormalities renders such safety investigations also beneficial for subjects not exposed to 
vilaprisan.
The safety of short-term treatment with vilaprisan is supported by the available pre-clinical 
and clinical data. Therefore, it is Bayer’s assessment that no acute or long-term risk is 
expected for the subjects who have been treated in any of the clinical studies performed with 
vilaprisan. 
With regards to efficacy vilaprisan has demonstrated in Phase 1 a dose-dependent ovulation 
inhibition and induction of amenorrhea in healthy women. Two Phase 2 studies (15788 –
ASTEROID 1 and 17541 – ASTEROID 2 with a treatment duration of up to 24 weeks were 
conducted in women with uterine fibroids. The results of both studies demonstrated a 
clinically meaningful reduction of symptoms associated with uterine fibroids, especially of 
HMB, improvements of patients’ health-related quality of life (HRQoL) and a reduction of 
fibroid size.
4.
Study objectives
The primary objective of this study is to evaluate the safety of vilaprisan in subjects with 
uterine fibroids in comparison to nonhormonal medical treatment in accordance with local 
standard of care. 
The secondary objective of this study is to evaluate the efficacy of vilaprisan in subjects with 
uterine fibroids in comparison to nonhormonal medical treatment in accordance with local 
standard of care. With the implementation of Protocol Amendment 10 (version 7.0), 
additional focus will be put on safety evaluations of the endometrium, adrenal glands and 
skin.
Other objectives of this study are to evaluate the variability in exposure in relation to the 
efficacy and safety for vilaprisan and to collect patient-reported outcome (PRO) and clinician-
reported outcome (ClinRO) data.
5.
Study design
This section was changed in Amendment 4, see Section 15.2.1.
Design overview
This is an open-label, parallel-group, randomized, multi-center study. 
The study is conducted in Europe, North America, South America, South Africa, and Asia 
Pacific.
An overview of the study design before the temporary pause is shown in Figure 5–1.


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With the implementation of Protocol Amendment 10 (version 7.0), this study design is no 
longer valid. No subjects will receive further study drug treatment. 
Figure 5–1: Design overview
Subgroup 1 (about 1 year of treatment)
A1 
SCR up 
to 90
days
RND
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
24 wk 
FUP
A2
SCR up 
to 90
days
RND
24 wk trt
B B
24 wk trt
24 wk 
FUP
A3
SCR up 
to 90
days 
RND
12 
wk 
trt
B B
12 
wk 
trt
B B
12 
wk 
trt
24 wk 
FUP
B 
SCR up 
to 90
days
RND
Symptomatic nonhormonal medical 
treatment as determined by the 
investigators and/or watch and wait
24 wk 
FUP
Subgroup 2 (about 2 years of treatment)
A1 
SCR up 
to 90
days
RND
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
12 
wk 
FUP
A2
SCR up 
to 90
days
RND
24 wk trt
B B
24 wk trt
B B
24 wk trt
B B
24 wk trt
12 
wk 
FUP
A3
SCR up 
to 90
days 
RND
12 
wk 
trt
B B
12 
wk 
trt
B B
12 
wk 
trt
B
B
12 
wk 
trt
B B
12 
wk 
trt
B
B
12 
wk 
trt
12 
wk 
FUP
B 
SCR up 
to 90
days
RND
Symptomatic nonhormonal medical treatment as determined by the 
investigators and/or watch and wait
12 wk 
FUP
Groups A1, A2, and A3 treated daily with vilaprisan 2 mg during treatment periods; Group B treated with standard of 
care symptomatic nonhormonal medical treatment as determined by the investigators and/or watch and wait.
B = bleeding episode; FUP = follow-up; RND = randomization; SCR = screening; trt = treatment; wk = week.
During the screening period, subjects had to demonstrate eligibility including presence of at 
least 1 uterine fibroid documented by ultrasound at screening and / or during a uterine 
preserving procedure within 3 months prior to screening, at least one symptom of uterine 
fibroid(s), and an endometrial biopsy result without significant histological disorder. If 
possible, fibroid-related symptom(s) should be confirmed before the endometrial biopsy is 
performed at Visit 2.
Eligible subjects were randomized to one of three vilaprisan treatment groups (Groups A1, 
A2, or A3) or the standard of care group (Group B) and started treatment as described in 


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Section 7.1. After the end of the treatment, subjects were planned to be followed up for 12 
weeks (Subgroup 2) or 24 weeks (Subgroup 1).
The primary safety variable is the percentage change in BMD of lumbar spine from baseline 
to about one year after SoT. With Protocol Amendment 10 (version 7.0) becoming valid, all 
subjects who received vilaprisan treatment will be asked to undergo a BMD at least 6 months 
after the last intake of vilaprisan, to document absence of bone loss or adequate recovery after 
the end of treatment.  
For secondary variables, see Sections 10.3.1.2 and 10.3.1.4.
Justification of the design
Comparators:
Standard of care symptomatic nonhormonal medical treatment and watch and wait were
considered appropriate to examine comparative safety and efficacy of vilaprisan versus 
available treatment option(s). Hormonal medical treatments and surgical interventions were
not permitted as comparators. The fact that in all study treatment arms active treatment was
provided, translated into a comparable level of benefit for all enrolled subjects.
Blinding:
Due to the character of the treatments in the control group, blinding of subjects and 
investigators is not possible in this study. However, the primary endpoint will be assessed by 
central readers who are blinded with regard to treatment of the subject.
Study design valid with the implementation of Protocol Amendment 10 (version 7.0): 
The study was temporarily paused since December 2018. No further subjects will be recruited 
and none of the enrolled subjects will receive further study drug treatment. Any subjects who 
have taken at least one dose of study medication (including the subjects who completed the 
study or were prematurely terminated) and SoC subjects who are still in the study will be 
asked to have comprehensive safety evaluation(s) (with particular focus on endometrial, 
adrenal and skin safety) performed. This also applies to subjects who have completed or 
discontinued the study before or during the temporary pause, provided they have taken at least 
one dose of study medication.
Efficacy / PD assessments:
Menstrual bleeding, symptoms and the impact uterine fibroids have on the subjects’ daily life 
are determined as efficacy parameters.
Fibroid size, uterus size (by ultrasound), endocrine hormone levels, and bleeding are
determined as PD parameters.
Safety monitoring:
Safety parameters are regularly and closely monitored throughout the study (eg, questioning 
for AEs, measurement of laboratory values, liver symptom inquiry, vital signs, endometrial 
thickness, abnormal menstrual bleeding, and size of follicle-like structures comprising 
follicles and functional ovarian cysts). A comprehensive screening program for adrenal 
tumors and a skin examination by a dermatology expert were implemented with the protocol
amendment 10 (Version 7.0).
Endometrial monitoring


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A careful endometrial safety monitoring assessment was applied in this study from the 
beginning, including regular ultrasound investigations during the treatment period,
observation of bleeding patterns, and endometrial biopsies at defined time points. Clear 
decision trees are outlined as to when to perform an unscheduled endometrial biopsy in case 
of endometrial thickening and/or on the clinical management of endometrial 
thickening/HMB/abnormal menstrual bleeding pattern (see Section9.6.3.2.1). Highly reliable 
diagnosis of any findings in the endometrial biopsies is ensured through the involvement of a 
panel of highly experienced and well renowned expert pathologists who will assess every 
biopsy sample taken from study subjects.
With Protocol Amendment 10 (version 7.0), additional requirements for endometrial safety 
screening are outlined for subjects who took at least one dose of study medication, see Section 
9.6.3.2.
Liver monitoring
A liver-related safety signal was observed with some selective progesterone receptor 
modulator (PRM) compounds which display differences in molecular structure compared to 
vilaprisan.
Monthly monitoring of liver parameters under treatment was introduced with an earlier 
version of this protocol (Protocol Amendment 6 [version 4.0]). With this protocol amendment
(Protocol Amendment 10 [version 7.0]), subjects who remained in the study during the 
temporary pause will receive one further laboratory assessment, including liver parameters. 
Adrenal monitoring
A comprehensive adrenal screening program was implemented with the protocol amendment
10 (Version 7.0) (Protocol Amendment 10 [version 7.0]). This program is described in more 
detail in Section 9.6.3.9. It encompasses adrenal imaging, as well as laboratory tests aimed at 
identifying overproduction of adrenal hormones in the context of tumors of the adrenal cortex. 
Tumors of the adrenal glands (cortical or medullary in origin, benign as well as malignant) are 
known to occur in a certain frequency (1) in the general population, independent of an 
exposure to the study drug vilaprisan. In case adrenal tumors are detected by the screening 
program in this study, a causal relationship to vilaprisan can therefore not be automatically 
assumed. However, it is expected that all subjects, irrespective of their exposure to vilaprisan, 
will benefit from detection of potential adrenal gland disorders through the study monitoring 
program.
Skin monitoring
In the above-mentioned carcinogenicity studies performed in mice and rats, skin sarcomas 
were found at a dose representing about 100 times the human therapeutic dose of 2 mg. The
tumors were derived from various cell lineages and were seen at various anatomical locations. 
The cause and the relevance of the skin tumors in mice is unclear but based on the high 
exposure at which these tumors were found, the relevance for humans treated at the intended 
therapeutic dose is regarded as limited. 
Nevertheless, all study subjects who took at least one dose of study medication in any of the 
currently paused clinical studies will be asked to undergo a thorough skin examination by a 
dermatology expert in order to demonstrate skin safety of repeated intermittent treatment with 
vilaprisan.
Assessment of effects on bone mineral density


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Selective PRMs such as vilaprisan induce a degree of ovulation suppression, accompanied by 
a moderate decrease in endogenous estradiol levels. To supplement data on estradiol levels 
under vilaprisan therapy this study examines bone mineral density (BMD) and any potential 
impact that changes in estradiol levels under treatment may have. BMD is assessed using 
dual-energy X-ray absorptiometry (DEXA). To increase the accuracy of the assessment, 2 
measurements are performed at each time point and location and the mean value will be used 
for evaluation. After the first measurement the subject should get up and should be re-
positioned for the second measurement to reduce influence of positioning on the results.
BMD measurement of the spine (lumbar anterior posterior, L1-L4) and hip/femoral neck is
performed using the same type of device for all measurements of any subject in this study. 
DEXA is associated with radiation exposure but the total exposure per examination is only 
approximately 0.005 mSV corresponding to 3 to 4 hours of natural background radiation. No 
contrast agent is needed for this examination.
All subjects who received vilaprisan treatment should have an off-treatment DEXA scan1
performed at the Safety closeout visit to document absence of bone loss or adequate recovery. 
Subjects randomized to Treatment group B who were still in the study when the protocol
amendment 10 (Version 7.0) became valid should also have undergone a DEXA scan at the 
safety closeout visit, unless they had a DEXA scan performed within the last 3 months prior to 
the safety closeout visit.
Effects related to study conduct
In addition to drug-related side effects, symptoms caused by the study conduct (eg, due to 
blood sampling, endometrial biopsy) are possible. However, possible risks are regarded as 
acceptable because the planned methods are used routinely in clinical studies, clinical and/or 
gynecological practice.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).
Primary completion
The primary completion event for this study is the last visit of the last subject.
The primary completion date for this study according to the Food and Drug Administration 
(FDA) Amendment Act is specified in a separate document (not part of this study protocol).
                                                
1 DEXA scans performed 5.5 to 6 months after last study drug intake are acceptable off-treatment DEXA scans


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6.
Study population
Eligibility
No longer valid, since no new subjects will be enrolled in this study with the 
implementation of Protocol Amendment 10 (version 7.0). Originally the study 
population had to fulfill the following criteria:  
Women with symptomatic uterine fibroids or at high risk for recurrence after surgery meeting 
all inclusion and presenting none of the exclusion criteria will be eligible for enrollment in the 
study.
Subjects who were screen failures from another ASTEROID study do not have to repeat the 
screening laboratory evaluations, cervical smear, and endometrial biopsy provided that the 
criteria for inclusion were met in the previous study and are within an acceptable time frame, 
ie, within 4 weeks for laboratory parameters and within 6 months for the cervical smear and 
endometrial biopsy).  In case endometrial thickness (double layer) >18 mm is detected during 
the ultrasound measurements at screening (ie, Visit 1 or 2), the subject should undergo an 
evaluation by endometrial biopsy.
6.1
Inclusion criteria
This section was changed in Amendment 4, see Section 15.2.1.
1. Signed and dated informed consent
2.
Women, 18 years or older at the time of Visit 1
3. Diagnosis of uterine fibroid(s) documented by ultrasound at screening AND/OR
during a uterine preserving procedure within 3 months prior to screening in subjects with
high risk for recurrence2
4. Symptoms of uterine fibroids documented by one or more of the following symptoms:

Heavy menstrual bleeding (HMB) > 80.00 mL documented by menstrual 
pictogram (MP) in a bleeding period3 during the screening period

HMB during 3 bleeding episodes within 6 months prior to screening as reported 
by the subject
                                                
2 High risk for recurrence is defined as satisfying at least one of the following criteria:

Subject had 2 or more uterine preserving procedures in the past

Subject has a positive family history for recurrent uterine fibroids

Subject is below age 35 at screening
3 To facilitate the assessment of the inclusion criterion 4 at the site during the screening period, a modified 
definition of bleeding episode (“bleeding period”) will be implemented in the programming of reports for the 
sites, based solely on data from the Menstrual Pictogram (MP). Thus, a bleeding period is defined as a period 
of time when use of sanitary products is reported in the MP, preceded and followed by 2 days when no sanitary 
products were reported. In cases where the screening period starts with a day or with several days in which 
sanitary products have been reported (ie, if a bleeding episode is ongoing at the start of the screening period 
and the very first eDiary entry is a day with use of sanitary protection), this will also be recognized as a bleeding 
period. This simplification will only be used in the programming of reports supporting the sites in assessing 
inclusion criterion 4. Information from the Uterine Fibroid Daily Bleeding Diary (UF-DBD), used in the standard 
definition of a bleeding episode (see Section 7.1), is not used for this definition of a “bleeding period”.


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
Pelvic pressure/pain likely to be associated with uterine fibroids during 3 months 
prior to screening as reported by the subject

Any of the symptoms above documented in the subject’s file before an uterine 
preserving procedure that was conducted within 3 months prior to screening in a
subject with high risk for recurrence 2
5. Good general health (except for findings related to uterine fibroids) as proven by medical 
history, physical and gynecological examinations, and laboratory test results
6. Normal or clinically insignificant cervical smear not requiring further follow-up.  The 
cervical smear may be waived if a normal result has been documented in the subject’s 
medical records within the previous 6 months.
Human papilloma virus (HPV) testing in subjects with atypical squamous cells of 
undetermined significance (ASCUS) can be used as an adjunctive test.  Subjects with
ASCUS can be included if they are negative for high-risk HPV strains.
7. An endometrial biopsy performed during the screening period, without significant 
histological disorder such as endometrial hyperplasia (including simple hyperplasia) or 
other significant endometrial pathology.  If the sample is inadequate, the biopsy can be 
repeated once within the screening period and must be repeated within 6 weeks from the 
first biopsy in order for the subject to continue.  No further repeated biopsies for 
inadequate samples are permitted.
8. Use of an acceptable nonhormonal method of contraception (ie, either male condom, cap, 
diaphragm or sponge, each in combination with spermicide) starting at Visit 1 until the 
end of the study.  (Short-acting hormonal contraception [oral, vaginal, or transdermal] are 
allowed up until the start of the menstrual cycle that follows Visit 1.)  This is not required 
if contraception is achieved by a permanent method, such as bilateral fallopian tube 
blockage of the subject (including Essure®) or vasectomy of the partner(s).
6.2
Exclusion criteria
This section was changed in Amendment 3, see Section 15.1.1., and in Amendment 4, see 
Section 15.2.1.
1. Pregnancy or lactation (less than 3 months since delivery, abortion, or lactation before 
start of treatment)
2. Hypersensitivity to any ingredient of the study drug
3. Any condition requiring immediate blood transfusion
4. Laboratory values outside inclusion range4 before randomization and considered as 
clinically relevant
5. Any diseases, conditions, or medications that can compromise the function of the body 
systems and could result in altered absorption, excessive accumulation, impaired 
metabolism, or altered excretion of the study drug including, but not limited to:

Impaired function of the kidneys (laboratory values outside of inclusion range4)
                                                
4 As specified in the laboratory manual and in the reports from the central laboratory


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
Abnormal liver parameters (presence of at least one of the following criteria, 
please see also Section 9.6.3.1 Laboratory evaluations)5:
-
2 x upper limit of normal (ULN) for glutamic oxaloacetic transaminase 
(GOT) / aspartate aminotransferase (AST)
-
2 x ULN for glutamic pyruvic transaminase (GPT) / alanine aminotransferase 
(ALT)
-
2 x ULN for alkaline phosphatase (AP)
-
Total bilirubin outside the outside the upper limit of normal 
6
-
International normalized ratio (INR) outside the upper limit of the normal 
range
7

Diagnosis of hepatitis B infection, i.e., Hbs-antigen positive at Visit 18

Diagnosis of hepatitis C infection, i.e., hepatitis C-antibodies and HCV-RNA 
positive at Visit 1 9

Chronic bowel diseases, eg, M. Crohn and Colitis ulcerosa

Intake of strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors within 
the last 2 weeks before the randomization visit and during the treatment period 
including: antivirals (eg, viekira pak, telaprevir, boceprevir), protease inhibitors 
(eg, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir), antifungals (eg,
itraconazole, voriconazole, posaconazole), antibiotics (eg, clarithromycin, 
telithromycin), grapefruit and any grapefruit containing food products (eg, 
grapefruit juice). Ketoconazole and other triazole antifungal drugs are allowed 
for topical/local use (including vaginal application). A detailed list is provided in 
Section 16.1.

Intake of strong CYP3A4 inducers (eg, rifampicin, carbamazepine, phenytoin, 
phenobarbital, St John´s wort [Hypericum]) within the last 2 weeks before the 
randomization visit and during the treatment period, unless randomized to 
treatment group B. A detailed list is provided in Section 16.2.
6. Any diseases or conditions that might interfere with the conduct of the study or the 
interpretation of the results, including

Known severe coagulation disorder

Known anemia for reason other than HMB

Known hemoglobinopathy
                                                
5 For the liver-related laboratory parameters ALT, AST, and AP the laboratory test also needs to be repeated if 
results of the first test at visit 1 are raised above the ULN, but still < 2x ULN (i.e. still within inclusion range). The 
subject is eligible only if the second test shows a stabilization or decline in those values (see Section 9.6.3.1 ).
6 As specified in the laboratory manual and in the reports from the central laboratory
7 As specified in the laboratory manual and in the reports from the central laboratory
8 This will be applied only to subjects newly enrolled into the study after protocol version 4.0 has become valid
9 This will be applied only to subjects newly enrolled into the study after protocol version 4.0 has become valid


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
History of or current uterine, cervical, ovarian, or breast cancer, except cervical 
cancers after curative treatment

One or more ovarian cysts >30 mm in diameter as measured by ultrasound
(except endometrioma)

Any ovarian tumors or pelvic masses of unclear etiology requiring further 
diagnostic procedures

Known or suspected uterine polyp >15 mm

Current bone and musculoskeletal disease (eg, osteoporosis, Morbus 
Scheuermann, osteogenesis imperfecta, hypo- or hyperparathyroidism, Paget’s 
disease, osteomalacia or other metabolic disease of bone, hypo- or 
hypercalcemia, uncontrolled vitamin D deficiencies10)

Screening DEXA results of the lumbar spine (L1-L4), femoral neck, or total hip 
BMD corresponding to 2.0 or more standard deviations below normal (Z score ≤
-2.0 SD) as per central read.11
7. Abuse of alcohol, drugs, or medicines (eg, laxatives)
8. Use of other treatments that might interfere with the conduct of the study or the 
interpretation of the results including:  

Short-acting hormonal contraception (oral, vaginal, or transdermal), if not 
stopped at the start of the menstrual cycle that follows Visit 1

Long-acting hormonal contraception (injectable), if last application was 
performed less than 1 application interval before the start of the menstrual cycle 
that follows Visit 1 

Contraceptive devices with or without hormone release (implant, intra-uterine 
device), if not removed at Visit 1 (not applicable in cases of bilateral fallopian 
tube blockage of the subject [including Essure®])

Other hormonal treatments for HMB or fibroids, if not stopped before the start 
of the menstrual cycle that follows Visit 1 (eg, androgens, estrogen receptor 
antagonists, selective estrogen receptor modulators). For progesterone receptor 
modulators see next bullet point.

Previous use of ulipristal acetate, if there were not at least two menstruations 
after the last intake before Visit 1

Gonadotropin-releasing hormone agonists (GnRHa), if not stopped at least one 
application interval before Visit 1

Tranexamic acid, traditional Chinese medicine for uterine fibroids or HMB, or 
other treatments for HMB, if not stopped at Visit 1

Subjects randomized to Treatment Group B will be allowed to take 
tranexamic acid as symptomatic nonhormonal treatment 
                                                
10 According to local guidance
11 This will be applied only to subjects newly enrolled into the study after protocol version 4.0 has become valid.


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
Anticoagulants, if not stopped at Visit 1

Raloxifene (or similar SERMs), fluoride, calcitonin, if not stopped 3 months 
before the start of the screening period 

Current intake (ie, at Visit 1) of bisphosphonates, parathyroid hormone, GnRH 
antagonists, vitamin D analogues, systemic corticosteroids or other agents 
known or suspected to affect bone metabolism 
9. Undiagnosed abnormal genital bleeding
10. Simultaneous participation in another clinical study with investigational medicinal 
product(s). Participation in another clinical trial prior to study entry that might have an 
impact on the study objectives. 
11. Close affiliation with the investigational site (eg, a close relative of the investigator), 
dependent person (eg, employee or student of investigational site, or sponsor’s staff)
12. Inability to cooperate with the study procedures for any reason, including the following 
examples:  language comprehension, psychiatric illness, inability to get to the study site, 
eDiary compliance
13. Previous enrollment to the study (ie, rescreening is only allowed as described in Section 
6.4.1)
14. Any other contraindication listed in the local labeling for medication used in Treatment 
Group B
6.3
Justification of selection criteria
The exclusion criteria are valid for known or suspected conditions and were chosen to ensure 
that subjects with specific risks for administration of the study drugs and/or subjects with 
conditions that may have an effect on the aims of the study are excluded.
6.4
Withdrawal of subjects from study
6.4.1
Withdrawal
No longer valid, since with the implementation of Protocol Amendment 10 (version 7.0)
no subjects will start or continue treatment in this study. Originally, the criteria for 
withdrawal from the study or from the study treatment were the following:  
This section was changed in Amendment 4, see Section 15.2.1.
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result.
At the specific request of the sponsor and in liaison with the investigator (eg, obvious 
non-compliance, safety concerns).
Pregnancy
Surgical treatment of uterine fibroids
Subjects must be withdrawn from study treatment if any of the following occurs:


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If, in the investigator's opinion, continuation of the study treatment would be harmful 
to the subject's well-being

GPT/ALT or GOT/AST 8 x ULN

GPT/ALT or GOT/AST 5 x ULN for more than 2 weeks 

GPT/ALT or GOT/AST 3 x ULN and total bilirubin >2 x ULN or international 
normalized ratio (INR) >1.5 
GPT/ALT or GOT/AST >3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper abdominal quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

Atypical hyperplasia, endometrial intraepithelial neoplasia (EIN) or malignant 
neoplasm
In the event excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-
score reading of <-2 standard deviations (SD) (determined either by the central reading 
imaging laboratory or by assessment at the site and confirmed by the central reading 
imaging laboratory at the 12 month visit or later).  For additional details and follow-up 
procedures for these subjects see Section 9.6.3.8
In case induction of bleeding becomes necessary more than once per subject during the 
study treatment
Subjects may be withdrawn from study treatment if any of the inclusion criteria are no longer 
fulfilled or if any of the exclusion criteria apply during treatment.
Follow-up of subject prematurely withdrawing from study treatment or during FUP
With the implementation of Protocol Amendment 10 (version 7.0), subjects who do not
consent to the updated study design and the additional safety measures will be regarded as 
“dropouts”.
Screening failure
A subject who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before randomization is regarded a “screening failure.” 
Dropout
A subject who discontinues study participation prematurely for any reason (including subjects 
who do not consent to this protocol amendment which defines safety measures before study 
closure) is defined as a “dropout” if the subject has already been randomized.
Those subjects who were randomized but never started study medication or SoC will not need 
to consent to the safety follow up, but will be handled as drop outs after having been informed 
about the study closure.
Contacting of treated subjects who already left the study
The investigator or designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be documented 
in the subject’s source document.


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General procedures
In all cases, the reason for withdrawal must be recorded in the electronic Case Report Form 
(eCRF) and in the subject's medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.4.2
Replacement
Dropouts will not be replaced.
6.5
Subject identification
At screening upon signing the informed consent and registering the subject in the interactive 
voice/web response system (IVRS/IWRS), each subject was assigned a unique multi-digit 
subject identification (SID) number by the site for unambiguous identification. The SID was
constructed as follows:

Digits 1 to 2:  unique country code 

Digits 3 to 5:  center code (unique within each country)

Digits 6 to 9:  unique subject code (unique within each center); the 6th digit will be “6”
for this ASTEROID 6 study 
Once allocated, the SID number identified the subject throughout the study.
On random assignment to treatment, each subject was assigned a unique randomization 
number.
7.
Treatments
Instructions in Section 7.1 to 7.4 are no longer valid, since with the implementation of 
Protocol Amendment 10 (version 7.0) no subjects will start or continue treatment in this 
study. 
Originally, the instructions in Sections 7.1 and 7.4 were the following:
7.1
Treatments to be administered
This section was changed in Amendment 4, see Section 15.2.1.
Approximately 60% of eligible subjects will be assigned to Subgroup 1 and the remaining 
eligible subjects will be assigned to Subgroup 2 with the following treatment groups:
Subgroup 1
•
A1:
4 treatment periods of 12 weeks, each separated by 1 bleeding episode
•
A2:
2 treatment periods of 24 weeks, separated by 2 bleeding episodes
•
A3:
3 treatment periods of 12 weeks, each separated by 2 bleeding episodes
•
B:
Standard of care as determined by the investigators
Subgroup 2


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•
A1:
8 treatment periods of 12 weeks, each separated by 1 bleeding episode
•
A2:
4 treatment periods of 24 weeks, each separated by 2 bleeding episodes
•
A3:
6 treatment periods of 12 weeks, each separated by 2 bleeding episodes
•
B:
Standard of care as determined by the investigators
The assignment to the 2 subgroups will be done in a sequential manner, with 60% being 
recruited into Subgroup 1 and the remainder into Subgroup 2. Subjects will be randomized to 
treatment groups A1:A2:A3:B in a 2:2:1:2 manner. Some of the local regulatory agencies 
requested a minimum number of subjects included into the study and well balanced with 
respect to treatment received. Therefore randomization to treatment will be stratified by 
region/country (US, Japan, China and all other countries).
In Groups A1 and A3, each treatment period will consist of 12 weeks (84 days).  In Group A2, 
each treatment period will be 24 weeks (168 days).  One tablet is taken daily during the 
treatment periods.  The tablets should be taken at about the same time every day.  Exceptions 
to this rule may occur before visits with PK blood sampling (see Section 9.5.1).
Start of treatment
Treatment Period 1 for all subjects will start within Days 3 to 7 of the first bleeding episode 
following randomization visit. In case a bleeding episode is ongoing at randomization visit, 
the subject can already start with the intake of study medication during Days 3 to 7 of this 
bleeding episode. A negative pregnancy test is a prerequisite for starting study drug (applies 
to all treatment periods).
The start of each treatment period following Treatment Period 1 will be as follows (see Figure 
5–1):

For Treatment Group A1, Treatment Period 2 and subsequent treatment periods will 
start within Days 3 to 7 of the first bleeding episode following the end of the previous 
treatment period. If no bleeding episode occurs within 7 weeks after end of the 
previous treatment period, sites were to proceed with the induction of bleeding.

For Treatment Groups A2 and A3, Treatment Period 2 and subsequent treatment 
periods will start within Days 3 to 7 of the second bleeding episode following the end 
of the previous treatment period.  If no bleeding episode occurs within 7 weeks after
the end of the previous treatment period or if the 2nd bleeding episode does not occur 
within 7 weeks after the end of the first bleeding episode, sites were to proceed with 
the induction of bleeding.
For the start of treatment, subjects will judge based on their experience whether their bleeding 
episode has started. In case of unusual patterns (eg, start with some days of spotting) subjects 
should consult with the investigator.  
For the statistical analysis, a bleeding episode is characterized by the following entries in the
electronic diary (eDiary):

Day(s) with bleeding/spotting of which at least one day is of intensity “mild” or higher 

Preceded and followed by at least 2 bleed-free days (in case the first bleeding episode 
starts directly after Visit 1, the preceding 2 bleed-free days may not be recorded for 
this first bleeding episode).
Subjects randomized to Treatment Group B will discuss with the investigators whether they 


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need any treatment to get relief from fibroid related symptoms or whether watch and wait is 
the appropriate option. During the study, a subject can switch from “watch and wait” to 
symptomatic nonhormonal treatment or vice versa.  If treatment is needed, the investigator
will prescribe the most appropriate symptomatic nonhormonal treatment to the subject, which 
will be documented in the eCRF.
Missed intake of study drug
If a subject in Treatment Groups A1, A2, or A3 misses a dose of study drug, she should take 
the tablet as soon as possible.  If the dose of study drug was missed by more than 12 hours, 
she should not take the missed dose and simply resume the usual dosing schedule on the 
following day.
Diet
Subjects will be allowed to eat and drink as usual. However, grapefruit and grapefruit juice 
must be excluded from the diets of subjects in Treatment Groups A1, A2, and A3 during
treatment because these foods contain constituents that inhibit cytochrome P450 3A4. 
7.2
Identity of study treatment
The investigational medicinal product vilaprisan is a round immediate-release tablet, 6 mm in 
diameter and coated with a dark red coat (see Table 7–1). Standard of care symptomatic 
nonhormonal medical treatment for uterine fibroids is not considered investigational 
medicinal product.
Table 7–1:
Identity of test drug/vilaprisan tablets 
Sponsor’s substance code
BAY 1002670
INN
Vilaprisan
Brand name
Not applicable
Formulation
Film-coated tablet
Tablet strength
2 mg 
Composition
Active ingredient: Vilaprisan micronized
Other ingredients:
Lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, magnesium stearate, dark red 
lacquer (containing hypromellose, macrogol 3350, talc, titanium 
dioxide, and red ferric oxide)
Packaging
28 tablets per package
Marketing Authorization Holder 
Not applicable
INN = International nonproprietary name.
All study drugs will be labeled consistent with the requirements of local law and legislation.  
Label text will be approved consistent with the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site on request.
For all study drugs, a system of numbering consistent with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies quality assurance group.
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor study file.


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Study drugs need to be stored in accordance with the label text.
7.3
Treatment assignment
At the Visit 3 (randomization), eligible subjects will be randomized via the IVRS/IWRS to
one of the treatment groups (see Section 7.1).
The site will receive confirmation on the completion of the randomization procedure from the 
IVRS/IWRS.  The confirmation will be considered as source documentation and should be 
maintained in the subjects’ files.  For additional details, refer to the separate IVRS/IWRS
instructions.
7.4
Dosage and administration
See Section 7.1 for administration details.
7.5
Blinding
Subjects and investigators are not blinded.
Central readers for BMD and endometrial biopsies will be blinded with regard to treatment 
group and time point of assessment.
7.6
Drug logistics and accountability
No longer valid, since with the implementation of Protocol Amendment 10 (version 7.0)
no subjects will start or continue treatment in this study and therefore no study 
medication will be newly distributed. All unused study drug should have been returned 
during the temporary pause and this should have been documented in the drug 
accountability section of the eCRF and on the appropriate drug dispensing form by the 
investigator or designee.
Receipt, distribution, return and destruction (if any) of the study drug must be properly 
documented consistent with the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
7.7
Treatment compliance
To monitor compliance, subjects were required to complete an electronic Diary (eDiary) daily 
throughout the study.  The date of each study drug intake was tracked via the eDiary.  The 
eDiary was dispensed at Visit 1 and the completeness of the eDiary data reviewed by the 
investigator or designee between the visits regularly, and together with the subject at every 
subsequent visit.


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8.
Non-study therapy
8.1
Prior and concomitant therapy
All concomitant medications administered after signing of informed consent until the 
completion of study participation12, including topical (eg, vaginal) preparations and over the 
counter drugs, are to be recorded in the eCRF (trade name, dose, unit, frequency, route, start 
and stop dates, and indication). This applies with specific focus for medications that could 
interfere with the testing of adrenal parameters. 
Restrictions regarding forbidden concomitant medications were valid before and during the 
treatment phase of this study, but were lifted during the treatment-free safety FUP phase that 
started during the temporary pause and continued with the protocol amendment 10 (Version 
7.0). Please see Section 6.2.
Subjects who withdrew from study drug and subjects who withdrew during FUP were asked 
to not take hormonal treatments before the first menstruation after EoT was completed and an 
endometrial biopsy was performed.
Calcium and vitamin D were not excluded for subjects in the study, but for assessment of 
possible influence on BMD measurements, the intake should be documented on the 
concomitant medication eCRF throughout the study.
Surgical and interventional treatment for fibroids must be documented in the eCRF if 
performed during the study period (ie, until the last visit of the subject) and should be 
regarded as AE if deemed appropriate by the investigator (see Section 9.6.1.1).
Reasonable efforts should be undertaken to capture such interventions also in subjects who 
had already left the study and are now returning.
8.1.1
Iron supplementation
In subjects with hemoglobin 10.9 g/dL in blood, iron supplementation should be offered in a 
standardized regimen consistent with local standards of practice and at the investigator’s 
discretion (see Section 9.7.1). Iron supplementation will not be considered a study medication
and will be documented as concomitant medication.  
8.1.2
Progestin therapy for induction of bleeding
If required, subjects were given an appropriate progestin therapy for induction of bleeding.  
Progestin therapy will not be considered as study medication and will be documented as 
concomitant medication.
8.2
Post-study therapy
This section was changed in Amendment 4, see Section 15.2.1.
Before the temporary pause, it was foreseen that subjects completing the treatment periods
will participate in the post treatment FUP without drug treatment. Subjects randomized to 
Treatment Group B continued with symptomatic nonhormonal medical treatment as 
                                                
12 Subjects who have completed or discontinued the study before or during the temporary pause, who are asked 
to participate in the safety evaluation, the concomitant medication used during the off study period until re-
consenting to this protocol amendment should also be recorded in the eCRF.


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determined by the investigators and/or watch and wait method. During the temporary pause, 
subjects randomized to Treatment Group B were not affected by the requirements of the 
temporary pause (as reflected in standalone Protocol Amendment 9 [version 6.0]) and were 
scheduled to continue with their originally planned visits and investigations. According to the 
rules of the temporary pause, subjects were required to not start any new treatment period and 
thereby those subjects entered a study drug free FUP phase if they agreed to remain in the 
study. Integrated Protocol Amendment 10 (version 7.0) now applies to all study subjects 
irrespective of the Treatment Group that they were assigned to.
At the individual end of study, the investigator will decide in consultation with each subject 
which treatment is further required and will choose from available treatment options.
After completion of the study, subjects will not be given free access to study drug, since 
alternative treatment options are available.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
No longer valid, since with the implementation of Protocol Amendment 10 (version 7.0) 
no subjects will be recruited and none of the enrolled subjects will receive further study 
drug treatment. All subjects who were randomized and started treatment before the 
temporary pause will be asked to have the comprehensive safety evaluation (with 
particular focus on endometrial, adrenal and skin safety) performed which is 
implemented with the protocol amendment 10 (Version 7.0). This also applies to subjects 
who have completed or discontinued the study before or during the temporary pause, 
provided they have taken at least one dose of study medication. Likewise, subjects 
randomized to SoC who are still in the study will be asked to undergo these procedures.
Those subjects randomized to Treatment group B who are still in the study when 
Protocol Amendment 10 (version 7.0) becomes valid are also asked to undergo a DEXA 
scan and the comprehensive safety evaluation.
All these subjects are asked to come to the site for the “Safety closeout visit” which is 
implemented with the protocol amendment 10 (Version 7.0). A second scheduled visit, 
the “Safety result reporting visit” can be done as a telephone visit.
The “Safety closeout visit” should be performed in all subjects as soon as possible after 
implementation of Protocol Amendment 10 (version 7.0). The following procedures are 
to be done:


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Table 9–1: Schedule of procedures
Visit
Safety closeout visit a
Safety result 
reporting visit
(Can be a telephone 
visit)
Timing
After implementation of the 
amendment
Once all safety 
results are available
Informed consent
X
Concomitant medications
→
→
AE assessments
→
→
Adrenal disorder signs and symptoms
incl. vital signs b
X
MRI of adrenal glands c
X
Dispense saliva test tubes d
X
Collect saliva test tubes
X
Referral to dermatology expert
X
Physical examination
X
Body weight
X
Gynecological/breast exam e
X
Urine pregnancy test
X
Cervical smear f
X
Ultrasound examination g
X
Endometrial biopsy h, i
X
Laboratory (blood) j
X
Bone mineral density k
X
Collection of unused study drug and 
empty drug packs/drug accountability
X
if applicable
Collection of eDiary device and review of 
bleeding data for unusual bleeding pattern
X
if applicable
Deactivation of the subject on the tablet 
computer without selecting a particular 
visit 
X
Communication of results from safety 
evaluations to the subject
X
a.
In most cases the procedures scheduled for this visit will not take place on the same day
b.
Blood pressure in triplicates and heart rate after 5 minutes of rest in a sitting position
c.
Negative pregnancy test is a prerequisite
d.
Saliva tests should be performed as soon as possible after dispense, to allow for a repeat in case 
of unevaluable results or for review by one of the adrenal experts in case of abnormal results. 
Saliva test tubes should be returned to site on the next day after samples have been taken on two 
consecutive days
e.
Only to be performed if subject did not have these performed with normal result after end of 
treatment.
f.
Only to be performed if subject did not have this performed with normal or clinically insignificant 
result after end of treatment. Negative pregnancy test is a prerequisite.
g.
The ultrasound must be done before the biopsy
h.
Only to be performed in subjects who did not have a post-treatment endometrial biopsy (defined 
as biopsy taken at the earliest 7 days before last study drug intake) with a normal result. This is 
defined as diagnosis of safety read and of all 3 individual components of the multiread to be 
“benign endometrium” in Part II of the evaluation form. In addition, the majority diagnosis needs to 
be “PAEC no” in Part IV of the evaluation form.
Furthermore, an endometrial biopsy may also be triggered by results of ultrasound examination or 
bleeding data (see Section 9.6.3.2.8).
i.
The biopsy CRF page needs to be completed for all subjects, including cases where according to 
protocol no biopsy is required
j.
In subjects who take biotin, the last dose of biotin should be at least 72 hours prior to hormone 
testing.


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k.
This DEXA scan can be waived, if the requirements described in Section 9.6.3.8 (BMD) are 
fulfilled. Negative pregnancy test is a prerequisite.
CRF = case report form, BMD = bone mineral density, DEXA = dual-energy X-ray absorptiometry, 
incl. = including, MRI = magnetic resonance imaging, PAEC = progesterone receptor modulator-
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9.2
Visit description
No longer valid, since with the implementation of Protocol Amendment 10 (version 7.0)
all subjects will need to come to the site for the “safety closeout visit”. In most cases the 
procedures scheduled for this visit will not take place on the same day. 
The second scheduled visit, the “Safety result reporting visit” can be done as a telephone 
visit. During this visit the subject will be informed about the results of the safety 
investigations. In case follow-up assessments required, these should be documented as 
unscheduled assessments.
9.2.1
Optional pre-screening phone contact
No longer valid, since with the implementation of Protocol Amendment 10 (version 7.0)
no new subjects will be recruited.
9.2.2
Scheduled visits
With the implementation of Protocol Amendment 10 (version 7.0) all subjects will need 
to come to the site for the safety closeout visit. For details regarding this safety closeout 
visit, please see Section 9.1.
The second scheduled visit, the “Safety result reporting visit” can be done as a telephone 
visit.
9.2.3
Unscheduled visits
If deemed necessary for an individual subject, the investigator or designee, at his/her 
discretion, may arrange visits in addition to the scheduled study visits.  A possible reason for
unscheduled visit would be the requirement for follow up investigations.
9.3
Population characteristics
With implementation of Protocol Amendment 10 (version 7.0), no new subjects will be 
recruited. This section describes the data collection performed in subjects enrolled 
before the temporary pause.
9.3.1
Demographic
Demographic data (eg, year of birth, age at Visit 1, race, ethnic group, educational level) and 
other population characteristics including smoking habits and alcohol consumption were
collected.
9.3.2
Medical history
Medical history findings (ie, previous diagnoses, diseases or surgeries) meeting all criteria 
listed below were collected as available to the investigator:

Not pertaining to the study indication

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility
Any condition that was stabilized by medication at the time of signing the informed consent 
should also be documented in the eCRF.  The medication had to be recorded in the prior and 
concomitant medication eCRF.


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All new or worsened findings after signing the informed consent had to be documented on the 
AE eCRF.
Detailed instructions on the differentiation between medical history and AEs can be found in 
Section 9.6.1.1.
9.3.3
Reproductive, menstrual, and fibroids history
Reproductive and menstrual history includes information on menarche, births, other 
pregnancies, and inability to conceive.
Fibroids history includes information on family history, onset of symptoms, diagnosis, and 
previous medical treatments and procedures, if applicable.
9.3.4
Heavy menstrual bleeding questions
This section was changed in Amendment 4, see Section 15.2.1.
This set of questions has been developed as a tool to identify women with HMB.  It could 
have been used at Visit 1 only and the responses could have been entered directly into the 
electronic data capturing system (RAVE), which is considered as primary source data. The 
questionnaire could also have been used as a pre-screening tool. A printed version of the 
questionnaire were provided to the sites as needed.
9.4
Efficacy 
This section details the procedures for collecting efficacy variables.  A concise listing of 
efficacy variables as collected before the temporary pause is given in Section 10.3.1.  The 
complete list of variables to be analyzed for this study will be provided in the Statistical 
Analysis Plan (SAP).
9.4.1
Ultrasound (efficacy) to assess uterine fibroids
This section was changed in Amendment 4, see Section 15.2.1.
Ultrasound examinations were performed by a well experienced examiner. If possible, the 
same examiner should have conducted all examinations of a subject throughout the study and 
the same ultrasound machine (per site) should have been used throughout the study.  For each 
subject, the most appropriate ultrasound method (transvaginal, abdominal or transrectal) had 
to be used depending on fibroid location and this method should have been used consistently 
throughout the study.
Ultrasound examinations were to be performed consistent with the schedule of procedures in 
Protocol Amendment 7 (version 5.0). The 3 largest fibroids were to be identified during the 
screening period.  The largest transverse, longitudinal, and antero-posterior diameters of these 
3 fibroids were to be documented at each efficacy ultrasound examination for volume 
calculation.
The dimensions of the uterus were also to be documented at the same time points.  This is of 
particular importance in subjects with multiple small fibroids.
The minimum source documentation included electronic or paper documentation from the 
ultrasound machine showing the 3 largest fibroids. The printouts had to be labeled 
unambiguously, containing at least the study number, subject number, time point, and longest 
diameter of 3 largest fibroids.


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It is also possible that the site has a CD with the ultrasound images available, when in the 
source the evaluation of the ultrasound images from the CD is available as well. The CRA has 
to be able to review the data on the CD and compare the images with the evaluations in the 
source during the onsite monitoring visits.
Furthermore, if the ultrasound machine is SESAC (Site Electronic Source Assessment
Checklist) conform, ie, GCP conform electronic data storage is possible, then no print out is 
needed.
For safety ultrasound procedures, see Section 9.6.3.6.
9.5
Pharmacokinetics / pharmacodynamics
With the implementation of Protocol Amendment 10 (version 7.0), no new subjects will 
be recruited and no study medication or standard of care symptomatic nonhormonal 
will be given to the subjects who have been enrolled in the study. This Section 9.5 
describes processes performed in subjects enrolled before the temporary pause.
9.5.1
Drug measurements
Blood samples for measurement of vilaprisan in plasma for PK were to be collected at the 
time points given in schedule of procedures in Protocol Amendment 7 (version 5.0) from 
subjects in Treatment Groups A1, A2, and A3 only. At the EoT Visit (Subgroup 1) and Visit 
6 (Subgroup 2, Treatment Group A3) and Visit 7 (Subgroup 2, Treatment Groups A1 and A2), 
3 PK samples were to be taken.  The first sample was to be taken before intake of study drug.  
Afterwards the subject should have taken her study drug under supervision at the site.  The 
second sample was to be taken 0.5 to 1 hour after drug intake and the third sample was to be 
taken 2 to 4 hours after drug intake.  The date and time of the last 2 vilaprisan doses prior to 
the first PK sample at each visit, the time of the supervised drug intake at the study site, and 
the time of all blood samples had to be documented in the eCRF.
For Subgroup 2 (Treatment Groups A1, A2, and A3), one PK sample was to be taken predose 
at the EoT visit.  The date and time of the last 2 vilaprisan doses prior to the PK sample, the 
time of the supervised drug intake at the study site, and the time of the blood sample had to be 
documented in the eCRF.   
If, for any reason, PK samples were taken outside of the pre-specified time window, the exact 
time that the sample was taken should have been recorded and not the time of the time 
window.
If a subject discontinued study treatment permanently, no blood sampling for PK was 
required.
In China, samples were to be collected in selected centers only, to achieve a minimum number 
of at least 30 Chinese subjects.
Pharmacokinetic analyses are based on a population modeling approach (see Section 9.5.2)
using valid PK samples. Blood samples are considered valid for the population PK analysis 
under the following conditions:
1) The dose amount and time of drug intake prior to the blood sample is known.
2) The time of the blood sample collection is known.
The samples were to be collected and processed as described in detail in the respective 
Sample Handling Sheets as a part of a separate Laboratory manual.


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Plasma concentrations of vilaprisan are determined using a validated liquid chromatography–
tandem mass spectrometry (LC-MS/MS). Quality control (QC) and calibration samples are
analyzed concurrently with study samples. The results of the calibration samples and QC 
samples will be reported in the Bioanalytical Reports, which will be included in the Clinical 
Study Report for this study. A re-opening of the database may become necessary in order to 
include the results of the PK measurements.
The bioanalyst will be unblinded for analysis of study samples.  
9.5.2
Population pharmacokinetic analysis of vilaprisan
Based on the plasma concentrations, the variability in vilaprisan PK will be analyzed using 
population PK modeling.  This analysis might start prior to database lock (eg, at the moment 
that approximately 80% of the expected PK samples have been measured
Population or nonlinear mixed effects PK models describe the relationship between dose, 
time, and the vilaprisan plasma drug concentration. A previously developed population PK 
model for vilaprisan based on Phase 1 and 2 data will be applied to all valid PK samples to 
evaluate the relationship between variability in PK and covariates (ie, intrinsic [eg, body 
weight, race] and extrinsic factors [eg, concomitant medication]) that are of clinical relevance.   
If necessary, the population PK model will be adapted to adequately fit the data. A separate 
Modeling and Simulation (M&S) Plan, providing details of the model development and 
evaluation will be provided before the start of the population PK analysis.  Evaluation of the 
data will be presented in a separate M&S Report.
9.5.3
Pharmacokinetic/pharmacodynamic relationship of vilaprisan
Optionally, population PK/PD modeling could be applied to describe the effect of vilaprisan 
exposure on PD data related to efficacy and safety such as bleeding intensity and endocrine 
hormone levels.  The final population PK model that will be used to describe the PK of 
vilaprisan as outlined in Section 9.5.1 will be linked to relevant PD parameters (ie, fibroid 
size, uterus size, endocrine hormone levels, and bleeding) to investigate the (PK/PD)
relationship between vilaprisan exposure and response.  Details of the model development and 
evaluation, if conducted, will be described in a separate M&S Analysis Plan and the results 
reported in a separate M&S Report.
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of AE
In a clinical study, an AE is any untoward medical occurrence (ie, any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing signed and dated informed consent for 
participation in the study.  Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. Treatment emergent adverse 
event (TEAE) is defined as any event that occurred on or after the first study drug intake (for 
Treatment Groups A1, A2, and A3) / randomization (for SoC group) until the end of FUP.


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A surgical procedure that was planned before the start of the study by any physician treating 
the subject should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal eg, physical examination findings, symptoms, diseases, and laboratory 
findings.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (eg, seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (eg, allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs.

In subjects who completed or discontinued before or during the temporary pause and 
now get reconsented, conditions that newly occurred or worsened during the off-study 
period should be documented as AEs.
Definition of SAE
A serious AE (SAE) is classified as any untoward medical occurrence that, at any dose, meets 
any of the following criteria (a – f):
a. Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
The admission results in a hospital stay of less than 12 hours
The admission is pre-planned (ie, elective or scheduled surgery arranged 
before the start of the study)
The admission is not associated with an AE (eg, social hospitalization for 
purposes of respite care)
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.  
Any fibroid surgery should always be reported as SAE, irrespective of associated 
hospitalization. 
d. Results in persistent or significant disability/incapacity


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Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e. Is a congenital anomaly/birth defect
f.
Is another medically important serious event as judged by the investigator and/or 
defined below:
All instances of liver parameter testing which meet the criteria for withdrawal defined in the 
original study protocol (see Section 6.4.1) of a subject from the study should be reported as 
SAEs.
Endometrial biopsies with a safety read diagnosis of “simple or complex atypical hyperplasia” 
(according to WHO 1994 criteria) or “EIN” (according to WHO 2014 criteria) (2) or in a 
diagnosis of “malignant neoplasm” (“endometrial” or “other”) should be reported as a serious 
adverse event. The subsequent multi-reader assessment should trigger a follow-up report and 
an update of the diagnosis should be considered, if the majority assessment is different from 
the initial safety read diagnosis.
Endometrial biopsies with a majority diagnosis based on the multi-reader assessment of 
“simple or complex atypical hyperplasia” (according to WHO 1994 criteria) or “EIN” 
(according to WHO 2014 criteria) or in a diagnosis of “malignant neoplasm” (“endometrial” 
or “other”) should be reported as a serious adverse event or trigger an update of the respective 
initial SAE report. 
A diagnosis of an adrenal tumor needs to be reported as an SAE.
Any dermatology expert´s diagnosis of a malignant skin lesion, including cutaneous sarcoma 
confirmed by biopsy diagnosis, needs to be reported as an SAE.
The following types of events are excluded from SAE reporting:

Elective abortion is considered as an ‘abnormal pregnancy outcome’ but is not 
considered an SAE.  (However, abortions are to be documented as SAEs if they match 
one of the following terms:  spontaneous abortion, missed abortion, infected abortion, 
or abortion induced incomplete.  If no specification for the abortion is available, then
one of these categories is assumed to have occurred and the ‘abortion’ is regarded as 
serious and must be recorded as an SAE.)

Hospitalizations for the evaluation or treatment of pre-existing conditions that do not 
worsen in severity or frequency during the subject’s participation in the study.  Such 
conditions must have been present before the subject’s participation in the study and 
reported as such in the corresponding eCRF.

Elective surgery performed for cosmetic reasons or because of pre-existing conditions 
as defined in Section 9.3.2.
Important medical event:  Any AE may be considered serious because it may jeopardize the 
subject and may require intervention to prevent another serious condition.  As guidance for
determination of important medical events, refer to the “World Health Organization (WHO) 
Adverse Reaction Terminology – Critical Terms List”.  These terms either refer to or might be 
indicative of a serious disease state.  Such reported events warrant special attention because of 
their possible association with a serious disease state and may lead to more decisive action 
than reports on other terms.


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9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined consistent with the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:

Mild

Moderate

Severe
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a clear alternative explanation, eg, mechanical bleeding at surgical 
site.
or
2. Non-plausibility, eg, the subject is struck by an automobile when no indication exists 
that the drug caused disorientation that may have caused the event; cancer developing 
a few days after the first drug administration.
An assessment of “yes” indicates that a reasonable suspicion exists that the AE is associated 
with the use of the study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:

The temporal sequence from drug administration:  The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated in 
the clinical context of the event.
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Subject’s response after de-challenge or subjects response after re-
challenge should be considered in the view of the usual clinical course of the event in 
question.

Underlying, concomitant, intercurrent diseases:  Each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.


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
Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might be suspected to cause the event in question.

Known response pattern for this class of drug: Clinical/preclinical

The pharmacology and PK of the study treatment: The PK properties (absorption, 
distribution, metabolism and excretion) of the study drug treatment, coupled with the 
individual subject’s PD should be considered.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose not changed

Not applicable (only option for Treatment Group B)

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
9.6.1.3
Assessments and documentation of adverse events
Attention is to be paid to the occurrence of AEs at all stages of the examination.  Thus, all 
subjects should be closely observed by the investigator.


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AEs observed, mentioned on open questioning by a member of the investigator team or 
spontaneously reported by the subject will be documented.  The observation period for AEs 
will start with signing of the informed consent and will end with the last visit. After the 
Safety reporting visit, there is no requirement to actively collect new AEs including deaths. 
The outcome of recorded non-serious AEs should be followed up between the signing of the 
informed consent and the end of the FUP phase. For adverse events of special safety interest, 
efforts should be made to follow them up until resolution or stabilization (even after the 
telephone visit, if applicable).
The investigator is responsible for the grading of each category listed in Section 9.6.1.2.  An 
assessment of the seriousness of the event will be made by the investigator using the 
electronic reporting tool in RAVE.  However, SAEs will also be recorded on the AE page of 
the eCRF.
For all SAEs the sponsor has to perform a separate assessment for expectedness, seriousness, 
and causal relationship to study drug.
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For details on monitoring algorithms see Section 9.7.
9.6.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 using the electronic 
reporting tool in RAVE (see Section 11.1) according to the detailed instructions for SAE 
reporting included in the Investigator File. 
SAEs occurring after the protocol-defined observation period will be processed by the sponsor 
consistent with all applicable regulations.
Notification of the IECs/IRBs
Notification of the Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
about all relevant events (eg, SAEs, suspected, unexpected, serious adverse reactions 
[SUSARs]) will be performed by the sponsor and/or by the investigator consistent with all 
applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (eg, SAEs, SUSARs) to the authorities will 
be done by the sponsor consistent with all applicable regulations.


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Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (eg, SUSARs) 
consistent with all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the IB.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor consistent with the applicable 
reference document and consistent with all local regulations.
9.6.1.6
Adverse events of special safety interest
This section was changed in Amendment 4, see Section 15.2.1.
The investigators will assess all AEs to determine if they are AEs of special interest (AESIs)
and document this in the eCRF.  Adverse events from the following areas should be 
considered for reporting as AESI according to the following guidance:

HMB (especially during treatment breaks or after EoT) should be recorded as an 
AE (and then it automatically qualifies as an AESI) only if one or more of the 
following applies: 

Leads to study discontinuation

Leads to diagnostic procedures

Requires any treatment

Shows a clinically significant worsening during the study that, in the 
judgment of the investigator, is not consistent with the expected clinical 
course

Meets any seriousness criterion and is to be recorded as an SAE
HMB will be documented in detail throughout the study (see Section 9.7.3).

Liver disorders:

For all cases which qualified for “close observation” before implementation of 
Protocol Amendment 10 (version 7.0) and/or qualify for “ruling out of alternative 
cause” after implementation of the protocol amendment 10 (Version 7.0) (see 
Section 9.6.3.10), the underlying event should be recorded as AESI in the AE 
eCRF.

Endometrial disorders:

Endometrial hyperplasia (all subcategories according to WHO 2014 [and WHO 
1994] classification), for monitoring and FUP see Section 9.6.3.2.

Endometrial thickening >18 mm: If endometrial thickness (double layer) 18 mm 
is detected after the start of treatment, the subject should undergo immediate 
evaluation by endometrial biopsy as described in Section 9.7.4.

Skin disorders:


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
Any dermatology expert´s diagnosis of a pre-cancerous or malignant skin lesion, 
including cutaneous sarcoma confirmed by biopsy diagnosis, qualify as an AESI. 
Malignant skin lesions should be reported as an SAE to ensure timely reporting to 
regulatory agencies.

Adrenal disorders

A robust adrenal safety monitoring program has been implemented in all ongoing 
vilaprisan studies, including MRI of the adrenal glands, laboratory parameters, and 
evaluation of signs and symptoms indicative of adrenal disorder. A systematic 
approach of assessment and evaluation of adrenal gland findings will be applied as 
described in Section 9.6.3.9. Any adrenal abnormality assessed as relevant by 
either the adrenal gland expert or the local specialist will need to be documented as 
an AESI and to be reported to the sponsor´s pharmacovigilance department 
following the same standard process (reporting timelines, AE CRF and AE 
complementary pages) as serious AE. Tumors of the adrenal glands (diagnosed by 
the MRI central read, the adrenal gland expert or the local specialist) should in 
addition be reported as SAEs to ensure timely reporting to regulatory agencies.
Progesterone receptor modulator-associated endometrial changes (PAEC) will be assessed and 
documented in a systematic way (see Section 9.6.3.2.4).  The results of the PAEC assessment 
will only be reported back to the investigators if they trigger the request for a repeat biopsy.  
Apart from cases where such a repeat biopsy is necessary, no clinical action for an individual 
subject is required based on the PAEC assessment results.  PAEC assessment results are 
systematically collected for all samples and will be reported in aggregated form at the end of 
the study.  They should therefore not be reported as AE for an individual subject.  

Relevant loss of BMD during treatment: 

BMD loss of >6% of the lumbar spine that is accompanied by a Z-score reading of <-2 
SD (determined either by central reading or by assessment at the site and confirmed by 
the central reading at the 12 months visit or later).

“Lack of adequate bone recovery in subjects treated with vilaprisan or significant bone 
loss in subjects randomized to Treatment group B” defined as BMD loss ≥3% bone 
loss at any site and/or Z-score of ≤-2 at any site compared to baseline, irrespective of 
the absolute bone loss in an off-treatment DEXA scan (determined either by central 
reading or by assessment at the site and confirmed by central reading).
A same systematic approach of assessment and evaluation will be applied to HMB (see 
Section 9.7.3), endometrial hyperplasia and endometrial thickening (see Sections 9.7.2 and 
9.7.4), and liver parameters. 
9.6.2
Pregnancies
This section was changed in Amendment 4, see Section 15.2.1.
An acceptable nonhormonal contraceptive method has to be used starting at Screening Visit 1 
and continued until the end of the study.  Barrier contraception, eg, condoms with spermicide 
will be dispensed as required by the subject. This is not required if contraception is achieved 
by a permanent method such as bilateral fallopian tube blockage (including Essure) of the 
subject or vasectomy of her partner(s). 


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Pregnancy tests will be performed at site visits and at home before the start of study drug in 
each treatment period.  Home pregnancy tests should also be performed in case the subject is 
concerned about being pregnant.  All home pregnancy tests will need to be documented in the 
eDiary. In case of a positive pregnancy test, study drug must be discontinued and the 
investigator must be informed immediately.
Any planned pregnancy should be postponed until the end of the study.  This is to be 
discussed with the subject at screening.  If an investigator becomes aware that a subject
wishes to conceive or plans an insemination directly after EoT (thereby deviating from study 
protocol), the subject should be reminded that she is participating in a clinical study with a 
new drug in clinical development. Therefore she should preferably complete the FUP phase 
(including endometrial biopsy) or should at least wait for 3 months/2 menstrual cycles after 
discontinuation of study drug treatment due to unknown effect of the study drug on the human 
embryo.
In subjects who were currently pregnant or lactating when the protocol amendment 10 
(Version 7.0) was implemented, timing of the safety evaluations required in the context of the 
safety closeout visit should have been decided case by case.
Pregnancies occurring during the study
The sponsor will closely monitor the occurrence of unintended pregnancies (based on the 
expedited reporting of pregnancies by the investigators) throughout the study.  If a pregnancy 
is detected before initiation of study drug, the subject will not be enrolled into the study (see 
Section 6.2).
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
the subject’s participation in this study.  The report should be submitted within the same 
timelines as an SAE (ie, no later than 24 hours of having gained knowledge of the event; see 
Section 9.6.1.4), although a pregnancy per se is not considered an AE or SAE.  The subject 
was instructed to contact the study site immediately if a pregnancy is suspected or detected.  
In such a case, an unscheduled visit should be arranged for the subject as soon as possible and 
the investigator or designee should confirm the pregnancy by a valid method (eg, ultrasound, 
serum beta human chorionic gonadotropin [-HCG] test).  If such confirmation cannot be 
achieved within 24 hours of the subject contacting the study center, the investigator must still 
report the pregnancy to the sponsor and then FUP with information once confirmation has 
been obtained.  A pregnancy will be reported on the forms provided by the sponsor.  The 
investigator is required to document the date of confirmatory testing, whether the pregnancy 
was confirmed, the estimated dates of conception, and the location of the pregnancy
implantation at time of diagnosis.
The investigator is required to provide any additional information (eg, early termination) as 
soon as it becomes available.
All pregnancies occurring during the treatment and FUP periods will be followed for the 
outcome for both the mother and fetus/child (in case of a live birth) until first birthday of the 
child.  The outcome will be documented on a pregnancy outcome form and a FUP report is 
requested at the first birthday of the child.
Any abnormal outcome of the mother or the child should also be reported as an SAE (eg,
spontaneous abortion, preterm birth, elective abortion triggered by medical concern).
For details on elective abortions, refer to Section 9.6.1.1.


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For all reports, the forms provided are to be used.
9.6.3
Further safety
9.6.3.1
Laboratory evaluations
This section was changed in Amendment 4, see Section 15.2.1.
Only blood and urine samples analyzed at the central laboratory will be considered for 
analysis. The name and address for the central laboratory service provider can be found in the 
documentation supplied by the vendor.    
The following parameters will be assessed at the safety closeout visit in subjects who 
remained in the study during the temporary pause:
Hematology:
Leukocytes, erythrocytes, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), platelets, neutrophils, eosinophils, basophils, lymphocytes, and 
monocytes.
Hemoglobin (Hb concentration)
Serum chemistry:
Creatinine, chloride, potassium, sodium, calcium, total protein, albumin, total cholesterol, 
high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, 
triglycerides, ALT, AST, AP, gamma-glutamyl transpeptidase (GT), and total bilirubin (in 
case the result is > 2xULN, conjugated and unconjugated bilirubin will be determined).
See Section 9.6.1.6 for procedure in case of elevated liver enzymes.
Biochemistry:
Glycosylated hemoglobin (HbA1c) and ferritin
Additional parameters13:
Hormones (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estradiol [E2], 
progesterone [P], prolactin, and thyroid-stimulating hormone [TSH]), bone markers (bone-
specific alkaline phosphatase, osteocalcin, and collagen type 1 cross-linked C-telopeptide 
[CTX]), and vitamin D (serum 25-hydroxyvitamin D.
In case of elevated liver enzymes requiring investigation of alternative cause the 
following parameters will have to be determined (in earlier CSP versions this was 
summarized in a particular section “close observation”): 
Serum chemistry panel (see above), A1AT level, conjugated bilirubin, ceruloplasmin, 
cholinesterase, CK, ferritin, full blood count (incl. eosinophilia), hemoglobin, INR, iron, 
LDH, platelets, PT, total iron binding capacity (TIBC), testing to rule out Hepatitis A-, 
Hepatitis B-, Hepatitis C, Hepatitis E-, Cytomegalo-, Epstein-Barr-, and Herpes simplex virus 
infection, brucellosis, leptospirosis, and toxoplasmosis, ANA/ANCA screening with further 
tests depending on result and IgA, IgG, and IgM, potentially also testing to rule out 
Hepatitis D.
                                                
13 Blood samples should be taken at least 72 hours after the intake of high doses of biotin, since the laboratory 
results of ferritin, TSH, FSH, LH, estradiol, prolactin, progesterone, cortisol, ACTH and -CTx may be affected, 
if the subject had a biotin intake at a concentration higher than 5 mg per day which occurred less than 72 hours 
before the sample is taken


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Parameters measured for adrenal monitoring:

serum cortisol (to be measured between 6 am and 10 am)
o
ACTH will be assessed from the same sampling if the cortisol measurement yields 
an abnormal value.

late night salivary cortisol (to be obtained between 11 PM and midnight)

serum dehydroepiandrosterone sulfate (DHEA-S)
o
the age-specific DHEA-S ratio (derived by dividing the patient’s DHEA-S value 
by the lower limit of the age-specific reference range) will be calculated. In case of 
an abnormal DHEA-S ratio ACTH will be assessed from the sample taken for 
serum cortisol measurement

serum total testosterone (tT)

serum glucose measurement under fasting conditions

serum potassium.
The following parameters will be assessed at the safety closeout visit in subjects who 
have completed or discontinued the study before or during the temporary pause:

estradiol

vitamin D (serum 25-hydroxyvitamin D)

Parameters measured for adrenal monitoring:

serum cortisol (to be measured between 6 am and 10 am)
o
ACTH will be assessed from the same sample if the cortisol measurement 
yields an abnormal value.

late night salivary cortisol (to be obtained between 11 PM and midnight)

serum dehydroepiandrosterone sulfate (DHEA-S)
o
the age-specific DHEA-S ratio (derived by dividing the patient’s DHEA-S
value by the lower limit of the age-specific reference range) will be calculated.
In case of an abnormal DHEA-S ratio ACTH will be assessed from the sample 
taken for serum cortisol measurement.

serum total testosterone (tT)

serum glucose measurement under fasting conditions

serum potassium

glycosylated hemoglobin (HbA1c).
For urine pregnancy test, see Section 9.6.3.7.


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9.6.3.2
Endometrial biopsies
9.6.3.2.1
Algorithm for evaluation of endometrial safety
Figure 9–1: Overview of the endometrial safety monitoring algorithm
1 Normal is defined as: Diagnosis of safety read of all 3 individual components of the multiread needs to be “benign endometrium” in Part II of the evaluation 
form. In addition, the majority diagnosis needs to be “PAEC no” in Part IV of the evaluation form.
2.Post-treatment biopsy is defined as biopsy taken at the earliest 7 days before last study drug intake. For subjects with menstrual cycles the endometrial biopsy 
should be taken between Day 7 to 15 (inclusive) of a menstrual cycle.
PAEC = progesterone receptor modulator-associated endometrial changes, TVU = transvaginal ultrasound


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9.6.3.2.2
Timing of last endometrial biopsy
Each subject should have an endometrial biopsy with a normal14 result documented from a 
timepoint taken at the earliest 7 days before last study drug intake.
For subjects with menstrual cycles the endometrial biopsy should be taken between Day 7 to 
15 (inclusive) of a menstrual cycle.
Subjects who did not have such a biopsy before or during the temporary pause or those who 
have an abnormality in TVU and/or bleeding pattern are required to undergo an endometrial 
biopsy at the safety closeout visit. 
This also applies to subjects who started treatment and have completed or discontinued the 
study before or during the temporary pause. At least three attempts and a certified letter 
should be made by the site to get in contact with such subjects. The attempts should be 
documented in the patient file.
The biopsy CRF page should be filled out for every subject at the safety closeout visit. This 
also applies to subjects who do not require a new biopsy according to the guidance above. The 
CRF page allows to capture the reason why a biopsy was not done.
Depending on the result of the last scheduled biopsy repeat unscheduled endometrial biopsies 
should be performed in addition. See Sections 9.6.3.2.5 and 9.6.3.2.7 for details.
9.6.3.2.3
Sampling of endometrial biopsies
All endometrial biopsies must be collected by a gynecologically well experienced physician.
A negative pregnancy test is a prerequisite for performing an endometrial biopsy. In addition, 
an ultrasound should be performed before each biopsy.
If a cervical smear sample is collected at the same visit, those procedures have to be 
performed before performing the biopsy.
The sterilized, disposable device Pipelle de Cornier will be used – a flexible and transparent 
polypropylene sheath with an internal plunger for aspiration. This device allows for gentle 
tissue sampling, without hysteroscopy, and generally requires no local anesthesia or cervical 
dilatation. 
The following contraindications have to be strictly adhered to: pregnancy (ie, positive urine 
pregnancy test), and local inflammation (eg, vaginitis, cervicitis). 
                                                
14 Normal defined as: Diagnosis of safety read and of all 3 individual components of the multiread needs to be “benign 
endometrium” in Part II of the evaluation form. In addition, the majority diagnosis needs to be “PAEC no” in Part IV of 
the evaluation form.


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Any procedure-related complaints will be documented as AEs. If necessary for pain 
prophylaxis or relief relating to the endometrial biopsy procedure, the use of an analgesic is 
permitted and will be documented as concomitant medication (investigator’s choice; however, 
no intake of acetylsalicylic acid or any other medication substantially influencing bleeding). 
9.6.3.2.4
Assessment of endometrial biopsies
Blinding and distribution of biopsy samples will be organized by the central laboratory.
Central assessment of endometrial biopsies will be performed in 2 steps, i.e. safety assessment 
and multi-reader assessment. In cases where an abnormality, e.g. atypia or malignancy, cannot 
be ruled out, readers will select the most severe diagnosis:
Safety assessment
The safety assessment will be performed by one pathologist who will be blinded regarding 
treatment group. The results of the safety assessment need to be available in time to 
document.

Any relevant pathology that requires further diagnostic or therapeutic measures 
according to local medical practice

Absence of clinically relevant endometrial pathology before the subject leaves the 
study 

A repeat endometrial biopsy will be requested, if sample is inadequate for evaluation 
in the safety assessment.

For follow-up of biopsies with abnormalities see Section 9.6.3.2.5.
Multi-reader assessment
The multi-reader assessment will be performed by a panel of pathologists who will be blinded 
regarding treatment group and time point of sample. 
A majority consensus diagnosis of the multi-reader assessment is derived from the individual 
diagnoses of the pathologist panel (single-reader diagnoses), according to pre-specified rules.
In the absence of a majority consensus, the most severe diagnosis is used. The derived 
diagnosis resulting from these rules will be used for primary analysis of endometrial biopsy 
data. The individual diagnoses of each reader will be captured in addition.  
Starting with this Protocol Amendment 10 (version 7.0), the majority diagnosis of the multi-
reader assessment including the single reader assessment (Part II of the evaluation form, i.e. 
the diagnoses of either benign endometrium, endometrial hyperplasia or malignant neoplasm) 
will be communicated to the study sites once the majority consensus diagnosis is available. 
A repeat endometrial biopsy will be requested, if sample is inadequate for evaluation in the 
majority multi-reader assessment.
For follow-up of biopsies with abnormalities see Section 9.6.3.2.5.
Besides standard safety criteria (e.g., proliferative/secretory/atrophic endometrium, 
endometrial hyperplasia, malignant neoplasm) the pathologists will document the presence of 
PAEC (see Section 9.6.3.2.6). The results of the PAEC assessment will not be reported back 
to the investigators except if in the last biopsy within the study, PAEC is still present and 
further biopsy sampling is needed.


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The main study evaluation will be based on the majority diagnosis of the multi-reader 
assessment. An analysis of single-reader diagnoses that is more severe than the majority 
diagnosis will be provided in the Study Report. 
While the relevant diagnosis for study purposes is the majority result of the multi-reader 
assessment, any single reader diagnosis that is more severe than the majority diagnosis, should 
be evaluated by the investigator (or by a gynecologist in case the investigator or sub-
investigator is not specifically trained in gynecology) for the necessity of therapeutic 
interventions. The minimal requirement for those cases is a follow up biopsy. For all follow-
up examinations and/or therapeutic interventions all efforts should be taken that these 
examinations are conducted according to the standards of this protocol (e.g. biopsies should 
undergo multi-reader assessment) and are documented within the study framework.
9.6.3.2.5
Follow-up of endometrial biopsies with abnormalities
Endometrial biopsies with a safety-reader diagnosis (Part II of the evaluation form) other than 
“benign endometrium” (i.e. “Malignant neoplasm”, “Endometrial Hyperplasia” with or 
without atypia) should undergo an expedited multi-reader assessment. If an expedited multi-
reader assessment is not possible (e.g. due to sample export regulations), follow-up 
procedures will be decided based on the safety-reader diagnosis.
Endometrial biopsies with a multi-reader majority diagnosis (Part II of the evaluation form) 
other than “benign endometrium” (i.e. “Malignant neoplasm”, “Endometrial Hyperplasia” 
with or without atypia) should be followed-up according to investigator15 assessment, i.e., 
either by performing endometrial biopsies, until resolution (i.e. until a follow-up biopsy 
shows a majority diagnosis of “Benign endometrium”) or by performing a therapeutic 
intervention as per local standard of care.
The timing of follow-up biopsies and/or possible therapeutic interventions according to local 
standard of care will be determined by the investigator (or by a gynecologist in case the 
investigator or sub-investigator is not specifically trained in gynecology) according to the 
observed abnormality. Typically, at least one endometrial shedding should have occurred 
before a follow-up biopsy is performed.
The follow-up biopsies should be performed within the study framework and analyzed by 
blinded multi-reader assessment. In case follow-up biopsies and/or other interventions are 
conducted at non-study sites, all efforts should be taken that results are obtained and 
documented appropriately.
For FUP of a majority diagnosis of “Benign endometrium – PAEC yes” please see Section
9.6.3.2.6.
For reporting of abnormal biopsy results as adverse event of special interest or SAE, please 
see Sections 9.6.1.1 and 9.6.1.6.
9.6.3.2.6
Follow-up of PAEC
Besides standard criteria (i.e., proliferative/secretory/atrophic endometrium, endometrial 
hyperplasia) presence of PAEC will be analyzed in all endometrial biopsy samples as part of 
the multi-reader assessment. The diagnosis of PAEC is based on a constellation of histologic 
                                                
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features that, taken together, are characteristic. None of the features is unique, and to some 
extent any may be seen in patients who have not been treated with PRMs. The common 
histologic features are endometrial glands showing cystic dilatation and an irregular 
architecture lined by inactive gland cells and compact, nondecidualized stroma. 
If PAECs have been detected in the biopsy at the last visit before leaving the study (i.e. at the 
scheduled FUP visit or at a premature discontinuation visit) according to the majority 
diagnosis resulting from the multi-reader assessment, the site will be informed and an 
additional FUP biopsy should be scheduled. In case PAEC findings are still present, the study 
site will be informed and an additional biopsy is to be taken to evaluate resolution, with the 
timepoint of this additional biopsy to be determined case-by-case. If needed, more than one 
repeated biopsy may be taken and analyzed, except for cases with PAEC already present in 
the pre-treatment biopsy.
9.6.3.2.7
Heavy menstrual bleeding / suspicious bleeding pattern
The study drug was administered in a study population with symptomatic heavy menstrual 
bleeding. The study drug itself leads to changes in bleeding pattern, mostly amenorrhea during 
treatment, but can also be associated with intermittent spotting or mild intermittent bleeding 
of short duration. Heavy menstrual bleeding is expected to return in the FUP phase after 
cessation of treatment.
Because unusual bleeding patterns or unusually heavy menstrual bleeding can also be a sign 
of endometrial pathology, the subject should be instructed to report changes in bleeding 
pattern or bleeding volume that seem unusual to her (and does not resemble the subject´s 
natural cycle or bleeding pattern). In case such unusual bleeding events are reported or are 
detected from the MP or UF-DBD the subject should undergo immediate evaluation by the 
investigator. With the safety closeout visit a review of the bleeding data entered during the 
temporary pause should rule out any suspicious bleeding that would need immediate 
evaluation.
Standard criteria for evaluation of unusual HMB or bleeding pattern identified from 
review of bleeding data or reports by the subject during the temporary pause
As guidance the following occurrences should be considered for further evaluation in the 
context of unusual bleeding: 

Prolonged bleeding:
Evaluation should be initiated if

Prolonged bleeding is reported by the subject and/or

the subject entered more than 10 consecutive days of bleeding in the e-diary 
(intensity of “mild” or more) during study drug intake (ie, during a treatment 
period).

Continuous spotting:
Evaluation should be initiated if

Continuous spotting is reported by the subject and/or


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
if the subject entered “spotting” into the bleeding diary component of the e-
diary consecutively for 10 days or more, with a maximum of 2 spotting-free 
days in between.

Unusual heavy bleeding:
Evaluation should be initiated if

Unusually heavy bleeding is reported by the subject and/or

If blood loss per bleeding episode is more than 50% higher than the subject´s 
baseline blood loss (when observed via the menstrual pictogram or alkaline 
hematin method). 
Evaluation plan for subjects with unusual HMB or bleeding pattern
The evaluation should include the following assessments:
o
Comparison of subject’s subjective report with documented bleeding pattern and 
amount of blood loss (UF-DBD and MP, if available from the months preceding the 
safety closeout visit).
o
Unscheduled ultrasound (if bleeding abnormality is reported outside of visit with 
scheduled ultrasound)
o
In case of HMB or prolonged bleeding, unscheduled blood sample to assess for 
anemia 
o
Possible contributing factors (eg, new concomitant medication, variability of disease, 
perception of increased HMB after period of amenorrhea)
An unscheduled endometrial biopsy should be conducted in case of
o
Endometrial thickness (double layer) > 18 mm and/or
o
Clinical suspicion of relevant endometrial pathology
Further follow-up measures will be determined by the outcome of the endometrial biopsy (see 
Section 9.6.3.2.5). 
HMB should be recorded as an AE only as specified in Section 9.6.1.6. If HMB fulfills the 
criteria of an SAE (see Section 9.6.1.1), if needed, an appropriate treatment as per local 
standard of care (eg, curettage) is to be performed after an endometrial biopsy has been taken.
9.6.3.2.8
Unscheduled endometrial biopsy
Unscheduled endometrial biopsies can result from the requirement to follow-up on abnormal 
results of a previous biopsy, see Section 9.6.3.2.5. In addition, also the following two findings 
trigger unscheduled biopsies:

In case of increased endometrial thickness (18 mm) 

Work up of suspicious bleeding pattern as described.
For unscheduled biopsies triggered by increased endometrial thickness or unusual bleeding 
events, the following procedure applies, depending on the result of the unscheduled 
endometrial biopsy:

Normal result of the endometrial biopsy: unscheduled ultrasound examination after 
about 4 weeks and close follow up of bleeding pattern. If endometrial thickness 
remains above 18 mm and/or unusually heavy bleeding occurs further procedures 


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should be performed according to local medical practice and as defined in Section
9.6.3.2.7.

For procedures in case of an abnormal result of the unscheduled biopsy, please see 
Section 9.6.3.2.5.
9.6.3.3
Cervical smear
This section was changed in Amendment 4, see Section 15.2.1.
The cervical smear should be obtained with the gynecological examination at the safety 
closeout visit in subjects who did not have this performed with normal result after end of 
treatment. As a guidance, a cervical smear should only be repeated once in case of insufficient 
material.
9.6.3.4
Physical and gynecological examinations
This section was changed in Amendment 4, see Section 15.2.1.
Complete physical examination will be done for all subjects. Gynecological examination, 
including breast palpation, will be performed in subjects who did not have this performed with 
normal result after end of treatment.  In case of any suspicious finding, further diagnostic 
investigations will be performed at the discretion of the investigator. Abnormal physical 
examination findings are recorded either as medical history or as adverse events (see Section 
9.6.1.1).
9.6.3.5
Vital signs, weight, and height
Vital signs (blood pressure in triplicates and heart rate) should be documented at the safety 
closeout visit. Blood pressure should be measured in triplicates after 5 minutes of rest, while 
the subject is sitting. Measurements should be made at least 1 minute apart using the same 
arm at each visit and should be recorded on the eCRF. Body weight will be determined once 
again at the safety closeout visit.
9.6.3.6
Ultrasound (safety)
This section was changed in Amendment 4, see Section 15.2.1.
Ultrasound examinations will be performed by a well experienced examiner.  If possible, the 
same examiner should conduct all examinations of a subject throughout the study and the 
same ultrasound machine (per site) should be used throughout the study. Preferably the safety 
evaluation should be performed by transvaginal ultrasound (TVU). However, if deemed
appropriate, transabdominal or transrectal ultrasound examinations can be performed instead. 
The chosen method should be used consistently throughout the study.
The following safety parameters will be documented at the safety closeout visit (see Table 9–
1):  endometrial thickness (double layer), evaluation of ovaries, and any pathology detected 
during the examination. Endometrial thickness will be measured in the medio-sagittal section 
as double-layer in millimeters.
If endometrial thickness (double layer) 18 mm is detected after the start of treatment, the 
subject should undergo immediate evaluation by endometrial biopsy as described in 
Section 9.6.3.2.8.


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If cyst like structures >30 mm without suspicious appearance (ie, functional cysts) are 
visualized in the ovaries after randomization, unscheduled ultrasound examinations to 
document regression/outcome of these findings should be performed as described in Section 
9.7.5.
In case of any suspicious finding, further diagnostic investigations will be performed at the 
discretion of the investigator.
The minimum documentation at the site will include electronic or paper documentation from 
the ultrasound machine showing the endometrium in sagittal section and both ovaries.  The 
printouts have to be labeled unambiguously, containing at least the study number, subject 
number, time point, endometrial thickness, and side (left/right) for ovaries.
It is also possible that the site has a CD with the ultrasound images available, when in the 
source the evaluation of the ultrasound images from the CD is available as well. The CRA 
should be able to review the data on the CD and compare the images with the evaluations in 
the source during the onsite monitoring visits.
Furthermore, if the ultrasound machine is SESAC (Site Electronic Source Assessment 
Checklist) conform, ie, GCP conform electronic data storage is possible, then no print out is 
needed.
For efficacy ultrasound procedures, see Section 9.4.1. 
9.6.3.7
Contraception and pregnancy test
With the implementation of Protocol Amendment 10 (version 7.0) no further restrictions 
apply to the use of contraception. New placement of intrauterine devices should only happen 
once it is clear that no further biopsies are needed.
At the safety closeout visit, a urine pregnancy test will be performed at the study site. A 
pregnancy test must also be performed in case of any further repeat endometrial biopsy. 
Any pregnancies during the study and during the off study period in subjects who return for 
the safety closeout visit must be reported as detailed in Section 9.6.2.
9.6.3.8
Bone mineral density
This section was changed in Amendment 4, see Section 15.2.1.
To document bone safety in all subjects leaving the study, a DEXA scan of the lumbar spine 
(lumbar anterior-posterior, L1-L4) and the hip/femoral neck will be performed as follows:
Every subject who received vilaprisan treatment should have a DEXA scan performed at the 
“safety closeout visit”, which in most subjects from active treatment arms corresponds to a 
timepoint of ≥12 months after last study drug intake. 
This DEXA scan may be waived if the following requirement is fulfilled:

an off-treatment DEXA scan was already performed at a timepoint with an interval of 
≥ 5.5 months (22 weeks) after last study drug intake, which is of sufficient quality 


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(evaluable) and shows either no BMD loss16 or adequate recovery, compared to 
baseline.

Adequate recovery is defined as ≤ 1.5% bone loss in the spine and ≤ 2.5% bone loss in 
the total hip compared with baseline and a Z-score >-2 at any site 
Subjects randomized to Treatment group B who are still in the study when Protocol 
Amendment 10 (version 7.0) becomes valid should also undergo a DEXA scan at the safety 
closeout visit, unless they had a DEXA scan performed within the last 3 months prior to the 
safety closeout visit.
The results of the DEXA scan performed at the safety closeout visit should be reviewed 
according to the following principles: 

If the safety closeout DEXA shows a BMD loss of ≥ 3% bone loss at any site and/or 
an abnormal Z-score (defined as ≤-2 at any site irrespective of the absolute bone loss) 
compared to baseline, the subject should be referred to a local bone specialist. The 
results of the assessment should be captured in RAVE via update of the AE report.
If referral to a bone specialist is not required based on the criteria above the subject does not 
require further FUP, but should be counseled adequately for supplementation with Vit D and 
calcium, taking into account the Vit D measurements performed in the study context.
Technical requirements for DEXA scans:
Bone mineral density measurements will be then taken for the lumbar spine, hip, and femoral 
neck. To increase accuracy of the assessment, 2 measurements per location will be performed 
at each time point and the mean value will be used for evaluation. After the first 
measurement, the subject should get up and should be re-positioned for the second 
measurement to reduce influence of positioning on the results.
The same type of device/manufacturer for all measurements of any subject in this study 
should be used.  Switching machine device/manufacturer during the study should be avoided.
Preferably, the same technician should conduct the examination throughout the study course 
of given subject. In addition to the measurement performed at the site, measurements will 
also be performed in a central reading by independent imaging technicians at the central 
reading imaging laboratory. Assessment of the screening DEXA results for subject’s study 
eligibility and subsequent study related BMD assessments and associated decisions will be 
based on the central reading. The final data evaluation will be performed on results that 
include the correction factor from cross-calibration. 
Bone mineral density measurements do not have to be done on the same day as other 
assessments of that visit, but have to be performed within the time window of the time points 
shown in Table 9–1. The BMD measurements are to be performed only after the subject has 
been tested negative for pregnancy using a urine pregnancy test.  
More details on the calibration and procedure of central reading will be provided in a separate 
manual.
Cross calibration
                                                
16 Defined as a percentage change from baseline of ≥0%


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Phantom image acquisition will be standardized across DEXA imaging facilities participating 
in the 16953 Asteroid 6 study. The responsibility to schedule, ship, and monitor the rotation of 
cross-calibration phantoms and to collect the cross-calibration imaging rests with the cross-
calibration central imaging provider. European Spine Phantoms (ESP) and a shipping 
container will be supplied by this provider. Instructions on cross-calibration will be specified 
in a manual that will be provided to all study sites. The ESP will be scanned according to the 
manual and the data will be sent to the cross-calibration central imaging provider for analysis. 
The cross-calibration central imaging provider will track the receipt of these scans and follow-
up on missing data. Statistical results will summarize the relative calibration and linearity of 
each system participating in the study. Correction factors will be provided by the cross-
calibration central imaging provider and applied by the DEXA central imaging provider.
The final data evaluation will be performed on results that include the correction factor from 
cross-calibration.
9.6.3.9
Adrenal monitoring
A robust adrenal safety monitoring program is implemented in all ongoing vilaprisan studies 
with this protocol amendment.
A plan for subjects showing adrenal neoplasms or hormonal abnormalities has been developed 
with the input of external endocrinology experts, see Adrenal monitoring algorithm below. 
A panel of three external clinical adrenal gland experts has been set up, that will support and 
guide further evaluations and/or referral to local specialists in case an abnormality is detected 
in a study subject. The assessment by the experts will be performed in 2 steps: 

A safety assessment of cases showing abnormalities will be performed by one of these 
experts. The results of this assessment will be available in time to document
•
Any relevant finding that requires further diagnostic or therapeutic 
measures according to local medical practice
•
Absence of clinically relevant adrenal findings before the subject 
discontinues from the study.
In case of a local specialist consult, the work-up and results will be captured in a dedicated 
CRF page.

In addition, the expert panel will perform a central evaluation of all cases after the 
outcome of the local specialist referral or other evaluations is available. The panel will 
meet once a sufficient number of cases is available to perform a comprehensive data 
analysis by using uniform diagnostic standards and classifications (see also Adrenal 
Monitoring Manual).


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Figure 9–2: Adrenal monitoring algorithm
Note: Adrenal monitoring also needs to be performed in subjects who started treatment and have completed or 
discontinued the study before or during the temporary pause.
Clinical signs and symptoms are to be evaluated in each subject. In case of relevant abnormalities, i.e. symptoms 
accompanied by laboratory abnormalities, the process described in this algorithm has to be followed.
MRI = magnetic resonance imaging
9.6.3.9.1
Timing of adrenal monitoring
Subjects will undergo scheduled adrenal monitoring at the safety closeout visit.


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Signs and symptoms possibly related to hypercortisolism (such as Cushing’s syndrome, and 
hirsutism/virilization) or hyperaldosteronism will be documented on a dedicated CRF page 
(see Section 9.6.3.9.4).
Adrenal monitoring also needs to be performed in subjects who started treatment and have 
completed or discontinued the study before or during the temporary pause. After re-
consenting, data related to adrenal monitoring and their results are to be reported and if 
applicable any related AEs and respective concomitant medications. At least three attempts 
should be made by the site to get in contact with such subjects. The attempts should be 
documented in the patient file.
9.6.3.9.2
Adrenal MRI
Non-contrast-enhanced (native) MRI will be implemented as the standard adrenal imaging 
modality. Due to the associated radiation exposure, non-contrast-enhanced (native) CT scan is 
permitted as an alternative option only if an MRI is not feasible, e.g., due to a subject having a 
contraindication to MRI or a site has no access to MRI. Further details on the procedures of 
the image acquisition and reading process will be provided in a separate Imaging Manual. 
The images will be evaluated by two central readers with an established adjudication process 
in case of discrepant results. Abnormalities indicative of an adrenal tumor or of any other 
relevant adrenal disorder need to be further evaluated (for details see Section 9.6.3.9 and 
Adrenal monitoring algorithm above). During the central review process, the independent 
reader may detect clinically significant pathological imaging findings that are not part of the 
primary review purpose, i.e., evaluating the adrenal glands. If deemed relevant, these 
incidental findings will be reported to GCIS at the discretion of the readers. GCIS will 
forward the incidental finding report to the study team, who will then inform the principal 
investigator.
Any procedure-related complaints will be documented as AEs. 
9.6.3.9.3
Laboratory testing
Adrenal monitoring: 

Serum cortisol, to be measured between 6 am and 10 am
o
ACTH will be assessed from the same sample if the cortisol measurement yields 
an abnormal value. 

Late night salivary cortisol (to be obtained between 11 PM and midnight) 
Subjects will be instructed to use the specifically provided saliva test tubes on two 
consecutive evenings for separate sampling. The time of sampling needs to be 
documented on the test tube / requisition form. Subjects will be asked to return 
samples to the site to ensure standardized transport and processing at the central 
laboratory (please see algorithm above). 

Serum glucose measurements under fasting conditions

Serum DHEA-s (Dehydroepiandrosterone sulfate) and total testosterone (tT) 
Furthermore, the age-specific DHEA-s ratio (derived by dividing the patient’s 


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DHEA-s value by the lower limit of the age-specific reference range) will be 
calculated 17.
9.6.3.9.4
Adrenal signs and symptom inquiry
Vital signs (blood pressure in triplicates and heart rate) will be documented at the safety 
closeout visit. Blood pressure should be measured in triplicates after 5 minutes of rest, while 
the subject is sitting. Measurements should be made at least 1 minute apart using the same 
arm at each visit and should be recorded on the eCRF18. 
During the visit the subject should also be evaluated for clinical signs and symptoms of 
adrenal disorders, such as Cushing’s syndrome, and hirsutism/virilization. A dedicated CRF 
page has been implemented to document those, if applicable.
9.6.3.10
Liver monitoring
In the past, investigators, subjects and their family members were instructed to be alert for 
nonspecific symptoms which may be associated with liver dysfunction, see Section 9.6.3.11. 
In addition, the liver inquiry had to be completed at regular intervals. Based on the long 
interval between implementation of Protocol Amendment 10 (version 7.0) and last intake of 
study drug this is no longer needed on a routine basis.
Investigation of potential alternative causes (which replaces the close observation procedures 
applied before this protocol amendment) has to be initiated and recorded in the dedicated liver 
case report form if at least one of the options below applies: 

GPT/ALT or GOT/AST value increases to 3 x ULN
or

GPT/ALT or GOT/AST value 2-fold increases above the lowest baseline value for 
subjects with elevated values before drug exposure
or

AP (alkaline phosphatase) value increases to > 2x ULN and irrespective of the level of 
transaminase (GPT/ALT or GOT/AST) values
o
in cases with baseline showing normal AP
o
in cases of at least 2 times the baseline values if slightly above the upper 
limit of normal at baseline
In those cases, a search for underlying causes should be performed including:
                                                
17 High levels of tT and/or DHEA-s may be indicators of an androgen-producing adrenal cortical tumor and are 
measured in this study in conjunction with adrenal imaging to support their early detection. Therefore, despite 
the fact that many confounders are present in the female study population (e.g., PCOS, influence of vilaprisan 
or other concomitant medications on hormone levels), tT and DHEA-s concentrations will be measured to 
screen for androgen-producing tumors. Highly abnormal values of one or both parameters, i.e., tT >150 ng/dL 
and/or DHEA-s > 600 µg/dL, will trigger an assessment by one of the external adrenal panel experts.
182018 Draft Guidance for Industry: Assessment of Pressor Effects of Drugs 
(https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinforma tion/guidances/ucm609185.pdf


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
Repeating a serum chemistry panel (including liver parameters and bilirubin).

Obtaining a more detailed history of the symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Ruling out acute viral hepatitis; autoimmune or alcoholic hepatitis; non-alcoholic 
steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and biliary tract disease. This 
may require performing additional procedures, e.g. ultrasound examinations.

Obtaining a history of exposure to environmental chemical agents. 

Obtaining additional tests to evaluate liver function as appropriate, (eg, international 
normalized ratio [INR], total bilirubin measurements). 

Referral for a liver ultrasound.
Any of these additional findings is to be recorded on the corresponding eCRF pages in RAVE.
9.6.3.11
Liver symptom inquiry
Investigators, subjects and their family members should be alert for non-specific symptoms 
which may be associated with liver dysfunction including anorexia, nausea, fatigue, right 
upper abdominal discomfort, vomiting, malaise, jaundice, fever, and rash. 
Before the implementation of Protocol Amendment 10 (version 7.0), investigators were asked
to regularly inquire about symptoms that according to their medical judgement may indicate 
liver disturbance and document the result of this inquiry in the respective eCRF page. This 
structured inquiry was used to determine withdrawal criteria and is therefore not needed at the 
safety closeout visit.
9.6.3.12
Skin monitoring
All subjects who have taken at least one dose of the study medication will undergo a thorough
skin examination by a dermatology expert.
The outcome of the dermatology expert’s examinations will be reported in the CRF. Any 
dermatology expert´s diagnosis of a pre-cancerous or malignant skin lesion, including 
cutaneous sarcoma confirmed by biopsy diagnosis, qualify as an AESI. Malignant skin lesions 
should be reported as an SAE to ensure timely reporting to regulatory agencies. (see Section
9.6.1.6).
Subjects who were randomized, started treatment, and have completed or discontinued the 
study before or during the temporary pause should be contacted by the site and asked to have 
the skin monitoring performed. After re-consenting, data related to the skin exam by a 
dermatology expert and the results are to be captured and if applicable any related AEs and 
respective concomitant medications. 
At least three attempts should be made by the site to get in contact with such subjects. The 
attempts should be documented in the patient file.


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9.6.3.13
Reporting of medical device failures (Japan only)
The investigator must report immediately all non-approved medical device failures that could 
cause health damage, as well as any health damage that may be causally associated with a 
non-approved medical device failure. For this reporting, the forms provided are to be used and 
sent to the designated recipient.
9.6.4
Hemoglobin
This section was moved in Amendment 4, see Section 15.2.1.
Hemoglobin concentrations in blood will be measured within the safety laboratory in blood 
samples taken at safety closeout visit.
9.7
Other procedures and variables
9.7.1
Iron supplementation
This section was changed in Amendment 4, see Section 15.2.1.
Subjects in whom causes for anemia unrelated to HMB are suspected should not have been
enrolled.
Moderate anemia is defined as hemoglobin 10.9 g/dL.(3) Iron supplementation should be 
offered to subjects with hemoglobin 10.9 g/dL consistent with local standards of practice and 
at the investigator’s discretion.  Iron supplementation will not be considered as study drug and 
should be documented as concomitant medication.  
9.7.2
Algorithm for monitoring of endometrial safety
See Section 9.6.3.2.1.
9.7.3
Heavy menstrual bleeding / suspicious bleeding pattern
See Section 9.6.3.2.7.
9.7.4
Unscheduled endometrial biopsy
See Section 9.6.3.2.8.
9.7.5
Monitoring of ovarian cysts
If cyst like structures >30 mm without suspicious appearance (ie, functional ovarian cysts) are 
visualized in the ovaries after randomization, unscheduled ultrasound examinations should be 
performed every 4 weeks or more frequently, if required due to symptoms, to document the 
regression/outcome.
If the subject demonstrates menstrual cyclicity, the ultrasound should be performed after 
menstruation as soon as possible, preferably in the early follicular phase. The monitoring will 
be continued until resolution, ie, until cyst can no longer be distinguished from functional 
follicles. If the cysts persist after 3 months or grow, decision of further treatment should be 
made according to local medical practice.
In the event of cyst like structures with suspicious appearance, further procedures should be 
performed according to local medical practice.


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9.7.6
Exploratory biomarker analysis
This section was changed in Amendment 4, see Section 15.2.1.
Biomarker investigations in this study will be whole genome expression profiling from 
endometrial biopsy samples. Each subject, except for women included in China, has the 
option to choose whether her biopsy tissue samples can be used for this biomarker research or 
not unless precluded by local guidelines.  From the subjects who have agreed by providing 
their particular consent, leftover material from the endometrial biopsies scheduled for 
histological examinations that were scheduled to be taken at the time points according to (see 
Table 9–1 and Section 9.6.3.2.1) will be used.
There will be no additional sampling for this part.
The explorative mRNA analysis is not part of the efficacy or safety assessment and may be 
performed at a later time point to characterize specific effects of vilaprisan on the 
endometrium. Results of this analysis will be detailed in a separate report.
Intra-individual and inter-individual analyses of the mRNA changes in the different treatment 
arms/regimen will be performed. This will reflect the pharmacodynamic effects of the 
treatment on the endometrium.
In addition to the whole genome expression profiling listed above, other biomarkers deemed 
relevant to gain further knowledge about the pathomechanism of the disease or about the drug 
(ie, mode of action related effect or safety of the drug) may be measured, based on newly 
emerging data from other ongoing studies and/or literature data.
Details on the collection, processing, storage, and shipment of samples for biomarker research 
will be provided in separate documents (eg, sample handling sheets or laboratory manual).
9.8
Appropriateness of procedures / measurements
All efficacy and safety parameters, as well as the methods to measure them, are standard 
variables/methods in clinical studies and/or clinical/gynecological practice. They are widely 
used and generally recognized as reliable, accurate, and relevant.
The measurement of BMD by DEXA is the gold standard method for investigation of bone 
mass. The type, number and frequency of the BMD measurements were determined to provide 
valid data while limiting the exposure of radiation to the required minimum.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analyses will be conducted by or under the supervision of the sponsor’s study 
statistician, except for the analysis of PK/PD data, which will be performed and reported 
under the supervision of the sponsor´s pharmacometrics group.
Statistical analyses will be performed using Statistical Analysis Software (SAS Institute Inc., 
Cary, North Carolina, US). The SAS version and further details on the statistical analyses will 
be provided in the SAP that will be approved before database release. 
All variables will be described according to their type using descriptive statistics frequencies 
or mean, SD, minimum, maximum, median, first and third quartiles. Where appropriate, the 
individual change from baseline to EoT will also be analyzed.


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10.2
Analysis sets
This section was changed in Amendment 4, see Section 15.2.1.
The documentation of important deviations from the protocol and validity findings and the 
assignment of subjects to analysis sets will be performed according to the sponsor’s applicable 
Standard Operating Procedures and/or Instruction Manuals. The definition of important 
deviations and validity findings will be provided in the Specification of assessment criteria 
and identification requirements.
The following statistical analysis sets will be defined:
Full analysis set (FAS): All subjects randomized to vilaprisan treatment groups, excluding 
randomized subjects who did not start treatment Period 1 due to the study being temporarily 
on hold and all subjects randomized to Treatment Group B will be included in the FAS.
Subjects will be analyzed as randomized. 
Safety analysis set (SAF): All subjects randomized who took at least 1 dose of study drug. 
Subjects will be analyzed as treated.
Modified SAF: will include all subjects in the SAF without any validity findings which may 
potentially affect the primary safety endpoint. Validity findings leading to exclusion from the 
modified SAF will be specified in the ‘Specification of assessment criteria and identification 
requirements’, which will be finalized before database lock. Subjects will be analyzed as 
treated.
All subjects randomized to Treatment Group B will be analyzed as treated, regardless whether 
they actually took any medication (ie, symptomatic, nonhormonal medical treatment).
All safety analyses will be performed on the SAF population. The FAS will be used for the 
display of all other variables. The analysis for the primary safety endpoint and all BMD 
related endpoints will be performed on the modified SAF as well.
10.3
Variables and planned statistical analyses
10.3.1
Variables
10.3.1.1
Primary safety variable
The primary safety variable is the percentage change in BMD of lumbar spine from baseline 
to about one year after SoT.
10.3.1.2
Secondary efficacy variable
This section was changed in Amendment 4, see Section 15.2.1.

Number of bleeding days from Day 1 of the first treatment period until the day before 
a new treatment period would start again following the last treatment period for that 
respective treatment group. Number to be normalized by 28 days 
10.3.1.3
Other efficacy variables
This section was changed in Amendment 4, see Section 15.2.1.

Volume of menstrual blood loss per 28 days (assessed by MP)


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
Volume of menstrual blood loss per bleeding episode (assessed by MP) for first, 
second, and third bleeding episode after the EoT

Amenorrhea (yes/no), defined as menstrual blood loss <2 mL during last 28 days, 
based on the MP

Absence of bleeding (spotting allowed) during the last 28 days of the treatment; based 
on the UF-DBD 

Time to onset of amenorrhea 
Onset of amenorrhea is defined by the first day for which the menstrual blood loss 
(assessed by MP) for all subsequent 28-day periods up to the end of the treatment 
period is <2 mL.

Time to onset of controlled bleeding for each treatment period
Onset of controlled bleeding is defined by the first day for which the menstrual blood 
loss (assessed by MP) for all subsequent 28-day periods up to the end of the treatment 
period is <80.00 mL. 

Time to start of bleeding after last study drug intake (assessed by the UF-DBD). If 
bleeding has to be induced, the subject´s data will be censored at that time point for the 
induction.

Percent change in volume of largest fibroid compared to baseline (baseline = last value 
obtained before randomization; measured by ultrasound examination)

Percent change in volume of 3 largest fibroids compared to baseline (measured by 
ultrasound)

Percent change in volume of uterus compared to baseline (measured by ultrasound)

Percentage of subjects with a volume reduction of 25% of the 3 largest fibroids 
(measured by ultrasound) 

Percentage of subjects with a reduction of 25% of uterine volume (measured by 
ultrasound)

Percentage of subjects undergoing surgical treatment

Change in UF-DSD individual items compared to baseline

Change in UFS-QoL scores compared to baseline

CGI_I
10.3.1.4
Secondary safety variables

Endometrial histology (eg, benign endometrium, presence or absence of hyperplasia or 
malignancy)

Endometrial thickness

Percentage change from baseline in BMD measured at lumbar spine (other time points 
not mentioned as primary safety variable), hip, and femoral neck by DEXA
10.3.1.5
Other safety variables

Endometrial histology (diagnosis of PAEC, individual features of PAEC)


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
Percentage of subjects with BMD decrease >6% and Z-score <-2 measured at the 
lumbar spine 

Change in Z-score over time

Ovarian cysts (number, size)

Laboratory parameters

AEs

Cervical smear

Vital signs

UF-DBD bleeding pattern per 28 days and 84 days

Change from baseline in hemoglobin, hematocrit, and ferritin

Percentage of subjects with normal hemoglobin 12 g/dL and normal hematocrit 36%

Percentage of subjects with moderate to severe anemia (ie, hemoglobin 10.9 g/dL)

Findings resulting from liver monitoring

Findings resulting from adrenal monitoring

Findings resulting from skin monitoring
10.3.2
Statistical and analytical plans 
10.3.2.1
Demographic and other baseline characteristics
Demographic variables and baseline characteristics will be summarized overall by means of 
descriptive statistics and/or frequency tables as appropriate.
Medical history findings will be coded by Medical Dictionary for Regulatory Activities 
(MedDRA) codes and medications by Anatomical Therapeutic Chemical (ATC) codes (World 
Health Organization Drug Dictionary [WHO-DD]).
10.3.2.2
Primary safety analysis
In this open-label study to assess the safety of vilaprisan as compared to standard of care. The 
primary analysis comprises the display of the percentage change in BMD of lumbar spine 
(using the central reading results corrected by the cross-calibration factor) from baseline to 
about one year after SoT separately in all randomized and treated subjects with measurements 
at baseline and about one year after SoT in each treatment group using descriptive statistical 
methods. Two-sided 95% confidence interval (CI) for the mean difference for the percentage 
change in BMD of lumbar spine from baseline to about one year after SoT will be calculated 
for each vilaprisan treatment group as compared to standard of care. 
The primary variable is assumed to be at least approximately normal distributed.
10.3.2.3
Secondary efficacy analysis
The secondary efficacy variables will be analyzed descriptively.
10.3.2.4
Other efficacy 
Other efficacy variables will be evaluated and presented by means of descriptive statistics.


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10.3.2.5
Secondary safety analysis
Percentage change in BMD of lumbar spine (other time points not mentioned as primary 
safety analysis), hip, and femoral neck from baseline will be analyzed using the same 
statistical methods as used for the primary variable. All secondary safety variables will be 
summarized using descriptive statistics.
10.3.2.6
Other safety analysis
Adverse events will be summarized using MedDRA. Other safety variables will be 
summarized using descriptive statistics.
10.3.2.7
Subgroup analysis
Subgroup analyses will be performed for Chinese women.
10.3.3
Missing data/drop outs 
In this study, no statistical hypothesis is planned to be tested. The observed study data 
including the occurrence of missing data will be displayed using descriptive statistical 
methods.
10.4
Determination of sample size
No longer valid, since with implementation of Protocol Amendment 10 (version 7.0) no 
new subjects will be recruited and no study medication or standard of care symptomatic 
nonhormonal will be given to the subjects who have been enrolled in the study. This 
section describes the original sample size planning prior to the decision to temporarily 
pause the study. The original planned sample size has not been reached. 
As an integral part of the development program, the sample size of this study was chosen to 
fulfill the regulatory requirement for safety data and is increased with this protocol version 
4.0. The increased sample size will contribute to the database in which safety events of 
interest can be evaluated, with the main area of interest being the generation of a robust 
database for the evaluation of the safety of vilaprisan with regards to adverse liver events. 
This regulatory requirement for safety data encompasses further areas of interest, amongst 
them the need for adequate characterization of the effects of vilaprisan on bone mineral 
density and the need for sufficient data on the occurrence of relevant endometrial pathology. 
These safety parameters will be evaluated based not only on the data from this study alone, 
but also in the context of an integrated analysis across several studies in the vilaprisan 
development program. 
A total of 1302 subjects are planned to be randomized as follows: 372 subjects each in 
Treatment Groups A1, A2, and B; 186 subjects in Treatment Group A3. It is assumed that 
about 20% and 10% of the randomized subjects will drop out during the first and second year, 
respectively. It is also assumed that about 10% of the BMD measurement will not be 
evaluable in the first and the second year, respectively. Moreover, 60% of subjects will be 
assigned to Subgroup 1 and about 50% of subjects will be enrolled from the US. In addition, 
it is described how the primary safety variable can be precisely estimated based on the chosen 
sample size. For the sample size consideration, a decrease of 0.5% and a SD of ~3% for the 
percentage change in BMD of lumbar spine per ~1 year in Treatment Group B, at least 
approximately normal distribution, one-sided t-test situation and alpha=0.025 are predicted.  
In order to evaluate what decrease would be viewed as indicative for a medically relevant 


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change in BMD of lumbar spine in the active treatment arms, a publication by Carr et al was 
consulted. (4) This publication refers to a consultation with FDA and assumes that in a 
population for which no physiological decline of BMD is anticipated, a mean BMD 
percentage change from baseline of -1.2% and -0.5% for the spine and femur, respectively, at 
Weeks 24 and 48 with the lower bound of the 2-sided 95% CI around the treatment group 
mean percentage change from baseline in BMD not lower than -2.2% would not constitute a 
relevant BMD decrease. Juxtaposing this assumption to a population with a higher mean age,
as it is anticipated for this study, which projects a physiological decline of BMD of about 
0.5% per year, we assume that no relevant decrease of BMD is concluded from the data of this 
study if the lower bound of the 2-sided 95% CI around the treatment group mean percentage 
change from baseline in BMD is not lower than -2.7% or not lower than -2.2% relative to 
Treatment Group B (comparison to the untreated Treatment Group B is expected to allow for 
differentiation between physiological BMD decline in the target population and effect induced 
by study drug). 
Table 10–1: Percentage change in BMD of lumbar spine from baseline to about one 
year after SoT relative to Treatment Group B can be ruled out with planned sample 
size and corresponding power
Sample size
Percentage change 
from baseline in BMD 
can be ruled out 
(relative to Treatment 
Group B)
Power
Overall population:
Treatment Group A1 or A2
versus Treatment Group B
268 versus 268
-0.84% or more
90%
US population:
Treatment Group A1 or A2
versus  Treatment Group B
134 versus 134
-1.19% or more
90%
Overall population:
Treatment Group A3
versus Treatment Group B
134 versus 268
-1.03 or more
90%
US population:
Treatment Group A3
versus Treatment Group B
67 versus 134
-1.46% or more
90%
BMD = bone mineral density; SoT = start of treatment


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Table 10–2: Power to rule out -2.2% (the clinical meaningful percent change in BMD of 
lumbar spine from baseline to about one year after SoT relative to Treatment Group 
B) with planned sample size
Sample size
Power
Overall population:
Treatment Group A1 or A2
versus Treatment Group B
268 versus 268
100%
US population:
Treatment Group A1 or A2
versus  Treatment Group B
134 versus 134
100%
Overall population:
Treatment Group A3
versus Treatment Group B
134 versus 268
100%
US population:
Treatment Group A3
versus Treatment Group B
67 versus 134
99.8%
BMD = bone mineral density; SoT = start of treatment
10.5
Planned interim analyses
With the implementation of Protocol Amendment 10 (version 7.0) a safety and efficacy 
analysis is planned after all subjects have completed their treatment period. Data of the 
follow-up period available at that time point will also be included in the analysis. Remaining 
data of the follow-up phase will be analyzed after all subjects have completed the follow-up 
period. For all other data this safety and efficacy analysis is considered the final analysis. 
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study is a validated, internet-based, electronic data capture 
(EDC) software system called RAVE. Subject data necessary for analysis and reporting will 
be entered/transmitted into a validated database or data system (Clinical Information 
Environment).
RAVE, which Bayer has licensed from Medidata Solutions Worldwide, has been validated by 
Medidata Solutions Worldwide and Bayer for use in its clinical studies. RAVE allows for the 
application of software logic to set-up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel. Bayer extensively applies 
the logic to ensure data are complete and reflect the clinical data requirements of the study. 
Data queries resulting from the application of the software logic are resolved by the site 
personnel. The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred on a periodic basis to Bayer's internal computer system via a 
secure Virtual Private Network.
Access to RAVE is through a password-protected security system that is part of the RAVE 
software. All Bayer and investigator site personnel must be trained before they are granted 
access. Training records will be maintained.


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All personnel with access to RAVE are supported by a Service Desk staffed with trained 
personnel to answer questions and ensure access is maintained so data entry can proceed in a
timely manner.
RAVE contains a system-generated audit trail that captures any changes made to a data field, 
including who made the change, why the change was made, and the date and time it was 
made. This information is available both at the investigator’s site and at Bayer. Data entries 
made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source documentation. 
A source document checklist (not part of this protocol) will be used at the site to identify the 
source data for key data points collected and the monitor will work with the site to complete 
this.
It is the expectation of the sponsor that all data have source documentation available at the site 
except for the data entered directly into the eCRF (eg, HMB questions) and ePRO data; these
data will be the source and no additional source documentation will be available. The data 
entered directly into the eCRF/ePRO are not needed for the subject’s routine medical care.
Data recorded from screening failures (screening failure confirmed at Visit 1)
At a minimum, the following data should have been recorded in the eCRF, which will be 
transferred to the respective database:

Demographic information (subject number, year of birth, age, race, ethnicity)

Date of informed consent

Date of Visit 1

Relevant inclusion/exclusion criteria

Reason for screening failure

Date of last visit 
For all subjects continuing after Visit 1, all data had to be reported until screen failure was 
declared or randomization occurred. Additionally to the above mentioned data these include:

All the data from Visit 1, Visit 2, and/or Visit 3 including visit independent folder 
data, if applicable (AE, concomitant medication, and medical history data )

Endometrial biopsies results and/or ultrasound/BMD (if done before screen failure was 
declared)

Reason for premature discontinuation, if applicable.
For screening failures with an SAE or a pregnancy, all information related to the 
SAE/pregnancy should be recorded in the eCRF (eg, the SAE, concomitant medication, 
medical history, other information needed for SAE/pregnancy complementary page).


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11.2
Monitoring
Consistent with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
contacted the site before the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion also included
identification and documentation of source data items.
The sponsor/designee is monitoring the site activity to verify that the:

Data are authentic, accurate, and complete

Safety and rights of subjects are being protected

Study is conducted consistent with the currently approved protocol (including study 
treatment being used consistent with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data management is performed consistent with applicable sponsor’s standards and data 
cleaning procedures. This is applicable for data recorded in the eCRF as well as for data from 
other sources (eg, IVRS/IWRS, laboratory, ePRO).
For data coding (eg, AEs, medication), internationally recognized and accepted dictionaries 
are used. MedDRA is used for AEs and medical history and WHO Drug Dictionary for prior 
and concomitant medication.
The results of endometrial biopsies taken after the FUP visit will be entered into the clinical 
database at a pre-planned database opening, if needed. These results will not be part of the 
clinical study report, but will be reported in a separate addendum to the report after all the 
relevant data are available if applicable. Also, a re-opening of the database may become 
necessary in order to include the results of the PK and BMD measurements and the biomarker 
analysis.
11.4
Missing data 
The main source of missing data in clinical trials is due to subjects who discontinue the
assigned treatment due to AEs or lack of efficacy. 
It should be underlined that the discontinuation of study treatment is not equivalent to 
withdrawal of informed consent. In case where a subject indicates she does not want to 
continue the study, the investigator must determine whether this refers to discontinuation of 
study treatment or unwillingness to attend the EoT visit. 
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.


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In addition, inspections by regulatory health authority representatives and IECs/IRBs are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change (eg,
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof [eg,
treatment groups, centers]) at any time, which may be due but not limited to the following 
reasons:

If risk-benefit ratio becomes unacceptable owing to, for example:

Safety findings from this study (eg, SAEs)

Results of any interim analysis

Results of parallel clinical studies

Results of parallel animal studies (eg, toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity)

If the study conduct (eg, recruitment rate, dropout rate, data quality, protocol 
compliance) does not suggest a proper completion of the study within a reasonable 
period.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.

All affected institutions (eg, IECs/IRBs, competent authority[ies], study center; head of 
study center) must be informed as applicable consistent with local law.


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
All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification given by the sponsor for destruction.

In case of a partial study closure, ongoing subjects, including those in post-study FUP, 
must be taken care of in an ethical manner.
Details for individual subject’s withdrawal can be found in Section 6.4.1.
13.
Ethical and legal aspects
13.1
Investigators and other study personnel
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (eg, health authority, ethics committee, sponsor) before 
subject recruitment may start at the respective center.  Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, about the conduct, evaluation, and documentation of 
this study, are designed to ensure that the sponsor and investigator abide by GCP guidelines 


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and under the guiding principles detailed in the Declaration of Helsinki.  The study will also 
be carried out in keeping with applicable local laws and regulations.
Documented approval from appropriate IECs/IRBs will be obtained for all participating 
centers/countries before start of the study, consistent with GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and forwarded to the sponsor.  The responsible unit (eg, IEC/IRB, 
head of the study center/medical institution) must supply to the sponsor, on request, a list of 
the IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates consistent with GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not change or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be performed by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
This section was changed in Amendment 4, see Section 15.2.1.
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.  Additional consent will be required for participation in the biomarker research.  
Electronic informed consent (eConsent) is planned to be used at sites in the US.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject, before her entry into the study (ie, before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
The subject’s consent covers end-of-study examinations as specified in the visit 
description described in the Protocol Amendment 7 (version 5.0) premature 
discontinuation visit section to be conducted after withdrawal of consent.  
The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the SAP
Subject-specific data on the basis of material obtained before withdrawal may be 


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generated after withdrawal (eg, image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the SAP.  The subject has the right to object to the generation and 
processing of this post-withdrawal data. The subject’s oral objection may be documented 
in the subject’s source data.
Each subject will have ample time and opportunity to ask questions and will be informed 
about the right to withdraw from the study at any time without any disadvantage and without 
having to provide reasons for this decision.
If a subject who has signed the informed consent for Subgroup 1 is in screening while the 
Subgroup 1 reaches the required number of subjects, this subject can be assigned to Subgroup 
2 if eligible by signing the informed consent for Subgroup 2 without repeating any of the 
screening procedures.
Only if the subject voluntarily agrees to sign the informed consent and has done so, may she 
enter the study.  Additionally, the investigator or designee will personally sign and date the 
form.  The subject will receive a copy of the signed and dated form.
The signed informed consent is to remain in the investigator site file or, if locally required, in 
the subject’s note/file of the medical institution.  A paper copy of the signed eConsent can be 
provided.
If the informed consent is obtained on the date that baseline study procedures are performed, 
the study record or subject’s clinical record must clearly show that informed consent was 
obtained before these procedures.
The informed consent and any other information provided to subjects will be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent, or there is an amendment to the protocol that necessitates a change to the content of 
the subject information and/or the informed consent.  The investigator will inform the subject 
of changes in a timely manner and will ask the subject to confirm her participation in the 
study by signing the revised informed consent.  Any revised informed consent text and other 
information must receive the IEC/IRB’s approval/favorable opinion before use.
13.5
Publication policy and use of data
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 


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of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.  
13.6
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the subjects will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (eg, pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor.  Study findings 
stored on a computer will be stored in accordance with local data protection laws.  As part of 
the informed consent process, the subjects will be informed that representatives of the 
sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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14.
Reference list 
1.
Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered 
adrenal masses. Endocr Rev. 1995;16(4):460-84.
2.
Emons G, Beckmann MW, Schmidt D, Mallmann P, for the Uterus commission of the 
Gynecological Oncology Working G. New WHO Classification of Endometrial 
Hyperplasias. GebFra - DGGG-Gesellschaftsausgaben. 2015(01):135-6.
3.
WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of 
severity (WHO/NMH/NHD/MNM/11.1). Available from: 
http://who.int/vmnis/indicators/haemoglobin.pdf, accessed 26 Jan 2016. 2011.
4.
Carr B, Dmowski WP, O'Brien C, Jiang P, Burke J, Jimenez R, et al. Elagolix, an oral 
GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the 
treatment of endometriosis: effects on bone mineral density. Reprod Sci. 
2014;21(11):1341-51.
15.
Protocol amendments
15.1
Amendment 3 – dated 13 JUN 2017
Amendment 3 is the first global amendment. The following is an overview of the changes 
made to the original Protocol Version 1.0.
15.1.1
Overview of the changes to the study
The protocol was amended to maintain consistency across vilaprisan Phase 3 studies and to 
reflect conclusions from data which was received from a drug-drug-interaction study.
The protocol was amended to exclude the use of strong CYP3A4 inducers.
Protocol sections affected include:

Section 6.2 Exclusion criteria

Section 8.1 Prior and concomitant therapy

Section 16.2 Strong CYP3A4 inducers
15.1.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as 
follows:
1. Addition of a whole new portion
Brief identification of the new portion
2. Removal of a whole portion
Complete display of the removed portion, formatted 
as crossed out


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3. Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out
in the “old text”. Additions are underlined in the 
“new text”. 
Tables / figures
The term “amended” is added to the caption.
Terminological changes
Brief specification of the terminological change
Thus, in this section, a terminological change (e.g. 
“period” versus “epoch”) is defined only once, 
without displaying “old text” versus “new text” for 
each appearance.
Corrections of typos are not highlighted in this section.
15.1.2.1
Section 6.2 Exclusion criteria
Exclusion criterion 5
Old text:
[…]

Intake of strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors within 
the last 2 weeks before first study drug intake and during the treatment period 
including: antivirals (eg, viekira pak, telaprevir, boceprevir), protease inhibitors 
(eg, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir), antifungals (eg,
itraconazole, voriconazole, posaconazole), antibiotics (eg, clarithromycin, 
telithromycin), grapefruit and any grapefruit containing food products (eg, 
grapefruit juice). Metronidazole, ketoconazole and other triazole antifungal 
drugs are allowed for topical/local use (including vaginal application) within the 
last 2 weeks before first study drug intake and during the treatment period.
New text:
[…]

Intake of strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors within 
the last 2 weeks before the randomization visit and during the treatment period 
including: antivirals (eg, viekira pak, telaprevir, boceprevir), protease inhibitors 
(eg, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir), antifungals (eg, 
itraconazole, voriconazole, posaconazole), antibiotics (eg, clarithromycin, 
telithromycin), grapefruit and any grapefruit containing food products (eg, 
grapefruit juice).  Metronidazole, ketoconazole and other triazole antifungal 
drugs are allowed for topical/local use (including vaginal application) within the 
last 2 weeks before the randomization visit and during the treatment period. A 
detailed list is provided in Section 16.1.

Intake of strong CYP3A4 inducers (eg, rifampicin, rifabutin, carbamazepine, 
phenytoin, phenobarbital, St John´s wort [hypericum]) within the last 2 weeks 


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before the randomization visit and during the treatment period. A detailed list is 
provided in Section 16.2.
15.1.2.2
Section 8.1 Prior and concomitant therapy
Old text:
[…]
For prohibited prior and concomitant medication, see Section 6.2. Prohibited strong CYP3A4 
inhibitors are listed in Table 16-1.
New text:
[…]
For prohibited prior and concomitant medication, see Section 6.2. Prohibited strong CYP3A4 
inhibitors are listed in Table 16-1 and strong inducers in Table 16-2.
15.1.2.3
Section 16.2 Strong CYP3A4 inducers 
New section, no old text
Table 16-2: Strong CYP3A4 inducers
Substance name
Inducer strength
Phenobarbital
Strong
Avasimibe
Strong
Carbamazepine
Strong
Enzalutamide
Strong
St. Johns Wort (Hypericum)
Strong
Lumacaftor
Strong
Methylphenobarbital
Strong
Mitotane
Strong
Phenytoin
Strong
Rifampicin
Strong
Rifamycin
Strong
15.2
Amendment 4 – dated 13 SEP 2017
15.2.1
Overview of the changes to the study
Amendment 4 is the second global amendment. The following is an overview of the changes 
made to the integrated protocol Version 2.0.
15.2.1.1
Change 1: Changes requested by health authorities
Changes requested by health authorities (HA) and updated wording based on discussions with 
other Health Authorities and Ethic Committees deemed to provide further helpful 
clarification.
Rationale:


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These changes were implemented as requested by the Norwegian HA and also the wording 
was updated based on discussions with other Health Authorities and Ethic Committees to 
provide further helpful clarification.
Sections affected by exact request of the Norwegian HA: Section 3 Introduction, Section 5 
Study design
Other affected sections: Section 6.4.1 Withdrawal, Sections 9.2.2.1-9.2.2.12 Visit 
descriptions, Section 9.6.2 Pregnancies, Section 9.6.3.7 Contraception and pregnancy test, 
Section 9.7.5 Induction of bleeding
15.2.1.2
Change 2: Removal of Rifabutin from the examples of strong CYP3A4 
inducers
Rifabutin was removed from the list of strong CYP3A4 inducers in exclusion criteria 4
Rationale:
Rifabutin is a moderate CYP3A4 inducer and was therefore removed from the examples of 
strong CYP3A4 inducers.
Affected section: Section 6.2 Exclusion criteria
15.2.1.3
Change 3: Revision of prior and concomitant therapy
Section 8.1 Prior and concomitant therapy was revised
Rationale:
This section was revised to minimize the risk that hormonal treatment is started before the 
endometrial biopsy is taken.
Affected section: Section 8.1 Prior and concomitant therapy
15.2.1.4
Change 4: Modifications on the tabular schedule of evaluations
Footnotes were modified.
Rationale:
Footnotes were revised to reflect the actual requirements correctly.
Affected section: Section 9.1 Tabular schedule of evaluations
15.2.1.5
Change 5: Gynecological examination was added to the premature 
discontinuation visit
Gynecological examination was added to the visit description of the premature 
discontinuation visit.
Rationale:
The visit description was revised to ensure that subjects who prematurely discontinue during 
the treatment phase get those gynecological examinations, including the cervical smear 


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performed in order to make sure that they did not develop any abnormalities during the 
treatment.
Affected section: Section 9.2.4 Premature discontinuation visit
15.2.1.6
Change 6: Ultrasound personnel
Ultrasound can be performed by an experienced examiner.
Rationale:
Revised to clarify that the ultrasound does not necessarily have to be performed by a 
physician as this is not common practice in all participating countries.
Affected sections: Section 9.4.2 Ultrasound (efficacy) to assess uterine fibroids, Section 
9.6.3.6 Ultrasound (safety)
15.2.1.7
Change 7: Section on Hemoglobin was moved
Section on hemoglobin was moved from efficacy to safety.
Rationale:
Changes in hemoglobin are regarded as safety parameter and therefore the section on 
hemoglobin was added to the safety section.
Affected sections: Section 9.4.3 Hemoglobin, Section 9.6.4 Hemoglobin
15.2.1.8
Change 8: Rewording sampling of endometrial biopsies
Rationale:
Description of sampling of endometrial biopsies was revised to make sure that the biopsy 
sampling via a disposable device Pipelle de Cornier does not require a hysteroscopy. 
Affected section: Section 9.6.3.2.2 Sampling of endometrial biopsies
15.2.1.9
Change 9: Correction of the number of enrolled subjects
Rationale:
The originally wrongly displayed number was corrected in order to be consistent with the 
planned number.
Affected section: Section 2 Synopsis
15.2.1.10 Change 10: Minor clarifications for consistency
Clarifications were made throughout the document to ensure readability, logic and 
consistency of the protocol and across studies.
Affected sections: Section 3 Introduction, Section 6.1 Inclusion criteria, Section 6.4.1 
Withdrawal, Section 7.1 Treatments to be administered, Section 8.2 Post-study therapy, 


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Section 9.3.4 Heavy menstrual bleeding questions, Section 9.6.1.6 Adverse events of special 
interest, Section 9.6.3.1 Laboratory evaluations, Section 9.6.3.2.3 Assessment of endometrial 
biopsies, Section 9.6.3.3 Cervical smear, Section 9.6.3.4 Physical and gynecological 
evaluations, Section 9.7.1 Iron Supplementation, Section 10.3.1.2 Secondary efficacy 
variable, Section 10.3.1.3 Other efficacy variables, Section 13.4 Subject information and 
consent
15.2.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as
follows:
4. Addition of a whole new portion
Brief identification of the new portion
5. Removal of a whole portion
Complete display of the removed portion, formatted 
as crossed out
6. Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out
in the “old text”. Additions are underlined in the 
“new text”. 
Tables / figures
The term “amended” is added to the caption.
Terminological changes
Brief specification of the terminological change
Thus, in this section, a terminological change (e.g. 
“period” versus “epoch”) is defined only once, 
without displaying “old text” versus “new text” for 
each appearance.
Corrections of typos are not highlighted in this section.
15.2.2.1
Section 2 Synopsis
Old text:
[…]
Number of subjects
About 2100 subjects will be enrolled in order to achieve the planned 
number of randomized subjects.
A total of 1050 subjects are planned to be randomized as follows: 
300 subjects each in Treatment Groups A1, A2, and B; 150 subjects in 
Treatment Group A3
The sample size was chosen to fulfill the regulatory requirements for safety 
data.
[…]


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New text:
[…]
Number of subjects
About 1750 subjects will be enrolled in order to achieve the planned 
number of randomized subjects.
A total of 1050 subjects are planned to be randomized as follows: 
300 subjects each in Treatment Groups A1, A2, and B; 150 subjects in 
Treatment Group A3
The sample size was chosen to fulfill the regulatory requirements for safety 
data.
[…]
15.2.2.2
Section 3 Introduction
Old text:
[…]
Not surprisingly, many women would prefer not to have surgery at all. A US based national 
survey revealed that 84% of women under the age of 40 with symptoms related to their 
uterine fibroids thought that it was important to have a leiomyoma treatment option that did 
not involve invasive surgery (7). Therefore, there is a great medical need for effective 
pharmacological treatment suitable for long-term treatment of uterine fibroids. Unfortunately, 
there is no approved medical therapy in the US that addresses this need for a prolonged 
treatment strategy that can serve as an acceptable alternative to surgery.
[…]
Safety data also showed a favorable safety profile with no relevant safety concerns.
The investigator’s brochure (IB) contains further comprehensive information on the study 
drug.
New text:
[…]
Not surprisingly, many women would prefer not to have surgery at all. A US based national 
survey revealed that 84% of women under the age of 40 with symptoms related to their 
uterine fibroids thought that it was important to have a leiomyoma treatment option that did 
not involve invasive surgery (7). Therefore, there is a great medical need for effective 
pharmacological treatment suitable for long-term treatment of uterine fibroids. Unfortunately, 
there is no approved medical therapy in the US and Japan that addresses this need for a 
prolonged treatment strategy that can serve as an acceptable alternative to surgery.
[…]
Safety data also showed a favorable safety profile with no relevant safety concerns. Based on 
the results of these studies it is expected that the significant benefits of vilaprisan shown over 
up to 2 treatment courses will translate to similarly significant benefits in patients randomized 
to vilaprisan treatment in the phase 3 studies, which will have a duration of up to 8 treatment 
courses.


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The investigator’s brochure (IB) contains further comprehensive information on the study 
drug.
15.2.2.3
Section 5 Study design
Old text:
[…]
During the screening period, subjects will have to demonstrate eligibility including presence 
of at least 1 uterine fibroid, at least one symptom of uterine fibroid(s), and an endometrial 
biopsy result without significant histological disorder.
[…]
Justification of the design
Comparators:
Standard of care symptomatic nonhormonal medical treatment and watch and wait are
considered appropriate to examine comparative safety and efficacy of vilaprisan versus 
available treatment option(s). Hormonal medical treatments and surgical interventions are not 
permitted as comparators.
[…]
It is anticipated that the number of days with HMB per time interval (eg, 12 months) will be 
reduced in the 6/2 and 3/1 regimens as compared to the 3/2 regimen, which is considered a 
clinically relevant benefit for patients.
[…]
Safety monitoring:
Safety parameters will be regularly and closely monitored throughout the study (eg, 
questioning for AEs, measurement of laboratory values, vital signs, endometrial thickness, 
abnormal menstrual bleeding, and size of follicle-like structures comprising follicles and 
functional ovarian cysts).  Normal or clinically insignificant results of these parameters as 
well as from an endometrial biopsy are prerequisites for randomization to treatment. Criteria 
for withdrawal of individual subjects or termination of the entire study are described in 
Sections 6.4 and 12, respectively.
[…]
Clear decision trees are outlined as to when to perform an unscheduled endometrial biopsy in 
case of endometrial thickening and/or on the clinical management of endometrial 
thickening/HMB/abnormal menstrual bleeding pattern (see Section 9.7.2).
PRMs such as vilaprisan induce a degree of ovulation suppression, accompanied by a 
moderate decrease in endogenous estradiol levels.
[…]
However, possible risks are regarded as acceptable because the planned methods are used 
routinely in clinical studies, clinical and/or gynecological practice. Adverse effects will be 
monitored throughout the study, with systematic monitoring of parameters of special interest
(eg, endometrial thickness and volume of menstrual bleeding).  


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The overall benefit-risk assessment for the present study is considered favorable based on the 
available data. It is expected that the information gained from the study will help in the 
development of better treatment for women with uterine fibroids in the future.
[…]
New text:
[…]
During the screening period, subjects will have to demonstrate eligibility including presence 
of at least 1 uterine fibroid documented by ultrasound at screening and / or during a uterine 
preserving procedure within 3 months prior to screening, at least one symptom of uterine 
fibroid(s), and an endometrial biopsy result without significant histological disorder.
[…]
Justification of the design
Comparators:
Standard of care symptomatic nonhormonal medical treatment and watch and wait are
considered appropriate to examine comparative safety and efficacy of vilaprisan versus 
available treatment option(s). Hormonal medical treatments and surgical interventions are not 
permitted as comparators. The fact that in all study treatment arms active treatment is 
provided, translates into a comparable level of benefit for all enrolled patients.
[…]
It is anticipated that the number of days with HMB per time interval (eg, 12 months) will be 
reduced in the 6/2 and 3/1 regimens as compared to the 3/2 regimen, which is considered a 
clinically relevant benefit for patients. The safety of all tested regimens is continuously 
monitored throughout the study, via scheduled assessment at pre-defined intervals and via pre-
defined criteria for unscheduled assessments (eg, unscheduled biopsies or temporary 
discontinuation in case of defined break-through bleeding as well as regular laboratory and 
ultrasound examinations).
[…]
Safety monitoring:
Safety parameters will be regularly and closely monitored throughout the study (eg, 
questioning for AEs, measurement of laboratory values, vital signs, endometrial thickness, 
abnormal menstrual bleeding, and size of follicle-like structures comprising follicles and 
functional ovarian cysts). Normal or clinically insignificant results of these parameters as 
well as from an endometrial biopsy are prerequisites for randomization to treatment. Criteria 
for withdrawal of individual subjects or termination of the entire study are described in 
Sections 6.4 and 12, respectively. Section 9.7 contains instructions for assessment and/or 
follow-up of specific findings such as eg, ovarian cysts or endometrial thickness over 18 mm.
[…]
Clear decision trees are outlined as to when to perform an unscheduled endometrial biopsy in 
case of endometrial thickening and/or on the clinical management of endometrial 
thickening/HMB/abnormal menstrual bleeding pattern (see Section 9.7.2). Highly reliable 


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diagnosis of any findings in the endometrial biopsies is ensured through the involvement of a 
panel of highly experienced and well renowned expert pathologists who will assess every 
biopsy sample taken from study participants.
PRMs such as vilaprisan induce a degree of ovulation suppression, accompanied by a 
moderate decrease in endogenous estradiol levels.
[…]
However, possible risks are regarded as acceptable because the planned methods are used 
routinely in clinical studies, clinical and/or gynecological practice. Adverse effects, both 
related to study drug and related to study procedures, will be monitored throughout the study, 
with systematic monitoring of parameters of special interest (eg, endometrial thickness and 
volume of menstrual bleeding).  
The overall benefit-risk assessment for the present study is considered favorable based on the 
available data. Vilaprisan is expected to provide efficacious long-term management of 
symptoms associated with uterine fibroids. Potential safety risks have been identified and will 
be closely monitored during the further clinical program.  It is expected that the information 
gained from the study will help in the development of better treatment for women with uterine 
fibroids in the future. For further information on the data available from previous studies with 
vilaprisan, please refer to the Investigator’s brochure (IB).
[…]
15.2.2.4
Section 6.1 Inclusion criteria
Old text:
[…]
4.
Symptoms of uterine fibroids documented by one or more of the following symptoms:
-
Heavy menstrual bleeding (HMB) 80.0 mL documented by menstrual pictogram 
(MP) in a bleeding period
2 during the screening period
[…]
New text:
[…]
4.
Symptoms of uterine fibroids documented by one or more of the following symptoms:
-
Heavy menstrual bleeding (HMB) 80.00 mL documented by menstrual pictogram 
(MP) in a bleeding period
2 during the screening period
[…]
15.2.2.5
Section 6.2 Exclusion criteria
Old text:
[…]


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
Intake of strong CYP3A4 inducers (eg, rifampicin, rifabutin, carbamazepine, 
phenytoin, phenobarbital, St John´s wort [hypericum]) within the last 2 weeks before 
the randomization visit and during the treatment period. A detailed list is provided in 
Section 16.2.
[…]

Anticoagulants, if not stopped at Visit 1 

Raloxifene, fluoride, calcitonin, if not stopped 3 months before the start of the 
screening period 

Current intake (ie, at Visit 1) of bisphosphonates, parathyroid hormone, GnRH 
agonists, GnRH antagonists, vitamin D analogues, systemic corticosteroids or other 
agents known or suspected to affect bone metabolism
[…]
New text:
[…]

Intake of strong CYP3A4 inducers (eg, rifampicin, carbamazepine, phenytoin, 
phenobarbital, St John´s wort [hypericum]) within the last 2 weeks before the 
randomization visit and during the treatment period. A detailed list is provided in 
Section 16.2.
[…]

Anticoagulants, if not stopped at Visit 1 

Raloxifene (or similar SERMs), fluoride, calcitonin, if not stopped 3 months before the 
start of the screening period 

Current intake (ie, at Visit 1) of bisphosphonates, parathyroid hormone, GnRH 
antagonists, vitamin D analogues, systemic corticosteroids or other agents known or 
suspected to affect bone metabolism
[…]
15.2.2.6
Section 6.4.1 Withdrawal
Old text:
[…]

At the specific request of the sponsor and in liaison with the investigator (eg, obvious 
non-compliance, safety concerns).

In case induction of bleeding becomes necessary more than once per subject during the 
study 

Pregnancy
[…]


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GPT/ALT or GOT/AST >3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 

Atypical hyperplasia, endometrial intraepithelial neoplasia (EIN) or malignant 
neoplasm 

In the event excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-
score reading of <-2 standard deviations (SD) (determined either by the central 
reading imaging laboratory or by assessment at the site and confirmed by the central 
reading imaging laboratory at the 12 month visit or later).  For additional details and 
follow-up procedures for these subjects see Section 9.6.3.8.
[…]
New text:
[…]

At the specific request of the sponsor and in liaison with the investigator (eg, obvious 
non-compliance, safety concerns).

Pregnancy
[…]
GPT/ALT or GOT/AST >3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper abdominal quadrant pain or tenderness, fever, rash, and/or eosinophilia 

Atypical hyperplasia, endometrial intraepithelial neoplasia (EIN) or malignant 
neoplasm 

In the event excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-
score reading of <-2 standard deviations (SD) (determined either by the central 
reading imaging laboratory or by assessment at the site and confirmed by the central 
reading imaging laboratory at the 12 month visit or later).  For additional details and 
follow-up procedures for these subjects see Section 9.6.3.8.

In case induction of bleeding becomes necessary more than once per subject during 
the study
[…]
15.2.2.7
Section 7.1 Treatments to be administered
Old text:
[…]
The assignment to the 2 subgroups will be done in a sequential manner, with the first 50% 
being recruited into Subgroup 1 and the remainder into Subgroup 2. Subjects will be 
randomized to treatment groups A1:A2:A3:B in a 2:2:1:2 manner.  Randomization to 
treatment will be stratified by region/country.
In Groups A1 and A3, each treatment period will consist of 12 weeks (84 days).  In Group A2, 
each treatment period will be 24 weeks (188 days).  One tablet is taken daily during the 


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treatment periods.  The tablets should be taken at about the same time every day.  Exceptions 
to this rule may occur before visits with PK blood sampling (see Section 9.5.1).
Start of treatment
Treatment Period 1 in Groups A1, A2, and A3 will start within Days 3 to 7 of the first
bleeding episode following randomization or which is ongoing at randomization.  A negative 
pregnancy test is a prerequisite for starting study drug (applies to all treatment periods).
[…]
New text:
[…]
The assignment to the 2 subgroups will be done in a sequential manner, with the first 50% 
being recruited into Subgroup 1 and the remainder into Subgroup 2. Subjects will be 
randomized to treatment groups A1:A2:A3:B in a 2:2:1:2 manner.  Some of the local
regulatory agencies requested a minimum number of subjects included into the study and well 
balanced with respect to treatment received. Therefore randomization to treatment will be 
stratified by region/country (US, Japan, China and all other countries).
In Groups A1 and A3, each treatment period will consist of 12 weeks (84 days).  In Group A2, 
each treatment period will be 24 weeks (168 days).  One tablet is taken daily during the 
treatment periods.  The tablets should be taken at about the same time every day.  Exceptions 
to this rule may occur before visits with PK blood sampling (see Section 9.5.1).
Start of treatment
Treatment Period 1 for all subjects will start within Days 3 to 7 of the first bleeding episode 
following randomization visit. In case a bleeding episode is ongoing at randomization visit, 
the subject can already start with the intake of study medication during Days 3 to 7 of this 
bleeding episode.  A negative pregnancy test is a prerequisite for starting study drug (applies 
to all treatment periods).
[…]
15.2.2.8
Section 8.1 Prior and concomitant therapy
Old text:
[…]
Subjects who withdraw from study drug and subjects who withdraw during FUP should not 
receive hormonal treatments before the first menstruation after EoT is completed and the EoT
biopsy was performed. This is true only for subjects randomized to Treatment Groups A1, A2, 
and A3.
[…]
New text:
[…]
Subjects who withdraw from study drug and subjects who withdraw during FUP should not 
receive hormonal treatments before the first menstruation after EoT is completed and an 
endometrial biopsy was performed. 
[…]


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15.2.2.9
Section 8.2 Post-study therapy
Old text:
Subjects completing the treatment period will participate in the post-treatment FUP without 
study drug treatment. 
[…]
New text:
Subjects completing the treatment period will participate in the post-treatment FUP without 
study drug treatment. Subjects randomized to Treatment Group B may continue with 
symptomatic nonhormonal medical treatment as determined by the investigators and/or watch 
and wait method. 
[…]
15.2.2.10 Section 9.1 Tabular schedule of evaluations
Old text:
[…]
Table 9–1
[…]
Ultrasound examination d
[…]
[…]
[…]
a 
If no bleeding episode occurs within 7 weeks after the end of a treatment period (for Groups A1, A2, 
and A3), or if the second bleeding episode does not occur within 7 weeks after the end of the first 
bleeding episode (for Groups A2 and A3 only), the scheduled ultrasound will be performed as planned 
after which bleeding will be induced.  The scheduled endometrial biopsy will be performed thereafter at 
Day 7 to 15 (inclusive) of the induced bleeding.  An ultrasound and pregnancy test will be performed 
before the endometrial biopsy as described in Section 9.6.3.2.2. See Section 9.7.5 for details. In case 
induction of bleeding becomes necessary more than once (per subject) no further treatment will be 
given to this subject.
[…]
d
If endometrial thickness (double layer) 18 mm is detected after the start of treatment, the subject 
should undergo immediate evaluation by endometrial biopsy as described in Section 9.7.4.  If cyst like 
structures >30 mm without suspicious appearance (ie, functional cysts) are visualized in the 
ovaries, unscheduled ultrasound examinations to document regression/outcome of these findings 
should be performed every 4 weeks or more frequently, if required due to symptoms.
[…]


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f
If no bleeding episode occurs within 7 weeks after the EoT, the scheduled ultrasound will be performed 
as planned after which bleeding will be induced.  The scheduled endometrial biopsy (ie, FUP visit) will 
be performed at Day 7 to 15 (inclusive) of the first menstrual cycle after the induced bleeding episode.
An ultrasound and pregnancy test will be performed before the endometrial biopsy as described in 
Section 9.6.3.2.2.  See Section 9.7.5 for details.
g 
The DEXA scan should be done between Week 50-54 after the start of treatment.  At Visit 5 at the 
latest, determine the exact date for the DEXA measurement and schedule the scan for the BMD visit. 
Instruct subjects to bring a home pregnancy test to the site to take before the DEXA scan. In the event 
excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-score reading of <-2 SD 
(determined either by the central reading imaging laboratory or by assessment at the site and confirmed 
by the central reading imaging laboratory at the 12 month visit or later), study drug must be 
discontinued.  For additional details and follow-up procedures for these subjects see Section 9.6.3.8.
[…]
Table 9–2
[…]
Ultrasound examination d
[…]
[…]
[…]
a 
If no bleeding episode occurs within 7 weeks after the end of a treatment period (for Groups A1, A2, 
and A3), or if the second bleeding episode does not occur within 7 weeks after the end of the first 
bleeding episode (for Groups A2 and A3 only), the scheduled ultrasound will be performed as planned 
after which bleeding will be induced.  The scheduled endometrial biopsy will be performed thereafter at 
Day 7 to 15 (inclusive) of the induced bleeding.  An ultrasound and pregnancy test will be performed 
before the endometrial biopsy as described in Section 9.6.3.2.2. See Section 9.7.5 for details. In case 
induction of bleeding becomes necessary more than once (per subject) no further treatment will be 
given to this subject.
[…]
d
If endometrial thickness (double layer) 18 mm is detected after the start of treatment, the subject 
should undergo immediate evaluation by endometrial biopsy as described in Section 9.7.4.  If cyst like 
structures >30 mm without suspicious appearance (ie, functional cysts) are visualized in the 
ovaries, unscheduled ultrasound examinations to document regression/outcome of these findings 
should be performed every 4 weeks or more frequently, if required due to symptoms.
[…]
f
If no bleeding episode occurs within 7 weeks after the EoT, the scheduled ultrasound will be performed 
as planned after which bleeding will be induced.  The scheduled endometrial biopsy (ie, FUP visit) will 
be performed at Day 7 to 15 (inclusive) of the first menstrual cycle after the induced bleeding episode.  
An ultrasound and pregnancy test will be performed before the endometrial biopsy as described in 
Section 9.6.3.2.2.  See Section 9.7.5 for details.
g 
The DEXA scan should be done between Week 50-54 after the start of treatment.  At Visit 5 at the 
latest, determine the exact date for the DEXA measurement and schedule the scan for the BMD visit. 
Instruct subjects to bring a home pregnancy test to the site to take before the DEXA scan. In the event 
excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-score reading of <-2 SD 
(determined either by the central reading imaging laboratory or by assessment at the site and confirmed 
by the central reading imaging laboratory at the 12 month visit or later), study drug must be 
discontinued.  For additional details and follow-up procedures for these subjects see Section 9.6.3.8.
[…]


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New text:
[…]
Table 9–1
[…]
Ultrasound examination d1, d2
[…]
[…]
[…]
a
If no bleeding episode occurs within 7 weeks after the end of a treatment period (for Groups A1, A2, 
and A3), or if the second bleeding episode does not occur within 7 weeks after the end of the first 
bleeding episode (for Groups A2 and A3 only), the scheduled ultrasound will be performed as planned 
after which bleeding will be induced.  See Section 9.7.5 for details. In case induction of bleeding 
becomes necessary more than once (per subject) no further treatment will be given to this subject.
[…]
d1 Ultrasound measurements do not have to be done on the same day as other assessments of that visit, 
but have to be performed as close to the specified visit as possible.
d2 If endometrial thickness (double layer) 18 mm is detected after the start of treatment, the subject 
should undergo immediate evaluation by endometrial biopsy as described in Section 9.7.4.  If cyst like 
structures >30 mm without suspicious appearance (ie, functional cysts) are visualized in the 
ovaries, unscheduled ultrasound examinations to document regression/outcome of these findings 
should be performed every 4 weeks or more frequently, if required due to symptoms.
[…]
f
If no bleeding episode occurs within 7 weeks after the EoT, the scheduled ultrasound will be performed 
as planned after which bleeding will be induced.  For group A1, the scheduled endometrial biopsy (ie, at 
endometrial biopsy FUP visit) will be performed at Day 7 to 15 (inclusive) of the induced bleeding 
episode.  For Groups A2, A3 and B, the planned endometrial biopsy will be performed at Day 7 to 15 
(inclusive) of the first menstrual cycle after the induced bleeding episode. An ultrasound and pregnancy 
test will be performed before the endometrial biopsy as described in Section 9.6.3.2.2.  See Section 
9.7.5 for details.
g 
The DEXA scan should be done between Week 50-54 after the start of treatment.  At Visit 5 at the 
latest, determine the exact date for the DEXA measurement and schedule the scan for the BMD visit.  
In the event excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-score reading of 
<-2 SD (determined either by the central reading imaging laboratory or by assessment at the site and 
confirmed by the central reading imaging laboratory at the 12 month visit or later), study drug must be 
discontinued.  For additional details and follow-up procedures for these subjects see Section 9.6.3.8.
[…]
Table 9–2
[…]
Ultrasound examination d1, d2
[…]
[…]
[…]


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a
If no bleeding episode occurs within 7 weeks after the end of a treatment period (for Groups A1, A2, 
and A3), or if the second bleeding episode does not occur within 7 weeks after the end of the first 
bleeding episode (for Groups A2 and A3 only), the scheduled ultrasound will be performed as planned 
after which bleeding will be induced.  See Section 9.7.5 for details. In case induction of bleeding 
becomes necessary more than once (per subject) no further treatment will be given to this subject.
[…]
d1 Ultrasound measurements do not have to be done on the same day as other assessments of that visit, 
but have to be performed as close to the specified visit as possible.
d2 If endometrial thickness (double layer) 18 mm is detected after the start of treatment, the subject 
should undergo immediate evaluation by endometrial biopsy as described in Section 9.7.4.  If cyst like 
structures >30 mm without suspicious appearance (ie, functional cysts) are visualized in the 
ovaries, unscheduled ultrasound examinations to document regression/outcome of these findings 
should be performed every 4 weeks or more frequently, if required due to symptoms.
[…]
f
If no bleeding episode occurs within 7 weeks after the EoT, the unscheduled ultrasound will be 
performed after which bleeding will be induced.  The scheduled endometrial biopsy (ie, at FUP visit) will 
be performed at Day 7 to 15 (inclusive) of the induced bleeding episode. An ultrasound and pregnancy 
test will be performed before the endometrial biopsy as described in Section 9.6.3.2.2.  See Section 
9.7.5 for details.
g 
The DEXA scan should be done between Week 50-54 after the start of treatment.  At Visit 5 at the 
latest, determine the exact date for the DEXA measurement and schedule the scan for the BMD visit.  
In the event excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-score reading of 
<-2 SD (determined either by the central reading imaging laboratory or by assessment at the site and 
confirmed by the central reading imaging laboratory at the 12 month visit or later), study drug must be 
discontinued.  For additional details and follow-up procedures for these subjects see Section 9.6.3.8.
[…]
15.2.2.11 Sections 9.2.2.1-9.2.2.12 Visit descriptions for visits 1-10, EoT Visit and 
FUP 1
Old text:
[…]

Dispense condoms with spermicide (see Section 9.6.3.7)
[…]
At Visit 5 at the latest, determine the exact date for the DEXA measurement at Visit 6 
(between Week 50 to 54 after the start of treatment) and schedule the scan for Visit 6. Instruct 
the subject to bring a home pregnancy test to the site to take before the DEXA scan.
New text:
[…]

Dispense barrier contraception, eg, condoms with spermicide (see Section 9.6.3.7)
[…]
At Visit 5 at the latest, determine the exact date for the DEXA measurement (between Week 
50 to 54 after the start of treatment) and schedule the scan for the BMD visit.


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15.2.2.12 Section 9.2.2.5 BMD Visit – Subgroups 1 and 2
Old text:
The following procedures will be performed during this visit:

Urine pregnancy test (see Section 9.6.3.7)
[…]
New text:
The following procedures will be performed during this visit:

Urine pregnancy test or result of a home pregnancy test done on the same day and as 
reported by subject (see Section 9.6.3.7)
[…]
15.2.2.13 Section 9.2.4 Premature discontinuation visit
Old text:
Subjects who discontinue the study prematurely during a treatment period should have the 
EoT visit performed.   If no endometrial biopsy is planned at the EoT visit (Subgroup 1), then 
a biopsy should be taken to document endometrial safety before the subject leaves the study.
[…]
New text:
Subjects who discontinue the study prematurely during a treatment period should have the 
EoT visit performed.   If no endometrial biopsy is planned at the EoT visit (Subgroup 1), then 
a biopsy should be taken to document endometrial safety before the subject leaves the study.
In addition to the assessments scheduled for the EoT visit, a gynecological examination 
including breast palpation and a cervical smear should be done for the subjects prematurely 
withdrawing during the treatment phase.
[…]
15.2.2.14 Section 9.3.4 Heavy menstrual bleeding questions
Old text:
[…]
The questionnaire can also be used as a pre-screening tool.
New text:
[…]
The questionnaire can also be used as a pre-screening tool. A printed version of the 
questionnaire can be provided to the sites as needed.


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15.2.2.15 Section 9.4.2 Ultrasound (efficacy) to assess uterine fibroids
Old text:
Ultrasound examinations will be performed by a physician well experienced in gynecology.
If possible, the same examiner should conduct all examinations of a subject throughout the 
study and the same ultrasound machine (per site) should be used throughout the study.  
[…]
New text:
Ultrasound examinations will be performed by a well experienced examiner. If possible, the 
same examiner should conduct all examinations of a subject throughout the study and the 
same ultrasound machine (per site) should be used throughout the study.  
[…]
15.2.2.16 Section 9.4.3 Hemoglobin
This was moved from Section 9.4.3 to Section 9.6.4.
15.2.2.17 Section 9.6.1.6 Adverse events of special interest
Old text:
[…]
Progesterone receptor modulator-associated endometrial changes (PAEC) will be assessed and 
documented in a systematic way (see Section 9.6.3.2.4).  The results of the PAEC assessment 
will normally not be reported back to the investigators and therefore not be reported as AE.  
The same systematic approach of assessment and evaluation will be applied to HMB (see 
Sections 9.4.1.1 and 9.7.3), endometrial hyperplasia and endometrial thickening (see Sections 
9.7.2 and 9.7.4), and liver function test.
New text:
[…]
Progesterone receptor modulator-associated endometrial changes (PAEC) will be assessed and 
documented in a systematic way (see Section 9.6.3.2.4).  The results of the PAEC assessment 
will only be reported back to the investigators if they trigger the request for a repeat biopsy. 
Apart from cases where such repeat biopsy is necessary, no clinical action for an individual 
subject is required based on the PAEC assessment results. PAEC assessment results are 
systematically collected for all samples and will be reported in aggregated form at the end of 
the study. They should therefore not be reported as AE for individual subject.  The same 
systematic approach of assessment and evaluation will be applied to HMB (see 
Sections 9.4.1.1 and 9.7.3), endometrial hyperplasia and endometrial thickening (see Sections 
9.7.2 and 9.7.4), and liver function test.


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15.2.2.18 Section 9.6.2 Pregnancies
Old text:
An acceptable nonhormonal contraceptive method has to be used starting at Screening Visit 1 
and continued until the end of the study.  Condoms with spermicide will be dispensed as 
required by the subject.  
[…]
New text:
An acceptable nonhormonal contraceptive method has to be used starting at Screening Visit 1 
and continued until the end of the study.  Barrier contraception, eg, condoms with spermicide 
will be dispensed as required by the subject.  
[…]
15.2.2.19 Section 9.6.3.1 Laboratory evaluations
Old text:
Only blood samples analyzed at the central laboratory will be considered for analysis. 
[…]
New text:
Only blood and urine samples analyzed at the central laboratory will be considered for 
analysis.  
[…]
15.2.2.20 Section 9.6.3.2.2 Sampling of endometrial biopsies
Old text:
[…]
The sterilized, disposable device Pipelle de Cornier will be used – a flexible and transparent 
polypropylene sheath with an internal plunger for aspiration. This device allows for gentle 
tissue sampling, and generally requires no local anesthesia or cervical dilatation.
[…]
New text:
[…]
The sterilized, disposable device Pipelle de Cornier will be used – a flexible and transparent 
polypropylene sheath with an internal plunger for aspiration. This device allows for gentle 
tissue sampling, without hysteroscopy, and generally requires no local anesthesia or cervical 
dilatation.
[…]


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15.2.2.21 Section 9.6.3.2.3 Assessment of endometrial biopsies
Old text:
[…]

Eligibility of the subject before randomization (biopsy at Visit 2)

Absence of clinically relevant endometrial pathology after about 1 year of treatment 
and before subjects will leave the study.
[…]
The results of the PAEC assessment will normally not be reported back to the investigators.
New text:
[…]

Eligibility of the subject before randomization (biopsy at Visit 2)

Any relevant pathology that requires further diagnostic or therapeutic measures 
according to local medical practice.

Absence of clinically relevant endometrial pathology after about 1 year of treatment 
and before subjects will leave the study.
[…]
The results of the PAEC assessment will normally not be reported back to the investigators.
Further details are included in the Operational Manual.
15.2.2.22 Section 9.6.3.3 Cervical smear
Old Text
[…]
Subjects with ASCUS can be included in the study if they have an HPV deoxyribonucleic acid 
test that is negative for high-risk HPV.
New text
[…]
Subjects with ASCUS can be included in the study if they have an HPV deoxyribonucleic acid 
test that is negative for high-risk HPV.
As a guidance, a cervical smear should only be repeated once in case of insufficient material.
15.2.2.23 Section 9.6.3.4 Physical and gynecological evaluations
Old text:
[…]
In case of any suspicious finding, further diagnostic investigations will be performed at the 
discretion of the investigator.


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New text:
[…]
In case of any suspicious finding, further diagnostic investigations will be performed at the 
discretion of the investigator. Abnormal physical examination findings are recorded either as 
medical history or as adverse events (see Section 9.6.1.1).
15.2.2.24 Section 9.6.3.6 Ultrasound (safety)
Old text:
Ultrasound examinations will be performed by a physician well experienced in gynecology.
[…]
New text:
Ultrasound examinations will be performed by a well experienced examiner.  
[…]
15.2.2.25 Section 9.6.3.7 Contraception and pregnancy test
Old text:
[…]
This is not required if contraception is achieved by a permanent method such as bilateral 
fallopian tube blockage (including Essure) of the subject or vasectomy of her partner(s).  
Condoms with spermicide will be dispensed as required by the subject.
[…]
New text:
[…]
This is not required if contraception is achieved by a permanent method such as bilateral 
fallopian tube blockage (including Essure) of the subject or vasectomy of her partner(s).  
Barrier contraception, eg, condoms with spermicide will be dispensed as required by the 
subject.
[…]
15.2.2.26 Section 9.6.3.8 Bone mineral density
Old text:
[…]


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The BMD measurements are to be performed only after the subject has been tested negative 
for pregnancy using a urine pregnancy test.  Subjects will be asked to bring a home pregnancy 
test to Visit 6 in order to take the test prior to the scan.
More details on the calibration and procedure of central reading will be provided in a separate 
manual.
New text:
[…]
The BMD measurements are to be performed only after the subject has been tested negative 
for pregnancy using a urine pregnancy test.  
More details on the calibration and procedure of central reading will be provided in a separate 
manual.
[…]
15.2.2.27 Section 9.6.4 Hemoglobin
This was moved from Section 9.4.3 to Section 9.6.4.
15.2.2.28 Section 9.7.1 Iron Supplementation
Old text:
If causes for anemia unrelated to HMB are suspected these subjects should not be enrolled.
Moderate anemia is defined as hemoglobin 10.9 g/dL.(10)  Iron supplementation should be 
offered to subjects with hemoglobin 10.9 g/dL consistent with local standards of practice and 
the Centers for Disease Control and Prevention recommendation, ie, 50 to 60 mg of oral 
elemental iron (the approximate amount of elemental iron in one 325 mg tablet of ferrous 
sulfate) twice daily for 3 months for the treatment of iron deficiency anemia.  Iron 
supplementation will not be considered as study drug and should be documented as 
concomitant medication.
[…]
New text:
If causes for anemia unrelated to HMB are suspected these subjects should not be enrolled.
Moderate anemia is defined as hemoglobin 10.9 g/dL.(10)  Iron supplementation should be 
offered to subjects with hemoglobin 10.9 g/dL consistent with local standards of practice and 
at the investigator’s discretion.  Iron supplementation will not be considered as study drug and 
should be documented as concomitant medication.
[…]


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15.2.2.29 Section 9.7.5 Induction of bleeding
Old text:
Subjects will be given an appropriate progestin therapy that in the experience and practice of 
the investigator will induce withdrawal bleeding in this particular subject.  Progestin therapy 
will not be considered as study medication and will be documented as concomitant 
medication.
During treatment breaks:  If no bleeding episode occurs within 7 weeks after the end of a 
treatment period (for Treatment Group A1, A2, and A3) or if the second bleeding episode 
does not occur within 7 weeks after the end of the first bleeding episode (for Treatment 
Groups A2 and A3 only), the scheduled ultrasound will be performed as planned after which 
bleeding will be induced.  The scheduled endometrial biopsy will be performed thereafter at 
Day 7 to 15 (inclusive) of the induced bleeding.  For details and prerequisites for the 
endometrial biopsy sampling, see Section 9.6.3.2.2
After EoT visit:  If spontaneous menstrual bleeding does not occur within 7 weeks after the 
EoT, the scheduled ultrasound will be performed as planned after which bleeding will be 
induced.  The scheduled endometrial biopsy (ie, FUP visit) will be performed at Day 7 to 15 
(inclusive) of the first menstrual cycle after the induced bleeding episode.  For details and 
prerequisites for the endometrial biopsy sampling, see Section 9.6.3.2.2.
[…]
New text:
A negative pregnancy test is a prerequisite for induction of bleeding. Subjects will be given an 
appropriate progestin therapy that in the experience and practice of the investigator will 
induce withdrawal bleeding in this particular subject.  Progestin therapy will not be 
considered as study medication and will be documented as concomitant medication.
During treatment breaks:  If no bleeding episode occurs within 7 weeks after the end of a 
treatment period (for Treatment Group A1, A2, and A3) or if the second bleeding episode 
does not occur within 7 weeks after the end of the first bleeding episode (for Treatment 
Groups A2 and A3 only), the scheduled ultrasound will be performed as planned after which 
bleeding will be induced.  For details and prerequisites for the endometrial biopsy sampling, 
see Section 9.6.3.2.2
After EoT visit:
- Subgroup 1: If spontaneous menstrual bleeding does not occur within 7 weeks after the EoT,
the scheduled ultrasound will be performed as planned after which bleeding will be induced. 
For Group A1, the scheduled endometrial biopsy (ie, at endometrial biopsy FUP visit) will be 
performed at Day 7 to 15 (inclusive) of the induced bleeding. For groups A2, A3 and B, the 
planned endometrial biopsy will be performed at Day 7 to 15 (inclusive) of the first menstrual 
cycle after the induced bleeding episode.  
- Subgroup 2: Subgroup 2: If spontaneous menstrual bleeding does not occur within 7 weeks 
after the EoT, an unscheduled ultrasound will be performed after which the bleeding will be 
induced. The scheduled endometrial biopsy (ie, at FUP visit) will be performed thereafter at 
Day 7 to 15 (inclusive) of the first menstrual cycle after the induced bleeding episode.
[…]


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15.2.2.30 Section 9.7.7 Exploratory biomarker analysis
Old text:
Biomarker investigations in this study will be whole genome expression profiling from 
endometrial biopsy samples.  Each subject has the option to choose whether her biopsy tissue 
samples can be used for this biomarker research or not unless precluded by local guidelines.
[…]
New text:
Biomarker investigations in this study will be whole genome expression profiling from 
endometrial biopsy samples.  Each subject, except for women included in China, has the 
option to choose whether her biopsy tissue samples can be used for this biomarker research or 
not unless precluded by local guidelines.
[…]
15.2.2.31 Section 10.2 Analysis sets
Old text:
[…]
Safety analysis set (SAF): All subjects randomized who took at least 1 dose of study drug. 
Subjects will be analyzed as treated.
All subjects randomized to Treatment Group B will be analyzed as treated, regardless whether 
they actually took any medication (ie, symptomatic, nonhormonal medical treatment).
All safety analyses will be performed on the SAF population. The FAS will be used for the 
display of all other variables.
New text:
[…]
Safety analysis set (SAF): All subjects randomized who took at least 1 dose of study drug. 
Subjects will be analyzed as treated.
All subjects randomized to Treatment Group B will be analyzed as treated, regardless whether 
they actually took any medication (ie, symptomatic, nonhormonal medical treatment).
All safety analyses will be performed on the SAF population. The FAS will be used for the 
display of all other variables.
Modified SAF: will include all subjects in the SAF without any validity findings which may 
potentially affect the primary safety endpoint. Validity findings leading to exclusion from the 
modified SAF will be specified in the ‘Specification of assessment criteria and identification 
requirements’, which will be finalized before database lock. Subjects will be analyzed as 
treated.
All subjects randomized to Treatment Group B will be analyzed as treated, regardless whether 
they actually took any medication (ie, symptomatic, nonhormonal medical treatment).


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All safety analyses will be performed on the SAF population. The FAS will be used for the 
display of all other variables. The analysis for the primary safety endpoint and all BMD 
related endpoints will be performed on the modified SAF as well.
15.2.2.32 Section 10.3.1.2 Secondary efficacy variable
Old text:

Number of bleeding days from Day 1 of the first treatment period until the day before 
the next treatment period after the last treatment period would start again normalized 
to 28 days 
New text:

Number of bleeding days from Day 1 of the first treatment period until the day before 
a new treatment period would start again following the last treatment period for that 
respective treatment group. Number to be normalized by 28 days
15.2.2.33 Section 10.3.1.3 Other efficacy variables
Old text:
[…]

Time to onset of controlled bleeding for each treatment period
Onset of controlled bleeding is defined by the first day for which the menstrual blood 
loss (assessed by MP) for all subsequent 28-day periods up to the end of the treatment 
period is <80.0 mL.
[…]
New text:
[…]

Time to onset of controlled bleeding for each treatment period
Onset of controlled bleeding is defined by the first day for which the menstrual blood 
loss (assessed by MP) for all subsequent 28-day periods up to the end of the treatment 
period is <80.00 mL. 
[…]
15.2.2.34 Section 13.4 Subject information and consent
Old text:
[…]
Only if the subject voluntarily agrees to sign the informed consent and has done so, may she 
enter the study.  Additionally, the investigator and other information provider (if any) will 
personally sign and date the form.  The subject will receive a copy of the signed and dated 
form.
[…]


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New text:
[…]
Only if the subject voluntarily agrees to sign the informed consent and has done so, may she 
enter the study.  Additionally, the investigator or designee will personally sign and date the 
form.  The subject will receive a copy of the signed and dated form.
[…]
15.3
Amendment 6 – dated 04 JUL 2018
Amendment 6 (04 JUL 2018) 
Overall Rationale for the Amendment
Overall Rationale: This amendment is based on guidance from Health Authorities’ feedback 
with specific request for monthly liver parameter monitoring, which is to be implemented in 
all vilaprisan studies including ASTEROID 6 study. In addition to health authority triggered 
changes additional updates had to be performed, which are listed below, together with the 
respective reasons for the updates.
Section # and 
Name
Description of Major Changes
Brief Rationale
3. Introduction
1) 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. 
1) EMA 
Pharmacovigilance Risk 
Assessment Committee 
(PRAC) review 
procedure concluded in
in May, 2018
5. Study design
1) Description of increased frequency of 
liver monitoring and its background in 
subsection “safety monitoring”
2) Creation of a separate section on Benefit 
Risk Assessment 
1) FDA feedback in 
January and May 2018; 
FDA Guidance for 
Industry Drug-Induced 
Liver Injury (July 2009)
2) Feedback received 
from health authorities in 
the initial submission of 
Asteroid protocols
6.2 Exclusion 
criteria
1) The criterion about abnormal liver 
parameters was revised
2) The diagnosis of hepatitis B / C infection 
was added to exclusion criteria.
3) The criterion about intake of strong CYP 
inducer was updated, correcting information 
1) + 2) To address FDA 
requirement on more 
robust liver safety data 
and to closely align with 
specific feedback 
received in Jan and May 
2018 and the 2009 FDA 


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about metronidazole.
4) A clarification that endometrioma are 
exempt was added to the criterion regarding 
ovarian cysts 
5) criterion regarding current bone and 
musculoskeletal disease were updated (Vit D 
deficiency was changed to “uncontrolled Vit 
D deficiency”)
6) A new exclusion criterion was added 
regarding a z-score of < -2 at baseline
7) The criterion about contraceptive devices 
was updated
8) Added “other hormonal treatments for 
HMB or fibroids, if not stopped before the 
start of menstrual cycle that follows Visit 1” 
as an exclusion criterion
9) Added “previous use of ulipristal acetate, 
if there were not at least two menstruations 
after the last intake before Visit 1” as an 
exclusion criterion
DILI guideline.
3) correction
4) clarification
5) clarification
6) Feedback received 
from FDA in May 2018
7), 8, 9) clarification
8.1.1 Iron 
supplementatio
n
Addition of “at the investigator’s discretion”
Clarification needed 
because of regional 
differences in medical 
practice
9.1 Tabular 
schedule of 
evaluations
9.2.2 Scheduled 
visits
Added additional visits (ie, 3.1, 3.2, 3.3, 4.1, 
4.2, 4.3, 5.1, 5.2, 5.3, 6.1, and 6.2) during the 
study treatment in treatment groups A1, A2, 
and A3 and also after 4 weeks during the 
drug-free interval between the treatment 
periods
To address FDA 
requirement on more 
robust liver safety data, 
and to closely align with 
specific feedback 
received in Jan and May, 
2018 and the 2009 FDA 
DILI guideline
9.6.1.1 
Definitions
Newly included sentences “Any fibroid 
surgery should always be reported as SAE, 
irrespective of associated hospitalization” 
and “All instances of liver parameter testing 
which meet criteria for withdrawal of a 
subject from the study treatment should be 
reported as serious.”
2) Added definition of TEAE
1) To address FDA 
recommendation in 
response to SPA for 
Asteroid 3 received in 
Jul 2017 and to align 
with FDA 2009 DILI 
guidance
2) For clarity


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9.6.1.3
Assessments 
and 
documentation 
of adverse 
events
Added details about follow up of AEs of 
special safety interest.
For clarity
9.6.1.6 Adverse 
events of 
special interest
Added more detailed instructions for the 
monitoring of liver parameters and liver 
disorders and for close observation in cases 
with increased liver enzymes and liver 
disorders; added a flow chart aiding the 
understanding of the intended processes for 
liver function monitoring 
FDA feedback in Jan  
and May 2018 regarding 
improved liver 
monitoring
9.6.3.1 
Laboratory 
evaluations
1) Added more details on laboratory 
parameters including liver related 
parameters, screening tests for hepatitis A, B, 
and C, hemoglobin, and additional 
parameters
2) Added parameters measured under close 
observation in cases of increased liver 
parameters after start of treatment
To address FDA 
requirement on more 
robust liver safety data 
received in Jan and May 
2018
9.6.3 Further 
safety
1) Added description for liver symptom 
inquiry.
2) Added more detailed instructions relating 
to the operative implementation of the new 
exclusion criterion regarding z-score, 
addition of clear instruction not to switch 
DEXA device during the study  
1) To address FDA 
requirement on more 
robust liver safety data 
received in Jan and May 
2018
2) clarification
9.6.3.2.2 
Sampling of 
endometrial 
biopsies
A repeat endometrial biopsy will be 
requested, if sample is inadequate for 
evaluation
To address FDA 
recommendation received 
in May 2018 
9.7.6 
Monitoring of 
ovarian cysts
The monitoring will be continued until 
resolution, ie, until cyst can no longer be 
distinguished from functional follicles.  
To address FDA 
recommendation received 
in May 2018
Section 10.3.1.5 
Other safety 
variables
1) Details for laboratory parameters were 
added
2) Liver symptom inquiry was added as  a 
safety variable
To address FDA 
requirement on more 
robust liver safety data 
received in Jan and May 
2018 


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For clarity and 
consistency
16.1 Strong 
CYP3A4 
inhibitors
Added delavirdine and troleandomycin to the 
listing of strong CYP3A4 inhibitors
New compounds which 
need to be added to the 
list of excluded 
concomitant medications
10.4 
Determination 
of sample size
The sample size will be increased from 1050 
to 1302.
The increased sample 
size will contribute to this 
database in which safety 
events of interest can be 
evaluated. Explanation 
added. 
15.4
Amendment 7 – dated 20 AUG 2018
Amendment 7 (20 AUG 2018) 
Overall Rationale for the Amendment
Update of mismatch between the tables and visit descriptions to avoid site and Health 
Authority ambiguity.
Section # and 
Name
Description of Major Changes
Brief Rationale
Table 9-1, 
Table 9-2, 
Table 9-3, and
Table 9-4: 
BMD visit at 
week 50-54
And Section 
9.2.2.7
The following inquiries/investigations are 
NOT to be performed (page 44 ff. of 
integrated CSP version 4.0):

Laboratory evaluations 
(Table 9-1)

Concomitant medications 

AE assessment 

Liver symptom inquiry 
The indicated crosses 
need to be deleted. For 
consistency with these 
deletions also in Section 
9.2.2.7, those 4 inquiries/ 
investigations are to be 
deleted (page 66 of inte-
grated CSP version 4.0)
Table 9-2 
Subgroup 2
Blood samples have to be collected at Visit 5 
(page 56 of integrated CSP version 4.0)
The indicated cross needs 
to be added (this is 
correctly displayed in the 
visit description sections)
Table 9-3, 
Subgroup 1
No laboratory investigations are needed at 
FUP2  (page 56 of integrated CSP version 
4.0)
The indicated cross needs 
to be deleted (this is 
correctly displayed in the 
visit description section).


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15.5
Amendment 9 – dated 11 DEC 2018
Global amendment 9 to the integrated study protocol version 6.0, dated 11 DEC 2018.
Overall Rationale for the Amendment:
Preliminary findings from 2-year animal carcinogenicity studies (rat/mouse) with vilaprisan 
that were received very recently showed evidence of an increased incidence in endometrial 
and adrenal neoplasms. While these unexpected findings and their relevance for humans are 
being further evaluated, Bayer decided to temporarily pause enrollment and randomization, 
and to temporarily discontinue study treatment in already randomized subjects after 
completion of the ongoing treatment periods. This global amendment provides background, 
justification, as well as a detailed description of the temporary measures to be taken.  Subjects 
in the standard of care arm of the study can continue the study course following the current 
valid version of the protocol.
15.5.1
Overview of Changes
Section # and 
Name
Description of Change
Brief Rationale
15.5 Global 
amendment leading 
to version 6.0
Added text specifying measures 
for temporary pause of the study
Temporarily pause enrollment and 
randomization, and temporarily withdraw 
study treatment in already randomized 
subjects after completion of the ongoing 
treatment periods
15.5.2
Changes to the protocol text 
15.5.2.1
Background and justification of changes
Preliminary data from carcinogenicity studies was presented. For the complete (outdated) 
text, please refer to global amendment 9 to the integrated study protocol, version 5.0.

The relevance to human situation was discussed. For the complete (outdated) text, 
please refer to global amendment 9 to the integrated study protocol, version 5.0.

The clinical data as of to date (end of 2018) was summarized. For the complete 
(outdated) text, please refer to global amendment 9 to the integrated study protocol, version 
5.0.
Monitoring measures in ongoing studies were presented. For the complete (outdated) text, 
please refer to global amendment 9 to the integrated study protocol, version 5.0.
15.5.2.2
Description of temporary measures
The temporary measures applied with implementation of amendment 9 (measures for subjects 
after start of treatment) or were already implemented with the 15-day report on 03 DEC 2018 
(temporary suspension of enrolment and randomization) were displayed as well as guidance 
for subjects awaiting next steps. As they are not of relevance for the restart of the study, they 
are not displayed here again, but can be found in global amendment 9 to the integrated study 
protocol, version 5.0. Special attention was drawn to signs and symptoms suggestive of 
increased levels of adrenal hormones (like hypercortisolism, phaeochromocytoma, and 
primary hyperaldosteronism).


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17 FEB 2020
Version 8.0
Page:  117 of 122
15.6
Amendment 10 – dated 21 NOV 2019
Global Protocol Amendment 10 to the integrated study protocol version 7.0, dated 21 NOV
2019.
Amendment 10 is presented using a different approach compared with previous amendments 
to this protocol. The rationale for changes in this amendment and all affected sections are 
provided in the ‘Protocol Amendment Summary of Changes Table’ directly before the Table 
of Contents in this document. A separate file with tracked changes as against the last 
integrated protocol version is available upon request.
The rationale for changes in Amendment 10 and all affected sections are provided as follows.
Overall Rationale for the Amendment
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018 (refer to Protocol Amendment 9 [version 6.0]) while pre-clinical 
toxicology findings and their relevance to humans were being further investigated. Although 
the outcome of Bayer’s investigation revealed that the observed pre-clinical findings are 
regarded to be of limited relevance to the human situation (refer to IB version 11.0 and 
Introduction Section 3), a comprehensive safety follow up will be conducted to provide 
additional confirmatory evidence. This amendment introduces measures and processes to 
prepare this study for an orderly closure, including safety follow up measures in all study 
subjects who received at least one dose of study drug. Also, subjects randomized to SoC who 
are still in the study will be asked to undergo these procedures.
15.6.1
Overview of Changes
Section # and 
Name
Description of Major Changes
Brief Rationale
3 Introduction
Information on carcinogenicity studies with 
vilaprisan in rodents as well as details 
regarding the additional safety measures 
were added to the section, included adrenal 
skin, and endometrial evaluation, added the 
new benefit-risk assessment
Provision of 
comprehensive 
information about recent 
events
To re-assess 
benefits/risks, including 
the findings from the 
carcinogenicity studies 
into consideration and 
address the newly 
introduced monitoring
4. Study 
objectives
Added additional focus on safety 
evaluations of the endometrium, adrenal 
glands and skin
To address FDA requests
5. Study design
Updated study design; irrelevant 
To address FDA requests


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17 FEB 2020
Version 8.0
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Section # and 
Name
Description of Major Changes
Brief Rationale
information deleted that is no longer 
relevant
With the implementation
of Protocol Amendment 
10 (version 7.0) no new 
subjects will be recruited 
and no study medication 
will be given to the 
subjects who have been 
enrolled in the study
6 Study 
population
7. Treatments
8. Non-study 
therapy
9.3 Population 
characteristics
9.4 Efficacy
9.5 
Pharmacokineti
cs/pharmacodyn
amics
11. Data 
handling and 
quality 
assurance
Updated based on new study design; 
irrelevant information deleted that is no 
longer relevant
To address FDA requests
9.1 Tabular 
schedule of 
evaluations
9.2 Visit 
description
Information deleted that is no longer 
relevant; added “Safety closeout visit” and
“Safety result reporting visit” 
To depict the procedures 
of the “Safety closeout 
visit” and the “Safety 
result reporting visit”.
9.6.1.1 
Definition
New criteria for SAE reporting for 
endometrial biopsies, adrenal tumors, and 
malignant skin tumors
To address FDA requests
9.6.1.6 AEs of 
special interest
New AESIs added for adrenal and skin 
disorders.
To address FDA 
requirements
9.6.3.1 
Laboratory 
evaluations
Added more details on laboratory 
parameters associated with adrenal 
disorders. Added requirement for Vit D 
measurement
To address FDA 
requirement on adrenal 
monitoring; Vit D 
measurement for 


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17 FEB 2020
Version 8.0
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Section # and 
Name
Description of Major Changes
Brief Rationale
harmonization of data 
across all studies
9.6.3 Further 
safety
Deleted “In addition, the subjects should be 
reminded regularly to contact the study site 
immediately, if they are concerned about 
such symptoms and testing for unscheduled 
liver parameters should be considered.”
No longer required as no 
further treatment will be 
administered
9.6.3.2
Endometrial 
biopsies
Added more details on endometrial biopsies
To address FDA requests
9.6.3.3 Cervical 
smear
9.6.3.4 Physical 
and 
gynecological 
examinations
9.6.3.5 Vital 
signs, weight, 
and height
9.6.3.6
Ultrasound 
(safety)
9.6.3.7
Contraception 
and pregnancy 
test
9.6.3.8 Bone 
mineral density
Revised to reflect the collection of the 
parameters at the safety closeout visit.
Update necessary due to 
new visit structure
9.6.3.9 Adrenal 
monitoring
Added description for adrenal monitoring 
(MRI, laboratory investigations and inquiry)
To address FDA requests
9.6.3.10 Liver 
monitoring
Content shifted from previous Section 
9.6.1.6 and added alkaline phosphatase (AP) 
value increasing to > 2x ULN in cases with 
normal baseline AP as a close observation 
criterion
To address FDA requests
9.6.3.12 Skin 
monitoring
New section added on skin monitoring
To address FDA requests


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17 FEB 2020
Version 8.0
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Section # and 
Name
Description of Major Changes
Brief Rationale
9.6.3.13 
Reporting of 
medical device 
failures (Japan 
only)
New section added on reporting medical 
device failures for Japan
To address country 
specific requirements
9.7.2 Algorithm 
for monitoring 
of endometrial 
safety
9.7.3 Heavy 
menstrual 
bleeding / 
suspicious 
bleeding pattern
9.7.4 
Unscheduled 
endometrial 
biopsy
Content shifted to Sections 9.6.3.2.1, 
9.6.3.2.7, and 9.6.3.2.8
To address FDA requests
10.2 Analysis 
sets
Adapted FAS definitions
FAS needed to be newly 
defined to take the 
handling of subjects into 
account who were not 
allowed to start TP1 due 
to the clinical hold. 
10.3.1.5 Other 
safety variables
Added adrenal monitoring and skin safety
To address FDA request
10.4 
Determination 
of sample size
Added text to clarify that the sample size 
calculation described is not valid anymore.
No new subjects will be 
included in the study. 
10.5 Planned 
interim analyses
Added text on additional analysis planned 
before the end of the study.
Added to reflect new 
analysis strategy


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17 FEB 2020
Version 8.0
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15.7
Amendment 11 - dated 17 FEB 2020
Amendment 11 is presented using the same approach as Amendment 10. The rationale for this 
amendment and all affected sections are provided in the “Protocol Amendment Summary of 
Changes Table” directly before the Table of Contents in this document. Changes are made 
directly in the protocol body without annotations. A separate file with tracked changes against 
the last integrated protocol version is available upon request.


Integrated Clinical Study Protocol
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17 FEB 2020
Version 8.0
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16.
Appendices
16.1
Strong CYP3A4 inhibitors 
Table 16–1: Strong CYP3A4 inhibitors
Substance name
Inhibitor strength
Boceprevir
Strong
Clarithromycin
Strong
Grapefruit juice
Depending on dose: Moderate or strong
Cobicistat
Strong
Conivaptan
Strong
Delavirdine
Strong
Idelalisib
Strong
Indinavir
Strong
Itraconazole
Strong
Ketoconazole
Strong
Lopinavir
Strong
Mibefradil
Strong
Miconazole
Strong
Nefazodone
Strong
Nelfinavir
Strong
Posaconazole
Strong
Ritonavir
Strong
Saquinavir
Strong
Telaprevir
Strong
Telithromycin
Strong
Tipranavir
Strong
Troleandomycin
Strong
Voriconazole
Strong
16.2
Strong CYP3A4 inducers
This section was added in Amendment 3, see Section 15.1.1.
Table 16–2: Strong CYP3A4 inducers
Substance name
Inducer strength
Phenobarbital
Strong
Avasimibe
Strong
Carbamazepine
Strong
Enzalutamide
Strong
St. John’s Wort (Hypericum)
Strong
Lumacaftor
Strong
Methylphenobarbital
Strong
Mitotane
Strong
Phenytoin
Strong
Rifampicin
Strong
Rifamycin
Strong

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
An open-label, parallel-group, randomized, multicenter study to 
assess the safety and efficacy of vilaprisan in subjects with uterine 
fibroids versus standard of care 
NCT Number: 
NCT03194646 
Document Date: 
04 Mar 2021 
 


Statistical Analysis Plan
Protocol No.: BAY 1002670/16953
Page: 1 of 48
Reference Number: RD-OI-0119
Supplement Version: 8
An open-label, parallel-group, randomized, multicenter study to assess the safety 
and efficacy of vilaprisan in subjects with uterine fibroids versus standard of 
care
Short title:  Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids
Bayer study drug
BAY 1002670  
Study purpose:
Safety and efficacy
Clinical study phase:
3
Date:
04 Mar 2021
Study No.:
16953
Version:
2.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document, whether in 
part or in full, to parties not associated with the clinical investigation or its use for any other 
purpose without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY 1002670/16953
Page: 2 of 48
Reference Number: RD-OI-0119
Supplement Version: 8
Table of Contents
1.
Introduction ..............................................................................................................6
2.
Study Objectives........................................................................................................7
3.
Study Design..............................................................................................................7
4.
General Statistical Considerations ............................................................................9
4.1
General Principles........................................................................................................................... 9
4.2
Handling of Dropouts .................................................................................................................... 9
4.3
Handling of Missing Data............................................................................................................. 9
4.4
Interim Analyses and Data Monitoring....................................................................................10
4.5
Data Rules ......................................................................................................................................10
4.6
Blind Review.................................................................................................................................19
5.
Analysis Sets............................................................................................................19
5.1
Assignment of analysis sets........................................................................................................19
6.
Statistical Methodology ...........................................................................................19
6.1
Population characteristics ...........................................................................................................19
6.1.1
Subject validity, disposition....................................................................................................20
6.1.2
Demographic, Baseline Characteristics................................................................................20
6.1.3
Medical History.........................................................................................................................20
6.1.4
Reproductive and menstrual history .....................................................................................21
6.1.5
Uterine Fibroids relevant history...........................................................................................21
6.1.6
Heavy menstrual bleeding questions ....................................................................................21
6.1.7
Prior/Concomitant Medication...............................................................................................21
6.1.8
Exposure and Compliance to Study Treatment ..................................................................23
6.1.8.1
Treatment duration................................................................................................................23
6.1.8.2
Extent of exposure ................................................................................................................23
6.1.8.3
Treatment compliance..........................................................................................................23
6.2
Efficacy...........................................................................................................................................24
6.2.1
Primary efficacy variable ........................................................................................................24
6.2.2
Secondary efficacy variable....................................................................................................24
6.2.3
Other efficacy variables...........................................................................................................24
6.2.3.1
Volume of menstrual blood loss related variables .........................................................24
6.2.3.2
Time to event related variables ..........................................................................................25
6.2.3.3
Ultrasound examination related variables........................................................................25
6.2.3.4
Percentage of subjects undergoing surgical treatment ..................................................26
6.2.3.5
Patient/Clinician-reported outcomes.................................................................................26


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 8
6.2.3.6
Variables related to laboratory parameters ......................................................................27
6.3
Pharmacokinetics/pharmacodynamics .....................................................................................27
6.4
Exploratory biomarker analysis.................................................................................................27
6.5
Safety...............................................................................................................................................27
6.5.1
Primary safety variable............................................................................................................28
6.5.2
Secondary safety variables......................................................................................................30
6.5.2.1
Endometrial histology (eg, benign endometrium, presence or absence of hyperplasia or 
malignancy)............................................................................................................................30
6.5.2.2
Endometrial thickness ..........................................................................................................32
6.5.2.3
Percentage change from baseline in BMD measured, hip, and femoral neck by DEXA
...................................................................................................................................................33
6.5.3
Other safety variables...............................................................................................................33
6.5.3.1
Endometrial histology (diagnosis of PAEC, individual features of PAEC) .............33
6.5.3.2
Percentage of subjects with BMD decrease >6% and Z-score < -2 measured at the 
lumbar spine...........................................................................................................................33
6.5.3.3
Change in Z-score over time...............................................................................................33
6.5.3.4
Ovarian cysts..........................................................................................................................33
6.5.3.5
AEs...........................................................................................................................................35
6.5.3.6
Laboratory parameters .........................................................................................................36
6.5.3.7
Estradiol ..................................................................................................................................37
6.5.3.8
Cervical smear .......................................................................................................................37
6.5.3.9
Vital signs ...............................................................................................................................37
6.5.3.10
Liver monitoring....................................................................................................................37
6.5.3.11
Adrenal monitoring...............................................................................................................39
6.5.3.12
Skin monitoring.....................................................................................................................40
6.5.3.13
UF-DBD bleeding pattern per 28 days and 84 days based on UF-DBD...................41
7.
Subgroup analyses...................................................................................................41
8.
Document history and changes in the planned statistical analysis...........................42
9.
References ...............................................................................................................42
Appendix 1: Handling of Patient-report outcomes............................................................................42
Appendix 2 : The maximum or minimum measurement for laboratory parameters ..................43
Appendix 3 : List of AESIs in current expert statement based on MedDRA Version 22.1 (version 
5.0, status 2020-02-19)................................................................................................................45
Appendix 4: Mapping of MP icons to MBL volume (mL)..............................................................47


Statistical Analysis Plan
Protocol No.: BAY 1002670/16953
Page: 4 of 48
Reference Number: RD-OI-0119
Supplement Version: 8
Abbreviations
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (also known as GPT)
AST
Aspartate aminotransferase (also known as GOT)
B
Bleeding episode
BHC
Bayer HealthCare
BMD
Bone mineral density
BMI
Body mass index
CGI-I
Clinical Global Impression - Investigator
CI
Confidence interval
ClinRO
Clinician-reported outcome
cm
Centimeter
CSR
Clinical Study Report
DEXA
Dual energy X-ray absorptiometry 
dL
Deciliter
eCRF
Electronic Case Report Form
eDiary
Electronic diary
eg
Exempli gratia, for example
EoT
End of treatment 
EoFUP
End of follow-up
ePRO
Electronic patient-reported outcomes
FAS
Full analysis set 
FUP
Follow-up 
g
Gram
HMB
Heavy menstrual bleeding 
HRQoL
Health-related quality of life
IB
Investigator’s brochure
ie
id est, that is
INR
International normalized ratio
IVRS/IWRS
Interactive voice/web response system
MedDRA
Medical Dictionary for Regulatory Activities
METW
Moving evaluation time windows 
mg
Milligram
mL
Milliliter
MP
Menstrual pictogram
N/A
Not applicable
PAEC
Progesterone receptor modulator-associated endometrial changes
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PRM
Progesterone receptor modulator
PRO
Patient-reported outcome
PT
Preferred term
RND
Randomization 
RAVE
Electronic data capturing system
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistics Analysis System
SCR
Screening
SD
Standard deviation


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 8
SOC
System organ class 
SoT
Start of treatment
TEAE
Treatment-emergent adverse event
TP
Treatment Period
trt
Treatment
TVU
Transvaginal ultrasound
UF-DBD
Uterine Fibroid Daily Bleeding Diary
UF-DSD
Uterine Fibroid Daily Symptom Diary
UFS-QoL
Uterine Fibroid Symptom and Quality of Life questionnaire
ULN
Upper limit of normal
US
United States
VPR
Vilaprisan
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
wk
Week


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 8
1.
Introduction
Uterine fibroids are benign tumors originating from smooth muscle cells of the myometrium. The 
pathophysiology of fibroids is not well understood. Genetic predisposition, exposure to steroid 
hormones, and growth factors play a role in formation and growth. Uterine fibroids typically appear 
and grow during reproductive years, but stabilize or regress after menopause. Therefore, they rarely 
require treatment after menopause. Clinically, uterine fibroids and associated symptoms are most 
prominent in the late reproductive years. The most common symptoms of uterine fibroids are heavy 
menstrual bleeding (HMB) and pelvic discomfort.
Uterine fibroids are the leading cause for hysterectomy. Hysterectomy is the only definitive 
treatment and eliminates the possibility of recurrence. Increasingly, more women desire to avoid 
hysterectomy, electing for a uterine preserving procedure. The surgical treatment options are 
numerous, and each carries both the risks for surgery itself, as well as the possibility that the woman 
may require subsequent surgery as new fibroids often develop over time and become symptomatic. 
Not surprisingly, many women would prefer not to have surgery at all. Therefore, there is a great 
medical need for effective pharmacological treatment suitable for long-term treatment of uterine 
fibroids.
The development of selective progesterone receptor modulators (PRMs) offers the potential for a 
novel, well tolerated medical treatment approach for women who are experiencing symptoms caused 
by their fibroids. Various studies have demonstrated the steroid-dependence of fibroid growth and 
that progesterone has a critical role.
This clinical study is part of the development program for vilaprisan. The rationale of the study is to 
assess the efficacy and the safety of vilaprisan in subjects with uterine fibroids in comparison to 
nonhormonal medical treatment in accordance with local standard of care.
The Statistical Analysis Plan (SAP) is based on following protocol versions:

Original protocol, Version 1.0, dated 17 MAR 2017

Amendment 03 forming integrated protocol Version 2.0, dated 13 JUN 2017

Amendment 04 forming integrated protocol Version 3.0, dated 13 SEP 2017

Amendment 06 forming integrated protocol Version 4.0, dated 04 JUL 2018

Amendment 07 forming integrated protocol Version 5.0, dated 20 AUG 2018

Amendment 09 forming global protocol Version 6.0, dated 11 DEC 2018

Amendment 10 forming integrated protocol Version 7.0, dated 21 NOV 2019

Amendment 11 forming integrated protocol Version 8.0, dated 17 FEB 2020

Amendment 12 dated 06 OCT 2020 (local amendment, valid for Turkey only)


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 8
2.
Study Objectives
The primary objective of this study is to evaluate the safety of vilaprisan in subjects with uterine 
fibroids in comparison to nonhormonal medical treatment in accordance with local standard of care. 
The secondary objective of this study is to evaluate the efficacy of vilaprisan in subjects with uterine 
fibroids in comparison to nonhormonal medical treatment in accordance with local standard of care.
With the implementation of Protocol Amendment 10 (version 7.0), additional focus will be put on 
safety evaluations of the endometrium, adrenal glands and skin.
Other objectives of this study are to evaluate the variability in exposure in relation to the efficacy 
and safety for vilaprisan and to collect patient-reported outcome (PRO) and clinician-reported 
outcome (ClinRO) data. 
3.
Study Design
This is an open-label, parallel-group, randomized, multi-center study.  
The study was planned to be conducted in Europe, North America, South America, South Africa, 
and Asia Pacific.
Originally it was planned to randomize 1050 subjects into the study. However, recruitment into the 
study and treatment in the study were stopped earlier than planned. 
An overview of the originally planned study design (before the modifications in study design
introduced with Amendment 9, version 6.0 and subsequent amendments) is shown in Figure 3-1.
Eligible subjects were randomized to one of three vilaprisan treatment groups (Groups A1, A2, or 
A3) or to the standard of care group (Group B).
The planned treatment duration was about one year (Subgroup 1) or two years (Subgroup 2), 
respectively. The assignment to the 2 subgroups was done in a sequential manner.
After the end of treatment (EoT), subjects were planned to be followed up for 24 weeks (Subgroup 
1) or for 12 weeks (Subgroup 2). 
With the implementation of protocol amendment 9 (Version 6.0), no further subjects were recruited.  
Subjects that started to a regimen with 3-months treatment courses should finish the treatment 
course as planned. Subjects that started to a regimen with treatment courses of 6 months duration 
should finish the first 3 months, if they are currently in the first 84 days of that treatment course, 
finish the second 3 months, if they are currently beyond day 84 of the treatment course. Thus, with 
the implementation of protocol amendment 9 and the originally foreseen study design outlined in 
Figure 3-1 is not applicable anymore for vilaprisan groups. Subjects in treatment group B can 
continue the study course following the current valid version of the protocol.
With the implementation of Protocol Amendment 10 (version 7.0), this study design as outlined in 
Figure 3-1is no longer valid. No subjects will receive further study drug treatment. All subjects who 
were randomized and started treatment before the temporary pause were asked to have a 
comprehensive safety evaluation (with particular focus on endometrial, adrenal and skin safety) 
performed. This also applies to subjects who have completed or discontinued the study before or 
during the temporary pause, provided they have taken at least one dose of study medication. 


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Reference Number: RD-OI-0119
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Likewise, subjects randomized to treatment group B who are still in the study will be asked to 
undergo these procedures.
At the time study treatment was terminated, no subjects in subgroup 2 had reached the second year 
of treatment. Therefore, the statistical analysis will include patients from both subgroups without 
any distinction.
Figure 3-1
Design overview 
Subgroup 1 (about 1 year of treatment)
A1 SCR up to 
90 days
RND
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
24 wk 
FUP
A2
SCR up to 
90 days
RND
24 wk trt
B B
24 wk trt
24 wk 
FUP
A3
SCR up 
to 90 
days 
RND
12 
wk 
trt
B B
12 
wk 
trt
B B
12 
wk 
trt
24 wk 
FUP
B 
SCR up to 
90 days
RND
Symptomatic nonhormonal medical 
treatment as determined by the 
investigators and/or watch and wait
24 wk 
FUP
Subgroup 2 (about 2 years of treatment)
A1 SCR up to 
90 days
RND
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
B
12 
wk 
trt
12 wk 
FUP
A2
SCR up to 
90 days
RND
24 wk trt
B B
24 wk trt
B B
24 wk trt
B B
24 wk trt
12 wk 
FUP
A3
SCR up 
to 90 
days 
RND
12 
wk 
trt
B B
12 
wk 
trt
B B
12 
wk 
trt
B
B
12 
wk 
trt
B B
12 
wk 
trt
B
B
12 
wk 
trt
12 wk 
FUP
B 
SCR up to 
90 days
RND
Symptomatic nonhormonal medical treatment as determined by the investigators 
and/or watch and wait
12 wk 
FUP
Groups A1, A2, and A3 treated daily with vilaprisan 2 mg during treatment periods 
Group A1: 4/8 treatment periods of 12 weeks, each separated by 1 bleeding episode (3/1 regimen)
Group A2: 2/4 treatment periods of 24 weeks, separated by 2 bleeding episodes (6/2 regimen)
Group A3: 3/6 treatment periods of 12 weeks, each separated by 2 bleeding episodes (3/2 regimen)
Group B treated with standard of care (SoC) symptomatic nonhormonal medical treatment as determined by the investigators 
and/or watch and wait.
B = bleeding episode; FUP = follow-up; RND = randomization; SCR = screening; trt = treatment; wk = week.
The primary safety variable is the percentage change in bone mineral density (BMD) of lumbar 
spine from baseline to about one year after start of treatment (SoT) (please refer to section 6.5.1 for 
details). With the implementation of Protocol Amendment 10 (version 7.0), the study is being 
prepared for closure. A thorough safety monitoring is performed in subjects before this closure, 
including a recovery BMD scan. All subjects who received vilaprisan treatment will be asked to 
undergo a BMD scan at least 6 months after the last intake of vilaprisan, to document absence of 


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Supplement Version: 8
bone loss or adequate recovery after the end of treatment. Subjects randomized to treatment group B 
who are still in the study with implementation of Protocol Amendment 10 (version 7.0) should also 
undergo a BMD scan at the safety closeout visit, unless they had a BMD scan performed within the 
last 3 months prior to the safety closeout visit.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.4 or higher 
(SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive statistical 
methods. The number of data available, mean, standard deviation, minimum, median and maximum 
will be calculated for metric data. 1st and 3rd quartiles will be provided for certain variables, which 
will be specified in the respective subsections. Frequency tables (counts and percentages) will be 
generated for categorical data. The category ‘missing’ will be included as a separate category in 
frequency tables, if applicable.
Tables, figures and listings (TLFs) will show the four treatment groups as defined in the 
randomization: A1, A2, A3 and B, and the corresponding total. In addition, all vilaprisan treatment 
groups will be displayed as Total VPR.
For time interval-based analyses of efficacy variables (except for fibroid surgeries), including 
analyses for the treatment break and FUP, analyses for the FUP will be based on data from subjects 
who have started the planned last TP. Data from FUP for subjects who did not start the planned last 
TP for any reason will be included in the analysis of the break period. For those subjects only 
efficacy-related data up to a theoretical end of the break will be considered (see ‘break period’ in 
Section 4.5 for details).
4.2
Handling of Dropouts
A subject who discontinues study participation prematurely for any reason is defined as a “dropout,” 
if the subject has already been randomized. Drop-outs in this study will not be replaced. The details 
for the handling of missing data due to drop-outs are described in Section 4.3.
4.3
Handling of Missing Data
All missing or partially missing data will be presented in the subject data listing as they are recorded 
on the Case Report Form (CRF) and electronic diary (eDiary). 
When appropriate and for a limited number of variables, certain rules described below will be 
implemented to avoid exclusion of subjects from statistical analyses due to missing or incomplete 
data.
Bleeding data
For bleeding pattern analyses, missing eDiary will be imputed based on the sponsor’s standard 
procedures (11). Missing bleeding data in the subject diaries will be imputed. For the uterine fibroid 
daily bleeding diary (UF-DBD), the worst case approach will be used for missing bleeding intensity 


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for the single or two consecutive missing days (ie, the maximum of the bleeding intensities of the 
day before and the day after the missing day[s] will be assumed).
After having imputed missing values in the UF-DBD, missing menstrual pictogram (MP) values are 
imputed in the next step. 
For days with bleeding intensity of “mild” or higher in the UF-DBD, missing MP values will be 
replaced by the mean value of MP values of the days with the same bleeding intensity. In case there 
are no MP values with the same bleeding intensity, the mean of the MP values of next higher 
intensity will be used. In case there is no intensity higher than the bleeding intensity of the missing 
MP values available, no replacement for the missing MP values will be done for such days.
4.4
Interim Analyses and Data Monitoring
With the implementation of the protocol amendment 10 (version 7.0) a safety and efficacy analysis 
is planned after all subjects have completed their treatment period. All data until 10Feb2021 will be 
cleaned and included in the analysis. The complete primary safety data and efficacy data has been 
collected until this point in time and will be used for the primary safety analysis and the efficacy 
analysis. Therefore, the primary safety analysis and efficacy analyses will be final at this point in 
time. Data of the follow-up period available at that time point will also be included in the analysis.
Remaining data of the follow-up phase will be analyzed after all subjects have completed the Safety 
closeout visit. For all other data this safety and efficacy analysis is considered the final analysis.
Data collected in the 5-year follow-up period after the safety closeout visit will be listed and 
reported in an addendum to the study report. This is only applicable for Turkey.
4.5
Data Rules
Reference Start/End dates 
For vilaprisan (VPR), the reference start and end dates refer to the first and last study drug intake 
and will be identified based on the eCRF entry (EXCATN=1). For subjects with study drug 
exposure unknown, the randomization date will be used as the reference start date, and the end date 
of last scheduled/ unscheduled visit according SV (Subject Visits dataset) will be used as the 
reference end date.
Missing or partially missing eCRF end dates will be replaced by the date of the last study drug 
intake according to the diary. In case there is no study drug intake recorded in the diary, the date of 
the last available visit/contact will be used, which is the maximum of the end date of last scheduled/ 
unscheduled visit according SV (Subject Visits dataset), and the “last visit” as collected on the eCRF 
page for Disposition dataset. For subjects randomized to VPR who did not take any treatment (FAS 
not SAF), the last available visit date will be used as the reference start date and the reference end 
date.
For treatment group B the reference start date is defined by the randomization date. The reference 
end date is defined by the start date of the End of Treatment (EoT) visit (unscheduled EoT visits not 
considered). Missing EoT visit dates will be replaced by the end date of the last available visit
before the safety closeout visit (refer to Table 4-1). If a subject in treatment group B has no safety 


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closeout visit, missing EoT visit dates will be replaced by the date of last scheduled/ unscheduled 
visit according SV (Subject Visits dataset).
For both VPR and treatment group B, the reference end date after the missing replacement with the 
rules defined above should be no earlier than the reference start date. Otherwise, the reference end 
date will finally be replaced by the reference start date.
For any analysis, if date of first study drug exposure/ date of last study drug exposure is used, the 
reference start/end date for treatment group B defined as above will be used for the analysis in 
treatment group B, if applicable.
Table 4-1 Replacement rules for missing reference start/end dates and TP start/end dates
Choice
VPR regimens
Treatment group B
Reference start date 
1st
eCRF
Randomization date
2nd
a.
If study drug exposure unknown, use 
randomization date 
b.
If no study drug exposure (FAS not SAF) use 
SV last visit end date
Reference end date / 
Last TP end date
1st
eCRF
EoT visit start date
2nd
Diary
Last visit before the safety closeout visit
3rd
Max (SV last visit end date, “last visit” from eCRF )
SV last visit end date
4th
If no study drug exposure (FAS not SAF) use SV last visit 
end date
Reference end date will finally be replaced by maximum of reference start date and reference end date.
TP start date
1st
eCRF (TP1: reference start date)
Exception 6/2 regimen: split protocol planned TPs with 168 
days, assign start and end dates of these with CRF collected 
for planned TPs and derived start and end dates of split TPs. 
TP1: reference start date
TPs will be defined as consecutive 84-
day time intervals starting with the date 
of randomization.
TP end date (excluding 
last TP)
1st
eCRF
exception 6/2 as above
TP end date (last TP)
1st
Reference end date
eCRF = electronic case report form; EoT = end of treatment; SV=subject visit; TP = treatment period; VPR = vilaprisan
Treatment period 
For subjects in treatment groups A1, A2, and A3, each treatment period (TP) consists of three 
subsequent 28-day periods. In case of premature discontinuation of study drug the last 28-day period 
of the respective treatment period might be shorter than 28 days. If a subject took the study drug for 
more than 84 days of a treatment period, the respective treatment period will be longer than 84 days, 
in contrast. Subjects treated in 3/1 and 3/2 regimens, have the first break after TP 1. Subjects treated 
in 6/2 regimens have two planned TPs before the first break. 
The definition of TP here described which will be used in the analysis, differs from the definition of 
TP used in the protocol and Section 3 to describe the 6/2 treatment regimen. The definition used in 
the analysis allows for a better comparison between treatment regimens and is consistent with the 
reporting of other studies of the VPR project. 
The first TP starts with the reference start date, the last TP ends with the reference end date. Start 
and end of a TP will be identified based on eCRF entries (EXCATN=1). 
In 6/2 regimen, the protocol plans for TPs with 168 days each. The CRF only collects start and end 
dates of these protocol planned TPs. 


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For the analysis, the planned protocol TPs are split into 2 Analysis TPs:

The first Analysis TP is assigned first available odd TP number and ends with day 84 (or the 
maximum number of available days if less than 84 days are reported). 

The second Analysis TP is assigned the next higher even TP number, starts with day 85 and 
ends with the last day reported in the original protocol TP, even if this exceeds a total of 168 
days. 
For example, protocol TP1 = analysis TP1 + analysis TP2. Protocol TP2 = analysis TP 3 + analysis 
TP 4 etc.
If the original planned protocol TP is less than 85 days, no such second evenly numbered Analysis 
TP will be assigned. As a result of this a subject in 6/2 regimen might have Analysis TP 1, TP 3 and 
TP 4, but no Analysis TP 2.
If the end date of the current treatment period is equal to the start date of the next treatment period
based on CRF entries, it is assumed that the current treatment period ended one day earlier. The end 
date of the current treatment period is therefore moved back by one day.
For all TPs excluding the last TP, in case end of TP date is still missing, it will be replaced by the 
date of the last study drug intake within the respective TP according to diary (EXCATN=5 and 
EXMEDN>=1).
Subjects in treatment group B don’t have any breaks. In the treatment group B TPs will be defined 
as consecutive 84-day time intervals starting with the date of randomization. 
Replacement rules for missing end date of the last TP are analogue to those described for reference 
end dates.
TPs will be numbered sequentially.
Time intervals
Due to the complex visit schedule of the studies, a time-interval based approach is chosen to present 
data over time. Therefore, time intervals are defined which are used for different analysis topics. 
The selection of time intervals used for a certain analysis topic will be described within each section.
An overview of the time intervals is given in Figure 4-1.
Figure 4-1: Time interval overview
Abbreviations: BL: Baseline, TP: Treatment Period, BR: Break (not applicable for Treatment group B), FUP: Follow-up, d: days, m: months.
Treatment periods and breaks will be identified as described above. Baseline/Pre-treatment phase 
starts with the date of informed consent and ends on the day before the start of the Treatment phase. 


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The Treatment phase starts and ends with the reference start and end date. The FUP phase starts on 
the day after the end of the treatment phase and ends on the maximum of the last date at which a 
visit took place (visit end date), and the “last visit” as collected on the eCRF page. For patients who 
did not complete the planned schedule of TPs, a break period will be defined after the end of the last 
TP, as described in the previous subsection ‘Break period’. This break period will be followed by 
the FUP.
Baseline, Treatment phase, FUP phase, TPs and breaks are subdivided into subsequent periods of 
different lengths (28, 84, or 168 days). Exit examination time intervals include the baseline 
measurement, i.e. the last non-missing value before reference start date, and the exit examination 
which is defined as the last non-missing value at or after the reference end date – 7 days, which is 
per definition the safety closeout visit for subjects who perform this visit.
For treatment group B, consecutive TPs (84-day time intervals) in the treatment phase will be used 
for intervals B and intervals C. Each TP will be subdivided into subsequent consecutive 28-day 
periods for intervals D. For intervals for assessing AEs in the treatment phase, consecutive TPs will 
be ended at day 60 after the reference end date. For the assessment in the follow-up phase, same 
rules will be used as VPR treatment groups.
Details on time intervals for AE presentation are given in Section 6.5.3.5. 
Details on time intervals for BMD presentation are given in Section 6.5.1. 
Break period
All VPR treatment groups include a treatment-free period following the end of TPs in 3/1 and 3/2
regiments, or end of TPs 2, 4, 6 etc. in 6/2 regimen. The length of the break period will vary 
depending on whether 1 or 2 bleeding episodes take place. In any case, the break period starts the 
day following the date of stop date of study drug administration in a particular TP, and ends the day 
before the study drug administration starts in the next TP. 
If a subject did not start the next planned TP, due to the clinical hold or any other reason, there is no 
end date for the break period. In this case, a theoretical end date will be generated. For this purpose, 
information on the start of the previous TPs will be used. If a subject started TP1 at the i-th Day of 
her bleeding episode, the theoretical start date of TP2 will be assumed as the i-th Day of the 
bleeding episode which would have triggered re-starting medication during the treatment break (first 
or second bleeding depending on treatment regimen). The theoretical end date of the break period 
will then be assumed as the day before the theoretical start date of TP2. For TPs beyond TP2 the 
average of the i-th Days of the menstrual cycles when previous TPs started will be calculated and 
considered as start of the theoretical absent TP. This definition for theoretical end date for the break 
period depends on the subject experiencing a bleeding episode following the end of the TP. If no 
bleeding episode starts (spontaneous or induced), then the break period is considered until the end of 
subject observation.
This theoretical end date will be used in the analysis of number of bleeding days.
For subjects in the 6/2 regimen the break period will follow the end of TP2 or any TP with an even 
number. If it is necessary to define a theoretical end of the break period, as described in the previous 
paragraph, this will only occur if the subject started TP2 or any TP with an even number. But for the 
calculation of the variable number of bleeding days, if a subject withdrew while receiving treatment,  


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in order to use all information available at the time of analysis, the theoretical end date for the break 
period of the incomplete TP will be generated regardless the TP with an even or odd number.
Baseline for general parameters
In general, the last valid, non-missing value prior to the Reference start date will be considered as 
baseline value. For variables analyzed by 28-day periods, the baseline period corresponds to the last 
28 days before the reference start date. This definition does not apply to analyses related to 
menstrual blood loss where a specific definition for baseline menstrual blood is defined (see baseline 
menstrual blood loss for 28 days).
Bleeding caused by conducting endometrial biopsy
If an endometrial biopsy was conducted, bleeding on the day of intervention and the 3 days 
thereafter will not be considered in the bleeding related evaluation, i.e., bleeding/spotting on the day 
of biopsy and 3 days thereafter will not be considered as day(s) with bleeding/spotting and MP 
values will be set to 0 mL. This rule is applicable for all bleeding related efficacy analyses.
A biopsy will be regarded as conducted if the intervention was attempted, either successfully or 
unsuccessfully. Successful means that the date of biopsy is given and ‘Biopsy sample obtained - Not 
done’ is not ticked in the eCRF. Unsuccessful means that the date of biopsy is given, ‘Biopsy 
sample obtained - Not done’ is ticked in the eCRF, and the reason ‘Unsuccessful attempt’ is selected.
Baseline menstrual blood loss for 28 days
Baseline menstrual blood loss for 28 days is defined as the sum of volume of menstrual blood loss 
data of respective days in the baseline cycle. If baseline cycle length is more than 28 days, only data 
from the first day of cycle to the 28th day of cycle will be used. If baseline cycle length is less or 
equal than 28 days, data from the first day of cycle to the last day of cycle will be used. 
Baseline menstrual cycle
The baseline menstrual cycle length is defined as the days from the first day of cycle until the last 
day of cycle. First day of the baseline cycle is Day 1 of the bleeding episode following screening 
Visit 1. Last day of cycle is the day preceding the next bleeding episode. This definition will apply,
if during this cycle the inclusion criterion of HMB diagnosis is fulfilled (menstrual blood loss 
> 80 mL). If HMB is not confirmed in the first bleeding episode following screening Visit 1, then 
the second bleeding episode will be considered. Similarly, the first day of the second cycle is the 
Day 1 of the second bleeding episode following screening Visit 1 and the day preceding the next 
bleeding episode will be considered the last day of the cycle. Again, this second bleeding episode
will be considered the baseline cycle only if the HMB criterion is fulfilled, otherwise the next 
bleeding episode, if recorded, will be inspected for the diagnosis of HMB. If none of the bleeding 
episodes preceding the first drug administration/ reference start date fulfill the HMB inclusion 
criterion, the first bleeding episode following screening Visit 1 will be considered for the baseline 
cycle. If no such bleeding episode exists, the bleeding episode already ongoing at screening Visit 1
will be considered for the baseline cycle, starting with Day 1.
During the screening period the diagnosis of HMB will be inspected using the definition of bleeding 
episode based on the MP, as explained in this subsection and in the protocol. In contrast, during the 
analysis only the definition of bleeding episode based on the UF-DBD will be used. Therefore, the 


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baseline cycle defined during the analysis here described is independently derived and may differ 
from the bleeding episode used to assess the HMB diagnosis during the screening period.
Bleeding episode (assessed by the UF-DBD)
Bleeding episode is defined as day(s) with bleeding/spotting of which at least one day is of intensity 
“mild” or higher, preceded and followed by at least 2 days with diary entry: “no vaginal bleeding”
(in case the first bleeding episode starts directly after Visit 1, the preceding 2 bleed-free days may 
not be recorded for this first bleeding episode).
This definition of bleeding episode, based on the UF-DBD, is the only bleeding definition 
implemented in the analysis to identify bleeding episodes. The protocol includes a definition of 
bleeding episode based on the MP, which will be implemented during the screening period to 
facilitate the assessment of the HMB inclusion criterion (criterion 4, MBL >80 mL) by clinical sites. 
This latter definition of bleeding period will not be used in the analysis.
Menstrual blood loss for 28 days
Menstrual blood loss for 28 days is defined as the sum of menstrual blood loss [mL] by MP in a 28-
day period. Non-overlapping 28-day periods will be created along the different study periods: TPs,
break periods (if applicable), and FUP phase. In case of premature discontinuation of study drug the 
last 28-day period of the respective treatment period might be shorter than 28 days. For details about 
the volume of MBL assigned to MP, see Appendix 4.
Volume of menstrual blood loss per bleeding episode after the reference end date
Volume of menstrual blood loss for a bleeding episode is the sum of volume of menstrual blood loss
[mL] data by MP in the respective episode after the reference end date.
Amenorrhea (defined as < 2 mL during last 28 days of treatment course) assessed by MP
method
Amenorrhea is defined as menstrual blood loss less than 2 mL during the last 28 days of the 
respective treatment period.  For missing data replacement please refer to section 4.3.
i)
the sum of the non-missing (i.e. original or imputed) MP values is ≥ 2 mL, or 
ii) there is at least one day with missing MP value and bleeding intensity of “mild” up to “very 
severe” after having applied the imputation rules, or
iii) the subject did not complete at least 8 weeks of treatment. 
If neither of i), ii) or iii) applies, the subject will be considered as having amenorrhea. 
The last days under treatment with 28 days with non-missing (i.e. original or imputed) MP data will 
be used to calculate whether amenorrhea occurred. Thus, if the last 28 days of treatment include 
days with missing MP data, the left margin of this interval will be displaced backwards in time and 
step-wise until the required number of 28 non-missing values are included.
The left margin may be displaced backwards at maximum up to the end of the first bleeding episode 
when treatment was started in respective treatment period. For TP with an even number in the 6/2 
regiment, the left margin may be displaced backwards at maximum up to the end of the first 
bleeding episode of the preceding odd-numbered TP from the same protocol defined 168-day TP 
when treatment was started.


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Absence of bleeding (spotting allowed) during the last 28 days of the treatment; based on the 
UF-DBD
Absence of bleeding is defined as no bleeding (spotting allowed) during the last 28 days of the 
respective treatment period based on the UF-DBD. For missing data replacement please refer to 
section 4.3.
The last days under treatment with 28 days with non-missing bleeding eDiary data will be used to 
calculate whether absence of bleeding occurred. Thus, if the last 28 days of treatment include days 
with missing bleeding eDiary data, the left margin of this interval will be displaced backwards in 
time and step-wise until the required number of 28 non-missing values are included.
The left margin may be displaced backwards at maximum up to the end of the first bleeding episode 
when treatment was started in respective treatment period. For TP with an even number in the 6/2 
regiment, the left margin may be displaced backwards at maximum up to the end of the first 
bleeding episode of the preceding odd-numbered TP from the same protocol defined 168-day TP 
when treatment was started.
Subjects who discontinue treatment prior to completion of 8 weeks of treatment in the respective TP 
will be considered as not experiencing absence of bleeding.
Number of bleeding days
Number of bleeding days is defined as number of bleeding days (based on the UF-DBD) from Day 1 
of the first treatment period until one day before the theoretical next treatment period would start 
after the last study treatment period. Definition of the day before theoretical next treatment period 
end date, i.e., theoretical end date for the break period, refers to the rules defined in break period 
above.
All information available at the time of analysis will be included. For example, for a subject 
allocated to treatment group A1 (3/1 regimen) in subgroup 1 who completed the full planned 
treatment, the number of bleeding days will be counted from the 1st day of TP1 until the date when 
a new TP would theoretically start following the end of TP4 and the required bleeding episode that 
follows TP4, without gaps. If a subject withdrew while receiving treatment in TP3, the number of 
bleeding days will be considered from the 1st day of TP1 until the date when a new TP would 
theoretically start following the end of TP3 and the required bleeding episode that follows TP3, 
irrespective of the length of the incomplete TP3.
For subjects who did not start the next planned TP, due to the study being temporarily paused or any 
other reasons, as described in the section ‘Break period’, a theoretical end of break period will be 
derived in these cases. The number of bleeding days will be counted until the derived end of break 
period.
The period for evaluation of “number of bleeding days” for the treatment group B starts on the 
reference start date and ends on the reference end date. A theoretical end of break period following 
the reference end date will not be generated.
The analysis of the number of bleeding days from these pre-determined evaluation periods will be 
normalized to 28 days and 365 days.
Onset of amenorrhea for analysing time-to-event data


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Onset of amenorrhea is defined by the first day for which the menstrual blood loss (assessed by MP) 
for all subsequent 28-day periods up to the end of the treatment period is <2 mL. Amenorrhea status 
will be assessed for each of the subsequent, overlapping 28-day periods within a treatment period.
The censoring mechanism is assumed to be non-informative and the subjects will be handled as 
right-censored, if applicable. If a subject completed the 84 days of a treatment period and did not 
experience an onset of amenorrhea, the subject will be censored on Day 57 of the treatment period. 
For prematurely discontinued subjects, censoring also depends on whether an onset of amenorrhea 
can be ruled out or not during the time the subject was in the respective treatment period. An onset 
of amenorrhea can be ruled out, if in the last 28-day period before the subject discontinued the 
respective treatment period, the sum of MP values exceeds 2 mL. If this is not the case, then an 
onset of amenorrhea cannot be ruled out for the respective treatment period. Thus, there are in 
principle the two possibilities:
1. In case the subject discontinued the respective treatment period prematurely and an onset can 
be ruled out, subjects will be treated as right-censored at the first day of the last 28-day period 
after which MP bleeding values for all further days are missing. 
2. If the subject prematurely discontinued the respective treatment period but an onset cannot be 
ruled out, the subject will be censored on the day before the first day of the first 28-day period 
which indicates that an onset may have taken place.
Onset of controlled bleeding
Defined by the first day for which the menstrual blood loss (assessed by MP) for all subsequent 28-
day periods up to the end of the treatment period is <80 mL. The first 28 days with non-missing MP 
values until the last 28 days with non-missing MP values under treatment in the respective treatment 
period will be considered for deriving the time to onset of controlled bleeding. Time to onset of 
controlled bleeding is derived in the same way as time to onset of amenorrhea. The only difference 
is the use of a less strict criterion (i.e. <80 mL instead of <2 mL).
Start of bleeding after last study drug intake (assessed by UF-DBD)
Defined by the first day for which bleeding intensity is “mild” or higher after the last study drug 
intake. If no start of bleeding after last study drug intake is documented,
-
Subjects will be censored at latest available date from the UF-DBD. 
-
If bleeding has to be induced, the subject´s data will be censored at the time point of bleeding 
induction. The bleeding induction information will be obtained from the concomitant 
medication page. 
-
For the analyses after last study drug intake in TPx, the subject will be censored at latest at 
TPx+1 start date if she starts TPx+1, where x=1,…, n.
Largest fibroid
The largest fibroid is defined as the fibroid which is the largest at baseline (measured by ultrasound). 
The fibroid identified at baseline as the largest will be followed up at each scheduled visit.
Fibroids volume measured by ultrasound (mL) (2)  
×××
	
  ) ;


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 = Largest diameter of the fibroid (cm),  = First diameter perpendicular to largest diameter (cm), $ = Second 
diameter perpendicular to largest diameter (cm)
If only 2 diameters are available, the formula will be the same but the third diameter will be replaced 
by the mean of the available two diameters.
If only 1 diameter is available, the formula will be: =
%××&'
(
 ;  * =
+,+-.+/.0 1-+20304 56 370 6-/45-1 (82) 
9
If one or two diameters are recorded as 0 cm, then those diameters will be considered missing and 
the rules above will apply.
Volume of 3 largest fibroids measured by ultrasound (mL)
Defined by the sum of the 3 largest fibroid volumes. If less than 3 fibroids are present, the volume of 
the actual number of fibroids will be summed.  The 3 fibroids identified at baseline as the largest 
will be followed up at each scheduled visit.
Uterine volume measured by ultrasound(mL) =
×××
	
  ;

 = Maximum width anteroposterior of uterus (cm),  = Maximum width transverse (cm)of uterus, c =
 Corpus +  cervix length (cm). 
If only 1 or 2 diameters are available, the calculation will follow the same rules defined for fibroids 
volume measured by ultrasound.
Volume of the largest cyst (mL) =
×××
	
 ;

 = largest diameter of largest cyst(cm), b = diameter perpendicular to the largest cyst(cm), c =
+B/
9 (cm)
If only 1 diameter is available, the calculation will follow the same rules defined for fibroids volume 
measured by ultrasound. If one diameter is recorded as 0 cm, then the value of the diameter will be 
considered missing and the rule above will apply.
BMD measurements
BMD is assessed using dual-energy X-ray absorptiometry (DEXA). To increase accuracy of the 
assessment, 2 measurements per location was to be performed at each time point and the mean value 
will be used for evaluation. If only one scan was performed per location and time point, or one of 
the two scans is not evaluable, the available valid value will be used as the mean value. Phantom 
image acquisition is standardized across DEXA imaging facilities according to the instructions 
specified in an imaging manual. The mean value and percentage change in BMD of each location 
(the central reading results) from baseline at each time point used for statistical analysis will be 
calculated by ICON’s Medical Imaging group and transferred to Bayer according to the Independent 
Review Charter. 
For BMD baseline, in general, if no Visit 2-repeat scan exists, Visit 2 scan will be used as baseline. 
Otherwise, Visit 2 -repeat scan will be used as baseline. The BMD baseline visit will be marked in 
the dataset transferred from ICON’s Medical Imaging group. 
Repeated measurements at the same visit
If more than one post-randomization measurement is available for a given visit, the first observation 
will be used in the data summaries if no special reason for the additional observation was provided 
by the investigator in the CRF, and all observations will be presented in the data listings.


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4.6
Blind Review
The results of the final data assessment will be documented in the final list of important deviations, 
validity findings and assignment to analysis set(s). Any changes to the statistical analysis prompted 
by the results of the review of study data will be documented in a SAP amendment and, if 
applicable, in a supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the review 
of study data and documented in the final list of important deviations, validity findings and 
assignment to analysis set(s) (see Section 4.6).
Full analysis set (FAS): All subjects randomized to vilaprisan treatment groups, excluding 
randomized subjects who did not start TP 1 due to the study being temporarily paused and all 
subjects randomized to treatment group B will be included in the FAS. Subjects will be analyzed as 
randomized. 
Safety analysis set (SAF):  All subjects randomized to vilaprisan treatment groups who took at least 
1 dose of study drug. will be included in the SAF. Subjects will be analyzed as treated.
All subjects randomized to treatment group B will be included in the SAF. Subjects will be analyzed 
as treated, regardless whether they actually took any medication (i.e., symptomatic, nonhormonal 
medical treatment).
Modified SAF: will include all subjects in the SAF without any validity findings which are those 
that may potentially affect the primary safety endpoint. Validity findings leading to exclusion from 
the modified SAF will be specified in the ‘Specification of assessment criteria and identification 
requirements’, which will be finalized before database lock. Subjects will be analyzed as treated.
All safety analyses will be performed on the SAF population. The FAS will be used for the display 
of all other variables. The analysis for the primary safety endpoint and all BMD related endpoints
will be performed on the Modified SAF as well.
Screened subjects who are not included in the FAS will be used solely in disposition tables and will 
be listed only in Section 16 of the clinical study report, as described elsewhere.
6.
Statistical Methodology
6.1
Population characteristics
In general, descriptive statistics will be presented for variables defined in this section. For 
continuous variables, number of observations, mean, standard deviation, minimum, median, and 
maximum will be presented. For categorical variables, number and percentage of subjects will be 
presented. Listings will be provided accordingly. 


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6.1.1 Subject validity, disposition
Study sample size (all enrolled), subject validity and reasons for excluding subjects from the 
analyses (all randomized), subject disposition (all enrolled) will be summarized by frequency tables
Enrolled means the subject signed the informed consent. The total number and percentage of 
subjects who prematurely discontinued each epoch with the reasons for discontinuation (all 
randomized), the number and percentage of subjects who performed adrenal monitoring, skin 
monitoring, endometrial monitoring and BMD within the safety closeout visit will be provided.
For the overall assessment of disposition, study completion means all phases of the study are 
completed up to and including the follow-up (FUP) visit.
6.1.2 Demographic, Baseline Characteristics 
Demographics and baseline characteristics will be recorded during screening period. As specified in 
Section 4.5, the measurement closest to the administration of study drug will be used as baseline. All 
demographic and baseline characteristics will be listed and summarized by treatment and in total 
according to current existing BHC Global Standard Tables. The descriptive statistics will be 
presented for the SAF, modified SAF, and FAS.
Demographic and baseline assessments to be summarized will include:

Age, region/ country and race, ethnicity

Weight, height, body mass index (BMI)

Categorized BMI group (<18.5, 18.5-<25, 25-<30, ≥30 kg/m2)

Smoking and alcohol consumption

Baseline BMD of lumbar spine, hip and femoral neck

Baseline BMD of lumbar spine, hip and femoral neck by scan type (Lunar, Holgic and other)

Baseline endometrial thickness

Uterine fibroids visualized at baseline (Yes/No)

The largest diameter of the largest fibroid, volume of largest fibroid, volume of 3 largest fibroids, 
location of largest fibroid (measured by ultrasound) at baseline. Baseline uterine volume, endometrial 
thickness (measured by ultrasound)

Baseline MBL (by MP) and categorized MBL group (≤80 mL, 80< -150 mL, 150 <- 300 mL, 300 < -
500mL and >500 mL) 

Baseline hemoglobin

Education (years of education, university/colleague degree)
6.1.3 Medical History
Medical history findings (ie, previous diagnoses, diseases or surgeries) will be coded by Medical 
Dictionary for Regulatory Activities (MedDRA) terms. Number and percentage of subjects with any 
medical history findings reported will be presented by primary system organ class (SOC) and 
preferred term (PT) based on the SAF.
All new or worsened findings after signing the informed consent should be documented on the AE 
eCRF page.


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6.1.4 Reproductive and menstrual history
The reproductive history will include information on age at menarche, number of pregnancies, 
number of births, years since last birth or abortion (at any time and during the last 1 year) and 
duration of unsuccessful attempts (in months).
For number of pregnancies and number of births, not only the statistics based on continuous 
variables but also a frequency table based on each specific number recorded in CRF will be 
presented. 
Reproductive history will be summarized for the SAF.
6.1.5 Uterine Fibroids relevant history
The uterine fibroids history includes information on family history, onset of symptoms, diagnosis, 
and previous medical treatments and procedures, if applicable. Reason for the initial diagnosis, 
symptoms/finding ever had/currently are collected as well. 
Medical treatments relevant for uterine fibroids received ever/ during the last 6 months prior to the 
study and procedures for uterine fibroids (history, concurrent and planned) will be recorded and 
presented in this section. Procedures for uterine fibroids (concurrent) will be presented in section of 
other efficacy variables.
Uterine Fibroids relevant history will be summarized for the SAF.
6.1.6 Heavy menstrual bleeding questions
This set of questions has been developed as a tool to identify women with HMB. It could have been 
used at Visit 1 only and the responses could have been entered directly into the electronic data 
capturing system (RAVE), which is considered as primary source data. The questionnaire could also 
have been used as a pre-screening tool. The questions from this questionnaire will be summarized by 
a frequency table for the SAF.
6.1.7 Prior/Concomitant Medication 
For prior/concomitant/post-treatment medications, the following definitions in accordance with the 
Global Standards Catalogue V4.0 will be used in the analysis (see Figure 6-1):
-
Prior medication: Medication taken before start of the study drug intake (regardless of when 
it ended).
-
Concomitant medication: Medication taken during Treatment phase, i.e. between first and 
last study drug intake (regardless of when it ended). In case it’s not clear if a medication is 
prior, concomitant or post-treatment (for example, due to partially missing dates), medication 
will be classified as “concomitant”.- Post-treatment medication: Medication taken after the 
Treatment phase, i.e. after last study drug intake.


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Figure 6-1: Categories of medication (example)
Categories are prior medication (A, B, C), concomitant medication (B, C, D, E) and post-treatment medication (F). Source: Global Standards 
Catalogue V4.0
Medication, recorded as prior, concomitant or post-treatment medication in the eCRF, will be coded 
according to the World Health Organization Drug Dictionary WHODRUG GLOBAL B3 (initially 
September 1, 2017, within Bayer referred to as ‘2017SEP’), to the respective Drug Codes with their 
corresponding Anatomical Therapeutic Chemical (ATC) classification.
The number of subjects taking prior or concomitant medication will be analyzed using frequency 
tables based on classified data. Analysis of prior and concomitant medication will be done on the 
SAF. 
Nonhormonal medical treatment for symptomatic uterine fibroids at/after the date of randomization 
for treatment group B will be recorded and coded to ATC codes according to the WHO Drug 
Dictionary. Subjects in treatment group B who took at least one nonhormonal symptomatic medical 
treatment will be summarized for prior/concomitant/post-treatment medications separately. 
Nonhormonal symptomatic medical treatment：

Analgesia producing opioids

Benzodiazepines

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Barbiturates and derivatives

Benzodiazepine derivatives

Adjunct antidepressant therapy

Herbal antidepressants

Monoamine oxidase A inhibitors

Monoamine oxidase inhibitors, non-selective

Non-selective monoamine reuptake inhibitors

Other antidepressants

Selective serotonin reuptake inhibitors

Antifibrinolytics

Blood coagulation factors


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
Other haemostatics

GnRH agonists

GnRH antagonists

Adjuvant pain medications

Analgesic drugs

Pituitary and hypothalamic hormones and analogues

Sex hormones and modulators of the genital system

Anti-inflammatory drugs

Acetylsalicylic acid and its salts
6.1.8 Exposure and Compliance to Study Treatment
Dose exposure and the compliance for treatment groups A1, A2 and A3 will be analyzed for SAF,
modified SAF and FAS. The treatment duration, extent of exposure and compliance will be 
summarized by treatment group.
6.1.8.1
Treatment duration
Treatment duration is calculated from eCRF page ‘Study Drug Exposure.’ Missing dates are not 
replaced, i.e. subjects with missing date of first or last tablet of TP will result in missing treatment 
duration of respective TP.
Treatment duration per TP (TPx, x=1,…, n) excluding breaks is defined as the number of days from 
the day of first drug administration until the day of last drug administration during the respective 
TPs, i.e. Date of last tablet of TPx – Date of first tablet of TPx +1. For treatment group A2, 
treatment duration excluding breaks by TP will be calculated based on a 168-day period. Overall 
treatment duration excluding breaks is the sum of available treatment durations of all TPs.  
Overall treatment duration including breaks is defined as reference end date – reference start date + 
1 without missing data replacement.
Treatment duration for subjects in treatment group B is defined as reference end date – reference 
start date + 1 without missing data replacement.
6.1.8.2
Extent of exposure
Extent of exposure of each TP is defined as the number of tablets taken during the respective TPs, 
using information from the Study Drug Accountability eCRF page and eDiary-entry respectively. 
Missing number of tablets taken based on the eCRF page will not be replaced, i.e. subjects with any 
missing number of tablets taken for a pack dispensed based on the eCRF page will result in missing
extent of exposure of respective TP. For treatment group A2, extent of exposure by TP will be 
calculated based on 168-day period. Overall extent of exposure based on the eCRF is the sum of 
available extent of exposure of all TPs. 
Missing number of tablets taken based on eDiary-entry will be replaced with 0. Overall extent of 
exposure base on eDiary is the sum of the extent of exposure of all treatment periods. 
6.1.8.3
Treatment compliance
Treatment compliance of study drug is calculated on the basis of both eCRF (i.e. data collected from 
drug accountability and study drug exposure pages) and eDiary-entry respectively.


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Treatment compliance based on the eCRF by TP is defined as
‘(
CD30E3 56 0DF5GH40 -E IJD (0KLM)
I40+320E3 1H4+3-5E -E IJD 0D8.H1-EN /40+O(0KLM)) × 100%’, where x=1,…, n. 
Overall treatment compliance based on eCRF is calculated as
‘ T
U,04+.. 0D30E3 56 0DF5GH40(0KLM)
U,04+.. 340+320E3 1H4+3-5E 0D8.H1-EN /40+OG(0KLM)V × 100%’.
Treatment compliance based on eDiary-entry by TP is defined as
‘ T
CD30E3 56 0DF5GH40 -E IJD (0W-+4X)
I40+320E3 1H4+3-5E -E IJD 0D8.H1-EN /40+O(0KLM)V × 100%,’ where x=1,…, n.
Overall treatment compliance based on eDiary is calculated as 
‘(
U,04+.. 0D30E3 56 0DF5GH40(0W-+4X)
U,04+.. 340+320E3 1H4+3-5E 0D8.H1-EN /40+OG(0KLM)) × 100%’.
For treatment group A2, treatment compliance by TP will be calculated based on a 168-day period.
Data on duration of treatment, compliance, and used tablets will be presented by listings.  
Extent of exposure and treatment compliance for treatment group B will not be analyzed.
6.2
Efficacy
6.2.1 Primary efficacy variable
Not applicable.
6.2.2 Secondary efficacy variable
The analyses for all the secondary efficacy variables will be conducted in the FAS population.
The secondary efficacy variable is number of bleeding days, as defined in Section 4.5.
Number of bleeding days will be shown by treatment groups for the treatment phase only plus 1 or 2 
bleeding periods following the end of the last TP depending on treatment regimen.
6.2.3 Other efficacy variables
The analyses for all other efficacy variables will be conducted in the FAS population.
6.2.3.1
Volume of menstrual blood loss related variables

Volume of menstrual blood loss per 28 days (assessed by MP)

Volume of menstrual blood loss per bleeding episode (assessed by MP) for first, second, 
and third bleeding episode after the end of treatment 

Volume of MBL per bleeding episode within the treatment break. All days of the 
bleeding episodes will be used even if some days of the episode lie outside the treatment 
break. The first, second and third bleeding episode will be considered. This endpoint is 
only applicable for VPR groups.

Amenorrhea (yes/no), defined as menstrual blood loss <2 mL during last 28 days of 
treatment, based on the MP


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
Absence of bleeding (spotting allowed) during the last 28 days of the treatment; based on
the UF-DBD
Analysis for volume of menstrual blood loss per 28 days will be done by treatment group and 
Time interval D (according to Figure 4-1). Amenorrhea and absence of bleeding will be 
analyzed by treatment group and TP. For treatment group B, volume of menstrual blood loss per 
bleeding episode (assessed by MP) for first, second, and third bleeding episode after the end of 
treatment will only be done after the reference end date. Volume of MBL per bleeding episode 
within the treatment break for treatment group B will not be analyzed.
6.2.3.2
Time to event related variables

Time to onset of amenorrhea for each treatment period

Time to onset of controlled bleeding for each treatment period

Time to start of bleeding after last study drug intake (assessed by the UF-DBD).
Time to event related variables and censoring rules are defined in Section 4.5.
Time to onset variables will be analyzed using the Kaplan-Meier estimates (including number of 
events, number of censored, 25th, median, and 75th percentiles). This analysis will be performed 
using the calendar time (days) as unit. Kaplan-Meier plots will also be presented. The analysis 
will done by treatment group and TP (time intervals B according to Figure 2, excluding 
screening and FUP). For treatment group A2, TP per 168-day defined in the protocol will be 
used and shown separately.
Time to start of bleeding after last study drug intake for treatment group B will not be analyzed.
6.2.3.3
Ultrasound examination related variables

Percent change in volume of largest fibroid compared to baseline (baseline = last value
obtained before randomization; measured by ultrasound examination)

Percent change in volume of 3 largest fibroids compared to baseline (measured by
ultrasound)

Percent change in volume of uterus compared to baseline (measured by ultrasound)

Percentage of subjects with a volume reduction of ≥25% of the 3 largest fibroids
(measured by ultrasound)

Percentage of subjects with a volume reduction of ≥25% of the largest fibroids
(measured by ultrasound)

Percentage of subjects with a reduction of ≥25% of uterine volume (measured by
ultrasound)
Analysis will be done by treatment group and visit/time interval B (according to Figure 4-1).
If multiple volume assessments by ultrasound are available for a time period, the smallest 
volume will be used for the baseline time period, and the largest volume will be used for any 
other time periods of Intervals B.


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6.2.3.4
Percentage of subjects undergoing surgical treatment
The number and percentage of subjects undergoing surgical treatment will be evaluated in a 
frequency table by treatment group and by TP and FUP (time interval B). In contrast to other 
efficacy variables, any fibroid surgeries performed during FUP of subjects who did not start the 
planned last TP, will be evaluated for FUP rather than for break period.
6.2.3.5
Patient/Clinician-reported outcomes
6.2.3.5.1
Change in UF-DSD individual items compared to baseline
The UF-DSD will be completed daily using the eDiary. The UF-DSD includes 2 items to assess 
swelling and bloating symptoms using a 5-graded Likert-type severity rating (‘no symptom’ to 
‘very severe symptom’), and 2 items using a 0 to 10 numerical rating scale to assess pain at its 
worst in the abdominal/pelvic and lower back areas with 0 indicating “no pain” and 10 “pain as 
bad as you can imagine.”
Bulk symptoms and pain represent potential domains. Additionally, intake of pain medication is 
investigated using a 4-point verbal rating scale (no; yes, over the counter (non-prescription) pain 
medication; yes, prescription pain medication; or yes, both over the counter and prescription pain 
medication).
Following variables for each domain will be summarized by treatment group and time interval D. 
For the vilaprisan treatment groups, this will be presented by TP, break, and FUP within 
treatment group. For the treatment group B, this will be presented by TP and FUP. Line plots
with standard deviation (SD) will be generated. 
Bulk symptoms (items 1 and 2)
-
Mean of subjects’ relative frequencies of the scores during baseline (last 28 days before 
first dose of study drug) and each 28-day period after start of treatment, as well as change 
from baseline
-
Mean of subjects’ worst 7 scores during baseline (last 28 days before first dose of study 
drug) and each 28-day period after start of treatment, as well as change from baseline
Pain (items 3 and 4)
-
Mean numerical rating score and absolute change from baseline (last 28 days before first 
dose of study drug) to each 28-day period after start of treatment
-
Mean numerical rating score of the 7 days with worst pain and absolute change from 
baseline (last 28 days before first dose of study drug) to each 28-day period after start of 
treatment
For medication intake (item 5), means of proportion of days with “Yes, over the counter (non-
prescription) pain medication”, “Yes, prescription pain medication” or “Yes, both (over the 
counter and prescription pain medication)”  during baseline (last 28 days before first dose of 
study drug) and each 28-day period after start of treatment will be summarized, as well as 
change from baseline. 


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6.2.3.5.2
Change in Uterine Fibroid Symptom and Quality of Life questionnaire 
(UFS-QoL) scores compared to baseline
The UFS-QoL consists of 37 items including an 8-item symptom severity scale and 29 health-related 
quality of life questions, which comprise 6 subscales: concern, activities, energy/mood, control, self-
consciousness, and sexual function. Details regarding the calculation of scales are provided in 
Appendix 1. For each subscale (including symptom severity scale, Revised Activities and Revised 
HRQoL total score), raw scores and transformed scores will be summarized by treatment group and 
time interval D, as well as change from baseline. The wort measurement within the time interval will 
be used for calculations. Largest value for Symptom Severity scale and lowest value for HRQoL 
scale.Line plots with SD will be generated.
6.2.3.5.3
CGI-I
Clinical Global Impression - Investigator (CGI-I) includes a single item that asks the investigator to 
describe the subject’s overall severity of uterine fibroids symptoms with the response options 
“none”, “very mild”, “mild”, “moderate”, “severe” and “very severe”.
CGII will be summarized by a frequency table with the number of observations and percentage by 
treatment group and visit. Stacked column bar charts will be created by visit.
6.2.3.6
Variables related to laboratory parameters
6.2.3.6.1
Change from baseline in hemoglobin, hematocrit, and ferritin
Hemoglobin, hematocrit, and ferritin will be analyzed in the same way as laboratory measurements 
described in section other safety variables (see section 6.5.3.6)
6.2.3.6.2
Percentage of subjects with normal hemoglobin >12 g/dL and normal 
hematocrit >36%
Frequency tables with number of observations and percentage will be displayed by treatment period 
within treatment group and by Intervals C. A listing will be provided. 
6.2.3.6.3
Percentage of subjects with hemoglobin ≤10.9 g/dL)
Frequency tables with number of observations and percentage will be displayed by treatment period 
within treatment group and by Intervals C. A listing will be provided. 
6.3
Pharmacokinetics/pharmacodynamics
A separate Pharmacokinetic (PK)/Pharmacodynamic (PD) Evaluation Plan, providing details of the 
model development and evaluation will be provided before the beginning of the population PK 
analysis. Evaluation of the data will be presented in a separate PK/PD Evaluation Report.
6.4
Exploratory biomarker analysis
Evaluation of biomarker related analysis will be performed and detailed in a separate document.
6.5
Safety
The safety analysis will be performed on the observed safety data for the safety analysis population. 


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6.5.1
Primary safety variable
The primary safety variable is the percentage change in BMD of lumbar spine (using the central 
reading results) from baseline to about one year after SoT. One year is defined as ‘Month 12 on 
treatment’ in Table 6-1, i.e. Day 300 after reference start date to Day 420 after reference start date, 
but no later than the reference end date + 60 days.
The primary safety variable will be analyzed using descriptive statistical methods and two-sided 
95% confidence interval (CI) for the mean difference for the percentage change in BMD of lumbar 
spine from baseline to about one year after SoT will be calculated for each vilaprisan treatment 
group as compared to treatment group B. Additionally, two-sided 95% CI for each treatment group 
will be calculated. The primary variable is assumed to be at least approximately normally 
distributed.
For the percentage change in BMD of lumbar spine from baseline to other time points defined in 
Table 6-1, the descriptive statistics will also be provided by treatment group. 
The percentage change in BMD of lumbar spine from EoT BMD will also be evaluated using 
summary statistics by treatment group and time interval or month for post treatment period defined 
in Table 6-1. 
The time intervals and month named in Table 6-1 will be presented in tables and figures unless 
otherwise specified. Month equals 30 days. 
Table 6-1: Definition of month and time intervals for BMD summary
Month
Time interval
Baseline
Baseline
Baseline
if no Visit 2-repeat scan exists, Visit 2 scan will be used as baseline. Otherwise, Visit 2 -repeat scan will be used. The 
BMD baseline visit will be marked in the dataset transferred from ICON’s Medical Imaging group. (refer to section 4.5 )
On 
treatment 
period：
From 
reference 
start date
to 
reference 
end date 
+ 60 
days
Month 1
N/A
If a BMD value performed after the reference start date has been marked as baseline value, it will be analyzed as baseline 
value and will be excluded from the analysis for on treatment period.
Month 2
Month 3
Month 4
Month 6 on treatment
Day 120 after reference start date to Day 240 after the reference start date, but no later than the reference end date + 60 
days
Month 5
Month 6
Month 7
Month 8
Month 9
N/A
Month 10
Month 12 on treatment
Day 300 after reference start date to Day 420 after reference start date, but no later than the reference end date + 60 days
Month 11
Month 12
Month 13
Month 14
>Month 14
N/A
In case of more than one measurement > Month 14, the worst measurement within the time interval will be used for 
calculations.


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N/A
EoT BMD
Reference end date ± 60 days
If two measurements are available during the EoT BMD time interval, the measurement closest to the reference end date 
will be use as EoT BMD measurement.
Post 
treatment 
period:
After 
reference 
end date 
+ 60 
days
Month 3
N/A
Month 4
Month 6 post treatment
Day 120 after the reference end date to Day 240 after the reference end date
Month 5
Month 6
Month 7
Month 8
Month 9
N/A
Month 10
Month 12 post treatment
Day 300 after the reference end date to Day 420 after the reference end date
Month 11
Month 12
Month 13
Month 14
>Month 14
N/A
In case of more than one measurement > Month 14, the worst measurement within the time interval will be used for 
calculations.
N/A
EoFUP BMD
The last measurement, but no earlier than the reference end date + 60 days
BMD = bone mineral density; EoT=end of treatment; EoFUP= end of follow-up; N/A=not applicable
Percentage change in BMD of lumbar spine from baseline with frequencies and percentages for the 
following categories: <-6%, ≥-6% -  < -3% ,  ≥-3% - < -1.5% , ≥-1.5% - ≤0%, >0% - ≤1.5%, 
>1.5% - ≤3% , >3% - ≤6% and >6% will also be summarized by treatment group. The worst 
outcome per subject during treatment period will be used in the analyses.
Frequency table for the status of BMD of lumbar spine at EoFUP compared with EoT will be 
provided by treatment group. The categories for the status of BMD of lumbar spine at EoFUP is 
defined in Table 6-2. Percentage of recovery is defined as change in BMD of lumbar spine from 
EoT BMD to EoFUP BMD divided by change in BMD of lumbar spine from Baseline to EoT BMD. 
It will be evaluated in subjects with partially recovered. Number and percentage of subjects for 
percentage of recovery by categories of ≥75 - < 100%, ≥ 50 - <75%, ≥25 - <50% and ≥0 - <25% 
will be provided for subjects with partially recovered.
Table 6-2: Status of BMD of lumbar spine at EoFUP
% change in BMD of 
lumbar spine from 
baseline to EoT BMD
(x)
% change in BMD of 
lumbar spine from 
baseline to EoFUP 
(y)
Status at EoFUP 
Percentage of recovery
< 0
≥ 0
Recovered, completely 
≥ 100%


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< 0
x ≤ y < 0
Recovered, partially
≥ 0% - <100%
< 0
y < x
Not recovered or further 
decrease
Not applicable
≥ 0
≥ 0
No decrease during both 
treatment and FUP period
Not applicable
≥ 0
< 0
No decrease during treatment 
period but worsening during 
FUP period
Not applicable
Mean-deviation plot for the percentage change in BMD of lumbar spine from baseline will be 
presented by treatment group for the entire study period (treatment period + post treatment period). 
Following listings will be provided separately:
1) subjects that had at least one DEXA scan during the treatment period with either BMD loss 
≥6% from baseline to EoT for any location or Z-score ≤ -2 SD for any location.
2) subjects with BMD loss ≥ 3% from baseline for any location or Z-score ≤ -2 SD for any 
location at EoFUP DEXA scan.
During the study, if the baseline scan at Visit 2 was missing or not evaluable based on the evaluation 
from the Medical Imaging group of ICON, the subject was requested to have a repeat scan. If it’s not 
possible to have this repeat scan performed before the reference start date, this repeat scan was 
allowed to be performed shortly after the start of the treatment. Considering the BMD will not 
change quickly, this can be accepted from a medical point of view. If a BMD value performed after 
the reference start date has been marked as baseline value, it will be analyzed as baseline value and 
will be excluded from the analysis for on treatment period defined in Table 6-1.
To make a further investigation, an additional analysis for the primary safety variable with subjects 
excluded who had their baseline scan later than 1 month after start of treatment will be provided. 
6.5.2
Secondary safety variables
6.5.2.1
Endometrial histology (eg, benign endometrium, presence or absence of 
hyperplasia or malignancy)
For endometrial histology evaluations the following time intervals will be considered:
-
Any time point
-
Intervals A (according to Figure 4-1)
-
Intervals B (according to Figure 4-1)
-
Exit examination (according to Figure 4-1)
-
Bleeding episode after last TP time windows in subjects with at least 56 days of treatment 
within the TP (by TP and overall)

From start of the subjects´ last treatment period until day 55 of the same TP


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
From day 56 of the same treatment period until last day of the1st bleeding episode after TP

After 1st bleeding episode of the same treatment period, i.e. from 1st day after end of the first 
bleeding episode to last day of 2nd bleeding episode

After 2nd bleeding episode of the same treatment period, i.e. from first day after end of 2nd
bleeding episode to last day of 3rd bleeding episode

After 3rd bleeding episode of the same treatment period, i.e. from first day after end of 3rd
bleeding episode to last day of 4th bleeding episode
Presentations will be done for 
-
the safety read (Reader #1 or #5)
-
the majority read (Readers #2-4)
-
all reads (Readers #1-5)
For the safety read only one result will be available per biopsy (based on either Reader #1 or #5), 
whereas for the “majority read” and “all reads” more than one reader result needs to be considered. 
Analyses will present the number and percentage of either subjects or biopsies. Analyses based on 
number of subjects will use a worst-case approach within each of the above-mentioned time 
windows, except “Exit biopsies” where the last available measurement will be used. 
Majority read definitions:
Majority read results will only be provided in case biopsy data from Readers #2, #3 and #4 are 
available.
Majority read will be determined for main results and subcategories (see Table 6-3Table 6-3). First, 
adequacy (for part II and III) or sufficiency (for part IV) of tissue will be investigated. If at least 2 of 
the 3 readers consider it adequate/sufficient, the majority for the main results will be determined. 
For the majority main result, the majority of the respective subcategories will be determined. If no 
majority result is available (3 different results in 3 readers, 2 different results in 2 readers), either 
“no consensus” or the worst case will be presented. Table 6-3 presents an overview of all biopsy 
endpoints including the approach which is used in case no majority is available.
For ‘tick all that apply’-subcategories, individual features will be considered the majority in case at 
least 2 readers have ticked the feature, i.e. for one biopsy more than one subcategory can be the 
majority.
All read definition:
All read results will be based on all biopsies with results from at least one reader. 
A biopsy is considered non-benign in case “Benign endometrium” = “No” or “Endometrial 
Hyperplasia (2014)” or “Endometrial Hyperplasia (WHO 1994)” or “Malignant Neoplasm” = “Yes”.
Worst case across time interval:
Worst case of biopsies or majority results across time windows is determined for each endpoint in
Table 6-3Table 6-3.


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Table 6-3: Overview of biopsy endpoints including majority result handling and worst case
Part
Endpoint
No majority 
available
Worst case 
across time 
intervals for 
subject based 
analyses
Main results
I
Main 
diagnosis
Adequate endometrial tissue
- (not possible)
“Yes”
II
Benign endometrium 
Endometrial Hyperplasia (WHO 2014)
Malignant Neoplasm 
Worst case:
List is ordered by 
severity, from low to 
high
List is ordered by 
severity, from low 
to high
III
Endometrial Polyp
Worst case: yes
“Yes”
IV
PAEC
Tissue sufficient for PAEC read
- (not possible)
“Yes”
PAEC present
Worst case: yes
“Yes”
Subcategories
II
Main diagnosis
Benign endometrium (select one)
 Atrophic  Inactive  Proliferative  Disordered
Proliferative  Secretory including progestin and OCP effect 
Menstrual  Endometritis  Other,specify
“no consensus”
- (will not be 
presented)
Endometrial Hyperplasia (WHO 2014) (select one)
 Hyperplasia without atypia  Atypical hyperplasia /
Endometrioid Intraepithelial Neoplasia (EIN) 
Worst case: Atypical 
hyperplasia / 
Endometrioid 
Intraepithelial 
Neoplasia (EIN)
Atypical 
hyperplasia / 
Endometrioid 
Intraepithelial 
Neoplasia (EIN)
III
Endometrial Polyp (select one)
 Atrophic  Functional  Hyperplastic
“no consensus”
- (will not be 
presented)
IV
PAEC
PAEC (tick all that apply)
 Pre-Decidua Absent  Extensive cysts Present  Secretory
Changes, Extensive  Mitoses (required, may be rare) 
Apoptosis  Abnormal Vessels
“no consensus”
- (will not be 
presented)
PAEC = progesterone receptor modulator-associated endometrial changes; WHO = World Health Organization
6.5.2.2
Endometrial thickness
For endometrial thickness the following time intervals will be considered:
-
Intervals A (according to Figure 4-1)
-
Intervals C (according to Figure 4-1)
-
Exit examination
Number of subjects with ultrasound performed will be presented. 
Summary statistics for change from baseline in endometrial thickness will be provided. In addition, 
the proportion of subjects with endometrial thickness > 18 mm will be investigated. A subgroup 
analysis by exposure group (treatment duration <=90 days, 91 to 180 days, etc.) will present the 
proportion of subjects with endometrial thickness > 18 mm and cyst like structure either ovary >= 
3cm.
To investigate the correlation of endometrial thickness and biopsy results, the proportion of biopsies 
with hyperplasia without atypia (WHO 2014), atypical hyperplasia / EIN (WHO 2014), PAEC 


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present, PAEC not present, Extensive cysts present, and Extensive cysts not present will be 
presented for endometrial thickness > 18mm in ultrasound and endometrial thickness <=18 mm in 
ultrasound.
6.5.2.3
Percentage change from baseline in BMD measured, hip, and femoral neck 
by DEXA
The percentage change in BMD of hip, and femoral neck will be summarized in the same way as 
described for the primary safety variable.
6.5.3
Other safety variables
6.5.3.1
Endometrial histology (diagnosis of PAEC, individual features of PAEC)
Diagnosis of PAEC, individual features of PAEC will be analyzed in the same way as Endometrial 
histology described in section Secondary safety variables (see section 6.5.2.1)
6.5.3.2
Percentage of subjects with BMD decrease >6% and Z-score < -2 measured 
at the lumbar spine 
Frequency table with number and percentage of subjects with BMD decrease >6% and Z-score <-2 
measured at the lumbar spine will be displayed by treatment group during treatment period.
6.5.3.3
Change in Z-score over time
The Z-score and the change in Z-score by BMD location will be summarized by treatment group and 
time intervals using descriptive statistics.
Z-score with frequencies and percentages for the following categories: <-2, ≥-2 - <-1.5 , ≥-1.5 - <-1 , 
≥-1 - ≤0, >0 - ≤1, >1 - ≤1.5, >1.5 - ≤ 2 and >2 will also be summarized by treatment group.
6.5.3.4
Ovarian cysts 
Ovarian cysts will be examined by ultrasound. All scheduled and unscheduled assessments will be 
considered for the analysis. Three analyses will be performed for ovarian cysts:
-
Number of subjects showing cyst like structures with largest diameter > 3 cm in the ovary
-
Analysis of ovarian cyst episodes (see below for definition)
-
Analysis of AEs associated with ovarian cysts
The analysis of Number of subjects with ovarian cyst like structures > 3 cm in largest diameter
in ovary will be shown by treatment group and by time intervals A and B (according to Figure 4-1). 
One table will be produced for time intervals A and one table for time intervals B.
For each time interval it will be determined whether an individual subject shows cysts like structures 
with a largest diameter > 3 cm at least once during that time interval.
In addition to the corresponding time intervals, both tables will contain the assessment for ‘Exit 
examination.’ 
Frequencies for the type of cyst like structures identified will be included in the table. Type of cyst 
like structures will be shown as recorded in the eCRF: ‘Follicle-like structure’, ‘Corpus luteum 
cyst’, ‘Endometrioma’ and ‘Other’.


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The overall assessment for both ovaries will be displayed, and information about ovary laterality 
will not be included in the table. 
If cyst like structures > 3 cm are visualized in the ovaries, unscheduled ultrasound examinations 
should be performed at least every 4 weeks to document the regression or outcome. An ovarian cyst 
episode is defined as the time period from occurrence of a cyst like structure > 3 cm until its 
resolution. Ovarian cyst episodes will only take account of the occurrence of follicle-like structures 
and corpus luteum cysts. Two different definitions of “resolution” are used in the analysis:
-
the subject does not show in the same ovary (left or right) a cyst like structure of the same 
type
-
the subject does not show in the same ovary (left or right) a cyst like structure of the same 
type with diameter ≤3 cm.
For both definitions, the date of the first observation of the cyst like structure is the start of the 
episode. The date when the cyst like structure appears for the first time as resolved (absence of cyst 
like structure or cyst like structure with diameter ≤3 cm) is considered the end of the episode. The 
length of time between start and end of the episode is the duration of the episode.
If the cyst resolution does not occur, then the length of time between the start of the episode and the 
last observation will be considered the cyst episode duration.
If only the start of the episode is recorded but no follow-up has been performed, then the duration of 
the episode is unknown.
The analysis will include cysts episodes occurring in both ovaries with no distinction of ovary 
laterality (left or right). Although the information of ovary laterality will not be displayed in the 
table, it will be critical to monitor the progression of individual cyst like structures.
The time intervals A and B (according to Figure 4-1) will be considered, therefore two sets of tables 
will be produced. Ovarian cyst episodes will be assigned to the time interval when the start of the 
episode occurs.
Two analyses will be produced for ovarian cyst episodes:

Number of subjects with at least one ovarian cyst episode by time intervals. 

Number of ovarian cyst episodes by time intervals including: i) summary statistics of ovarian 
cyst episode duration, ii) by categorization of the duration by 4-week intervals, and iii) 
summary statistics of largest diameter of the cyst like structure per episode and per time 
interval.
Two tables will be produced for these two analyses, one for each definition of cyst episode 
resolution.
The analysis of adverse events related to ovarian cysts by time intervals will include AEs 
identified by the Bayer MedDRA query (BMQ) for ‘Benign ovarian cyst and associated 
complications’ [V21], ], which include the preferred terms (PTs): Haemorrhagic ovarian cyst, 
Ovarian cyst, Ovarian cyst ruptured and Ovarian cyst torsion.


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The table will show number of subjects with AEs, non-serious AE and SAEs. For each one of these 
AE categories the table will include severity, whether the AE led to drug withdrawal and AE 
duration. In addition, SAEs will include the reason for being classified as serious as recorded in the 
eCRF.
The analysis will be shown by treatment group and will be done for pre-treatment AEs, TEAEs and 
post-treatment AE. AEs will be assigned to the time interval when the AE starts. AEs with onset 
during a treatment period or up to 8 days after last drug intake in any treatment period will be 
considered ‘on-treatment’. AEs with onset after date of last study drug intake in any treatment 
period + 8 days and before the start of the next treatment period will be considered ‘off-treatment’. 
The summary table for TEAEs will be presented by overall AEs, on-treatment AEs and off-
treatment AEs.
6.5.3.5
AEs
All AEs will be coded by MedDRA terms (current version at time point of analysis) and classified 
into pre-treatment AEs, treatment-emergent (TEAE) and post-treatment AEs. 
All AEs will be flagged as treatment-emergent adverse event (TEAE) except all AEs where there is 
clear evidence that the event starts before date of first study drug exposure (pre-treatment AEs) or 
after the date of last study drug exposure + 60 days (post-treatment AE). For Treatment group B, the 
reference start/end dates (as defined in section 4.5 Data Rules) will be used for this derivation, rather 
than date of first study drug exposure/ date of last study drug exposure. AEs with clear evidence of 
start before the date of first study drug exposure are flagged as pre-treatment AE unless the AE 
worsens at or after the date of first study drug exposure and before or at the date of last study drug 
exposure + 60 days. AEs starting before but worsening at or after the date of first study drug 
exposure and before or at the date of last study drug exposure + 60 days will be considered as two 
events, a pre-treatment AE and a TEAE. The pre-treatment AE will stop at the time of worsening 
and the new TEAE will start at the time of worsening. Same applies in case an AE starts at or after 
the date of first study drug administration, but before the date of last study drug administration + 60 
days and worsens afterwards then e.g. leading to a TEAE and a post-treatment AE.
Reasons for worsening of an AE are listed below.
-
AE intensity/grade is worsened (e.g.: moderate to severe)
-
AE changed to a serious event
-
AE ends with death
-
AE is drug-related
TEAEs will further be categorized into on-treatment and off-treatment events. 
All TEAEs should be flagged as on-treatment events except all TEAEs where there is clear evidence 
that the event starts outside all on-treatment phases. Each on-treatment phase starts with the date of 
first study drug exposure and ends with the date of last study drug exposure during a treatment 
period plus 8 days. For subjects in the VPR-6/2 treatment group, TEAEs with an onset within 8 days 
after end of TP1 (or TP3 or any TP with an odd number), but after start of TP2 (TP4 or after any TP 
with even number) will be reported as on-treatment for TP2 (TP4 and so on).


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TEAEs with clear evidence of start outside all on-treatment phases will be flagged as off-treatment 
events unless the TEAE worsens during an on-treatment phase. TEAEs starting during off/on-
treatment phase, but worsening during an on/off-treatment phase will be considered as two events, 
an off/on-treatment TEAE and an on/off-treatment TEAE. The off/on-treatment TEAE will stop at 
the time of worsening and the on/off-treatment TEAE will start at the time of worsening.
Imputation
Missing “Causality to Protocol Procedure” will be imputed with “yes” in case “Causality to study 
drug” is “no”, and with “no” in case “Causality to study drug” is “yes”. 
Presentation
The tabulation will follow in principle the Bayer Global Standard Tables catalogue (currently V 4.0 
default), with the necessary modifications like for on- and off-treatment TEAEs. 
Adverse events of special interest (AESIs) will be identified in two different ways
1) The investigators will assess all AEs to determine if they are AEs of special interest (AESIs) 
and document this in the eCRF. The following AEs are included:
a.
HMB
b. Liver disorders
c.
Endometrial disorders
d. Skin disorders
e.
Adrenal disorders
f.
Relevant loss of BMD during treatment
2) Adverse events will be categorized into AE groupings of special interest based on MedDRA 
groupings as defined within expert statement for compound vilaprisan (Selection of coding 
conditions applicable for AESIs as defined in the study protocols of vilaprisan phase II/III 
studies). List of AESIs in current expert statement based on MedDRA Version 22.1 is 
provided in Appendix 3.
AESIs based on investigator assessment and AESIs based on MedDRA groupings will be presented 
separately. They will be presented by AESI group (if available), MedDRA primary SOC and PT and 
study drug. Summary tables for AESIs by maximum intensity and by worst outcome will be 
produced. Furthermore, listings will be provided.
6.5.3.6
Laboratory parameters
For immunology and coagulation parameters Intervals ‘BL/Post baseline’ will be used, while for all 
other laboratory measurements the following time intervals will be considered:
-
Intervals C (according to Figure 4-1)
The tabulation will follow in principle the Bayer Global Standard Tables catalogue (currently V 4.0 
default), with the necessary modifications like for time interval presentation instead of visit 
presentation. 


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The maximum or minimum measurement within the time interval will be used for calculations, 
following a worst-case approach (for details please refer to Appendix 2). Scheduled as well as 
unscheduled measurements will be considered. 
Central as well as local lab measurements are available. Summary statistics will be provided based 
on central lab. Local lab measurements will be listed. 
Values below the lower limit of quantification (LLOQ) will be set to LLOQ/2.
Values above the upper limit of quantification (ULOQ) will be set to ULOQ.
6.5.3.7
Estradiol
Absolute values will be analyzed using descriptive statistics by treatment group using time intervals 
C and D. The lowest value (i.e. “worst case”) per subject per time interval will be used in the 
analyses.
The distribution of estradiol values by treatment group using time intervals C and D like above will 
be graphically depicted with boxplots. The time course will be shown using line plots depicting the 
mean and 95% confidence interval (two-sided) and using time intervals C and D as described above. 
Time intervals including data from less than 10 of randomized subjects in the respective group will 
be excluded from plots.
For estradiol frequency tables with number and percentage of subjects with estradiol (pg/mL) <13, 
<30 will be displayed by treatment group and time intervals A and B. For each time interval, the 
subjects with at least one lower value based on each cut-off in any visit during that time interval will 
be counted. 
6.5.3.8
Cervical smear
Cervical smears findings will be summarized by treatment group and visit with a frequency table.
A listing will be provided with cervical smear results for each subject.
6.5.3.9
Vital signs
Vital signs (heart rate, systolic blood pressure and diastolic blood pressure, and weight) will be 
summarized by treatment group and visit grouped by TP, including change from baseline where 
appropriate, using descriptive statistics. Boxplot for absolute values at each visit will be presented 
by treatment group. The time course by visit and by treatment group will be shown using line plots 
depicting the mean and 95% CI (two-sided).
For safety closeout visit blood pressure will be measured as triplicates, mean value of triple 
measurements will be reported in tables.
6.5.3.10
Liver monitoring
Hepatic safety will be evaluated based on the following time intervals:
-
BL/Post baseline
-
Intervals A


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The following parameters will be investigated in addition to the standard lab presentations: 
-
aspartate aminotransferase (U/L) (AST), 
-
alanine aminotransferase (U/L) (ALT), 
-
alkaline phosphatase (U/L) (AP), 
-
bilirubin in serum (mg/dL). 
In case of more than one measurement within a time interval, a worst case approach will be used, i.e. 
the maximum value will be used for calculations.
Frequency tables presenting number and percentage of subjects fulfilling the following criteria will 
be produced:
-
Normal, >1xULN – <3xULN, ≥3xULN – <5xULN, ≥5xULN – < 8xULN; ≥8xULN -
<10xULN; ≥10xULN – <20xULN, ≥20xULN of ALT and AST respectively
-
<=1xULN; 1xULN - 2xULN; >=2xULN of Bilirubin
-
<=1xULN; 1xULN - 1.5xULN, >=1.5xULN of AP
-
≥ 3×, 5×, 8×, 10×, and 20×ULN of ALT
-
≥ 3×, 5×, 8×, 10×, and 20×ULN of AST
-
≥ 3×, 5×, 8×, 10×, and 20×ULN of ALT or AST
-
>1xULN, > 2×ULN of bilirubin
-
>1.5 of AP 
-
>3xULN of ALT or AST accompanied by >1.5xULN Bilirubin (any time point)
-
>3xULN of ALT or AST accompanied by >2 xULN in Bilirubin (any time point)
Combined parameters based on Hy’s Law criteria
Frequency tables will be provided for 
-
≥3×ULN of ALT or AST accompanied by ≥2×ULN of bilirubin (within 30 days afterwards).
The event will be assigned to the time interval of the ALT/AST elevation.
Time to event analysis
Kaplan Meier analysis will be performed by time intervals as described above. Time to ALT > 
3xULN after start date of the respective time interval will be presented. If no such an increase is 
observed within the time interval, this is considered a censored observation and the end date of the 
time interval will be used as date. Tables with number of subjects under risk, cumulative number of 
ALT >3xULN increases, and estimated probability of increase including 95% confidence intervals 
within the respective time interval will be presented per 28-day intervals. Furthermore, Kaplan 
Meier plots will be provided.
Figures and individual subject presentations


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An 
-
eDISH plot (maximum of ALT and AST within time interval × maximum of total bilirubin 
within 30 days thereafter) and a
-
Scatter plot (maximum ALT within time interval x maximum AST within time interval) 
will be provided by time interval as described above.
Individual subject presentations
For subjects meeting the following criteria, figures on individual time courses will be presented:
-
≥ 3 x ULN of ALT at any time point
The following lab parameters will be presented: ALT, AST, bilirubin, and AP relative to ULN over 
time within one figure per subject on absolute scale. It will be indicated within the figure on which 
days study drug was taken (i.e. start and stop of treatment periods). Furthermore, listings will be 
provided with laboratory information on liver related parameters, i.e. ALT, AST, bilirubin, AP 
(relative to upper limit of normal).
6.5.3.11
Adrenal monitoring
Subjects were asked to undergo scheduled adrenal monitoring at the safety closeout visit. The 
adrenal monitoring comprises the following assessments: 
-
Adrenal gland imaging
-
Laboratory testing
-
Signs and symptoms suggestive of hypercortisolism, hyperaldosteronism
All tables generated within this adrenal monitoring section will contain the absolute number of 
subjects and percentage among subjects who performed the safety closeout visit.
An overview table will be provided. This table includes the number and percentage of subjects 
taking part at the specific adrenal monitoring assessments. The following numbers and percentages 
of subjects will be provided in addition:
-
Subjects with abnormal result in at least one of the assessments. 
-
Subjects with abnormal result for each specific assessment separately.
-
Subjects for whom an external expert recommendation was obtained. Among those, also the 
number and percentage of subjects with any findings suspicious of an adrenal disorder and 
recommendation for further handling will be provided.
-
Subjects who have seen a local specialist (including information on type of specialist).
Details of the final diagnosis by the expert panel will be provided in another table. This table 
contains the number and percentage of subjects assessed by an expert, subjects needed expert panel 
meeting, subjects where expert panel met,  and subjects with at least one diagnosis by the expert 
panel. Among those, the following numbers and percentages of subjects will be provided:


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-
Subjects with agreement of the diagnosis among all three experts.
-
Subjects with a specific diagnosis (multiple diagnoses are possible). 
A listing of subjects with other diagnosis (i.e. diagnosis entered by the expert panel in a text field) 
will be provided. A listing of subjects with adrenal tumor will presented as well. It includes 
diagnosis, time from last study drug until date of panel assessment and possible causal relationship 
to study drug. Cases where the three experts did not agree on a diagnosis, are presented in a separate 
listing including also the diagnosis of the local specialist.
A third table will summarize the diagnosis by a local specialist. This table contains the number and 
percentage of subjects with at least one diagnosis by the local specialist. Among those, the numbers 
and percentages of subjects with a specific diagnosis (multiple diagnoses are possible) will be 
reported.
A listing of subjects with other diagnosis (i.e. diagnosis entered by a local expert in a text field) will 
be provided as well as a listing of reasons if a local specialist consultation did not take place despite 
referral.
A listing of local laboratory measurements will be provided (no descriptive analyses will be 
performed on those). 
A table with results of the adrenal glands imaging will be provided. This table contains the number 
and percentage of subjects who did and who did not perform adrenal imaging (and reasons if not 
performed), and who have at least one evaluable image. Among subjects having performed adrenal 
glands imaging the type of procedure (e.g. CT scan with contrast) will be reported. The following 
numbers and percentages of subjects will be derived among subjects with at least one evaluable 
image:
-
Subjects with one or two evaluable lateralities. 
-
Subjects with adrenal mass (if yes, in one or in both adrenal glands).
-
Subjects with specified diagnostic benign imaging features.    
-
Subjects with specified indeterminate imaging features.   
Reader results where an adjudicator was needed due to discrepant diagnoses between the two 
readers will be provided in a listing. 
6.5.3.12
Skin monitoring
Findings resulting from skin monitoring will be analyzed descriptively by treatment group. All 
subjects who consent for safety follow-up and attend the Safety closeout visit will undergo a 
thorough skin examination by a dermatology expert. The information will be recorded on the eCRF 
assigned to the safety closeout visit. The analysis will show the number of subjects who consented 
to participate in the Safety Follow-up, how many were assessed by a dermatologist or other 
clinician, which diagnostic tests were used and the results of the assessment as follows: number of 


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normal and abnormal findings; and following an abnormal finding which type of abnormality as 
recorded in the eCRF: ‘Precancerous skin lesion’, ‘Cutaneous sarcoma’, ‘Other malignant skin 
tumor’ and ‘Other skin abnormality’.
Relevant cases will be reported as AEs, potentially as an AESI, and a narrative will be written.
6.5.3.13
UF-DBD bleeding pattern per 28 days and 84 days based on UF-DBD
The bleeding data recorded on the UF-DBD will be summarized using descriptive statistics in the 
safety analysis set by treatment groups using time intervals C and time intervals D. A reference 
period of 28 days will be used for most analyses, which corresponds with the time interval D. When 
a reference period of 84 days is used the time intervals D will be modified accordingly.
The bleeding intensity will be summarized by bleeding category using frequency tables by reference 
period of 28 days and 84 days. 
The maximum bleeding intensity will be summarized using frequency tables by 28 days reference 
period. 
The number of bleeding days will be analyzed by 28 days reference period and with the following 
bleeding categories: 

non-bleeding, 

spotting-only, 

bleeding (category of bleeding intensity ≥ mild)

bleeding including spotting (category of bleeding intensity ≥ spotting)

mild

moderate

severe

very severe
For the safety bleeding analysis, and in contrast with the analysis of efficacy variables based on 
bleeding data, bleeding induced by endometrial biopsies will not be excluded.
An incomplete period which does not comprise 28 (or 84, respectively) days will be analyzed for 
any of the considered time periods of Intervals C. The analysis of this incomplete period is based on 
all subjects for whom the length of the considered time period is not a multiple of 28 (or 84, 
respectively) days. Subject’s data from the last x < 28 (x < 84) days of the considered time period 
will be included. 
7.
Subgroup analyses
Subgroups for endpoints as described in section 6.2.2 and 6.2.3.1
1) Subjects who fulfill the inclusion criteria of HMB > 80.00 mL by MP during screening period
(depicted by Baseline Volume of menstrual blood loss per 28 days) and at least one fibroid > 3 
cm at baseline by Ultrasound vs. subjects who did not fulfill these criteria at baseline.


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8.
Document history and changes in the planned statistical analysis
SAP version 1.0. dated 31 Jul 2017
9.
References
1. Recording and Evaluation of Bleeding Data Version 6.0 (BHC-RD-OI-107 )
2. Nikica Živković1, Krešimir Živković2, etal. Measuring the volume of uterine fibroids using 2-
and 3- dimensional ultrasound and comparison with histopathology. Acta Clin Croat.  2012; 
51:579-589
Appendix 1: Handling of Patient-report outcomes
UFS-QoL scores 
To calculate a symptom score for symptom severity, create a summed score from the items listed 
below and then use the formula below the table to transform the value. This will provide 
symptom scores where higher score values are indicative of greater symptom severity or bother 
and lower scores will indicate minimal symptom severity (high scores= bad).
Table 9-1 Formula for calculating symptom score for symptom severity
Scale
Sum Item Values
Lowest and 
Highest Possible 
Raw Scores
Possible Raw 
Score Range
Symptom 
Severity
Sum 1-8
8, 40
32
Transformation for Symptom Severity raw scores ONLY:
Transformed Score =
(\$]^
_ *
` a$b*c −_b`ca] ebaaf_c *
` a$b*c) 
gbaaf_c *
` a$b*c *
hic
× 100%
For the HRQoL subscales (concern, activities, energy/mood, control, self-conscious, and 
sexual function), create summed scores of the items listed below for each individual subscale.  
To calculate the HRQoL total score, sum the value of each individual subscale (do not sum 
individual items).  Use the formula below the table to transform all values.  Higher scores will 
be indicative of better HRQoL (high = good).
Table 9-2 Formula for calculating HRQoL subscales and total score
Scale
Sum Item Values
Lowest and Highest
Possible Raw Scores
Possible Raw Score
Range
Concern
9+15+22+28+32
5,25
20
Activities
10+11+13+19+20+27+29
7,35
28


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Energy/mood
12+17+23+24+25+31+35
7,35
28
Control
14+16+26+30+34
5,25
20
Self-conscious
18+21+33
3, 15
12
Sexual function
36+37
2, 10
8
HRQoLTOTAL
Sum of 6 Subscale Scores
29, 145
116
Revised activities
11+13+19+20+27
5,25
20
Revised 
HRQLTOTAL
Sum of 6 Subscale Scores 
(replacing activities with 
revised activities)
27,135
108
Formula for transformation of HRQoL raw scores ONLY:
Transformed Score =
(jfiℎca] ebaaf_c a$b*c−\$]^
_ *
` a$b*c) 
gbaaf_c *
` a$b*c *
hic
× 100%Missing Items
For the subscale analyses, if< 50% of the scale items are missing, the scale should be 
retained with the mean scale score of the items present used to impute a score for the 
missing items. If ≥50% of the items are missing, no scale score should be calculated, the 
subscale score should be considered missing. If a subscale score is missing, the HRQoL
total cannot be calculated. 
Appendix 2 : The maximum or minimum measurement for laboratory parameters
Table 9-3 The maximum or minimum measurement for laboratory parameters
Laboratory category
Laboratory test
lowest
highest
VITAMINS
25-Hydroxyvitamin D
X
COAGULATION
Activated Partial Thromboplastin Time
X
HORMONES
Adrenocorticotropic Hormone
X
X
GENERAL CHEMISTRY
Alanine Aminotransferase
X
GENERAL CHEMISTRY
Albumin
X
GENERAL CHEMISTRY
Alkaline Phosphatase
X
IMMUNOLOGY
Alpha-1 Antitrypsin
X
IMMUNOLOGY
Anti Mitochondiral Antibody
X
IMMUNOLOGY
Antinuclear Antibodies
X
GENERAL CHEMISTRY
Aspartate Aminotransferase
X
HEMATOLOGY
Basophils
X
X
HEMATOLOGY
Basophils/Leukocytes
X
GENERAL CHEMISTRY
Bilirubin
X
URINALYSIS
Bilirubin
X
URINALYSIS
Blood
X
GENERAL CHEMISTRY
Bone Specific Alkaline Phosphatase
X
MICROBIOLOGY
Brucellae
X
GENERAL CHEMISTRY
Calcium
X
X
PROTEINS
Ceruloplasmin
X
GENERAL CHEMISTRY
Chloride
X
GENERAL CHEMISTRY
Cholesterol
X
Choriogonadotropin Beta
X
HORMONES
Choriogonadotropin Beta
X


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Reference Number: RD-OI-0119
Supplement Version: 8
URINALYSIS
Choriogonadotropin Beta
X
HORMONES
Cortisol
X
X
GENERAL CHEMISTRY
Creatine Kinase
X
GENERAL CHEMISTRY
Creatinine
X
IMMUNOLOGY
Cytomegalovirus DNA
X
GENERAL CHEMISTRY
Direct Bilirubin
X
HEMATOLOGY
Eosinophils
X
HEMATOLOGY
Eosinophils/Leukocytes
X
IMMUNOLOGY
Epstein-Barr Capsid IgG Antibody
X
IMMUNOLOGY
Epstein-Barr Capsid IgM Antibody
X
IMMUNOLOGY
Epstein-Barr Nuclear Antigen 1 IgG Ab
X
HEMATOLOGY
Ery. Mean Corpuscular Hemoglobin
X
HEMATOLOGY
Ery. Mean Corpuscular Volume
X
HEMATOLOGY
Erythrocytes
X
HORMONES
Estradiol
X
GENERAL CHEMISTRY
Ferritin
X
HORMONES
Follicle Stimulating Hormone
X
GENERAL CHEMISTRY
Gamma Glutamyl Transferase
X
URINALYSIS
Glucose
X
IMMUNOLOGY
HCV PCR Viral Load
X
GENERAL CHEMISTRY
HDL Cholesterol
X
X
HEMATOLOGY
Hematocrit
X
HEMATOLOGY
Hemoglobin
X
GENERAL CHEMISTRY
Hemoglobin A1C
X
IMMUNOLOGY
Hepatitis A Virus Antibody
X
IMMUNOLOGY
Hepatitis A Virus Antibody IgM
X
IMMUNOLOGY
Hepatitis B Virus Core Antibody
X
IMMUNOLOGY
Hepatitis B Virus DNA
X
IMMUNOLOGY
Hepatitis B Virus Surface Antibody
X
IMMUNOLOGY
Hepatitis B Virus Surface Antigen
X
IMMUNOLOGY
Hepatitis C Virus Antibody Surface
X
IMMUNOLOGY
Hepatitis D Virus Antibody
X
IMMUNOLOGY
Hepatitis D Virus IgG Antibody
X
IMMUNOLOGY
Hepatitis D Virus IgM Antibody
X
IMMUNOLOGY
Hepatitis D Virus RNA
X
IMMUNOLOGY
Hepatitis E Virus Antibody
X
IMMUNOLOGY
Hepatitis E Virus IgG Antibody
X
IMMUNOLOGY
Hepatitis E Virus IgM Antibody
X
IMMUNOLOGY
Hepatitis E Virus RNA
X
IMMUNOLOGY
Herpes Simplex Virus 1 IgG Antibody
X
IMMUNOLOGY
Herpes Simplex Virus 1 IgM Antibody
X
IMMUNOLOGY
Immunoglobulin A
X
IMMUNOLOGY
Immunoglobulin G
X
IMMUNOLOGY
Immunoglobulin M
X
GENERAL CHEMISTRY
Iron
X
URINALYSIS
Ketones
X
GENERAL CHEMISTRY
Lactate Dehydrogenase
X
GENERAL CHEMISTRY
LDL Cholesterol
X
MICROBIOLOGY
Leptospirae
X
HEMATOLOGY
Leukocytes
X
URINALYSIS
Leukocytes
X
HORMONES
Luteinizing Hormone
X
HEMATOLOGY
Lymphocytes
X
HEMATOLOGY
Lymphocytes/Leukocytes
X
HEMATOLOGY
Monocytes
X
HEMATOLOGY
Monocytes/Leukocytes
X
IMMUNOLOGY
MPO ANCA
X
HEMATOLOGY
Neutrophils
X
HEMATOLOGY
Neutrophils/Leukocytes
X
URINALYSIS
Nitrite
X
GENERAL CHEMISTRY
Osteocalcin
X


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Reference Number: RD-OI-0119
Supplement Version: 8
HEMATOLOGY
Platelets
X
GENERAL CHEMISTRY
Potassium
X
x
IMMUNOLOGY
PR3 ANCA
X
HORMONES
Progesterone
X
HORMONES
Prolactin
X
GENERAL CHEMISTRY
Protein
X
URINALYSIS
Protein
X
COAGULATION
Prothrombin Intl. Normalized Ratio
X
COAGULATION
Prothrombin Time
X
GENERAL CHEMISTRY
Pseudocholinesterase
X
IMMUNOLOGY
Smooth Muscle Antibody
X
GENERAL CHEMISTRY
Sodium
X
HORMONES
Testosterone
X
HORMONES
Thyrotropin
X
X
GENERAL CHEMISTRY
Time to event
X
GENERAL CHEMISTRY
Total Iron Binding Capacity
X
IMMUNOLOGY
Toxoplasma gondii antibody
X
GENERAL CHEMISTRY
Triglycerides
X
GENERAL CHEMISTRY
Type I Collagen C-Telopeptides
X
URINALYSIS
Urobilinogen
X
all parameters not otherwise specified
X
Appendix 3 : List of AESIs in current expert statement based on MedDRA Version 
22.1 (version 5.0, status 2020-02-19)
Table 9-4 List of AESIs
#
AESI
Grouping
1
HMB (especially after end of treatment): HMB 
will be documented in detail throughout the study 
MTG: [BMQ] Increased female 
genital bleeding[V8]
2
Progesterone receptor modulator-associated 
endometrial changes (PAEC) (not an AESI in 
16953)
PT selection:
PT: Endometrial thickening 
PT: Endometrial disorder
PT: Endometrial hypertrophy 
PT: Biopsy endometrium abnormal
PT: Biopsy uterus abnormal
3
Ovarian cysts (), not an AESI in study 16953)
MTG: [BMQ] Benign ovarian cyst 
and associated complications[V21]
4
Liver enzymes 
SMQ: Drug related hepatic 
disorders - comprehensive search 
(SMQ)[V29]
5
Endometrial hyperplasia (all subcategories 
according to WHO 2014 (and WHO 1994) 
classification 
PT selection:
PT:  Endometrial hyperplasia
PT:  Biopsy endometrium abnormal
PT:  Endometrial dysplasia
PT:  Endometrial metaplasia


Statistical Analysis Plan
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Page: 46 of 48
Reference Number: RD-OI-0119
Supplement Version: 8
PT:  Biopsy uterus abnormal
6
Endometrial thickening >18 mm
PT selection:
PT: Endometrial thickening 
PT: Endometrial disorder
PT: Endometrial hypertrophy
7
Loss of BMD 
SMQ: Osteoporosis/osteopenia 
(SMQ) (V21)
8 
Adrenal neoplasms, Adrenal diagnoses related to 
cortical hyperfunction and cortical hypofunction 
PBMQ: Adrenocortical gland 
pathology including tumors and 
related hormonal changes and 
conditions vilaprisan(narrow scope)
PT Addison's disease
PT Adrenal adenoma
PT Adrenal androgen deficiency
PT Adrenal atrophy
PT Adrenal calcification
PT Adrenal cortex dysplasia
PT Adrenal cortex necrosis
PT Adrenal cyst
PT Adrenal disorder
PT Adrenal gland abscess
PT Adrenal gland cancer
PT Adrenal gland cancer metastatic
PT Adrenal gland injury
PT Adrenal gland tuberculosis
PT Adrenal glomerular zone abnormal
PT Adrenal haematoma
PT Adrenal haemorrhage
PT Adrenal insufficiency
PT Adrenal insufficiency neonatal
PT Adrenal mass
PT Adrenal neoplasm
PT Adrenal suppression
PT Adrenal thrombosis
PT Adrenalitis
PT Adrenocortical carcinoma
PT Adrenocortical insufficiency acute
PT Adrenocortical insufficiency neonatal
PT Adrenogenital syndrome
PT Adrenoleukodystrophy
PT Adrenomegaly
PT Benign neoplasm of adrenal gland
PT Catecholamine crisis
PT Congenital adrenal gland hypoplasia
PT Congenital anomaly of adrenal gland
PT Cortisol deficiency
PT Cushingoid
PT Cushing's syndrome
PT Familial glucocorticoid deficiency
PT Glucocorticoid deficiency
PT Haemorrhagic adrenal infarction
PT Hyperadrenalism
PT Hyperadrenocorticism
PT Hyperaldosteronism
PT Hypercorticoidism
PT Hypoaldosteronism
PT Metastases to adrenals
PT Mineralocorticoid deficiency


Statistical Analysis Plan
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Page: 47 of 48
Reference Number: RD-OI-0119
Supplement Version: 8
PT Myelolipoma
PT Primary adrenal insufficiency
PT Primary hyperaldosteronism
PT Pseudohypoaldosteronism
PT Secondary adrenocortical insufficiency
PT Secondary aldosteronism
PT Steroid withdrawal syndrome
PT Triple A syndrome
9
Cutaneous sarcomas 
PT selection:
PT: Dermatofibrosarcoma protuberans
PT: Atypical fibroxanthoma
PT: Leiomyosarcoma
PT: Liposarcoma
PT: Skin angiosarcoma
PT: Kaposi´s sarcoma
PT: Malignant fibrous histiocytoma
PT: Soft tissue sarcoma
Appendix 4: Mapping of MP icons to MBL volume (mL)
Sanitary product
Menstrual spot shape
Menstrual blood loss (mL)
always Ultra normal
Towel pictogram a
0.79
Towel pictogram b
1.51
Towel pictogram c
3.08
Towel pictogram d
4.64
Towel pictogram e
6.75
Towel pictogram f
11.91
always Ultra night
Towel pictogram a
0.74
Towel pictogram b
2.2
Towel pictogram c
4.21
Towel pictogram d
6.84
Towel pictogram e
9.42
Towel pictogram f
15.2
always Ultra long
Towel pictogram a
1.36
Towel pictogram b
1.89
Towel pictogram c
3.68
Towel pictogram d
6.12
Towel pictogram e
8.69
Towel pictogram f
13.41
Other Towel
Towel pictogram a
2.29
Towel pictogram b
2.84
Towel pictogram c
3.29
Towel pictogram d
7.46
Towel pictogram e
15.18
Towel pictogram f
20.12
o.b. Pro Comfort light
Tampon pictogram a
0.16
Tampon pictogram b
0.55
Tampon pictogram c
1.19
Tampon pictogram d
2.98
o.b. Pro Comfort regular
Tampon pictogram a
0.35
Tampon pictogram b
1.31
Tampon pictogram c
2.09
Tampon pictogram d
5.66


Statistical Analysis Plan
Protocol No.: BAY 1002670/16953
Page: 48 of 48
Reference Number: RD-OI-0119
Supplement Version: 8
Sanitary product
Menstrual spot shape
Menstrual blood loss (mL)
o.b. Pro Comfort super
Tampon pictogram a
1.29
Tampon pictogram b
1.87
Tampon pictogram c
3.49
Tampon pictogram d
9.37
o.b. Pro Comfort super plus
Tampon pictogram a
1.34
Tampon pictogram b
3.36
Tampon pictogram c
5.81
Tampon pictogram d
12.23
Tampax light
Tampon pictogram a
1.24
Tampon pictogram b
1.52
Tampon pictogram c
1.73
Tampon pictogram d
3.1
Tampax regular
Tampon pictogram a
0.63
Tampon pictogram b
1.58
Tampon pictogram c
2.2
Tampon pictogram d
5.62
Tampax super
Tampon pictogram a
1.29
Tampon pictogram b
2.38
Tampon pictogram c
4.01
Tampon pictogram d
7.76
Tampax super plus
Tampon pictogram a
1.2
Tampon pictogram b
2.56
Tampon pictogram c
4.98
Tampon pictogram d
9.49
Other Tampon
Tampon pictogram a
3.55
Tampon pictogram b
4.33
Tampon pictogram c
6.25
Tampon pictogram d
8.3