Clinical trial NCT03573336
Conditions: Endometriosis
Sponsor: Bayer
Start date: 2018-07-04; Completion date: 2020-11-26
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study was to assess the efficacy and safety of two doses of vilaprisan compared to placebo in women with symptomatic endometriosis.

The secondary objective of this study was to evaluate the safety and tolerability of two different doses of vilaprisan in women with symptomatic endometriosis.

With the implementation of protocol version 4.0 dated 11-Dec-2018, no new subjects were enrolled. The objectives above cannot be reached as only limited data is available from subjects recruited before the temporary pause.

Detailed description:

Arms: arm 1: Premenopausal women 18 years and older with endometriosis with randomized ratio = 1:1:1 Vilaprisan: 2 mg arm 2: Premenopausal women 18 years and older with endometriosis with randomized ratio = 1:1:1 Vilaprisan: 4 mg arm 3: Premenopausal women 18 years and older with endometriosis with randomized ratio = 1:1:1
Interventions: intervention 1: Vilaprisan (BAY1002670) intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Intake orally, once daily intervention 2: Intake orally, once daily

Protocol documents:
Prot_001.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A randomized, double-blind, parallel-group, multicenter Phase 2b 
study to assess the efficacy and safety of two different doses of 
vilaprisan (BAY1002670) versus placebo in women with 
symptomatic endometriosis 
NCT Number: 
NCT03573336 
Document Date: 
17 FEB 2020 
 


Global Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
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Cover page of the integrated protocol
A randomized, double-blind, parallel-group, multicenter Phase 2b study to assess the 
efficacy and safety of two different doses of vilaprisan (BAY 1002670) versus placebo 
in women with symptomatic endometriosis
This protocol version is an integration of the following documents / sections:

Amendment 09 (global amendment described in Section 15.6 and the Protocol 
Amendment Summary of Changes Table)
forming integrated protocol Version 7.0, dated 17 FEB 2020

Amendment 08 global amendment described in Section 15.5
forming integrated protocol Version 6.0, dated 28 NOV 2019

Amendment 07 (global amendment described in Section 15.4)
forming integrated protocol Version 5.0, dated 19 NOV 2019

Amendment 06 (global amendment described in Section 15.3)
forming global stand-alone amendment Version 4.0, dated 11 DEC 2018 

Amendment 03 (global amendment described in Section 15.2)
forming integrated protocol Version 3.0, dated 26 JUN 2018

Amendment 02 (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 20 MAR 2018

Original protocol, Version 1.0, dated 06 DEC 2017
Local amendments not included in this integrated global protocol:

Amendment 05 (dated 06 NOV 2018)
local amendment, valid for Germany only

Amendment 04 (dated 27 AUG 2018)
local amendment, valid for Japan only

Amendment 01 (dated 19 DEC 2017)
local amendment, valid for South Africa only


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Version 7.0
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1.
Title page
A randomized, double-blind, parallel-group, multicenter Phase 2b study to assess the 
efficacy and safety of two different doses of vilaprisan (BAY 1002670) versus placebo in 
women with symptomatic endometriosis
Short title:  Assess safety and efficacy of vilaprisan in subjects with endometriosis
Acronym:  VILLENDO
Test drug:
BAY 1002670  / Vilaprisan
Study purpose:
Dose finding, safety
Clinical study phase:
2b 
Date:
17 FEB 2020    
EudraCT no.:
2013-004768-72
Version 
7.0
Study no.:
BAY 1002670 / 15792    
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory:  Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, United States 
Geographical scope of 
amendment:
Global
Medical Monitor Name and Contact Information will be provided separately
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) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.


PPD
PPD


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Signature of the investigator
The signatory agrees to the content of the final protocol amendment 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
Title
A randomized, double-blind, parallel-group, multicenter Phase 2b study to 
assess the efficacy and safety of two different doses of vilaprisan (BAY 
1002670) versus placebo in women with symptomatic endometriosis 
Short title
Assess safety and efficacy of vilaprisan in subjects with endometriosis 
Acronym
VILLENDO
Clinical study phase
2b 
Study objective(s)
Primary objective:

assess efficacy of  two doses of vilaprisan compared to placebo in 
women with symptomatic endometriosis 
Secondary objective:

evaluate the safety and tolerability of two different doses of 
vilaprisan in women with symptomatic endometriosis 
Exploratory objective:

explore efficacy and safety in sub-populations (e.g. subjects with 
endometriosis diagnosed by imaging vs subjects with surgically 
confirmed endometriosis) 
Other objectives:

evaluate the variability in exposure in relation to the efficacy and 
safety for vilaprisan in subjects with symptomatic endometriosis 

confirm psychometric properties of the newly developed Patient-
Reported Outcomes (PRO) instruments: Endometriosis Symptom 
Diary (ESD v8.0a) and Endometriosis Impact Scale (EIS v5.0) 
(will be analyzed and reported separately) 

evaluate biomarkers to investigate the drug (i.e. mode-of-action-
related effect and / or safety) and / or the pathomechanism of the 
disease including assessments of exploratory biomarkers to 
investigate disease activity 
With the implementation of Protocol Amendment 7, no new subjects will 
be enrolled. The objectives above cannot be reached as only limited data is 
available from subjects recruited before the temporary pause. Safety 
evaluations, including the added safety evaluations of the endometrium, 
adrenal glands, and skin may add to the understanding of the safety of 
vilaprisan.
Test drug(s)
Not any longer applicable due to the closing of the clinical study. With the 
implementation of Protocol Amendment no. 7 and aligned with the 
previous temporary pause measures, no new subjects will be recruited and 
no study medication will be given to the subjects who have been enrolled 
in the study. Originally, the information and instructions related to the 
                                                
a Currently version 8.1 of the ESD is in use


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test drug were the following:
Vilaprisan  
Name of active ingredient
Vilaprisan (BAY 1002670) 
Dose(s)
2 mg or 4 mg once daily 
Route of administration
Oral 
Duration of treatment
Treatment Group 1: 2 mg
Dose-finding phase: 1 treatment period of 24 weeks
Safety extension phase: 1 treatment period of 24 weeks
The two treatment periods will be separated by a drug-free interval 
encompassing 2 bleeding episodes
Treatment Group 2: 4 mg
Dose-finding phase: 1 treatment period of 24 weeks
Safety extension phase: 1 treatment period of 24 weeks
The two treatment periods are to be separated by a drug-free interval 
encompassing 2 bleeding episodes
Reference drug 
Not any longer applicable due to the closing of the clinical study. With the 
implementation of Protocol Amendment no. 7 no new subjects will be 
recruited and no study medication 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:
Matching Placebo 
Name of active ingredient
Not applicable 
Dose(s)
Not applicable, once daily 
Route of administration
Oral 
Duration of treatment
Treatment Group 3
Dose-finding phase: 1 treatment period of 24 weeks
Safety extension phase: 1 treatment period of 24 weeks
The two treatment periods are to be separated by a drug-free interval 
encompassing 2 bleeding episodes
Indication
Endometriosis 
Diagnosis and main criteria 
for inclusion /exclusion
With the implementation of Protocol Amendment no. 7 no new subjects 
will be enrolled in the study.
Originally, the study population had to fulfill the following criteria:
Premenopausal women 18 years and older with endometriosis confirmed by 
laparoscopy or laparotomy within 10 years but not less than 8 weeks before 
Visit 1. 
Expansion cohort: endometriosis diagnosed by imaging (i.e. endometriotic 
lesion(s) detected by transvaginal ultrasound [TVU] or magnetic resonance 


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imaging [MRI]) is acceptable. If the endometriosis was diagnosed by TVU, the 
lesion needs to be visualized by TVU also at the Visit 1. If the endometriosis 
was diagnosed by MRI, the diagnosis must have been made within 12 months 
before Visit 1. 
Moderate to severe endometriosis-associated pelvic pain (EAPP) of ≥4 in last 
28 days before Visit 1 measured on the Numerical Rating Scale (NRS, 4 week 
recall period). 
At randomization: subject must demonstrate adherence to the study procedures 
during the screening period, i.e. at least 24 diary entries of ESD item 1 are 
required during the first 28 consecutive days after the screening visit (Visit 1), 
and an average score of the available ESD item 1 (‘worst pain’ on the daily 
NRS) entries during this period must be ≥ 3.5 (corresponding to a sum score of 
at least 84 (by 24 diary entries) or 98 (by 28 diary entries). 
Otherwise women should be in good general health. 
Study design
Multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study.
Study will consist of a screening period, a placebo-controlled dose-finding 
phase, followed by a drug-free interval encompassing 2 menstrual bleeding 
episodes, a placebo-controlled extension phase, and a follow-up phase.
Methodology
With the implementation of Protocol Amendment no. 7 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 anything in the 
electronic diary (eDiary). 
Any subjects who have taken at least one dose of study medication
vilaprisan (including the subjects who prematurely terminated the study) 
will be asked to undergo a DEXA scan and the safety evaluation 
procedures described in this document. 
At their safety closeout visit they are not any more asked to complete the 
PRO questionnaire(s) on the tablet computer at the site.
OLD WORDING VALID prior to the temporary pause:
Efficacy:
- Patient-Reported Outcomes (PROs):

Endometriosis Symptom Diary 

Endometriosis Impact Scale 

Visual Analogue Scale for EAPP (VAS for EAPP, 4 week recall 
period)

Patient Global Impression of Severity (PGI-S)

Patient Global Impression of Change (PGI-C)

Short-Form Health Survey with 36 questions, version 2.0 (SF-36v2)

European Quality of Life 5 dimension 5 Level Scale (EQ-5D-5L)
- Clinician-Reported Outcomes (ClinROs):

Clinical Global Impression assessed by Investigator (CGI-S and CGI-
C)

Modified Biberoglu & Behrman (B&B) severity profile for pelvic 
symptoms and findings
- Treatment compliance 


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Safety:

Standard screening examination including medical history, physical 
and gynecological examination (including breast palpation), vital 
signs including blood pressure, pulse rate, body weight, height and 
body mass index (BMI)

Blood/urine laboratory parameters including hematology, clotting 
status, clinical chemistry, hormones, bone markers. Liver parameters 
will be monitored monthly during treatment.

Adverse events

Endometrial histology

Cervical cytology

Transvaginal ultrasound for endometrial thickness and 
endometrial/myometrial/ovarian changes

Bone mineral density
Pharmacokinetics:

The (population) pharmacokinetics (PK) and the effect of intrinsic and 
extrinsic factors on the variability in exposure will be assessed by 
population PK analysis using sparse vilaprisan concentration samples
Type of control
Not any longer applicable as with the implementation of Protocol 
Amendment no. 7 no new subjects will be recruited and no study 
medication will be given to the subjects who have been enrolled in the 
study
Placebo 
Number of subjects
With the implementation of Protocol Amendment no. 7 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 
vilaprisan (including the subjects who prematurely terminated the study) 
will be asked to undergo a DEXA scan and the safety evaluation
procedures described in this document. 
Originally, a total of 315 subjects were planned to be randomized, which 
includes: 

At least 210 subjects with surgically diagnosed endometriosis from all 
countries except for China / Taiwan for primary efficacy analysis

An expansion cohort of up to 105 subjects with endometriosis 
diagnosed by imaging,
Countries / regions: US/Canada, Europe, Japan, China/Taiwan,
Subjects were planned to be randomized in ratio 1:1:1 to one of the treatment 
groups described above. 
Primary variable(s)
Change in the subject’s 7-day mean ‘worst pain’ from baseline to Month 3 of 
the first 24-week treatment period measured on a daily NRS. 
The subject’s 7-day mean ‘worst pain’ will be calculated for consecutive 28 
days intervals using the sum of the subject’s 7 ‘worst’ daily assessments of the 
ESD item 1 (“worst pain” during the last 24 hours) divided by 7. For baseline, 
the first 28 consecutive days after the screening visit (Visit 1) will be 
considered and for the Month 3 evaluation, the 3rd 28 days after start of 
treatment (usually Day 57 to 84). 


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Time point/frame of 
measurement for primary 
variable(s)
Baseline to Month 3, 3rd 28 days after start of treatment 
Plan for statistical analysis
All data will be presented in the subject data listing as they are recorded. 


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Protocol Amendment Summary of Changes Table
Amendment no. 9 (17 FEB 2020)
Overall Rationale for this Protocol Amendment
Recently Bayer received comments from FDA regarding details of the safety follow-up 
measures introduced in the protocol amendments 7 and 8. The current amendment (protocol 
amendment 9, version 7.0) implements these FDA recommendations. 
Protocol Amendment Summary of Changes Table for the Protocol Amendment no. 9
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 Procedures 
and variables, 
9.6.3.5 Physical 
and gyneco-
logical 
examinations
Adjusted text and deleted footnote to 
“Physical examination” as this needs to be 
performed in all subjects.
To address FDA requests
9.6.3.3 
Laboratory 
evaluations
Revised the interval for blood sampling in 
after intake of high doses of biotin from 8 to  
72 hours.
To address FDA requests
6.3.8.3 
Laboratory 
testing
Text was adjusted to trigger an assessment 
by one of the external adrenal panel experts 
in case tT level >150 ng/dL
To address FDA requests


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Short summary for sites:
With the implementation of Protocol Amendment no. 7 no new subjects will be enrolled in 
the study and no subjects will re-start treatment. All subjects who were randomized and 
started treatment with vilaprisan before the temporary pause will be asked to have the 
comprehensive safety evaluation (with particular focus on endometrial, adrenal, bone and skin 
safety) performed, which is implemented with Protocol Amendment no. 7. This applies also 
to subjects who have discontinued the study before or during the temporary pause, provided 
they have taken at least one dose of vilaprisan. 
All these subjects are asked to come to the site for the “Safety Closeout Visit” which is 
implemented with Protocol Amendment no. 7. 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:

Re-consenting 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 cytology

Urine pregnancy test

Ultrasound examination 

Endometrial biopsy  (in case a valid post-treatment biopsy is not already available)

Laboratory (blood sampling)

DEXA scan measurement for bone mineral density

Collection of unused study drug and empty drug packs/drug accountability, if 
applicable 

Collection of eDiary device

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 Protocol Amendment no. 7. 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 
counseled about medical follow up according to local practice.


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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 documents.
For subjects who received placebo treatment prior to the temporary pause, no further 
procedures are required except for the collection of eDiary device and deactivation of the 
subject on the tablet computer.


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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 the investigator ................................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Protocol Amendment Summary of Changes Table............................................................. 10
Table of contents..................................................................................................................... 13
Table of tables......................................................................................................................... 16
Table of figures....................................................................................................................... 16
List of abbreviations............................................................................................................... 17
Definitions of terms ................................................................................................................ 20
3.
Introduction..................................................................................................................... 21
4.
Study objectives............................................................................................................... 24
5.
Study design..................................................................................................................... 26
6.
Study population ............................................................................................................. 32
6.1
Eligibility ....................................................................................................................... 32
6.2
Inclusion criteria ............................................................................................................ 32
6.3
Exclusion criteria ........................................................................................................... 33
6.4
Justification of selection criteria.................................................................................... 36
6.5
Withdrawal of subjects from study................................................................................ 36
6.5.1
Withdrawal ................................................................................................................. 36
6.5.2
Replacement ............................................................................................................... 37
6.6
Subject identification ..................................................................................................... 37
7.
Treatments....................................................................................................................... 38
7.1
Treatments to be administered....................................................................................... 38
7.1.1
Start and end of study treatment................................................................................. 38
7.1.2
Missed intake of study drug ....................................................................................... 39
7.1.3
Rescue pain medication.............................................................................................. 39
7.1.4
Other pain medication ................................................................................................ 40
7.1.5
Diet ............................................................................................................................. 40
7.2
Identity of study treatment............................................................................................. 40
7.3
Treatment assignment.................................................................................................... 41
7.4
Dosage and administration............................................................................................. 41
7.5
Blinding ......................................................................................................................... 41
7.5.1
Blinding measures ...................................................................................................... 42
7.5.2
Unblinding.................................................................................................................. 42
7.5.3
Emergency unblinding by the investigator................................................................. 42
7.6
Drug logistics and accountability................................................................................... 42


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7.7
Treatment compliance.................................................................................................... 42
8.
Non-study therapy........................................................................................................... 43
8.1
Prior and concomitant therapy....................................................................................... 43
8.1.1
Progestin therapy for induction of bleeding ............................................................... 43
8.2
Post-study therapy.......................................................................................................... 43
9.
Procedures and variables ............................................................................................... 44
9.1
Tabular schedule of evaluations .................................................................................... 44
9.2
Visit description............................................................................................................. 46
9.2.1
Unscheduled visits...................................................................................................... 46
9.2.2
Optional pre-screening phone contact........................................................................ 46
9.2.3
Scheduled visits.......................................................................................................... 46
9.3
Population characteristics .............................................................................................. 46
9.3.1
Demographic .............................................................................................................. 46
9.3.2
Medical history........................................................................................................... 46
9.3.3
Reproductive, menstrual, and endometriosis history.................................................. 47
9.4
Efficacy.......................................................................................................................... 47
9.4.1
Patient-reported outcomes.......................................................................................... 47
9.4.1.1
Endometriosis Symptom Diary (ESD).................................................................... 47
9.4.1.2
Endometriosis Impact Scale (EIS) .......................................................................... 47
9.4.1.3
Numeric Rating Scale (NRS) for EAPP.................................................................. 48
9.4.1.4
Visual Analogue Scale (VAS) for EAPP ................................................................ 48
9.4.1.5
Patient Global Impression of Severity (PGI-S)....................................................... 48
9.4.1.6
Patient Global Impression of Change (PGI-C) ....................................................... 48
9.4.1.7
EQ-5D-5L................................................................................................................ 48
9.4.1.8
Short Form 36 Health Survey Version 2 (SF-36v2) ............................................... 49
9.4.2
Clinician-Reported Outcomes (ClinROs)................................................................... 49
9.4.2.1
Clinical Global Impression of Change and Severity (CGI-C and CGI-S) .............. 49
9.4.2.2
Modified Biberoglu and Behrman severity profile for symptoms and findings ..... 49
9.4.3
Ultrasound (efficacy) to assess endometriosis lesions ............................................... 49
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 50
9.5.1
Drug measurements.................................................................................................... 50
9.5.2
Population pharmacokinetic analysis of vilaprisan .................................................... 50
9.5.3
Pharmacokinetic/pharmacodynamic relationship....................................................... 51
9.6
Safety ............................................................................................................................. 51
9.6.1
Adverse events............................................................................................................ 51
9.6.1.1
Definitions............................................................................................................... 51
9.6.1.2
Classifications for adverse event assessment.......................................................... 53
9.6.1.3
Assessments and documentation of adverse events ................................................ 55
9.6.1.4
Reporting of serious adverse events ........................................................................ 55
9.6.1.5
Expected adverse events.......................................................................................... 56
9.6.1.6
Adverse events of special safety interest................................................................. 56
9.6.2
Pregnancies................................................................................................................. 58
9.6.3
Further safety.............................................................................................................. 60
9.6.3.1
Endometrial biopsies............................................................................................... 60
9.6.3.2
Bone mineral density............................................................................................... 66
9.6.3.3
Laboratory evaluations............................................................................................ 68
9.6.3.4
Cervical cytology .................................................................................................... 69


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9.6.3.5
Physical and gynecological examinations............................................................... 69
9.6.3.6
Ultrasound............................................................................................................... 70
9.6.3.7
Vital signs, weight, and height................................................................................ 70
9.6.3.8
Adrenal monitoring ................................................................................................. 70
9.6.3.9
Liver monitoring ..................................................................................................... 74
9.6.3.10
Skin monitoring....................................................................................................... 75
9.6.3.11
Reporting of medical device failures (Japan only).................................................. 75
9.7
Other procedures and variables...................................................................................... 75
9.7.1
Induction of bleeding.................................................................................................. 75
9.7.2
Histology of endometriotic lesion .............................................................................. 76
9.7.3
Monitoring of ovarian cysts........................................................................................ 76
9.7.4
Biomarker investigation ............................................................................................. 76
9.8
Appropriateness of procedures / measurements ............................................................ 77
10. Statistical methods and determination of sample size ................................................. 77
10.1
General considerations................................................................................................... 77
10.2
Analysis sets .................................................................................................................. 77
10.3
Variables and planned statistical analyses..................................................................... 77
10.3.1
Variables..................................................................................................................... 77
10.3.1.1
Efficacy variable ..................................................................................................... 77
10.3.1.2
Pharmacokinetics (PK)............................................................................................ 77
10.3.1.3
Safety variables ....................................................................................................... 77
10.3.2
Statistical and analytical plans.................................................................................... 78
10.4
Determination of sample size......................................................................................... 78
10.5
Planned interim analyses ............................................................................................... 79
11. Data handling and quality assurance............................................................................ 79
11.1
Data recording................................................................................................................ 79
11.2
Monitoring ..................................................................................................................... 81
11.3
Data processing.............................................................................................................. 81
11.4
Audit and inspection ...................................................................................................... 82
11.5
Missing data................................................................................................................... 82
11.6
Archiving ....................................................................................................................... 82
12. Premature termination of the study .............................................................................. 83
13. Ethical and legal aspects................................................................................................. 83
13.1
Investigator(s) and other study personnel...................................................................... 83
13.2
Funding and financial disclosure ................................................................................... 84
13.3
Ethical and legal conduct of the study........................................................................... 84
13.4
Subject information and consent.................................................................................... 85
13.5
Publication policy and use of data ................................................................................. 86
13.6
Compensation for health damage of subjects / insurance.............................................. 86
13.7
Confidentiality ............................................................................................................... 86
14. Reference list.................................................................................................................... 87
15. Protocol amendments...................................................................................................... 87
15.1
Overview of changes of AMD 2 triggered by Health Authority feedback.................... 87
15.2
Overview of changes of AMD 3 triggered by FDA recommendation........................... 90
15.3
Overview of changes of AMD 6 triggered by FDA recommendation........................... 94


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15.4
Overview of changes of AMD 7 to prepare this study for an orderly closure............... 95
15.5
Overview of changes of AMD 8.................................................................................... 98
15.6
Overview of changes of AMD 9.................................................................................... 98
16. Appendices....................................................................................................................... 99
16.1
CYP3A4 inhibitors ........................................................................................................ 99
16.2
CYP3A4 inducers .......................................................................................................... 99
Table of tables
Table 7–1: Identity of test drug/vilaprisan tablets and matching placebo................................ 41
Table 9–1: Schedule of procedures .......................................................................................... 45
Table 15–1:
Proposed update of the design of the Villendo study (Treatment Period 1)..... 88
Table 15–2:
Proposed update of the design of the Villendo study (Treatment Period 2)..... 88
Table 16–1:
Strong CYP3A4 inhibitors................................................................................ 99
Table 16–2:
Strong CYP3A4 inducers ................................................................................. 99
Table of figures
Figure 5–1: Study Design......................................................................................................... 26
Figure 9–1: Overview of the endometrial safety monitoring algorithm .................................. 61
Figure 9–2: Adrenal monitoring algorithm .............................................................................. 72


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List of abbreviations
25(OH)D
25-hydroxyvitamin D 
ACTH
Adrenocorticotropic hormone
AE
Adverse event
AESI
AEs of special interest
ALP/AP
Alkaline phosphatase
ALT
Alanine aminotransferase (also known as GPT)
AMD
Amendment
AP
Alkaline phosphatase
ASCUS
Atypical squamous cells of undetermined significance
AST
Aspartate aminotransferase (also known as GOT)
ASTEROID
Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids (studies)
AT
Aminotransferase (ALT or AST)
B&B
Biberoglu & Behrman severity profile for pelvic symptoms and findings
BM
Biomarker
BMD
Bone mineral density
BMI
Body mass index
CD
Compact disk
CDISC
Combined Data Interchange Standard Consortium 
CGI-C 
Clinical Global Impression (assessed by investigator) of Change 
CGI-S
Clinical Global Impression (assessed by investigator) of Severity
ClinRO
Clinician-Reported Outcome
COC
Combined oral contraceptive
CRF
Case report form
CRO
Clinical research organization
CSP
Clinical Study Protocol
CT
Computed tomography
CYP3A4
Cytochrome P450 enzyme 3A4
DHEA-S
Dehydroepiandrosterone sulfate
DEXA
Dual-energy X-ray absorptiometry
DYS
Dysmenorrhea 
EAPP
Endometriosis-associated pelvic pain
eCRF
Electronic case report form
EDC
Electronic data capture
e.g.
exempli gratia, for example
EIN
Endometrial intraepithelial neoplasia
EIS 
Endometriosis Impact Scale 
EMA
European Medicines Agency
EoT
End of treatment
ePRO
Electronic Patient-Reported Outcome (device)
EQ-5D-5L
European Quality of Life 5 dimension 5 Level Scale
ESD 
Endometriosis Symptom Diary 
EU
European Union


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FAS
Full analysis set
FDA
United States Food and Drug Administration
FUP
Follow up
GCP
Good Clinical Practice
-GT
Gamma-glutamyl transpeptidase
GMP
Good Manufacturing Practice
GnRH-a
Gonadotropin-releasing hormone agonists
GOT
Glutamic oxaloacetic transaminase
GPT
Glutamic pyruvic transaminase
HA
Health Authority
HAV
Hepatitis-A-Virus
Hb
Hemoglobin
HBs-Ag
Hepatitis-B-Virus surface antigen
HCV
Hepatitis-C-Virus
HMB
Heavy menstrual bleeding
HPA
Hypothalamic-pituitary-adrenal axis
HPV
Human papilloma virus
HRQoL
Health-related quality of life 
IB
Investigator’s brochure
ICH-GCP
International Conference on Harmonization- Good Clinical Practice
i.e.
id est, that is
IEC
Institutional Ethics Committees
Ig
Immunoglobulin
IME
Important medical event
INN
International nonproprietary name
INR
International normalized ratio 
IRB
Institutional Review Boards 
IU
International unit
IVRS/IWRS 
Interactive Voice Response System / Interactive Web Response System 
M&S
Modeling and Simulation 
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
g
Microgram
mRNA
Messenger RNA
MRI
Magnetic resonance imaging
NASH
Nonalcoholic steatohepatitis
NMPP
Non-menstrual pelvis pain
NRS
Numerical Rating Scale
PAEC
Progesterone receptor modulator-associated endometrial changes
PD
Pharmacodynamic(s)
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetic(s)
PR (A; B)
Progesterone receptor (A; B)
PPS
Per protocol set


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PRM
Progesterone receptor modulator
PRO
Patient-Reported Outcome
QA
Quality Assurance
QC
Quality control
RAVE
electronic data capturing system
RNA
Ribonucleic acid
ROC
Receiver operating characteristic
ROW
Rest of world
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
Standard deviation
SDTM-QS
Study Data Tabulation Model Questionnaire domain
SF-36v2
Short-Form health survey with 36 questions, version 2
SID
Subject identification (number)
SUSAR
Suspected, unexpected serious adverse reaction
TP
Treatment period
TSH
Thyroid-stimulating hormone
tT
Total testosterone
TVU
Transvaginal ultrasound
ULN
Upper limit of normal
UPA
Ulipristal acetate
US
United States (of America)
ULN
Upper limit of normal
VAS
Visual Analogue Scale
VPR
Vilaprisan
WHO
World Health Organization
WHO-DD ATC
WHO Drug Dictionary anatomical-therapeutic-chemical (classification system)


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Definitions of terms
6/2 regimen
6 months (i.e., 6 x 28 days) of treatment with 2 bleeding episodes between 
treatment periods
month
equals 28 days when referring to treatment (i.e., 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 no. 7 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 vilaprisan (including the subjects who prematurely terminated
the study) will be asked to undergo a DEXA scan and the safety procedures described in this 
protocol amendment, as applicable.  
Based on findings in preclinical carcinogenicity studies in rats and mice all vilaprisan clinical 
studies were temporarily paused since December 2018 (refer to Protocol Amendment no. 6). 
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 and 50 times the 
human therapeutic doses of 2 mg and 4 mg, respectively. 
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018. Bayer performed a thorough evaluation of these preclinical findings 
and their potential relevance to humans. 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 vilaprisan Investigator’s Brochure [IB] version 11.0 including the 
associated amendment and Introduction section), Bayer decided to not re-start drug treatment. 
Instead, Bayer will conduct a comprehensive safety follow up to provide additional 
confirmatory evidence. Subsequently, all clinical studies with vilaprisan will be closed.
Protocol Amendment no. 7 introduces measures and processes to prepare this study for an 
orderly closure, including safety follow up measures in all study participants who received at 
least one dose of study drug vilaprisan.
Protocol Amendment no. 7 introduces an endometrial, adrenal, and skin safety evaluation 
with the aim to confirm that the carcinogenicity study findings do 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 collected safety 
data will be thoroughly evaluated in addition to the already collected efficacy data (applicable  
for the uterine fibroids indication only).
Further detailed information and assessment of the carcinogenicity study findings are 
described below and also in the current version (V 11.0 including the associated amendment)
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 


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significance at the high dose of 60 mg/kg in female mice only. This corresponds to 50 fold of 
the daily dose of 4 mg and 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 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 within the special setting of 
the carcinogenicity studies. 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 doses of 2 or 4 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 studies 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.

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 


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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 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 participants 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 evaluation 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 participants who took at least one dose of vilaprisan in any of the 
currently paused clinical studies will also 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 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.


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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 
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.
With the implementation of Protocol Amendment no. 7 no new subjects will be enrolled in 
the study. Since only limited data is available from subjects enrolled before the temporary 
pause (8 out of the planned 315), no statistical analysis will be performed for this study. Data 
collected so far from subjects who received placebo treatment will not be analyzed. Therefore, 
further unnecessary invasive procedures of the safety evaluation in these subjects are not 
justified for ethical reasons. 
In conclusion, only subjects who have taken at least one dose of vilaprisan (including the 
subjects who prematurely terminated the study) will be asked to undergo the safety 
procedures described in this protocol amendment. The safety data of vilaprisan treated 
patients including the added safety evaluations of the endometrium, adrenal glands, and skin 
may add to the understanding of the safety of 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 studies a dose-dependent 
ovulation inhibition and induction of amenorrhea in healthy women. Based on the Phase 1 
data vilaprisan was expected to provide efficacy in reducing endometriosis associated pelvic 
pain and to improve the negative impact endometriosis has on subjects’ daily life.
4.
Study objectives
Primary objective:

assess efficacy of two doses of vilaprisan compared to placebo in women with 
symptomatic endometriosis.
Secondary objective:

evaluate the safety and tolerability of two different doses of vilaprisan in women 
with symptomatic endometriosis.
Exploratory objective:

explore efficacy and safety in sub-populations (e.g. subjects with endometriosis 
diagnosed by imaging vs subjects with surgically confirmed endometriosis).
Other objectives:

evaluate the variability in exposure in relation to the efficacy and safety for 
vilaprisan in subjects with symptomatic endometriosis.


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
confirm psychometric properties of the newly developed Patient-Reported 
Outcomes (PRO) instruments: Endometriosis Symptom Diary (ESD) and 
Endometriosis Impact Scale (EIS) (will be analyzed and reported separately).

evaluate biomarkers to investigate the drug (i.e. mode-of-action-related effect and / 
or safety) and / or the pathomechanism of the disease including assessments of 
exploratory biomarkers to investigate disease activity.
With the implementation of Protocol Amendment no. 7 no further recruitment is possible. 
With the data available from subjects recruited before the temporary pause the objectives 
above cannot be reached. Safety evaluations including the added safety evaluations of the 
endometrium, adrenal glands, bone, and skin may add to the understanding of the safety of 
vilaprisan.


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5.
Study design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
The study originally includes the following phases: a screening phase, a placebo-controlled 
dose-finding phase, followed by a drug-free interval encompassing 2 menstrual bleeding 
episodes2, a placebo-controlled extension phase, and a follow-up phase.
Endometriosis symptoms and their impact on subjects’ daily life was to be documented 
throughout the study, i.e. from start of the screening until the follow-up phase. 
With the implementation of Protocol Amendment no. 7, this study design is no longer 
valid. No subjects will receive further study drug treatment. 
Study design valid with the implementation of Protocol Amendment no. 7: 
The study was temporarily paused since December 2018. With the implementation of 
Protocol Amendment no. 7 no further subjects will be recruited and none of the enrolled 
subjects will receive further study drug treatment. All subjects who were randomized and 
started vilaprisan before the temporary pause will be asked to have a comprehensive safety 
evaluation (with particular focus on endometrial, adrenal, and skin safety) performed, which 
is implemented with Protocol Amendment no. 7. This also applies to subjects who have 
discontinued the study before or during the temporary pause, provided they have taken at least 
one dose of vilaprisan.
Figure 5–1 displays an overview of the original study design.  
Figure 5–1: Study Design
                                                
2 i.e, a 6 months treatment period followed by a drug-free interval encompassing 2 menstrual bleeding episodes 
(6/2 regimen)


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Screening phase
Subjects who fulfilled the eligibility criteria entered the screening phase of at least 28 days 
after the Screening visit (Visit 1) and up to a maximum of 75 days to collect complete results 
of all screening assessments. 
Immediately after Visit 1, subjects started to document their endometriosis symptoms and the 
impact of the symptoms on their lives in the Endometriosis Symptom Diary (ESD; 24-hour 
recall period) and the Endometriosis Impact Scale (EIS; 7-day recall period). During the 
screening period, the subjects stayed on their individual endometriosis treatment; if this was 
allowed according to the protocol until stopping it for a withdrawal bleeding prior to the 
randomization visit (see Section 7.1.1).  The use of rescue analgesics was standardized (see 
Section 7.1.3).  All other analgesics for the treatment of endometriosis symptoms were
stopped at Visit 1. Use of prophylactic analgesics during the screening phase (and throughout 
the study) was explicitly discouraged.  
If subject required a wash out period from prior hormonal treatment with drugs or devices not 
allowed for the study (e.g. long-acting hormonal contraception, contraceptive device, PRM, 
GnRH-a, see Section 7.1.1), the occurrence of normal menses before the screening phase was 
to be documented in the subject’s source documents. All subjects who stopped their hormonal 
contraceptives prior to Visit 3 needed to use a non-hormonal method of contraception starting 
from the time of discontinuation of their contraceptive. 
At the end of the screening phase, subjects’ eligibility was confirmed and eligible subjects 
were randomized to one of the treatment groups.  
With respect to pain, subjects should have entered the ESD item 1 “worst pain” measured by 
the daily Numerical Rating Scale (NRS) in the hand-held device on at least 24 days of the first 
28 consecutive days after the screening visit (Visit 1) and the average score of the available 
ESD item 1 (‘worst pain’ on the daily NRS) entries during this period were to be ≥ 3.5 
(corresponding to a sum score of at least 84 (by 24 diary entries) or 98 (by 28 diary entries). 
Dose-finding phase
For all subjects, the treatment period consisted of daily tablet intake for 24 weeks (168 days).
At the randomization visit (Visit 3) eligible subjects were randomized equally to one of the 
following treatment groups (see Section 9.1) and received study drug as follows: 

Treatment Group 1: 2 mg vilaprisan tablet once daily orally for 168 days or

Treatment Group 2: 4 mg vilaprisan tablet once daily orally for 168 days or

Treatment Group 3: matching placebo tablet once daily orally for 168 days.
Extension phase
After the first treatment period, there was a drug-free interval encompassing 2 bleeding 
episodes to assess the safety, the persistence of treatment effect, and/or recurrence of 
endometriosis symptoms. 
Starting during the 2nd bleeding episode following the drug-free interval, subjects continued
their respective study treatment for an additional 168 days. 


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Follow-up phase
After the end of study treatment in the extension phase, subjects were planned to be followed 
up for up to 24 weeks.  During the follow-up phase, safety and efficacy parameters were 
planned to be further evaluated, and endometrial biopsies must demonstrate normal or benign 
findings.  If the end of study (EoS) biopsy was abnormal (i.e. hyperplasia or worse), 
additional biopsy(ies) were planned to be scheduled until a normal result would be obtained 
or a clear outcome is given. Abnormal findings were to be followed-up according to standard 
practice.
Subjects who discontinued the study treatment prematurely during a treatment period should 
have the end of treatment (EoT) visit immediately and should return for follow up (FUP)1 
visit; subjects who discontinued the study prematurely during the drug-free interval or the 
post-treatment FUP period before FUP1 should return for the FUP1 visit.
Primary variable
Primary variable
The primary efficacy variable is the change in the subject's 7-day mean ‘worst pain’ from 
baseline to Month 3 measured on a daily NRS (item 1 of the ESD)3. 
Justification of the design
For justification of Protocol Amendment no. 7, see Section 3.
Justification of the original design
Comparators and blinding
A randomized, double-blind, placebo-controlled, parallel-group design was considered 
standard and appropriate to differentiate drug effects from the natural course of disease and 
background findings and to derive valid dose-effect information. The efficacy endpoints of 
this study include pain and other PROs are prone to bias by knowledge of the treatment 
received. Evaluation of such subjective endpoints requires a double-blind setting. Due to a 
high and variable placebo response rate in pain trials it is in principle necessary to show 
superiority to placebo. To minimize subject burden due to randomization to placebo 
treatment, standardized pain medication will be provided throughout the study. Intake of pain 
medication will be clearly documented to allow appropriate analysis. 
Dose and regimen:
Selection of the doses was based on the data of Phase 1 studies in healthy young women and 
Phase 2 in subjects with uterine fibroids (ASTEROID 1 and 2). In summary, exposure-
response analysis of vilaprisan on induced amenorrhea, ovulation inhibition, and on estradiol 
(E2) levels supported the used of 2 mg and 4 mg doses for the study because 

doses < 2 mg/day can be excluded because they do not achieve the desired maximum 
effect on induction of amenorrhea and provide insufficient ovarian suppression. 
                                                
3 3rd 28 days after start of treatment


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
a dose > 2 mg/day may provide additional benefit on endometriosis symptoms which 
could not be detected in the available data generated in healthy women and subjects 
with uterine fibroids. 

an intermediate dose is not proposed because there is a considerable overlap in 
exposure with 2 mg/day and 4 mg/day and thus testing is not expected to provide any 
additional information.
Justification of original regimen:
PRMs are applied either short-term or in an intermittent treatment regimen to minimize or 
avoid endometrial changes that may result in episodes of heavy menstrual bleeding (HMB) 
after cessation of treatment. 
Data from ASTEROID 1 show that efficacy of vilaprisan with regard to HMB is achieved 
rapidly after start of treatment and is maintained during treatment. However, ASTEROID 1 
also shows that symptoms return quickly after cessation of treatment, i.e., there is no relevant 
persistence of treatment effect during the treatment-free interval. This pattern was also 
observed for other efficacy parameters and is reflected in the assessment of health-related 
quality of life (HRQoL) which improves during treatment and slightly drops again during the 
treatment-free phase. 
In the absence of data in endometriosis subjects, it is assumed that, like in uterine fibroids, 
efficacy of long-term (i.e., repeated-intermittent) treatment will be more favorable if treatment 
phases are longer, because this will result in fewer time with endometriosis-associated pelvic 
pain (EAPP) and will reduce the slight drops in HRQoL during the treatment-free phases. 
Therefore, this study intended to investigate a 6/2 regimen (6 month treatment followed by 2 
menstrual bleeding episodes) for long-term, repeated-intermittent treatment with vilaprisan. 
Duration of treatment:
Extension of this dose-finding study with a long-term safety study results in a total treatment 
duration of 12 months was planned. This design was considered justified, because substantial 
amount of safety data from healthy women and those with uterine fibroids, including repeated 
treatment courses, was expected to become available. Furthermore, ongoing medical review 
of study data was conducted to ensure subjects’ safety during the study. In subjects with 
safety findings like suspicious bleeding pattern, increased endometrial thickness or increased 
liver enzymes treatment was interrupted.
Efficacy / pharmacodynamic assessments:
The endometriosis treatment effect is assessed by investigating the change in the key 
symptoms of endometriosis (e.g. worst daily pelvic pain, non-menstrual pelvic pain, 
dysmenorrhea, dyspareunia).  In the absence of biomarkers, and considering the inherently 
subjective nature of the symptoms, this can only be rated appropriately by the subjects 
themselves, using Patient-Reported Outcomes (PROs) which substantiates the clinical 
investigation. 
Ultrasound assessment of endometriosis lesions, hormone levels, and bleeding will be 
determined as pharmacodynamic (PD) parameters.


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Safety monitoring:
Safety parameters were regularly and closely monitored throughout the study (eg, questioning 
for adverse events (AEs), measurement of laboratory values, vital signs, endometrial safety 
monitoring, endometrial thickness, abnormal menstrual bleeding, and size of follicle like 
structures comprising follicles and functional ovarian cysts).  A comprehensive evaluation for 
adrenal tumors and a skin examination are implemented with Protocol Amendment no. 7.
Endometrial monitoring
A careful endometrial safety monitoring assessment was applied in this study from the 
beginning including regular ultrasound investigations, observation of bleeding patterns, and 
endometrial biopsies at defined time points. Clear decision trees are outlined as to when to 
perform an additional unscheduled endometrial biopsy in case of endometrial thickening 
and/or on the clinical management of endometrial thickening/HMB/ suspicious bleeding 
pattern (see Section 9.6.3.1). 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 participants.
With Protocol Amendment no. 7, additional requirements for endometrial safety monitoring
are outlined for subjects who took at least one dose of study medication vilaprisan, see section 
9.6.3.1.2.   
Liver monitoring
A liver-related safety signal was observed with some 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. With this protocol amendment, subjects will receive one further 
laboratory examinations, including liver parameters. 
Adrenal monitoring
A comprehensive adrenal screening program is implemented with Protocol Amendment no. 7. 
This program is described in more detail in Section 9.6.3.8. It encompasses adrenal imaging, 
as well as laboratory tests aimed at identifying overproduction of adrenal cortical hormones in 
the context of tumors of the adrenals. Tumors of the adrenal glands (cortical or medullary in 
origin, benign as well as malignant) are known to occur in a certain frequency in the general 
population, independent of an exposure to the study drug vilaprisan (5). For adrenal tumors 
detected by the screening program in this study, a causal relationship to vilaprisan can 
therefore not be automatically assumed. 
Skin monitoring
In the above-mentioned carcinogenicity study performed in mice, skin sarcomas were found 
at a dose representing about 100 and 50 times the human therapeutic doses of 2 mg and 4 mg, 
respectively. 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. 


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Nevertheless, all study participants who took at least one dose of vilaprisan 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 
Selective PRMs such as vilaprisan induce a degree of ovulation suppression, accompanied by 
a moderate decrease in endogenous estradiol levels. BMD is assessed in this study using 
dual-energy X-ray absorptiometry (DEXA). 
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 scan 
performed at a timepoint at least 22 weeks after last intake of vilaprisan, to document absence 
of bone loss or adequate recovery. 
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. 
Pregnancy
Due to the mode of action of the tested study drug, information on teratogenic potential of 
vilaprisan is limited. Therefore clear instructions with regards to contraceptive methods and 
regular pregnancy testing have been implemented in order to avoid exposure to the study drug 
during pregnancy.
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 last patient last visit (LPLV).
The primary completion date for this study according to the Food and Drug Administration 
Amendment Act is specified in a separate document (not part of this study protocol).


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6.
Study population
No longer valid, since no new subjects will be enrolled in this study with the 
implementation of Protocol Amendment no. 7. 
Originally the study population had to fulfill the following criteria:
6.1
Eligibility
Women with endometriosis presenting with moderate to severe endometriosis-associated 
pelvic pain (EAPP) who meet all inclusion criteria and none of the exclusion criteria will be 
eligible for enrollment to the study.
6.2
Inclusion criteria
The inclusion criteria are as follows:
1.
Signed and dated informed consent 
2.
Age: Pre-menopausal women 18 years (inclusive) and above at the time of Visit 1 
3.
Women with endometriosis confirmed (via direct visualization with or without biopsy) 
by laparoscopy or laparotomy within the last ten years but not less than 8 weeks before 
the Visit 1. 
OR 
Women with endometriosis diagnosed based on imaging (i.e. endometriosis lesion was 
detected by transvaginal ultrasound [TVU] or magnetic resonance imaging [MRI]). If 
the subject was diagnosed by TVU, the lesion needs to be visualized by TVU at the 
screening visit. If the subject was diagnosed by MRI, the diagnosis must have been 
made within 12 months before the Visit 1. 
4. Moderate to severe endometriosis-associated pelvic pain (EAPP) of ≥4 in the last 28 
days before the Visit 1 as measured on the NRS (0-10) (4-week recall period) by the 
subject.
5. At the randomization visit (Visit 3): 
a.
Adherence to the study procedures during the screening period, at least 24 
diary entries of ESD item 1 during the first 28 consecutive days after the 
screening visit (Visit 1), and an average score of the available ESD item 1 
(‘worst pain’ on the daily NRS) entries during this period must be ≥ 3.5  
(corresponding to a sum score of at least 84 (by 24 diary entries) or 98 (by 28 
diary entries). 
6. Willingness to use only standardized pain medication if needed, according to 
investigator’s instruction and not use any prophylactic pain medication for EAPP.
7. Good general health (except for findings related to endometriosis) as proven by 
medical history, physical and gynecological examinations, and laboratory test results.
8. Normal or clinically insignificant cervical cytology not requiring further follow-up (a 
cervical cytology sample has to be taken at the screening visit (Visit 1) or a normal 
result has to be documented within the previous six months prior to Visit 1). Human 
papilloma virus (HPV) testing in subjects with atypical squamous cells of 


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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. As a guidance, 
cervical cytology should only be repeated once in case of insufficient material.
9. An endometrial biopsy performed at the screening phase 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 phase and must be repeated within 6 weeks 
from the first biopsy in order for the subject to continue.  No further repeated biopsies 
in case of inadequate samples are permitted. 
10. Use of an acceptable non-hormonal method of contraception (i.e. either male condom, 
cap, diaphragm or sponge, each in combination with spermicide) starting at Visit 1 
until the end of the study. This is not required if safe contraception is achieved by a 
permanent method, such as bilateral fallopian tube occlusion (including Essure®) or 
vasectomy in the partner(s). (Short-acting hormonal contraception [oral, vaginal, or 
transdermal] for treatment of EAPP are allowed during screening, but need to be 
stopped and withdrawal bleeding has to be initiated before the randomization visit 
[Visit 3], see also Section 7.1.1). 
11. Willingness / ability to comply with electronic diary entry for the duration of study 
participation
6.3
Exclusion criteria
The exclusion criteria are as follows:
1. Pregnancy or lactation (less than 3 months since delivery, abortion, or lactation before 
Visit 1) 
2. Hypersensitivity to any ingredient of the study treatments 
3. Laboratory values outside the inclusion range4 before randomization, and considered 
clinically relevant 
4. Any diseases or conditions 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 are not limited to: 
a.
Impaired function of the kidneys (laboratory values outside of inclusion range) 
b. Abnormal liver parameters (presence of at least one of the following criteria)5: 
i. 2 x upper limit of normal (ULN) for glutamic oxaloacetic transaminase 
(GOT) / aspartate aminotransferase (AST) 
ii. 2 x ULN for glutamic pyruvic transaminase (GPT) / alanine 
aminotransferase (ALT) 
iii. 2 x ULN for alkaline phosphatase (AP) 
                                                
4 As specified in the laboratory manual and in the reports from the central laboratory
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 patient is eligible only if the second test shows a stabilization or decline in those values .


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iv. Total bilirubin outside the upper limit of normal
v. International normalized ratio (INR) outside the upper limit of normal 
c.
Positive hepatitis B surface antigen (HBs-Ag) indicating chronic hepatitis B 
infection
d. Positive hepatitis C antibodies (anti-HCV) and HCV-messenger RNA (mRNA)
indicating chronic hepatitis C infection.
e.
Chronic bowel diseases, eg, Crohn’s disease and ulcerative colitis.
f.
Intake of strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors (see 
Section 16.1) 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).
g. Intake of strong CYP3A4 inducers (see Section 16.2) (eg, rifampicin, 
carbamazepine, phenytoin, phenobarbital, St John´s wort) within the last 2 
weeks before start of study drug intake and during the treatment periods. 
5. Any diseases or conditions that might interfere with the conduct of the study or the 
interpretation of the results, including 
a. A known severe coagulation or fibrinolytic disorder 
b. Severe hepatic disorders 
c. History of or current anxiety or depression unless stable with or without 
medical treatment ≥ 6 months
d. History of or current fibromyalgia 
e. History of or current uterine, cervical, ovarian, or breast cancer, except cervical 
cancers after curative treatment
f.
History of hysterectomy 
g. One or more ovarian cysts ≥3 cm in diameter as measured by ultrasound 
(except endometrioma) 
h. Any ovarian tumors or pelvic masses of unclear etiology requiring further 
diagnostic procedures 
i.
Irritable bowel syndrome or other bowel disorders 
j.
Current bone and musculoskeletal disease (eg, osteoporosis, Scheuermann’s 
disease, osteogenesis imperfecta, hypo- or hyperparathyroidism, Paget’s 
disease, osteomalacia or other metabolic disease of bone, hypo- or 
hypercalcemia)
k. Screening DEXA results of the lumbar spine (L1-L4), femoral neck, or total hip 
BMD corresponding to 2.0 or more standard deviations (SD) below normal 
(Z score ≤–2.0 SD) as per central read
6. Undiagnosed abnormal genital bleeding
7. Abuse of alcohol, drugs, or medicines (e.g. laxatives) as evaluated by the investigator


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8. Use of other treatments that might interfere with the conduct of the study or the 
interpretation of the results: 
a.
Short-acting hormonal contraception (oral, vaginal or transdermal 
formulations, cyclic or extended regimens) or progestin treatment, if not 
stopped and if a withdrawal bleeding has not been initiated before 
randomization visit (Visit 3) 
b. Long-acting hormonal contraception (injectable), if last application was 
performed less than 1 application interval before Visit 1 and subject has not 
resumed normal menses before Visit 1. 
c.
Contraceptive devices with or without hormone release (subdermal implant, 
intrauterine device) if not removed before Visit 1 and if subject has not 
resumed normal menses before Visit 1 
d. Progesterone Receptor modulator, if not stopped at least 28 days before Visit 1 
and if subject has not resumed normal menses before Visit 1 
e.
Gonadotropin-releasing hormone agonist, if not stopped at least one 
application interval before Visit 1 and if subject has not resumed normal 
menses before Visit 1 
f.
Traditional Chinese medicine or herbal remedies for painful conditions 
including endometriosis or heavy menstrual bleeding
g. Raloxifene (or similar selective estrogen receptor modulators [SERMs]), 
fluoride, calcitonin, if not stopped 3 months before Visit 1
h. Current intake (ie, at Visit 1) of agents known or suspected to affect bone 
metabolism, e.g. bisphosphonates, parathyroid hormone, systemic 
corticosteroids, if not stopped before Visit 1 
9. Endometriosis-specific treatments for symptom relief except short-acting 
contraceptives or progestins (as outlined in exclusion criterion # 8a) used during the 
screening period and rescue pain medication according to protocol 
10. Simultaneous participation in another clinical trial with investigational medicinal 
product(s). Participation in another trial prior to study entry that might have an impact 
on the study objectives, at the discretion of the investigator 
11. Major surgery scheduled during the study period 
12. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of investigational site, or sponsor’s staff) 
13. 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 
14. Previous assignment to treatment (e.g. randomization) during this study (allowing 
previously randomized subjects to be re-included into the study may lead to bias) 
15. Hypersensitivity to any ingredient of standardized pain medication 
16. Contraindication for standardized rescue pain medication (according to local label) 
17. Wish for pregnancy during the study 


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18. Regular use of pain medication due to other underlying diseases 
19. Any findings that require further diagnostic procedures to avoid harm to the subject 
(e.g. ovarian tumors of uncertain origin or pelvic masses of unclear etiology, etc.) 
20. Non-responsiveness of EAPP to GnRH-a. 
6.4
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, which may have an effect on the aims of the study, are excluded.
6.5
Withdrawal of subjects from study
6.5.1
Withdrawal
No longer valid, since with the implementation of Protocol Amendment no. 7 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:  
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, for further follow-up, see Section 9.6.2

Surgical treatment of endometriosis, for further follow-up, see Sections 9.7.2 and 
9.6.1.4 (in case of an serious adverse event (SAE))

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being 
Subjects must be withdrawn from study treatment if any of the following occurs:

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 

Loss of BMD >6% at the lumbar spine compared to baseline accompanied by a Z-
score reading of ≤-2 SD (standard deviation) (determined either by the central 
reading imaging laboratory or by assessment at the site and confirmed by the 


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central reading imaging laboratory at the end of the 1st 6 months treatment period 
visit).
Subjects may be withdrawn from study treatment if any of the following occurs: 

Any of the inclusion criteria are no longer fulfilled 

Any of the exclusion criteria apply during treatment. 
Screening failure
A subject who, for any reason (eg, failure to satisfy the selection criteria), terminated the 
study before randomization, is regarded a “screening failure”.  
Dropout
A subject who discontinues study participation prematurely for any reason (including subject 
who does not consent to this protocol amendment which defines safety measures to be 
performed at the study closeout visit) is defined as a “dropout” if the subject has already been 
randomized.  
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 subjects´ source document.
General procedures
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in 
the subject's source documents. Any medical treatment and interventions are documented.
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 (Premature termination of the study).
6.5.2
Replacement
Dropouts will not be replaced. 
6.6
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)
Once allocated, the SID number identifies the subject throughout the study.
On random assignment to treatment, each subject was assigned a unique randomization 
number.


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7.
Treatments
Instructions in Sections 7.1 to 7.4 are no longer valid, since with the implementation of 
Protocol Amendment no. 7 no subjects will start or continue treatment in this study. 
Originally, the instructions in Sections 7.1 to 7.4 were the following:
7.1
Treatments to be administered
Dose-finding phase (treatment period 1):

Treatment Group 1: One 2 mg vilaprisan tablet once daily orally for 24 weeks 

Treatment Group 2: One 4 mg vilaprisan tablet once daily orally for 24 weeks 

Treatment Group 3: One placebo tablet matching vilaprisan once daily orally for 24 
weeks 
Extension phase (treatment period 2):

Treatment Group 1: One 2 mg vilaprisan tablet once daily orally for 24 weeks 

Treatment Group 2: One 4 mg vilaprisan tablet once daily orally for 24 weeks 

Treatment Group 3: One placebo tablet matching vilaprisan once daily orally for 24 
weeks 
7.1.1
Start and end of study treatment
There will be two treatment periods (Treatment period (TP) 1 during the dose-finding phase 
and TP 2 during the extension phase) separated by a drug-free interval containing 2 bleeding 
episodes. Each treatment period will consist of 24 weeks (168 days) of once-daily tablet 
intake. 
Study treatment (TP 1) will be started at the clinic during the randomization visit (Visit 3) and 
according to the following rules depending on subject’s endometriosis treatment during the 
screening period:
1.
A subject without any hormonal treatment will start study treatment during the 
randomization visit (Visit 3).  Visit 3 should be scheduled between expected Day 3 and 
Day 7 of her menstrual cycle.
2. A subject on treatment with a short-acting progestin or with an extended regimen of COC 
will stop her progestin or COC before scheduling the randomization visit and wait for 
withdrawal bleeding. Visit 3 should be scheduled between Day 3 and Day 7 of the 
withdrawal bleeding and study treatment started during the randomization visit (Visit 3)
3.
A subject on treatment with cyclic combined hormonal contraception (oral, vaginal, or 
transdermal) will finish the complete cycle and wait for the withdrawal bleeding.  Visit 3 
should be scheduled between Day 3 and Day 7 of this withdrawal bleeding and study 
treatment started during the randomization visit (Visit 3)
TP 2 will start within Day 3 and Day 7 of the second bleeding episode following the end of 
the TP 1.  If no bleeding episode occurs within 7 weeks after end of the TP 1, or if the second 
bleeding episode does not occur within 7 weeks after the end of the first bleeding episode, 
proceed with the induction of bleeding according to Section 9.7.1. The subject will call the 
site on the day of first pill intake for TP2 to schedule the Visits 8.1 – 12.


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For the start of TP 2, subjects will determine, based on their own experience, when a bleeding 
episode has started. In case of unusual patterns (eg, start with some days of spotting) subjects 
should consult with the investigator.
All subjects who stop their hormonal contraceptives prior to Visit 3 need to use a non-
hormonal method of contraception starting from the time of discontinuation of their 
contraceptive. 
A negative pregnancy test is a prerequisite for starting study drug treatment for both treatment 
periods.
7.1.2
Missed intake of study drug
If a subject 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 
but simply resume the usual dosing schedule on the following day.
7.1.3
Rescue pain medication
Rescue pain medication for endometriosis-associated pain is prescribed for subjects by the 
investigator and is limited to ibuprofen tablets (containing ibuprofen 400 mg per tablet [in 
Japan, ibuprofen 200 mg per tablet]).  In addition to ibuprofen, a country-specific narcotic 
analgesic may be prescribed to subjects who do not obtain sufficient relief from study drug 
and ibuprofen. The narcotic analgesic is defined depending on availability and common use 
for the indication in the individual country (ie, only one narcotic analgesic is allowed for each 
country), and is specified in a separate guidance document (i.e. “Rescue Pain Medication 
Guide”).  
The number of tablets and dosing interval of the rescue pain medications can be determined 
by the investigator and should be in line with the product prescribing information for that 
particular dosage form in that country. 
Investigators prescribed these rescue pain medications for subjects at the time of subject entry 
into the screening phase, taking into consideration the subject's preference and/or historical 
use of analgesics. The same rescue pain medication (type and dose preparation) used during 
the screening phase should be used as needed for rescue during the treatment phase. Subjects 
are instructed not to increase their total daily dose or frequency of rescue pain medication or 
to switch the category of analgesic used (e.g., switching from ibuprofen to country specific
narcotic analgesic) unless it is necessary for treatment of worsening endometriosis-associated 
pain that does not respond to their current analgesic medications. Subjects are instructed to 
contact the site if a change in their analgesic medication is needed, such that appropriate 
adjustments can be made. All use of analgesic medication should be according to the product 
prescribing information. 
Subjects are instructed to use pain medication only as rescue analgesia; use of prophylactic 
analgesics at any time during the study is explicitly discouraged.
Daily use of rescue pain medications was recorded by the subject in the hand-held device 
(ESD item 9a, 9b, 9c, and 9d) during the entire study. This included specific dosing 
information on the permitted rescue pain medications, including dose and total number of 
pills/tablets within a 24-hour period and the information whether it was taken for pain in the 
target area or not. 


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7.1.4
Other pain medication
Use of all other analgesics beyond the permitted rescue pain medication is discouraged during 
the study since it will potentially disturb the study outcome. 
If, for any reason, analgesics other than the permitted rescue pain medication are taken (ESD 
item 10a and 10b), this will be documented in the concomitant medication electronic case 
report form (eCRF) page. 
If analgesic medications is used for pain related to other conditions (e.g., headache, joint pain) 
these conditions should be recorded as adverse events, and analgesics used for their treatment 
should be documented in the eCRF.
Note that for any additional pain medication (beyond the permitted rescue pain 
medication for EAPP), it must be specified in eCRF whether it was taken for EAPP or other 
pain.
7.1.5
Diet
Subjects will be allowed to eat and drink as usual. However, grapefruit and grapefruit juice 
must be excluded from the subject's diet 2 weeks before start of study treatment and during 
treatment because these foods contain constituents that inhibit cytochrome P450 3A4.
7.2
Identity of study treatment
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance 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 batch of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance (QA) group. 
A complete record of batch numbers and expiry dates of all study drugs as well as the labels 
will be maintained in the sponsor’s study file.


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Table 7–1: Identity of test drug/vilaprisan tablets and matching placebo
Sponsor’s substance code
BAY 1002670 
INN
Vilaprisan
Brand name
Not applicable
Formulation
Film-coated tablet
Tablet strength
2 mg; 4 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)
Marketing Authorization Holder
Not applicable
Sponsor’s substance code
Placebo (to BAY 1002670) 
INN
Not applicable
Brand name
Not applicable
Formulation
Film-coated tablet
Tablet strength
Not applicable 
Composition
Ingredients:
Lactose monohydrate, microcrystalline cellulose, magnesium 
stearate, dark red lacquer (containing hypromellose, 
macrogol 3350, talc, titanium dioxide, and red ferric oxide)
Marketing Authorization Holder
Not applicable
INN = International nonproprietary name.
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 Interactive Voice 
Response System / Interactive Web Response System (IVRS/IWRS) to one of the three
treatment groups equally. 
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 subject files.  For additional details, refer to the separate IVRS/IWRS 
instructions.
Randomization to treatment will be stratified by countries/regions (eg, US/Canada, Europe, 
Japan, China/Taiwan) and by the method of endometriosis diagnosed (surgery or imaging). 
Randomization to time point of the second endometrial biopsy (at the end of TP1 or TP2) will 
be stratified by treatment.
7.4
Dosage and administration
See Section 7.1 for administration details.
7.5
Blinding
Forward looking instructions regarding blinding are no longer valid, since with the 
implementation of Protocol Amendment no. 7 subjects will no longer start or continue 
on treatment. The initial database lock for all subjects in the randomized double-blind 
parallel group will occur with the database cleaned for safety only, in order to allow for 


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unblinding of the existing data. Once the database is locked the subjects will be 
unblinded and subjects treated with vilaprisan will continue into the open label safety 
follow up. This additional safety data will be cleaned and the open label portion will be 
locked. 
7.5.1
Blinding measures
Vilaprisan tablets containing 2 mg or 4 mg vilaprisan and placebo tablets are identical in 
appearance (size, shape, color). The packaging and labeling were designed to maintain the 
blinding of the investigator’s team, the Bayer study team, and the subjects.
For control of possible bias in investigators assessments (ClinROs), PROs to be completed at 
the study site will be completed prior to the investigators assessments. The exact value of the 
inclusion criteria 4 (at Visit 1) and 5 (at Visit 3 / Randomization) provided by the subject on 
the PRO device will be hidden (ie, only “eligible yes/no” will be shown to the investigator). 
At no time is the investigator/site personnel allowed to respond to questions other than the 
subjects’ technical questions for the completion of PROs.
7.5.2
Unblinding
In compliance with applicable regulations, in the event of a suspected, unexpected serious 
adverse reaction (SUSAR, see Section 9.6.1.5) related to the blinded treatment, the subject’s 
treatment code will usually be unblinded by the sponsor’s Pharmacovigilance department 
before reporting to the health authorities. Notifications of the ethics committees and 
investigators will be done according to all applicable regulations (see Section 9.6.1.4). 
7.5.3
Emergency unblinding by the investigator
In case of emergency or any finding that requires unblinding, the investigator can break the 
blind for an individual subject via IVRS/IWRS consistent with the unblinding instructions 
provided.  This will allow breaking the blind for an individual subject without impairing the 
study as a whole.
If it becomes necessary to know the individual treatment during the study and thus to break 
the code for that subject, the date, and reason are to be recorded in the relevant eCRF page.  
The investigator is required to promptly document and explain to the sponsor any premature 
unblinding (eg, unblinding because of a serious adverse event) of the study drug. In case of 
unblinding, the subject will not be automatically withdrawn from study treatment.
7.6
Drug logistics and accountability
No longer valid, since with the implementation of Protocol Amendment no. 7 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.
7.7
Treatment compliance
Any discrepancies between actual and expected amount of returned study medication were
discussed with the subject at the time of the visit, and any explanation was documented in the 
source records.  To monitor compliance, subjects were required to complete an electronic 
diary (on a hand-held device) daily throughout the study.  The date of each study drug intake 


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was tracked via the hand-held device.  The hand-held device was dispensed at Visit 1 and the 
completeness of the electronic diary data was reviewed by the investigator or designee 
between the visits regularly, and together with the subject at every subsequent visit.
8.
Non-study therapy
8.1
Prior and concomitant therapy
All concomitant medications administered after signing of informed consent until the 
completion of study participation6, 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, see Section 6.3. 
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 continues with Protocol Amendment no. 7. Please see 
also Section 6.3. 
Subjects who withdrew from study drug and subjects who withdrew during FUP were asked 
to not take hormonal treatments before the first menstruation after end of treatment (EoT) was 
completed and the endometrial biopsy performed.
Surgical and interventional treatment for endometriosis was to be documented in the eCRF if 
performed during the study period (ie, until the last visit of the subject) and should be 
regarded as Adverse Event (AE) if deemed appropriate by the investigator (see Section 
9.6.1.1 and 9.7.2).  Calcium and vitamin D are not excluded for subjects in the study, but for 
assessment of possible influence on bone mineral density (BMD) measurements, the intake 
should be documented on the concomitant medication eCRF throughout the study.
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
Progestin therapy for induction of bleeding
If required, subjects were given an appropriate progestin therapy for induction of bleeding.  
Progestin therapy is not considered as study medication and is documented as concomitant 
medication, see Section 9.7.1 for details).
8.2
Post-study therapy
Initially it was planned that subjects completing the treatment periods participate in the post-
treatment follow-up without study drug treatment.  The standardized rescue pain medication 
as specified in section 7.1.3 is to be prescribed, if needed and so maintained until end of the 
study.
With implementation of Protocol Amendment no. 7, all subjects who started vilaprisan
treatment before the temporary pause (including those who are in the prolonged break and 
                                                
6 In subjects who have discontinued the study 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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those who discontinued from study prematurely for any reason) will be asked to undergo a 
“Safety Closeout visit” with a set of safety follow up procedures, followed by a “Safety 
Result Reporting visit”, which will be individual subjects’ end of study visit.    
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 study the subjects will not be given free access to study drug, since 
alternative treatment options are available. Hormonal treatments for EAPP should be started 
only after the first menstruation after the end of the study (or after premature discontinuation 
of the study).
9.
Procedures and variables
9.1
Tabular schedule of evaluations
No longer valid, since with the implementation of Protocol Amendment no.7 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 with vilaprisan before the temporary 
pause will be asked to have the “Safety Closeout visit” with a comprehensive safety 
evaluation (with particular focus on endometrial, adrenal and skin safety) which is 
implemented with Protocol Amendment no. 7. This also applies to subjects who have 
discontinued the study before or during the temporary pause, provided they have taken at 
least one dose of study medication vilaprisan. The second scheduled visit, the “Safety Result 
Reporting visit” can be done as a telephone visit.
This “Safety Closeout visit” should be performed in all subjects as soon as possible after 
implementation of Protocol Amendment no.7. The following procedures are to be done:


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Table 9–1: Schedule of procedures
Visit
Safety Closeout Visit 7
Safety Result Reporting 
visit
(can be Telephone visit)
Timing
After approval of Protocol 
Amendment no. 7
Once all safety results are 
available
Informed consent
X
Concomitant medications
→
→
AE assessments
→
→
Adrenal disorder signs and symptoms
incl. vital signs8
X
MRI of adrenal glands9
X
DEXA scan for bone mineral density10
Dispense saliva test tubes
X
X
Collect saliva test tubes11
X
Referral to dermatology expert
X
Physical examination
X
Body weight
X
Gynecological/breast exam12
X
Urine pregnancy test
X
Cervical cytology13
X
Ultrasound examination14
X
Endometrial biopsy15
X
Laboratory (blood)16, 17
X
Collection of unused study drug and empty drug 
packs/drug accountability
X   
if applicable
Collection of eDiary device and review of 
bleeding data and assessment of any abnormal 
bleeding pattern
X    
if applicable
Deactivation of subject on tablet computer 
without selecting a particular visit 
X
Communication of results from safety evaluations 
to the subject
X
                                                
7 In most cases the procedures scheduled for this visit will not take place on the same day
8 Blood pressure in triplicates and heart rate after 5 minutes of rest in a sitting position
9 Negative pregnancy test is a prerequisite
10 Negative pregnancy test is a prerequisite
11 Saliva tests should be performed as soon as possible after this visit to allow for a repeat in case of unevaluable 
results or for review by one of the adrenal experts in case of abnormal results. The two samples should be returned to 
the study site preferably on the day after collection of the last sample.
12 Only to be performed if subject did not have these performed with normal result after end of treatment
13 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; for subjects with menstrual cycles the endometrial biopsy should be 
taken between Day 7 to 15 (inclusive) of a menstrual cycle
14 The ultrasound must be done before the biopsy
15 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 9.6.3.1). The biopsy CRF page 
needs to be completed for all subjects, including cases where according to protocol no biopsy is required.
16 The blood should be withdrawn under fasting conditions between 6 am and 10 am.
17 In subjects who take biotin, the last dose of biotin should be at least 72 hours prior to hormone testing.
AE = adverse event, DEXA = dual-energy X-ray absorptiometry, MRI = magnetic resonance imaging, PAEC = 
progesterone receptor modulator-associated endometrial changes


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Subjects who received treatment with placebo prior to the temporary pause will be asked to 
return the eDiary device. Thereafter, subjects will be deactivated on the tablet computer.
9.2
Visit description
No longer valid, since with the implementation of Protocol Amendment no. 7 all subjects 
treated with vilaprisan will need to come to the site for one scheduled “Safety Closeout 
visit” only. In most cases the procedures scheduled for this visit will not take place on 
the same day. 
A 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 are required, these should be documented as 
unscheduled assessments.
9.2.1
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 
an unscheduled visit would be the requirement for follow up investigations.
9.2.2
Optional pre-screening phone contact
No longer valid, since with the implementation of Protocol Amendment no. 7 no new 
subjects will be recruited.
9.2.3
Scheduled visits
With the implementation of Protocol Amendment no. 7 all subjects treated with 
vilaprisan will need to come to the site for one scheduled “Safety closeout visit”. A 
second scheduled visit, the “Safety result reporting visit” can be done as a telephone 
visit. For details regarding the safety closeout visit and the safety result reporting visit
please see section 9.1.
9.3
Population characteristics 
With implementation of the amendment 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 consistent with the original schedule of procedures (Protocol Amendment no. 3).
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below were collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.


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Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
9.3.3
Reproductive, menstrual, and endometriosis history
Reproductive and menstrual history includes information on menarche, births, other 
pregnancies, and inability to conceive.
Endometriosis history includes information on family history, onset of symptoms, diagnosis, 
and previous medical treatments and procedures, if applicable.
9.4
Efficacy
With the implementation of Protocol Amendment no.7 no new efficacy data will be 
collected.
This section details the procedures for collecting efficacy variables before implementation of 
Protocol Amendment no. 7.
9.4.1
Patient-reported outcomes
9.4.1.1
Endometriosis Symptom Diary (ESD)
The ESD was filled in daily using the electronic hand-held device consistent with the original 
schedule of procedures (Protocol Amendment no. 3).
The ESD is a newly developed PRO instrument designed to assess the subject’s experience of 
endometriosis symptoms.  Designed as an electronic hand-held device, the ESD was
completed by the subject each evening (between 18:00 and 23:59) in the electronic hand-held 
device, when the subject was to reflect on her experiences in the past 24 hours.  Subjects were
asked to rate their endometriosis associated pelvic pain (worst EAPP, short term and constant 
EAPP) in the target area and dyspareunia (painful sexual intercourse) in the past 24 hours. 
These symptoms were reported using an 11-point (0 to 10) numerical rating scale (NRS): 0 
represents no pain while 10 represents unbearable pain. Any use of rescue pain medication 
(prescribed by the investigator) and the information whether it was taken for pain in the target 
area or not was recorded.  The instrument also consists of a series of dichotomous yes/no 
questions and others items that are rated based on categorical responses.  Bleeding intensity 
was also be assessed by one of the items, i.e. the subjects were asked to select the response 
that best describes their vaginal bleeding during the past 24 hours.  
9.4.1.2
Endometriosis Impact Scale (EIS)
The EIS was filled in once per week using the same electronic hand-held device consistent 
with the original schedule of procedures (Protocol Amendment no. 3). The EIS was
completed by the subject, when she was to reflect on her experiences during the past 7 days.
The EIS is a newly developed PRO instrument designed to assess the effect of the primary 
defining symptoms of endometriosis (i.e. pain) on the subjects’ lives, describing effects on 
physical activities, emotional effect, social and leisure activities, paid work or study, 
household activities, sexual activities, ability to concentrate, and ability to sleep.  Subjects 
were asked to complete the EIS weekly in the evening (between 18:00 and 23:59) of the same 
day of the week (e.g. always on Mondays) in an electronic hand-held device, when the 
subjects were to reflect on the effect of endometriosis pain on their daily lives during the “past 
7 days”.


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9.4.1.3
Numeric Rating Scale (NRS) for EAPP
The NRS for EAPP was filled in once at the Screening visit (Visit 1) consistent with the 
original schedule of procedures (Protocol Amendment no. 3).
Subjects were asked to rate their pelvic pain on a single-item 11 point (0 to 10) NRS, using a 
recall period of 4 weeks.  Zero represents no pain at all while 10 represents the worst 
imaginable pain.  
The NRS is a commonly used and easily understood format for the assessment of pain in 
various indications. 
9.4.1.4
Visual Analogue Scale (VAS) for EAPP
The VAS for EAPP was filled in using the electronic hand-held device consistent with the 
original schedule of procedures (Protocol Amendment no. 3).
Subjects were asked to rate their EAPP on the VAS, using a recall period of 4 weeks with a 
single vertical mark on a horizontal line anchored verbally between “no pain” and 
“unbearable pain” shown on the eDiary screen.  The eDiary technology provides the single 
vertical line with 101 (0-100) individually selectable points on the horizontal line VAS 
ensuring that the subject’s single vertical mark can be translated into any number/score from 
0-100 for the rating of pain. This methodology has been validated (2, 3) and was accepted by 
the regulatory authorities (FDA, European Medicines Agency [EMA]) in the past.
The VAS (on paper) has been used in the past as a primary endpoint in Phase 3 clinical 
studies to determine the efficacy of medicinal products indicated for the treatment of 
endometriosis.  
9.4.1.5
Patient Global Impression of Severity (PGI-S)
The PGI-S was filled in using the electronic hand-held device consistent with the original 
schedule of procedures (Protocol Amendment no. 3).
Subjects were asked to describe their overall endometriosis symptom severity, using a 6-point 
verbal rating scale (no symptoms, very mild, mild, moderate, severe, and very severe).  
9.4.1.6
Patient Global Impression of Change (PGI-C)
The PGI-C was filled in using the electronic hand-held device consistent with the original 
schedule of procedures (Protocol Amendment no. 3).
The PGI-C is a patient-rated instrument that measures change in the subjects’ overall 
endometriosis symptom in the past 4 weeks on a 7-point Likert scale ranging from 1 (very 
much better) to 7 (very much worse).  Higher scores indicate a change for the worse.  
9.4.1.7
EQ-5D-5L
The EQ-5D-5L was filled in using the tablet computer at the site consistent with the original 
schedule of procedures (Protocol Amendment no. 3).
The EQ-5D-5L is a widely used measure of health status with well-documented reliability, 
validity and responsiveness in the general population as well as in various diseases. Use of 
this instrument enables a comparison of the effects of endometriosis on health-related quality 
of life with an age-matched normative sample. The instrument comprises five domains and an 
overall assessment of health status on a visual analogue scale. The five domains include: 


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mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, where 
‘1’ indicates no problem, ‘2’ indicates a moderate problem, and ‘3’ indicates a severe 
problem. Descriptive assessment was done on the basis of the VAS assessment and on the 
single-dimension basis. A preference weighted or utility score can be calculated in a further 
step using statistical algorithms producing values ranging from -0.594 to 0 (dead) to 1.0 (full 
health).
9.4.1.8
Short Form 36 Health Survey Version 2 (SF-36v2)
The SF-36v2 was filled using the tablet computer at the site consistent with the original 
schedule of procedures (Protocol Amendment no. 3).
The SF-36v2 is a widely used measure of health status with well-documented reliability, 
validity, and responsiveness in the general population as well as in various disease 
indications.  It consists of 36 items.  The SF-36v2 comprises 8 domains:  physical function, 
physical role, bodily pain, general health, vitality, social functioning, emotional role, and 
mental health.  
9.4.2
Clinician-Reported Outcomes (ClinROs)
The following assessments were based on the investigator’s clinical evaluation of the subject 
and entered in the eCRF by the investigator consistent with the original schedule of 
procedures (Protocol Amendment no. 3).
9.4.2.1
Clinical Global Impression of Change and Severity (CGI-C and CGI-S)
The investigators completed the Clinical Global Impression Investigator (CGI-C and CGI-S).  
The CGI-C askes the investigator to rate the change of the subject’s symptoms since start of 
study treatment with the following response options:  very much better, much better, a little 
better, no change, a little worse, much worse, and very much worse.  The CGI-S askes the 
investigator to describe the subject’s overall severity of symptoms with the response options: 
none, very mild, mild, moderate, severe and very severe.
9.4.2.2
Modified Biberoglu and Behrman severity profile for symptoms and 
findings
The modified Biberoglu and Behrman (B&B) severity profile for symptoms and findings 
were filled in.  
9.4.3
Ultrasound (efficacy) to assess endometriosis lesions
A qualified expert in performing gynecologic ultrasound exams conducted ultrasound 
examinations consistent with the original schedule of procedures (Protocol Amendment no. 
3).  Ultrasound measurements did not have to be done on the same day as other assessments 
of that visit, but had to be performed as close to the specified visit as possible.
For each subject, the most appropriate ultrasound method(s) (transvaginal, abdominal or 
transrectal) was to be used depending on location of the possibly visualizable endometriosis 
lesion(s) (e.g., endometrioma, deep infiltrating endometriosis, adenomyosis) and this 
method(s) was to be used consistently throughout the study.
The minimum source documentation included printouts and/or compact disk (CD)s with 
images from the ultrasound machine showing the lesions. The printouts and/or CDs with 
images were to be labeled unambiguously, containing at least the study number, SID number, 
time point, and diameter of the lesions. 


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For safety ultrasound procedures, see Section 9.6.3.6.
9.5
Pharmacokinetics / pharmacodynamics
With the implementation of Protocol Amendment no. 7 no new subjects will be recruited 
and no study medication will be given to the subjects who have been enrolled in the 
study. This section describes processes performed in subjects enrolled before the 
temporary pause.
9.5.1
Drug measurements
Blood samples for measurement of vilaprisan for pharmacokinetics were taken at several time 
points after start of study treatment unless precluded by local regulatory and/or IEC guidelines
consistent with the original schedule of procedures (Protocol Amendment no. 3).  The 
samples were collected and processed as described in detail in the Sample Handling Sheet as a 
part of a separate Laboratory Manual.  At Visit 3, 2 PK samples were to be taken. The first 
sample was to be taken 0.5 to 1 hour after drug intake; the second sample was to be taken 2 to 
4 h after study drug intake under supervision. At Visit 5 and 7, 2 PK samples were to be 
taken.  The first sample was to be taken before intake of study drug.  Afterwards the subject 
was to take her study drug under supervision at the site.  The second sample was to be taken 
0.5 to 4 hour after drug intake.  The date and time of the last 2 doses of study drug prior to the 
first PK sample at each visit, the exact time of the supervised drug intake at the study site, and 
the exact time (not the time window) when the blood samples were taken was to be 
documented in the eCRF.
PK plasma concentrations of vilaprisan were to be determined using a validated liquid 
chromatography/tandem mass spectrometry method.  Quality control (QC) and calibration, 
samples were to be analyzed concurrently with study samples.  The results of calibration 
samples, QC samples and study samples were to be reported in the bioanalytical report, which 
was to be included in the clinical study report for this study.  Study responsible bioanalytical 
personnel was to remain unblinded for analysis of study samples.  For subjects receiving 
placebo, no blood samples were to be analyzed to determine the plasma PK.
9.5.2
Population pharmacokinetic analysis of vilaprisan
Blood samples for PK will be taken according to the original schedule of procedures (Protocol 
Amendment no. 3). Deviations from the specified time points are taken into account when 
calculating the PK parameters. Those deviations do not qualify as protocol deviations.  The 
times of study drug intake will be documented in the eCRF.  
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. As a result, 
dedicated people (ie, involved in bioanalytics and population PK analysis) may be unblinded. 
Appropriate measures will be taken to maintain blinding of the study team, which will be 
described in a Data Operations Plan, which will be provided to the study team.
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 Phase 2 data will be applied to all valid PK 
samples to evaluate the relationship between variability in PK and covariates (i.e. intrinsic 
[e.g. body weight, race] and extrinsic factors [e.g. concomitant medication]) that are of 


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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
The relationship between vilaprisan exposure and efficacy and safety parameters such as pain 
response, bleeding intensity and endocrine hormone levels might be evaluated.  In such a 
case, the final population PK model that will be used to describe the PK of vilaprisan as 
outlined above will be linked to relevant PD parameters (pain, endocrine hormone levels, and 
bleeding) to investigate the (PK/PD) relationship between vilaprisan exposure and response.  
Details of the model development and evaluation will be described in a separate M&S 
Analysis Plan and the results reported in a separate M&S Report, if applicable.
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written 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.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an 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 e.g. physical examination findings, symptoms, diseases, laboratory, and 
electrocardiogram.

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 (e.g. 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 (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses.

In subjects who discontinued the study during the temporary pause and now get 
reconsented, conditions that newly occurred or worsened during the off-study period 
should be documented as AEs.


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Definition of serious adverse event (SAE)
A serious adverse event (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
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures)
- The admission is not associated with an AE 
(e.g. 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.
All instances of liver parameter testing which meet criteria for withdrawal of a subject 
from the study treatment should be reported as SAE.
d. Results in persistent or significant disability / incapacity
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 serious or important medical event (IME) as judged by the investigator
All instances of liver parameter testing which meet criteria for withdrawal 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) (13) 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.


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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: An 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 adverse events that may be indicative of a serious disease state, the 
Important Medical Events (IMEs) list published by the EMA, will be periodically 
reviewed against the non-serious adverse events reported during the study. The 
investigator may be asked to review and confirm, when deemed necessary, if an event 
meets the criteria for seriousness, in his/her opinion.
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 according to 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 CRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.


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Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication 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 that the AE is reasonably 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 re-challenge should be 
considered in 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.
- 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 have caused the event in question.
- Known response pattern for this class of drug: Clinical/preclinical
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event
- The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.
- The assessment is not possible
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.


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
Drug withdrawn

Drug interrupted

Dose not changed

Not applicable

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
The investigator has to record on the respective CRF pages all adverse events occurring in the 
period between the signing of the informed consent and the end of the follow-up phase; after 
the end of the follow-up phase there is no requirement to actively collect AEs including 
deaths.  The type of information that should be assessed and recorded by the investigator for 
each AE is listed in Section 9.6.1.2  
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to study drug.
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 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 


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AE page in the CRF as well as the complementary pages provided in the Investigator File 
must be completed for each SAE.  
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the Institutional Review Boards (IRBs), Institutional Ethics Committees 
(IECs) 
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5 Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) / summary of product characteristics (for standardized rescue
pain medication).
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 according to the applicable 
reference document and according to all local regulations.
9.6.1.6
Adverse events of special safety interest
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:

Liver disorders:

For all cases which qualified for “close observation” before implementation of 
Protocol Amendment no. 7 and/or qualify for “ruling out of alternative cause” after 
implementation of Protocol Amendment no. 7 (see Section 9.6.3.9), 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 9.6.3.1


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
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 9.6.3.1.4.

Skin disorders:

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 9.6.3.8. 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.

Relevant loss of BMD: 

During treatment: BMD loss of > 6% of the lumbar spine compared to baseline 
that 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).  

Lack of adequate bone recovery in subjects treated with vilaprisan, defined as
BMD loss ≥3% compared to baseline at any site and/or Z-score of ≤- 2 at any 
site irrespective of the absolute bone loss in an off-treatment DEXA scan
(determined either by the central reading imaging laboratory or by assessment at 
the site and confirmed by the central reading imaging laboratory).

HMB (during treatment periods, during the drug-free interval, or after EoT, see also 
Section 9.6.3.1.7) 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

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 (see also Section 
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
Worsening of EAPP: EAPP will be documented in detail throughout the study (see 
Section 9.4.1). EAPP should be recorded as an AE (and then it automatically qualifies as 
an adverse event of special safety interest) only if one or more of the following applies: 

Leads to study discontinuation 

Leads to diagnostic or surgical procedures (the surgery/laparoscopy will not be a 
study procedure and will lead to exclusion from the study)   

Requires any treatment other than the standardized pain medication (see Section 
7.1.3)

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 (see Section 
9.6.1.1, and 9.6.1.4)
Progesterone receptor modulator-associated endometrial changes (PAEC) will be assessed 
and documented in a systematic way (see Section 9.6.3.1.4).  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.  
A systematic approach of assessment and evaluation will also be applied to EAPP (see 
Sections 9.4.1.1 and 9.4.1.3), endometrial hyperplasia, endometrial thickening (see Sections 
9.6.3.1 and 9.6.3.4), liver function test (Section 9.6.3.9), adrenal monitoring (Section 9.6.3.8), 
skin monitoring (9.6.3.10), and BMD (9.6.3.2).
9.6.2
Pregnancies
Contraception and pregnancy test
An acceptable nonhormonal method of contraception (ie, either male condom, cap, diaphragm 
or sponge, each in combination with spermicide) has to be used starting at Visit 1 and 
continued until the end of the study.  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.
At the time points shown in in the original schedule of procedures (Protocol Amendment no. 
3), urine pregnancy tests will be performed at the study site.  A pregnancy test must be 
performed before the start of study drug treatment in each treatment period (by the subject at 
home), and always before BMD and endometrial biopsy. 
Additional tests should be performed at home if the subject is concerned about being 
pregnant.  All home pregnancy tests will be documented in the hand-held device.
A positive urine pregnancy test shall be confirmed at the study site, for example, with serum 
pregnancy test or transvaginal ultrasound.  
If any pregnancy test performed at Visits 1 or 2 (screening) or Visit 3 (randomization) is 
confirmed positive, the subject will not be included in the treatment period.  If a pregnancy 
test shows a positive result during treatment, the subject must stop study drug treatment and 


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contact the study site immediately.  If pregnancy is confirmed, the subject will be 
discontinued from the study.
Any planned pregnancy should be postponed until after 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), subject should be made aware that she is participating in a clinical study with a new 
drug in early 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.
With the implementation of Protocol Amendment no. 7, 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, an urine pregnancy tests will be performed at the study site. A 
pregnancy test must also be performed in case of any further repeat endometrial biopsy. 
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 6.3).
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 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 follow-up 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 date 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 follow-up periods will be followed for the 
outcome for both the mother and fetus/child (in case of a life birth) until first birthday of the 
child.  The outcome will be documented on a pregnancy outcome form and a follow-up 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 all reports, the forms provided are to be used.  


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9.6.3
Further safety
9.6.3.1
Endometrial biopsies
9.6.3.1.1
Algorithm for evaluation of endometrial safety
A careful endometrial safety monitoring is applied in this study which included regular 
ultrasound investigations during the active treatment period (see Section 9.6.3.11 for 
description of procedure), endometrial biopsies (see Section 9.6.3.1), and observation of 
bleeding patterns (see Section 9.6.3.1.7). With implementation of Protocol Amendment no. 7
one more examination is planned according to the algorithm below.


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Figure 9–1: Overview of the endometrial safety monitoring algorithm


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9.6.3.1.2
Timing of last endometrial biopsy
Each subject should have an endometrial biopsy with a normal18 result documented from a 
timepoint after 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 transvaginal ultrasound (TVU) and/or bleeding pattern are required to 
undergo an endometrial biopsy at the safety closeout visit. 
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 captures the reason why a biopsy was not done.
Depending on the result of this last scheduled endometrial biopsy, repeat unscheduled 
endometrial biopsies should be performed in addition. See Sections 9.6.3.1.5 and Figure 9–1
for details.
9.6.3.1.3
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 cytology 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). 
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). 
9.6.3.1.4
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.
                                                
18 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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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 9.6.3.1.5.
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. This assessment will be performed as 
batch reads when a sufficient number of samples are available. 
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 Protocol Amendment no. 7, the majority diagnosis of the multi-reader 
assessment (Part II of the evaluation form, i.e. the diagnoses 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 9.6.3.1.5.
Besides standard safety criteria (e.g., proliferative/secretory/atrophic endometrium, 
endometrial hyperplasia, malignant neoplasm) the pathologists will document the presence of 
PAEC (see Section 9.6.3.1.6). 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.
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. Investigators will be informed in addition 
about a single-reader diagnosis (Part II of the evaluation form) that is more severe than the 
majority diagnosis (Malignant neoplasm > Endometrial Hyperplasia > Benign endometrium). 
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 


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interventions. The minimal diagnostic 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.
9.6.3.1.5
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 investigator19 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 evaluated 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 
9.6.3.1.6.
For reporting of abnormal biopsy results as adverse event of special interest or SAE, please 
see Sections 9.6.1.6 and 9.6.1.4.
9.6.3.1.6
Follow-up of PAEC
Besides standard diagnostic 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 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 Safety closeout visit or at a premature discontinuation visit) according to the 
majority diagnosis resulting from the multi-reader assessment, the site will be informed and 
                                                
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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.
9.6.3.1.7
Heavy menstrual bleeding / suspicious bleeding pattern
The study drug may lead to changes in bleeding pattern, mostly amenorrhea during treatment, 
but can also be associated with intermittent spotting or mild intermittent bleeding of short 
duration. 
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). Further the site was asked to actively contact subjects who 
upon review of the ESD Item 4 have entered more than 10 consecutive days of bleeding 
(intensity of “mild” or more) during study drug intake (ie, during a treatment period). In case 
such unusual bleeding events are reported or are detected from the ESD (item 4) 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 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 eDiary 
(ESD item 4, intensity of “mild” or more) with a maximum of 2 non-bleeding 
days in between.

Continuous spotting:
Evaluation should be initiated if

Continuous spotting is reported by the subject and/or

if the subject entered more than 10 consecutive days of spotting in the e-diary 
with a maximum of 2 non-spotting in between.

Unusual heavy bleeding:
Evaluation should be initiated if

Unusually heavy bleeding is reported by the subject 
Evaluation plan for subjects with unusual HMB or bleeding pattern
The evaluation should include the following assessments:
o
Unscheduled ultrasound (if bleeding abnormality is reported outside of visit with 
scheduled ultrasound)


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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 9.6.3.1.5). 
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 9.6.1.2.1), it should be reported as such. An appropriate 
treatment as per local standard of care (eg, curettage) is to be performed after an endometrial 
biopsy has been taken.
9.6.3.1.8
Unscheduled endometrial biopsy
Unscheduled endometrial biopsies can result from the requirement to follow-up on abnormal 
results of a previous biopsy, see Section 9.6.3.1.5. 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 
should be performed according to local medical practice and as defined in Section 
9.6.3.1.7.

For procedures in case of an abnormal result of the unscheduled biopsy, please see 
Section 9.6.3.1.5.
9.6.3.2
Bone mineral density
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.
Technical requirements for DEXA scans: 
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 be 
also 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 will be based on the central reading.


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In the event excessive loss of BMD >6% at the lumbar spine is accompanied by a Z-score 
reading of ≤-2 standard deviation (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 end of the TP 1, the subject must have been withdrawn from study drug. 
Such a decrease constitutes twice the assumed SD in the population included in this study. In 
addition, the accompanying Z-score measurement of ≤-2 SD can be taken as an indicator that 
the measured BMD value is below the average BMD for subjects of same age, sex, and 
ethnicity. Subjects should have had the EoT visit (Visit 10) examinations performed, and 
should have been asked to come to the FUP 1 and FUP 2 visits. Additional diagnostic 
procedures, including a further BMD measurement and treatments should have been initiated, 
as deemed necessary by the investigator. 
Cross calibration
Phantom image acquisition will be standardized across DEXA imaging facilities participating 
in the 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 radiology 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.
DEXA scan performed at the safety closeout visit
Every subject who received vilaprisan treatment should have a DEXA scan performed at the 
“Safety Closeout visit”, which in most subjects corresponds to a timepoint of ≥12 months 
after EoT. 
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% at any site and/or an
abnormal Z-score (defined as ≤-2 at any site irrespective of the absolute bone loss) 
compared to the baseline BMD, the subject should be referred to a local bone 
specialist. The results of the assessment should be captured in the eCRF 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 vitamin D 
and calcium, taking into account the vitamin D measurements performed in the study context.
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 the original schedule of procedures (Protocol Amendment no. 3). The BMD 
measurements are to be performed only after the subject has been tested negative for 
pregnancy. Subjects will be asked to perform a home pregnancy test on the day of the visit 
prior to the scan.  More details on the calibration and procedure of central reading will be 
provided in a separate manual.


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9.6.3.3
Laboratory evaluations
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.
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
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, hemoglobin (Hb), hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), platelets, neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes.
Blood test for hepatitis A, B, and C (only in case of elevated liver enzymes requiring 
further follow up): anti-HAV Immunoglobin M (IgM), HBs-Ag, anti-HCV, and HCV-
mRNA (assessed only in cases with a positive result for anti-HCV).
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 parameters.
Biochemistry: glycosylated hemoglobin (HbA1c) and ferritin. 
Additional parameters20: 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-, potentially also Hepatitis D- Hepatitis E-, Cytomegalo-, Epstein-
Barr-, and Herpes simplex virus infection, brucellosis, leptospirosis, and toxoplasmosis, 
ANA/ANCA screening test with further tests depending on result and IgA, IgG, and IgM.
                                                
20 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)

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 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.
For urine pregnancy test, see Section 9.6.2.
9.6.3.4
Cervical cytology
The cervical cytology 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, cervical cytology should only be repeated once in case of 
insufficient material.  
9.6.3.5
Physical and gynecological examinations
Complete physical examinations will be done for all subjects. Gynecological examinations, 
including breast palpation, will be performed in subjects who did not have this performed 


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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.
9.6.3.6 Ultrasound
Ultrasound examinations (evaluated for efficacy and safety) will be performed by a qualified 
expert in performing gynecologic ultrasound exams.  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.  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 within the visit window.
The following safety parameters will be documented:  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 start of treatment, the subject 
should undergo immediate evaluation by endometrial biopsy.
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 as described in Section 9.7.3.
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 printouts and/or CDs with images from 
the ultrasound machine showing the endometrium in sagittal section and both ovaries. The 
printouts and/or CD images have to be labeled unambiguously, containing at least the study 
number, subject number, time point, endometrial thickness, and side (left/right) for ovaries.
For efficacy ultrasound procedures, see Section 9.4.3. (valid only before implementation of 
Protocol Amendment no. 7).
9.6.3.7
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 and BMI will be 
determined once again at the safety closeout visit.
9.6.3.8
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. 


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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 participant. 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
o
Any relevant finding that requires further diagnostic or therapeutic 
measures according to medical standard
o
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 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.
EoT = end of treatment, MRI = magnetic resonance imaging
9.6.3.8.1
Timing of adrenal monitoring
Subjects will undergo scheduled adrenal monitoring at the safety closeout visit.
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 9.6.3.8.4).
Adrenal monitoring also needs to be performed in subjects who started treatment and have 
discontinued the study before or during the temporary pause. After re-consenting, data related 


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to adrenal monitoring and their results will be documented in the CRF 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.
9.6.3.8.2
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 9.6.3.8 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. 
9.6.3.8.3
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 subject’s 
DHEA-s value by the lower limit of the age-specific reference range) will be 
calculated.
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 


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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 (see also Figure 9–2).
9.6.3.8.4
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 eCRF (4). 
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.
9.6.3.9
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 9.6.3.9.1. 
In addition, the liver inquiry had to be completed at regular intervals. Based on the long 
interval between implementation of Protocol Amendment no. 7 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) however 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 alternative explanations should be performed including:

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. 


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
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.
9.6.3.9.1
Liver symptom inquiry
In the past, 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. 
Therefore, investigators should ask subjects 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 structures inquiry was used to determine withdrawal criteria 
and is therefore not needed at the Safety Closeout Visit.
9.6.3.10
Skin monitoring
All subjects who have taken at least one dose of the study medication vilaprisan will undergo 
a thorough skin examination by a dermatology expert. 
The outcome of the dermatology expert’s examinations will be reported in the eCRF. 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 vilaprisan treatment, and have 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, and if applicable any related AEs and respective 
concomitant medications are to be captured. 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.
9.6.3.11
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.
9.7
Other procedures and variables
9.7.1
Induction of bleeding
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 (see Section 8.1.1).  
During the drug-free interval: If, for any of the treatment groups, no bleeding occurs within 
7 weeks after the end of TP1 or if the second bleeding episode does not occur within 7 weeks 


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after the end of the first bleeding episode, an ultrasound will be performed (in an unscheduled 
visit) after which bleeding will be induced. TP2 should only start within Day 3 and Day 7 of 
the second bleeding episode following the end of the TP1, and if one of the two bleeding 
episodes being spontaneous. If induction of bleeding is required more than once, the 
investigator should consider any underlying conditions, and assess continued participation of 
the subject.
After EoT visit: If spontaneous menstrual bleeding does not occur within 7 weeks after the 
EoT of TP2, an ultrasound will be performed after which the bleeding will be induced.  The 
planned endometrial biopsy (ie, at FUP visit) will be scheduled at Cycle Day 7 to 15 
(inclusive) of the first menstrual cycle after the induced bleeding episode (i.e. after the 
induced and the first spontaneous bleeding). 
9.7.2
Histology of endometriotic lesion 
If any subject is scheduled to have pelvic surgery during the study, every attempt should be 
made to obtain histologic data from any visible focus of endometriosis. Surgical excision of 
any endometriotic lesions during treatment will have to be reported by the sites. A histologic 
assessment of endometriotic lesions will be performed by expert pathologists as further 
described in the Operational Manual.
9.7.3
Monitoring of ovarian cysts
If cyst like structures >30 mm without suspicious appearance (ie, functional ovarian cysts) are 
visualized in the ovaries, unscheduled ultrasound examinations are recommended to 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 on 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.
9.7.4
Biomarker investigation
The biomarker (BM) investigation will be exploratory. Blood samples and endometrial 
biopsies (only remaining material from the endometrial biopsies after its safety assessment 
will be used for exploratory BM investigations) will be collected.
The biomarker investigation is not applicable for China due to regulatory guidance.
Details on the collection, processing, storage and shipment of BM samples will be provided in 
a separate document (e.g. sample handling sheet or lab manual). 
The objective of the BM investigation is to monitor the disease activity and therapeutic 
efficacy of vilaprisan by molecular BMs (i.e. disease activity BMs). Disease activity BMs will 
be measured including but not limited to cancer antigen 125, urocortin, annexin V, high 
sensitivity C-reactive protein and brain derived neurotrophic factor.


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Exploratory BM analysis on the expression of endometrial genes/proteins will be performed.
In addition to the BMs listed above, other BMs deemed relevant to gain further knowledge 
about the pathomechanism of the disease or about the drug (i.e. mode of action related effect 
or safety of the drug, disease modifying potential and therapeutic efficacy) may be measured, 
based on newly emerging data from other ongoing studies and / or literature data.
The monitoring BMs will be investigated by utilizing multiplex immunolabelling approaches 
(e.g. Luminex technology). BMs not available for multiplexing will be evaluated separately 
(e.g. by enzyme-linked immunosorbent assay [ELISA] assays).
Details on the description of the methods and the results of the conducted BM analysis will be 
reported in a separate document (i.e., BM report). 
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.
10.
Statistical methods and determination of sample size
10.1
General considerations
All data will be presented in the subject data listing as they are recorded. Generation of 
listings will be conducted by or under the supervision of the sponsor’s study statistician.
Listings will be generated using Statistical Analysis System (SAS) software after all safety 
data has been cleaned, locked and released for analysis. 
Apart from listing generation no further statistical analysis or summary table 
generation will be conducted. No interim analysis will be conducted.
10.2
Analysis sets
Safety analysis set (SAF):  All subjects who took at least 1 dose of study drug.  
10.3
Variables and planned statistical analyses
10.3.1
Variables
10.3.1.1
Efficacy variable
Efficacy data will be listed as they are recorded on the Case Report Form (CRF) and 
electronic diary (eDiary). Efficacy variables will be not derived. 
10.3.1.2
Pharmacokinetics (PK)
Exposure data listings will be generated.
10.3.1.3
Safety variables
Safety variables include the following variables:

Adverse events

Vital signs


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
Endometrial histology (classical histology, diagnosis of PAEC, individual features 
of PAEC)

Endometrial thickness and endometrial/ myometrial/ ovarian changes based on 
ultrasound

Laboratory parameters 

Findings resulting from liver monitoring

Findings resulting from adrenal monitoring

Findings resulting from skin monitoring Cervical cytology

Bone mineral density 

Vaginal bleeding pattern 
Safety data will be listed as recorded.
10.3.2
Statistical and analytical plans
NA
10.4
Determination of sample size
No longer valid, since with approval of Protocol Amendment no. 7 no new subjects will 
be recruited and no study medication 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.
This Phase 2b dose-finding study was powered for an analysis of the primary efficacy 
variable in the study population with surgically confirmed endometriosis from North America 
(US and Canada), Japan, and Europe, i.e. excluding China and Taiwan. Subjects from China 
and Taiwan and subjects with endometriosis diagnosed based on imaging (MRI and/or 
transvaginal ultrasound) were planned to be excluded from the primary analysis because these 
subjects might differ from subjects with surgically confirmed endometriosis in North 
America, Japan and Europe.
In a Phase 2 study (in the context of another Bayer endometriosis project) in subjects with 
surgically diagnosed endometriosis, a change of -2.4 units in the subject’s 7-day mean ‘worst 
pain’ from baseline to end of the 3-month treatment course was observed in placebo treated 
subjects. For subjects treated with an active comparator (leuprorelin / leuprolide acetate) a 
change of about -3.7 units and a standard deviation of 2.3 units were observed. The drop-out 
rate in the placebo arm was 15% and in the active comparator treatment arm the rate was 
12.5%.
These estimates were used to determine the sample size for the Dunnett test design of this 
study using a simulation with the sample size program Pass 13 (Version 13.0.11 Multiple 
comparisons vs. a control [simulation]).
The simulation of a one-way design with 2 treatment groups and one control group resulted in 
an average group sample size of 59 subjects for a total sample size of 177 subjects. In the 
simulation an any-pair power of 0.903 and an all-pair power of 0.696 using the Dunnett's Test 
procedure for comparing each treatment mean with the control mean were achieved. The 
target family-wise two-sided error rate was 0.050 and the simulation family-wise error rate 


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was 0.049. The average within group standard deviation assuming the alternative distribution 
was 2.3. These results are based on 2000 Monte Carlo samples from the null distributions: the 
change of all three treatment groups is normal distributed with mean value of -2.4 units and 
standard deviation of 2.3 units and the alternative distributions: the change of all three 
treatment groups is normal distributed with standard deviation of 2.3 units and a mean value 
of -2.4 units for placebo and -3.7 units for 2 mg vilaprisan and 4 mg vilaprisan.
Seventy subjects for a total sample size of 210 subjects were planned to be randomized in 
each treatment arm to achieve 59 subjects with data after the first 3-month treatment interval
assuming a dropout rate of 15% during the first 3-month treatment interval. 
It was planned to randomize about 50% of the 210 subjects with surgically diagnosed 
endometriosis in centers from the US / Canada, 30% in centers from Europe, and 20% in 
centers from Japan.
To assess the safety of Vilaprisan, approximately 100 actively treated subjects (Vilaprisan 2 
mg or Vilaprisan 4 mg) with a treatment duration of one year were planned to be observed. 
The dropout rate for a one-year treatment was assumed to be 50%. In order to achieve 100 
active vilaprisan-treated subjects with a treatment duration of one year, the calculated sample 
size of 210 subjects was planned to be increased by a further 105 subjects.
These additional 105 subjects could have been either surgical or imaging diagnosed. 
However, it should have been ensured that the number of imaging diagnosed subjects does 
not fall significantly below 63.
10.5
Planned interim analyses
With implementation of Protocol Amendment no. 7, the initially planned interim analysis is 
cancelled. 
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 was 
entered/transmitted into a validated database or data system (Clinical Information 
Environment).
Data required according to this protocol was recorded by investigational site personnel via 
data entry into the internet based electronic data capture software system RAVE, which Bayer 
has licensed from Medidata Solutions Worldwide.  RAVE had 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.


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All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software.  All internal Bayer and external investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer's clinical studies.  Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System 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 was available both at the investigator’s site and at Bayer.  Data 
entries made in the RAVE EDC screens were 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 electronic 
Patient-Reported Outcome (device) (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
At a minimum, the following data should be 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


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For all subjects continuing after Visit 1, all data have to be reported until screen failure was 
declared or randomization occurred. Additionally to the above mentioned data these will 
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).  
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to 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 will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance 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 will be 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
will be used. MedDRA will be used for AEs and medical history and WHO Drug Dictionary
for prior and concomitant medication.
The results of endometrial biopsies taken after the FUP/Safety Closeout 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.


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11.4
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.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) 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.
11.5
Missing data 
Possible sources of missing data in clinical trials are 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 the equivalent to 
withdrawal of informed consent.  In cases where subjects indicate they do not want to 
continue the study investigators must determine whether this refers to discontinuation of study 
treatment or unwillingness to attend the EoT visit.  For subjects prematurely discontinuing the 
study treatment, safety and efficacy data should be further collected until the final visit.
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 
(e.g. 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.


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12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; 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 (e.g. SAEs)
- Results of any interim analysis
- Results of parallel clinical studies
- Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
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 (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

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 is given by the sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 6.5.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
All study personnel 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 (e.g. 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.


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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, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
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 according to 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 modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented 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.


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13.4
Subject information and consent
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.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject), prior to his/her entry into the study (i.e. 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 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 statistical analysis plan. 

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. 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 statistical analysis plan.  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.
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study.  Additionally, the investigator or designee will personally sign and date 
the form.  The subject / legal representative or proxy consenter will receive a copy of the 
signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that 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 prior to these procedures.
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness.
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters 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 
written informed consent form.  The investigator will inform the subject / legal representative 


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or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use.
13.5
Publication policy and use of data
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 
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 subject 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 CRF, and if the subject name appears on any other document (e.g. 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 in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their source documents 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. Kennedy, S., Bergqvist, A., Chapron, C., D'Hooghe, T., Dunselman, G., Greb, R., 
Hummelshoj, L., Prentice, A. & Saridogan, E. 2005. ESHRE guideline for the 
diagnosis and treatment of endometriosis. Hum Reprod, 20, 2698-704.
2. Cook AJ, Roberts DA, Henderson MD, Van Winkle LC, Chastain DC, and Hamill-
Ruth RJ 2004 Electronic pain questionnaires: a randomized, crossover comparison 
with paper questionnaires for chronic pain assessment. Pain;110:310-7. 
3. Jamison RN, Gracely RH, Raymond SA, Levine JG, Marino B, Herrmann TJ, Daly M, 
Fram D, and Katz NP 2002 Comparative study of electronic vs. paper VAS ratings: a 
randomized, crossover trial using healthy volunteers. Pain;99:341-7.
4. 2018 Draft Guidance for Industry: Assessment of Pressor Effects of Drugs 
(https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinforma 
tion/guidances/ucm609185.pdf
5. Kloos RT, Gross MD, Francis, IR, Korobkin, M, Shapiro, B. Incidentally discovered 
adrenal masses. Endocr. Rev. 1995; 16(4):460-84
15.
Protocol amendments
Amendment 2 is presented using an updated amendment approach. The rationale for changes 
in this amendment and all affected sections are provided right before the Table of Contents in 
this document. A detailed description of changes compared to the last global Clinical Study 
Protocol (CSP) version is replaced by a track change protocol, separate from this document. 
15.1
Overview of changes of AMD 2 triggered by Health Authority feedback
This amendment is based on FDA’s request on more robust liver safety data because of a 
possible liver safety signal observed with another drug in the same product group of selective 
progesterone receptor modulators (PRMs) as vilaprisan.


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Table 15–1:
Proposed update of the design of the Villendo study (Treatment Period 1)
Trial Periods
Screening phase (Maximum 
75 days)
Dose-finding phase
Treatment-period (TP) 1
Drug-free 
interval
Visit Number
1
2
3
4
5
6
7
8
Time Window
>28 days 
before 
randomi-zation
If biopsy or 
BMD not taken 
at Visit 1u
Randomi-
zation
Week 4-6 
Day 
22 – 42 
Week 12 
Day 
78 – 84 
Week 18 
Day 
120 – 126
Week 24 
Day 
162 - 168
6 weeks after 
last study drug 
intake
Safety laboratory and urinalysis 
(including coagulation)
X
Xu
Safety laboratory and urinalysis 
Xu
X
X
X
X
X
u
For subjects with any elevation of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, and total bilirubin) 
greater than ULN observed at Visit 1, a repeat blood test for serum chemistry panel will be done and will be considered as baseline values in case the subject is randomized. For those subjects 
who are randomized, an additional blood test for serum chemistry panel after 2-3 weeks of treatment will be done.
Table 15–2:
Proposed update of the design of the Villendo study (Treatment Period 2)
Trial Periods
Extension phase 
Treatment Period (TP) 2
Follow-up phase
Visit Number
9
10 
End of Treatment
11 
Follow-up visit 1
12 
Follow-up visit 2
Time Window
Week 12 
Day 78 – 84 
after start of TP 2
Week 24 
Day 162 – 168 
after start of TP 2
Weeks 10 – 14 
after last study drug 
Week 22 – 24
after last study drug
Safety laboratory and urinalysis 
X
X
X


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FDA proposed to draw attention to signs and symptoms which may be associated with 
liver dysfunction.
The section on Adverse Events of Special Interest will be updated with the following new 
additions (underlined) described below, putting emphasis on patients proactively reporting 
symptoms that they perceive as unusual or of concern will result in medically meaningful 
interactions with the investigators. This is because many symptoms associated with liver 
disorders are also unspecific and may be known to the patients or occur in the context of 
minor illnesses. Therefore patient judgement with regards to unusualness of symptoms is an 
important component.  
9.6.1.6 Adverse events of special safety interest
[…]

Liver enzymes and liver disorders:
The study subjects should be made aware of the potential signs and symptoms that could 
indicate the onset of a relevant liver disorder and should be reminded regularly to contact the 
study site immediately, if they concerned about such symptoms. Symptoms can include 
anorexia, nausea, fatigue, right upper abdominal discomfort, vomiting, malaise, jaundice, 
fever, and rash. 

If the GPT/ALT or GOT/AST value increases to x ULN after start of study drug 
treatment, a close observation has to be initiated. This should include
-
repeating liver enzymes and serum bilirubin measurements 2 to 3 times per 
week; 
-
obtaining a more detailed history of the symptoms, obtaining a history of 
concomitant drug use, alcohol use, recreational drug use, and special diets, 
ruling out acute viral hepatitis, additional tests to evaluate liver function as 
appropriate, (eg, international normalized ratio [INR], direct bilirubin 
measurements). 
-
Any of these additional findings is to be recorded on the corresponding eCRF 
pages (eg, for concomitant medication, lab assessment) in RAVE. The intense 
monitoring should be performed until resolution or stabilization of the 
corresponding lab values.

Subjects have to be withdrawn from treatment in the following cases:
GPT/ALT or GOT/AST value increases to 8 x ULN
GPT/ALT or GOT/AST > 5 x ULN for more than 2 weeks
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
GPT/ALT or GOT/AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5

As an additional measure, subjects with mild increases of liver enzyme levels not 
exceeding the limits for inclusion at Visit 1 (Section6.3, 4b) will undergo two 
additional serum chemistry panel blood tests, i.e.: 


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-
one within screening phase at Visit 2. A subject will be only eligible if no 
further increases of liver enzyme levels as compared to those measured at Visit 
1, and 
-
If a subject is randomized, one additional serum chemistry panel blood tests
within 3 weeks after start of treatment at an unscheduled visit, prior to Visit 4.
Other changes compared to the last global CSP version are marked in the separate track 
change protocol.
15.2
Overview of changes of AMD 3 triggered by FDA recommendation 
Overall Rationale:. The purpose of this amendment is to address specific recommendations 
from a Health Authority for liver safety monitoring due the potential risk of liver injury 
observed with another drug in the same product group of selective progesterone receptor 
modulators (PRMs) as vilaprisan.
Amendment 3 is presented using a different approach compared with previous amendments to 
this protocol. The rationale for changes in this amendment and affected sections are provided 
in the “Protocol Amendment Summary of Changes table “ directly before the Table of 
Contents on this document. A separate document with tracked changes as against the last 
integrated protocol version is available on request.
Modification 1: Addition / change of exclusion criteria
Exclusion criteria regarding liver symptoms and parameters were updated upon request of the 
FDA (FDA feedback on 19 January 2018 and 18 May 2018 regarding improved liver 
monitoring and feedback regarding the inclusion of subjects based on their baseline DEXA Z-
score aligned with Asteroid 6 study in the uterine fibroid indication) (see Section6.3):
a.
Abnormal liver parameters (presence of at least one of the following criteria): 
i.
2 x upper limit of normal (ULN) for glutamic oxaloacetic transaminase (GOT) / 
aspartate aminotransferase (AST) 
ii.
2 x ULN for glutamic pyruvic transaminase (GPT) / alanine aminotransferase (ALT) 
iii.
2 x ULN for alkaline phosphatase (AP) 
iv.
Total bilirubin outside the upper limit of normal range
v.
International normalized ratio (INR) outside the upper limit of the normal range
21.
Screening DXA Z score ≤ –2.0 SD for lumbar spine (L1-L4), OR femoral neck, OR total hip 
BMD as per central reading.
Modification 2: Additional blood tests in all patients in the study: monthly during treatment 
and also after 4 weeks during the drug-free interval between the treatment periods following 
the FDA request (more robust liver safety data, additional liver parameter tests in all patients 
with elevated baseline liver parameters).


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9.1 Tabular schedule of evaluations and 9.2.3 Scheduled  visits displays the modified visit 
schedule:
Visit 4: Week 4 Day 22-28 (from previous time window Day 22-42);
Visit 4.1: Week 8 Day 50 - 56 (new);
Visit 5: Week 12 Day 78 – 84 (no change); 
Visit 5.1: Week 16 Day 106 – 112 (new);
Visit 6 Week 20 Day 134 – 140 (from Day 120-126)
Visit 7: Week 24 Day 162 - 168 (no change);
Visit 8: Week 4-6 after last study drug intake
Day 22-42 (from 6 weeks after last study drug intake)
Visit 8.1: at Week 4 (Day 22-28) after start of TP 2 (new), 
Visit 8.2: at Week 8 (Day 50 - 56) after start of TP 2 (new), 
Visit 9: at Week 12 (Day 78 - 84) after start of TP 2 (no change), 
Visit 9a: at Week 16 (Day 106 – 112) after start of TP 2 (new), 
Visit 9b: at Week 20 (Day 134 – 140) after start of TP 2 (new)
Visit 10: Week 24 after start of TP2 Day 162 to 168 (no change)
Section 9.1 Tabular schedule of evaluations was updated accordingly with additional visits 
4.1, 6.1, 8.1, 8.2, 9.1, and 9.2 and modification of visit windows.
Table: Update of the design of the Villendo study (Treatment Period 1)
Trial Periods
Screening phase 
(Maximum 75 days)
Dose-finding phase
Treatment-period (TP) 1
Drug-free 
interval
Visit Number
1
2
3
Rando-
mization
4
4.1*
5
5.1*
6*
7
8
Time Window
>28
days 
before 
randomi
-zation
If biopsy 
or BMD 
not 
taken at 
Visit 1u
Week 4 
Day 
22 – 28 
Week 8 
Day
50 - 56
Week 12 
Day 
78 – 84
Week 
16 
Day 
106 –
112 
Week 
20 Day 
134 –
140
Week 
24 
Day 
162 -
168
Week 4-6 after 
last study drug 
intake
Day 22-42
Safety 
laboratory and 
urinalysis 
(including 
hormones, 
cortisol, 
coagulation, 
blood test for 
hepatitis A, B, 
and C)q
X
Xu
X
X
X
X
Safety 
laboratory for 
serum 
chemistry 
(including at 
least ALT, 
AST, AP, total 
bilirubin, g GT, 
and albumin)
X
X
X
X
Liver symptom 
inquiry
X
X
X
X
X
X
X
X
X
X
q.
Coagulation, blood test for hepatitis A, B, and C will be only checked at screening.


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  92 of 99
u.
The safety laboratory tests may be repeated once during the screening period if laboratory values are outside the 
inclusion range and assessed as clinically relevant (this repeat is not considered rescreening). 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 patient is eligible only if the second test 
shows a stabilization or decline in those values...
X visit deleted from schedule  X  visit added to schedule  
* These visits do not necessarily have to be performed at the study site


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  93 of 99
Table: Update of the design of the Villendo study (Treatment Period 2)
Trial Periods
Extension phase Treatment Period (TP) 2
Follow-up phasea
Visit Number
8.1*
8.2*
9
9.1*
9.2*
10 
EoTl
11 
FUP1l
12 
FUP2
Time Window
Week 4 
(Day 22 -
28) after 
start of 
TP 2
Week 8 
(Day 50 -
56) after 
start of 
TP 2
Week 12 
(Day 78 -
84) after 
start of 
TP 2
Week 16
(Day 106 
- 112) 
after start 
of TP 2
Week 20
(Day 134 
- 140) 
after start 
of TP 2
Week 24 
(Day 162 
to 168) 
after start 
of TP 2
Weeks 10 
to 14 after 
last study 
drug 
Day 64-98
Week 22 to 24
after last study 
drug intake 
Day 148-168
Safety laboratory 
and urinalysis 
(including hormones 
and cortisol) 
X
X
X
Safety laboratory 
for serum 
chemistry
(including at least 
ALT, AST, AP, 
total bilirubin, g 
GT, and albumin)
X
X
X
X
Liver symptom 
inquiry
X
X
X
X
X
X
X
X
* These visits do not necessarily have to be performed at the study site, X  visit added to schedule  
Modification 3: Need for closer observation of AESIs as described in Section 9.6.1.6 AEs as 
per Health Authority request (and the 2009 FDA Drug-Induced Liver injury [DILI] guideline) 
lead to following changes
Liver enzymes and liver disorders:
If the GPT/ALT or GOT/AST value increases to 3 x ULN 
OR
2-fold increases above the lowest baseline value after (for subjects with elevated values at 
baseline) start of study drug treatment, a close observation has to be initiated (see below) and 
recorded in the dedicated liver case report form. 
Study drug can be continued with close observation as long as withdrawal criteria based 
on liver parameters specified below are not met.
Close observation includes:
-
Repeating a serum chemistry panel (including liver enzymes and bilirubin) 
measurements 2 to 3 times per week. Frequency of retesting can decrease to once a 
week or less if abnormalities stabilize.
-
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; NASH; 
hypoxic/ischemic hepatopathy; and biliary tract disease. This may require performing 
additional procedures, e.g. ultrasound examinations.


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  94 of 99
-
Obtaining a history of exposure to environmental chemical agents. 
-
Obtaining additional tests to evaluate liver function as appropriate, (eg, 
international normalized ratio [INR], direct bilirubin measurements). 
Any of these additional findings is to be recorded on the corresponding eCRF pages (eg, 
for concomitant medication, lab assessment) in RAVE. A structured overview on this 
to-be-collected data can be provided to the site. 
Close observation should continue regardless of time point in the study (ie Treatment 
Periods, drug free intervals, follow up). If liver parameters stabilize to inclusionary 
range during the drug free interval (no further increase during 3 consecutive 
measurements) and did not reach withdrawal criteria (as specified below) during the 
period of close observation, subjects can continue with planned study drug intake in 
the next treatment period as scheduled, after consultation with the sponsor
Minor changes and typo corrections are not mentioned in this compilation.
15.3
Overview of changes of AMD 6 triggered by FDA recommendation 
Preliminary findings from 2-year animal carcinogenicity studies (rat/mouse) with vilaprisan 
that were received in 2018 showed evidence of an increased incidence in endometrial and 
adrenal neoplasms. While these unexpected findings and their relevance for humans were 
being further evaluated, Bayer decided to temporarily pause enrollment and randomization,  
and to temporarily stop study treatment in already randomized patients after completion of the 
ongoing treatment period. Global Protocol Amendment 6 (version 4.0) provided background, 
justification, as well as a detailed description of the temporary measures to be taken. 
Section # and 
Name
Description of Change
Brief Rationale
15.3 Global 
amendment leading 
to version 4.0
Added text specifying measures for 
temporary pause of the study
Temporarily pause enrollment and 
randomization, and to temporarily stop 
study treatment in already randomized 
patients after completion of the ongoing 
treatment period
Background and justification of changes 
with AMD 6 were added, the relevance 
to the human situation explained,  
clinical data collected up to the amd 
summarized, and measures of monitoring 
in ongoing studies were stated
Rationale and description of temporary 
measures triggered by preliminary 
findings in 2-year animal carcinogenicity 
studies were to be communicated to 
patients, investigators and HAs
Enrollment was to be stopped and no 
patients were to be randomized and/or 
newly start treatment, procedures for 
those patients who were randomized and 
had study drug intake of at least one dose 
were detailed depending on whether they 
were in a scheduled treatment break or a 
treatment period at that time
In addition to the 15-day report on 
03 DEC 2018 (temporary suspension of 
enrolment and randomization) more 
details were specified with the amd


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  95 of 99
Section # and 
Name
Description of Change
Brief Rationale
Signs and symptoms suggestive of 
increased levels of adrenal hormones 
were communicated
15.4
Overview of changes of AMD 7 to prepare this study for an orderly 
closure
Amendment no. 7 (19 NOV 2019)
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 no. 6) 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 and introduction section 3), 
Bayer will conduct a comprehensive safety follow up to provide additional confirmatory 
evidence. This amendment (Protocol Amendment no.7) introduces measures and processes to 
prepare this study for an orderly closure, including safety follow up measures in all study 
participants who received at least one dose of study drug vilaprisan.
Section # and 
Name
Description of Major Changes
Brief Rationale
2 Synopsis; 3 
Introduction and 
subsections, and 
4 Study 
objectives
Information on carcinogenicity studies 
with vilaprisan in rodents as well as 
details regarding the additional safety 
measures were added to the section, 
included adrenal monitoring, 
endometrial monitoring, 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
5 Study design; 
Dose and 
regimen
Safety 
Monitoring
6 Study 
population
6.5.1 
Safety monitoring: adrenal and skin 
safety section added
Information deleted that is no longer 
relevant
Safety monitoring: adrenal, liver and 
skin safety section added
Assessment of effects on bone mineral 
density
To address FDA request 
With the implementation of this 
amendment no new subjects will 
be recruited and no study 
medication will be given to the 
subjects who have been enrolled 
in the study
To address FDA 
recommendations; to characterize 
any potential adrenal effects of 
vilaprisan or effect on skin


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  96 of 99
Section # and 
Name
Description of Major Changes
Brief Rationale
Withdrawal
7 Treatments
Study medication will not be 
dispensed again
No study medication will be 
given to the subjects who have 
been enrolled in the study
7.5 Blinding
Unblinding will be introduced for all 
subjects
To avoid invasive procedure in 
subjects not treated with 
vilaprisan, since no efficacy data 
will be analyzed in this study..
8 Non-study 
therapy, 8.2 
Post-study 
therapy
Specification given for post-temporary 
pause period
To address the newly introduced 
Safety Close out visit” and the 
“Safety Result Reporting visit”
9.1 Tabular 
schedule of 
evaluations
Information deleted that is no longer 
relevant; added “Safety Closeout visit” 
and “Safety Result Reporting visit” 
To depict the procedures of the 
“Safety Close out visit” and the 
“Safety Result Reporting visit”.
9.2 Tabular 
schedule of 
evaluations and
9.2.3 Scheduled 
visits; 9.2.4 Pre-
mature disconti-
nuation visit; 
9.2.2 Optional 
pre-screening 
phone contact; 
9.4 Efficacy
information deleted that is no longer 
relevant
To address the newly introduced 
Safety Close out visit” and the 
“Safety Result Reporting visit”
9.6.1.1 
Definitions
New criteria for SAE reporting for 
endometrial biopsies, adrenal tumors, 
and malignant skin tumors
To address FDA request.
9.6.1.6 AEs of 
special interest
New AESIs added for adrenal and skin 
disorders, relevant loss of BMD, and 
liver disorder
To address FDA request. 
9.6.3.1 
Endometrial 
biopsies and 
subsections 
Content reorganized from Section 
9.7.2
Timing of last endometrial biopsy 
described, algorithm updated
newly created section with 
Extended safety monitoring to 
address FDA request, measures at 
close-out of the study, to facilitate 
investigators’ and HA´s review 


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  97 of 99
Section # and 
Name
Description of Major Changes
Brief Rationale
consolidated content to clarify and 
describe in greater detail process for 
abnormal endometrial biopsies follow 
up within study framework with multi-
reader assessment.
9.6.3.3 
Laboratory 
evaluations
Added more details for laboratory 
parameters associated with adrenal 
disorder
To address FDA request on 
extended safety monitoring 
(adrenal monitoring)
9.6.3.2 Bone 
mineral density 
and 9.6.3.6 
Ultrasound
Content of Section 9.6.2 and 9.6.3 
shifted to Section 9.6.3.5 Ultrasound 
and 9.6.3.6 and revised to reflect 
collection of parameters at the safety 
closeout visit
To facilitate investigators’ and 
health authority (HA)´s review, 
update necessary due to new visit 
structure
9.6.3.1.7 Heavy 
menstrual 
bleeding
Content reorganized from Section 
9.7.3. New section of Standard criteria 
and evaluation plan for patients with 
unusual HMB or new onset bleeding 
pattern added.
To facilitate investigators’ and 
HA´s review of previous and 
newly introduced measurements
9.6.3.8 Adrenal 
monitoring
New section to describe adrenal 
monitoring (MRI, laboratory 
investigations and symptom inquiry) 
and findings that require referral to 
expert
To address FDA request
9.6.3.9
Liver 
monitoring
Combined descriptions of liver 
monitoring from previous locations 
(e.g., in Section 9.6.1.6)
To facilitate investigators’ and 
HA´s review of previous and 
newly introduced measurements 
of improved liver monitoring
9.6.3.10 Skin 
monitoring
New section to describe skin exam 
To address FDA request
10. Statistical 
Methods and 
determination of 
sample size
Deletion of all statistical analyses and 
summary statistics
To reflect that only few subjects 
were randomized to treatment
Minor changes and typo corrections are not mentioned in this compilation.


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  98 of 99
15.5
Overview of changes of AMD 8
Modification:
This amendment (Protocol Amendment no.8) adds a clarification present in the other study 
protocols of the vilaprisan development project uterine fibroids, i.e. that in subjects who 
discontinued the study during the temporary pause and now get reconsented, conditions that 
newly occurred or worsened during the off-study period should be documented as AEs.
A separate document with tracked changes as against the last integrated protocol version 
(AMD 3) is available on request.
Section # and 
Name
Description of Major Changes
Brief Rationale
9.6.1.1 
Definitions
In subjects who discontinued the study 
during the temporary pause and now 
get reconsented, conditions that newly 
occurred or worsened during the off-
study period should be documented as 
AEs
For alignment with the other 
protocols of the uterine fibroids 
indication of vilaprisan.
15.6
Overview of changes of AMD 9
The rationale for the HA requested 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


Amendment no. 9 to
Clinical Study Protocol
No.  BAY 1002670 / 15792
Version 7.0
Page:  99 of 99
16.
Appendices
16.1
CYP3A4 inhibitors
Table 16–1:
Strong CYP3A4 inhibitors
Substance name
Inhibitor strength
Boceprevir
Strong
Clarithromycin
Strong
Grapefruit juice
Depend 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
CYP3A4 inducers
Table 16–2:
Strong CYP3A4 inducers
Substance name
Inducer strength
Phenobarbital
Strong
Avasimibe
Strong
Carbamazepine
Strong
Enzalutamide
Potent
Hypericum (St John's Wort)
Strong
Lumacaftor
Strong
Methylphenobarbital
Potent
Mitotane
Potent
Phenytoin
Strong
Rifampicin
Strong
Rifamycin
Strong

SAP_000.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A randomized, double-blind, parallel-group, multicenter Phase 2b 
study to assess the efficacy and safety of two different doses of 
vilaprisan (BAY1002670) versus placebo in women with 
symptomatic endometriosis 
NCT Number: 
NCT03573336 
Document Date: 
15 JAN 2020 
 


Statistical Analysis Plan
BAY 1002670/ 15792
Page: 1 of 5:
Reference Number: RD-SOP-1119
Supplement Version: 10
Title page
A randomized, double-blind, parallel-group, multicenter Phase 
2b study to assess the efficacy and safety of two different doses of 
vilaprisan (BAY 1002670) versus placebo in women with 
symptomatic endometriosis
Assess safety and efficacy of vilaprisan in subjects with endometriosis
Bayer study drug
BAY 1002670 / Vilaprisan
[Study purpose:]
Dose finding, safety
Clinical study 
phase:
IIb
Date:
15 Jan 2020
Study No.:
BAY 1002670 / 
15792
Version:
1.0
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/ 15792
Page: 2 of 5:
Reference Number: RD-SOP-1119
Supplement Version: 10
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 2
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 3
4.
General Statistical Considerations .................................................................................. 4
4.1
General Principles............................................................................................................ 4
4.2
Blind Review ................................................................................................................... 4
5.
Analysis Sets ...................................................................................................................... 4
5.1
Assignment of analysis sets ............................................................................................. 4
6.
Statistical Methodology .................................................................................................... 4
6.1
Population characteristics ................................................................................................ 4
6.2
Efficacy............................................................................................................................ 5
6.2.1
Biomarker..................................................................................................................... 5
6.3
Pharmacokinetics/pharmacodynamics............................................................................. 5
6.4
Safety ............................................................................................................................... 5
7.
Document history and changes in the planned statistical analysis............................... 5
Abbreviations
CRF
Case Report Form
CSR
Clinical Study Report
EIS
Endometriosis Impact Scale
ESD
Endometriosis Symptom Diary
PAEC
Progesterone receptor modulator-associated endometrial changes
PRO
Patient-Reported Outcomes
SAP
Statistical Analysis Plan


Statistical Analysis Plan
Protocol No.: BAY 1002670/ 15792
Page: 3 of 5:
Reference Number: RD-SOP-1119
Supplement Version: 10
1.
Introduction
The Statistical Analysis Plan (SAP) is based on the following clinical study protocol (CSP) 
version:

Amendment 07 and 08 global amendments forming integrated protocol 
Version 6.0, dated 28 NOV 2019
2.
Study Objectives
Originally, the study includes the following objectives:
Primary objective:

assess efficacy of two doses of vilaprisan compared to placebo in women with 
symptomatic endometriosis 
Secondary objective:

evaluate the safety and tolerability of two different doses of vilaprisan in women 
with symptomatic endometriosis 
Exploratory objective:

explore efficacy and safety in sub-populations (e.g. subjects with endometriosis 
diagnosed by imaging vs subjects with surgically confirmed endometriosis) 
Other objectives:

evaluate the variability in exposure in relation to the efficacy and safety for 
vilaprisan in subjects with symptomatic endometriosis 

confirm psychometric properties of the newly developed Patient-Reported 
Outcomes (PRO) instruments: Endometriosis Symptom Diary (ESD) and 
Endometriosis Impact Scale (EIS) (will be analyzed and reported separately) 

evaluate biomarkers to investigate the drug (i.e. mode-of-action-related effect and / 
or safety) and / or the pathomechanism of the disease including assessments of 
exploratory biomarkers to investigate disease activity 
With the implementation of the protocol amendments 07 and 08 no further recruitment is 
possible. With the data available from subjects recruited before the temporary pause the 
original study objectives cannot be reached. Safety evaluations including the added safety 
evaluations of the endometrium, adrenal glands, bone, and skin may add to the understanding 
of the safety of vilaprisan.
3.
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
The study originally includes the following phases: a screening phase, a placebo-controlled 
dose-finding phase, followed by a drug-free interval encompassing 2 menstrual bleeding 
episodes, a placebo-controlled extension phase, and a follow-up phase.
Endometriosis symptoms and their impact on subjects’ daily life was to be documented 
throughout the study, i.e. from start of the screening until the follow-up phase. 


Statistical Analysis Plan
Protocol No.: BAY 1002670/ 15792
Page: 4 of 5:
Reference Number: RD-SOP-1119
Supplement Version: 10
With the implementation of the protocol amendments 07 and 08, this study design is no 
longer valid. No subjects will receive further study drug treatment. 
Study design valid with the implementation of amendments 07 and 08:
The study was temporarily paused since December 2018. With the implementation of 
amendments 07 and 08 no further subjects will be recruited and none of the enrolled subjects 
will receive further study drug treatment. All subjects who were randomized and started 
vilaprisan before the temporary pause will be asked to have a comprehensive safety 
evaluation (with particular focus on endometrial, adrenal, and skin safety) performed, which 
is implemented with this amendment. This also applies to subjects who have discontinued the 
study before or during the temporary pause, provided they have taken at least one dose of 
vilaprisan.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). 
All data will be presented in the subject data listing as they are recorded. Generation of 
listings will be conducted by or under the supervision of the sponsor’s study statistician.
Listings will be generated after all safety data has been cleaned, locked and released for 
analysis. 
Apart from listing generation no further statistical analysis or summary table generation will 
be conducted. 
4.2
Blind Review
For all data collected prior to the protocol amendments 07 and 08, the results of the final data 
assessment for the assignment to analysis sets will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s) which will be finalized before 
the initial database lock. No important deviations and validity findings will be documented 
and evaluated at the final database lock.
5.
Analysis Sets
5.1
Assignment of analysis sets
Safety analysis set (SAF)
The safety analysis set population consists of all randomized subjects who received at least 1 
dose of study medication after randomization.
6.
Statistical Methodology
6.1
Population characteristics

Demographics and baseline characteristics

Medical history

Endometriosis relevant history


Statistical Analysis Plan
Protocol No.: BAY 1002670/ 15792
Page: 5 of 5:
Reference Number: RD-SOP-1119
Supplement Version: 10

Endometriosis treatment eligibility questionnaire

Reproductive and menstrual history

Drug accountability, treatment exposure and study drug expose

Prior/concomitant medication
Population characteristics will be be listed as recorded.
6.2
Efficacy
Efficacy data will be listed as they are recorded on the Case Report Form (CRF) and 
electronic diary (eDiary). Efficacy variables will be not derived. 
6.2.1
Biomarker 
The listings will be provided, if applicable.
6.3
Pharmacokinetics/pharmacodynamics
The listings will be provided, if applicable
6.4
Safety
Safety variables include the following variables:

Adverse events

Vital signs

Endometrial histology (classical histology, diagnosis of PAEC, individual features 
of PAEC)

Endometrial thickness and endometrial/ myometrial/ ovarian changes based on 
ultrasound

Laboratory parameters 

Findings resulting from liver monitoring

Findings resulting from adrenal monitoring

Findings resulting from skin monitoring

Cervical cytology

Bone mineral density 

Vaginal bleeding pattern 
Safety data will be listed as recorded.
7.
Document history and changes in the planned statistical analysis
All derivations of efficacy variables, all statistical analyses and summary statistics were 
deleted from the protocol with the implementation of the protocol amendment 07 and 08 to 
reflect that only a few subjects were randomized and/or received study medication.