Conditions: Uterine Fibroids
Keywords: Heavy menstrual bleeding
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
The primary objective of this study was to show superiority of vilaprisan in the treatment of heavy menstrual bleeding (HMB) in subjects with uterine fibroids compared to placebo

The secondary objectives of this study were to additionally evaluate the efficacy and safety of vilaprisan in subjects with uterine fibroids

Detailed description:

Arms:
arm 1: Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode. arm 2: Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode. arm 3: Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

Interventions: intervention 1: Vilaprisan (BAY1002670) intervention 2: Placebo
Intervention descriptions: intervention 1: Orally, coated tablet 2 mg, once daily intervention 2: Orally, coated tablet, once daily

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A randomized, parallel-group, double-blind and placebo-
controlled, multicenter study to assess the efficacy and safety of 
vilaprisan in subjects with uterine fibroids 
NCT Number: 
NCT03400956 
Document Date: 
17 FEB 2020 
 
 


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Cover page of the integrated protocol
A randomized, parallel-group, double-blind and placebo-controlled, multicenter study 
to assess the efficacy and safety of vilaprisan in subjects with uterine fibroids
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 04 SEP 2017

Amendment 01 (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 15 NOV 2017

Amendment 02 (global amendment described in Section 15.2)
forming integrated protocol Version 3.0, dated 04 JUL 2018

Amendment 04 (global amendment)
forming global protocol Version 4.0, dated 11 DEC 2018

Amendment 05 (global amendment described in Section 15.3)
forming integrated protocol Version 5.0, dated 20 NOV 2019

Amendment 06 (global amendment described in Section 15.4)
forming integrated protocol Version 6.0, dated 17 FEB 2020
Local amendments not forming part of this integrated global protocol:

Amendment 03 (dated 27 AUG 2018)
(local amendment, valid for Japan only)


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1.
Title page
A randomized, parallel-group, double-blind and placebo-controlled, multicenter study 
to assess the efficacy and safety of vilaprisan in subjects with uterine fibroids
Short title: Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids;
Acronym: ASTEROID 4
Test drug:
BAY 1002670 / Vilaprisan
Clinical study phase:
3
Date:
17 FEB 2020
Registration:
EudraCT no.2016-003561-26 Version no.:
6.0
Sponsor’s study no.:
15790
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981-0915, 
US
Sponsor’s medical expert:
Bayer U.S. LLC Pharmaceuticals 
Study Medical Experts Women’s Health
11 Waterview Blvd
Parsippany, NJ 07054, USA
Tel:
Email: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. 
Hence, the appearance of product names without these symbols does not imply that these names are not 
protected.
PPD
PPD
PPD


PPD
PPD


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


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2.
Synopsis
This section was changed in Amendment 1, see Section 15.1.1.
Title
A randomized, parallel-group, double-blind and placebo-controlled, 
multicenter study to assess the efficacy and safety of vilaprisan in subjects 
with uterine fibroids
Short title
Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids 
Acronym
ASTEROID 4 
Clinical study phase
3 
Study objective(s)
The primary objective of this study is to show superiority of vilaprisan in 
the treatment of heavy menstrual bleeding (HMB) in subjects with uterine 
fibroids compared to placebo. 
The secondary objectives of this study are to additionally evaluate the 
efficacy and safety of vilaprisan in subjects with uterine fibroids. With the 
implementation of this amendment (protocol amendment 5, Version 5.0), 
additional focus will be put on safety evaluations of the endometrium, 
adrenal glands and skin.
The other objectives of this study are to evaluate the variability in exposure 
in relation to the efficacy and safety for vilaprisan and to collect patient-
reported outcome (PRO) and clinician-reported outcome (ClinRO) data. 
Test drug
Not any longer applicable due to the closing of the clinical study. With 
the implementation of theprotocol amendment 5, Version 5.0 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 test drug were the following:
Vilaprisan (BAY 1002670) 
Name of active ingredient
Vilaprisan (BAY 1002670) 
Dose
2 mg, once daily 
Route of administration
Oral 
Duration of treatment
Treatment Group A1: vilaprisan, 2 treatment periods of 12 weeks, separated 
by 1 bleeding episode
Treatment Group B1: placebo, 1 treatment period of 12 weeks and 
vilaprisan, 1 treatment period of 12 weeks, separated by 1 bleeding episode
Treatment Group B2: vilaprisan, 1 treatment period of 12 weeks and 
placebo, 1 treatment period of 12 weeks, separated by 1 bleeding episode


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Reference drug
Not any longer applicable due to the closing of the clinical study. With
the implementation of theprotocol amendment 5, Version 5.0 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 reference- drug were the following:
Placebo 
Name of active ingredient
Not applicable 
Dose
Dose not applicable, once daily 
Route of administration
Oral 
Duration of treatment
See Treatment Groups B1 and B2 above 
Indication
Uterine fibroids 
Diagnosis and main criteria for 
inclusion /exclusion
With the implementation of the protocol amendment 5, Version 5.0 and 
aligned with the previous temporary pause measures, no new subjects 
will be enrolled in the study.
Originally, the study population had to fulfill the following criteria:
Women, 18 years or older, with at least 1 uterine fibroid documented by 
ultrasound at screening with largest diameter ≥30 mm and <120 mm and 
HMB in at least 2 bleeding periods during the screening period each with 
blood loss volume >80.00 mL, documented by the alkaline hematin (AH) 
method, will be eligible for enrollment in the study. Women who are 
pregnant, lactating, or have hemoglobin values ≤6 g/dL or any condition 
requiring immediate blood transfusion are not eligible. 
Study design
This is a randomized, parallel-group, double-blind, placebo-controlled, 
multicenter study. 


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Methodology
With the implementation of the protocol amendment 5, Version 5.0 no 
new subjects will be recruited and no study medication will be given to 
the subjects who have been enrolled in the study.
Subjects are not any longer required to document anything in the 
electronic diary (eDiary).
Any subjects who have taken at least one dose of study medication 
(including the subjects who completed the study or were permanently 
terminated) will be asked to undergo the safety evaluation procedures 
described in this document.
Prior to the temporary pause subjects were asked to document the intensity 
of their daily menstrual bleeding in the Uterine Fibroid Daily Bleeding
Diary (UF-DBD) and assess the intensity of their menstrual blood loss daily 
using a visual scoring system (Menstrual Pictogram [MP]) in an electronic 
diary (eDiary). Subjects were to collect the sanitary products used during
the study to analyze the volume of blood loss using the AH method.
Uterine fibroids were to be assessed during the study through ultrasound.
Patient-reported outcome (PRO) data were t collected using the Uterine 
Fibroid Daily Symptom Diary (UF-DSD) and the Uterine Fibroid Symptom 
and Quality of Life questionnaire (UFS-QoL). Clinician-reported outcome 
(ClinRO) data were collected using the Clinical Global Impression 
Investigator (CGI_I).
Safety is assessed by the evaluation of adverse events (AEs), laboratory 
parameters, endometrial biopsies, cervical smears, physical and 
gynecological examinations including ultrasound, and vital signs. In 
addition, liver parameters were monitored on a monthly basis during 
treatment.
The (population) pharmacokinetics (PK) and the effect of intrinsic and 
extrinsic factors on the variability in exposure were assessed by population 
PK analysis using sparse vilaprisan concentration samples.
Type of control
Not any longer applicable as with the implementation of theprotocol 
amendment 5, Version 5.0 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 theprotocol amendment 5, Version 5.0 no 
new subjects will be enrolled in the study and no subjects will be 
treated.
Any subjects who have taken at least one dose of study medication
(including the subjects who completed the study or were permanently 
terminated) will be asked to undergo the safety evaluation procedures 
described in this document.
Based upon the anticipated screen failures rates (60% in the US, 30% in
Japan, and 50% in other countries) about 329 subjects were planned to be 
enrolled to achieve the planned number of randomized subjects.
A total of 156 subjects were planned to be randomized as follows (52
subjects in each treatment group). 
Primary variable
Amenorrhea (yes/no), defined as menstrual blood loss (MBL) <2 mL during 
the last 28 days of treatment


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Time point/frame of 
measurement for primary 
variable
Presence of amenorrhea after 12 weeks of treatment in Treatment Period 1 
Plan for statistical analysis
The primary efficacy will be assessed by testing the amenorrhea rates of 
vilaprisan after 12 weeks of treatment in Treatment Period 1 versus placebo 
after 12 weeks of treatment using two-sided Cochran-Mantel-Haenszel test
at a 0.05 significance level. A hierarchical (fixed sequence) testing 
procedure will be used, involving the primary efficacy variable amenorrhea 
and key secondary efficacy variables HMB response, time to onset of 
amenorrhea and time to onset of controlled bleeding.
In addition, efficacy and safety variables will be summarized by descriptive 
statistics.


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Protocol Amendment Summary of Changes Table
Amendment 6 (17 FEB 2020)
Overall Rationale for the Amendment:
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018 (protocol amendment 4, Version 4.0) while pre-clinical toxicology 
findings and their relevance to humans were being further investigated. Although the outcome 
of Bayer’s investigation revealed that the observed pre-clinical findings are regarded to be of 
limited relevance to the human situation (refer to vilaprisan Investigator’s Brochure (IB)
version 11.0 including the associated amendment and Introduction section), a comprehensive 
safety follow up will be conducted to provide additional confirmatory evidence. The protocol 
amendment 5 (version 5.0) introduced measures and processes to prepare this study for an 
orderly closure, including safety follow up measures in all study subjects who received at 
least one dose of study drug.
Recently Bayer received comments from FDA regarding details of the safety follow-up 
measures introduced in the protocol amendment 5 (version 5.0). The current amendment 
(protocol amendment 6, version 6.0) implements these FDA recommendations.
Section # and 
Name
Description of Major Changes
Brief Rationale
Short summary 
for sites
Described how subjects will be counseled 
when test results (e.g., hormone, liver, 
physical examination) are abnormal but still 
below the thresholds to trigger outside 
evaluation in the context of the study. In 
such cases subjects should at least be 
counseled about medical follow up 
according to local practice.  
To address FDA requests
9.1 and 9.6.3.4
Procedures and 
variables
Text adjusted and footnote "Physical 
examination" deleted, as physical 
examination needs to be performed to all 
subjects.
To address FDA requests
9.6.3.1
Laboratory 
evaluations
Revised the interval for blood sampling after 
intake of high doses of biotin from 8 to 72 
hours.
To address FDA requests
Added glycosylated hemoglobin (HbA1c) to 
the parameters measured for adrenal 
monitoring also in subjects who have 
completed or discontinued the study before 
or during the temporary pause.
To address FDA requests


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Short summary for sites:
With the implementation of the protocol amendment 5, Version 5.0) no new subjects will be 
enrolled in the study and no subjects will re-start treatment. All subjects who were 
randomized and started treatment before the temporary pause will be asked to have the 
comprehensive safety evaluation (with particular focus on endometrial, adrenal and skin
safety) performed. This also applies to subjects who have completed or discontinued the study 
before or during the temporary pause, provided they have taken at least one dose of study 
medication1. 
All these subjects are asked to come to the site for the “Safety closeout visit” which is 
implemented with the protocol amendment 5, Version 5.0. In most cases the procedures 
scheduled for this safety closeout visit will not take place on the same day. The second 
scheduled visit, the “Safety result reporting visit” can be done as a telephone visit.
The following procedures are to be performed in the context of the “Safety closeout visit”: for 
details please refer to Sections 9.1 and 9.2:

Reconsenting the subject 

Documentation of concomitant medication and AEs

Check for adrenal disorder signs and symptoms, incl. vital signs and body weight

MRI of adrenal glands

Dispensation and collection of saliva test tubes
                                                
1 In subjects with exceptional circumstances, e.g., pregnancy, timing of the safety evaluations should be decided 
case by case.
9.6.3.2.7 Heavy 
menstrual 
bleeding / 
suspicious 
bleeding pattern
Described that, for comparison of subject’s 
subjective report with documented bleeding 
pattern and amount of blood loss, bleeding 
data of UF-DBD, MP, and/or AH method, if 
available, from the months preceding the 
safety closeout visit will be used.
To address FDA requests
9.6.3.8.3 
Laboratory 
testing
Footnote was adjusted to trigger an 
assessment by one of the external adrenal 
panel experts in case tT level >150 ng/dL
To address FDA request
10.2 Analysis 
sets
Added clarification that all randomized 
subjects belong to the FAS, excluding 
randomized subjects who did not start 
Treatment Period 1 due to the study being 
temporarily on hold.
As a result of partial 
clinical hold and FDA 
requests.


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
Referral to dermatology expert

Physical examination

Gynecological/breast exam

Cervical smear

Urine pregnancy test

Ultrasound examination 

Endometrial biopsy

Laboratory (blood sampling)

Collection of unused study drug and empty drug packs/drug accountability, if 
applicable

Collection of eDiary devices and review of bleeding data for unusual bleeding pattern 
(see Section 9.6.3.2.7)

Deactivation of the subject on the tablet computer without selecting a particular visit
At the second scheduled visit (“Safety result reporting visit”), the investigator is asked to 
communicate the results from the safety evaluations to the subject. This can be done as a 
telephone visit.
Details regarding the safety evaluation procedures and algorithms for identified abnormalities 
can be found in the respective sections of the protocol amendment 5, Version 5.0. Test results 
(e.g., hormone, liver, physical examination) may be abnormal but still below the thresholds to 
trigger outside evaluation in the context of the study. In these cases subjects should at least be 
counselled about medical follow up according to local practice.
Before a subject is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject’s medical record.


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Protocol Amendment Summary of Changes Table............................................................... 9
Table of contents..................................................................................................................... 12
Table of tables......................................................................................................................... 14
Table of figures....................................................................................................................... 14
List of abbreviations............................................................................................................... 15
Definition of terms.................................................................................................................. 17
3.
Introduction..................................................................................................................... 18
4.
Study objectives............................................................................................................... 21
5.
Study design..................................................................................................................... 21
6.
Study population ............................................................................................................. 24
Inclusion criteria ............................................................................................................ 25
6.1
Exclusion criteria ........................................................................................................... 26
6.2
Justification of selection criteria.................................................................................... 28
6.3
Withdrawal of subjects from study................................................................................ 29
6.4
6.4.1
Withdrawal ................................................................................................................. 29
6.4.2
Replacement ............................................................................................................... 30
Subject identification ..................................................................................................... 30
6.5
7.
Treatments....................................................................................................................... 30
Treatments to be administered....................................................................................... 31
7.1
Identity of study treatment............................................................................................. 32
7.2
Treatment assignment.................................................................................................... 33
7.3
Dosage and administration............................................................................................. 33
7.4
Blinding ......................................................................................................................... 33
7.5
7.5.1
Blinding measures ...................................................................................................... 33
7.5.2
Unblinding.................................................................................................................. 33
7.5.3
Emergency unblinding by the investigator................................................................. 33
Drug logistics and accountability................................................................................... 34
7.6
Treatment compliance.................................................................................................... 34
7.7
8.
Non-study therapy........................................................................................................... 34
Prior and concomitant therapy....................................................................................... 34
8.1
8.1.1
Iron supplementation.................................................................................................. 35
8.1.2
Progestin therapy for induction of bleeding ............................................................... 35
Post-study therapy.......................................................................................................... 35
8.2
9.
Procedures and variables ............................................................................................... 35


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Tabular schedule of evaluations .................................................................................... 35
9.1
Visit description............................................................................................................. 37
9.2
9.2.1
Unscheduled visits...................................................................................................... 37
9.2.2
Optional pre-screening phone contact........................................................................ 37
9.2.3
Scheduled visits.......................................................................................................... 37
Population characteristics .............................................................................................. 37
9.3
9.3.1
Demographic .............................................................................................................. 37
9.3.2
Medical history........................................................................................................... 37
9.3.3
Reproductive, menstrual, and fibroids history............................................................ 38
9.3.4
Heavy menstrual bleeding questions.......................................................................... 38
Efficacy.......................................................................................................................... 38
9.4
9.4.1
Alkaline hematin method to assess HMB................................................................... 38
9.4.2
Ultrasound (efficacy) to assess uterine fibroids ......................................................... 38
Pharmacokinetics / pharmacodynamics......................................................................... 39
9.5
9.5.1
Drug measurements.................................................................................................... 39
9.5.2
Population pharmacokinetic analysis of vilaprisan .................................................... 40
9.5.3
Pharmacokinetic/pharmacodynamic relationship of vilaprisan.................................. 40
Safety ............................................................................................................................. 41
9.6
9.6.1
Adverse events............................................................................................................ 41
9.6.2
Pregnancies................................................................................................................. 48
9.6.3
Further safety.............................................................................................................. 49
Other procedures and variables...................................................................................... 63
9.7
9.7.1
Iron supplementation.................................................................................................. 63
9.7.2
Algorithm for monitoring of endometrial safety........................................................ 63
9.7.3
Heavy menstrual bleeding / suspicious bleeding pattern ........................................... 63
9.7.4
Unscheduled endometrial biopsy ............................................................................... 63
9.7.5
Monitoring of ovarian cysts........................................................................................ 63
Appropriateness of procedures / measurements ............................................................ 63
9.8
10. Statistical methods and determination of sample size ................................................. 64
General considerations................................................................................................... 64
10.1
Analysis sets .................................................................................................................. 64
10.2
Variables and planned statistical analyses..................................................................... 64
10.3
10.3.1
Variables..................................................................................................................... 64
10.3.2
Statistical and analytical plans.................................................................................... 67
10.3.3
Missing data/drop outs ............................................................................................... 69
Determination of sample size......................................................................................... 70
10.4
Interim analysis.............................................................................................................. 71
10.5
11. Data handling and quality assurance............................................................................ 72
Data recording................................................................................................................ 72
11.1
Monitoring ..................................................................................................................... 73
11.2
Data processing.............................................................................................................. 74
11.3
Missing data................................................................................................................... 74
11.4
Audit and inspection ...................................................................................................... 74
11.5
Archiving ....................................................................................................................... 74
11.6
12. Premature termination of the study .............................................................................. 75
13. Ethical and legal aspects................................................................................................. 75


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Investigators and other study personnel......................................................................... 75
13.1
Funding and financial disclosure ................................................................................... 76
13.2
Ethical and legal conduct of the study........................................................................... 76
13.3
Subject information and consent.................................................................................... 77
13.4
Publication policy and use of data ................................................................................. 78
13.5
Compensation for health damage of subjects / insurance.............................................. 78
13.6
Confidentiality ............................................................................................................... 78
13.7
14. Reference list.................................................................................................................... 79
15. Protocol amendments...................................................................................................... 79
Amendment 1 – Dated 15 NOV 2017 ........................................................................... 79
15.1
15.1.1
Overview of the changes to the study......................................................................... 79
15.1.2
Changes to the protocol text....................................................................................... 81
Amendment 2............................................................................................................... 106
15.2
Amendment 5............................................................................................................... 108
15.3
15.3.1
Overview of the changes .......................................................................................... 109
Amendment 6 - dated 17 FEB 2020 ............................................................................ 112
15.4
16. Appendices..................................................................................................................... 113
Strong CYP3A4 inhibitors........................................................................................... 113
16.1
Strong CYP3A4 inducers............................................................................................. 113
16.2
Table of tables
Table 7–1: Identity of test drug/vilaprisan tablets and matching placebo................................ 32
Table 9–1: Schedule of procedures .......................................................................................... 36
Table 16–1: Strong CYP3A4 inhibitors................................................................................. 113
Table 16–2: Strong CYP3A4 inducers................................................................................... 113
Table of figures
Figure 5–1: Design overview - amended ................................................................................. 22
Figure 9–1: Overview of the endometrial safety monitoring algorithm .................................. 51
Figure 9–2: Adrenal monitoring algorithm .............................................................................. 59


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List of abbreviations
AE(s)
adverse event(s)
AESI
adverse event of special safety interest
AG
Aktiengesellschaft, incorporated company
AH
alkaline hematin
ALT
alanine aminotransferase (also known as GPT)
AP
alkaline phosphate
aPTT
activated partial thromboplastin time
ASCUS
atypical squamous cells of undetermined significance
AST
aspartate aminotransferase (also known as GOT)
ATC
Anatomical Therapeutic Chemical
-HCG
beta human chorionic gonadotropin
CD
Compact disk
CGI_I
Clinical Global Impression Investigator 
ClinRO
clinician-reported outcome
CRA
Clinical research associate
CRO
contract research organization
CSR
Clinical study report
CYP3A4
cytochrome P450 isoenzyme 3A4
DHEA-s
Dehydroepiandrosterone sulfate
dL
deciliter
E2
estradiol
EA
endometrial ablation
eCRF
electronic case report form
EDC
electronic data capture
eDiary
electronic Diary
eg
exempli gratia, for example
EIN
endometrial intraepithelial neoplasia
EoT
end-of-treatment visit
ePRO
electronic patient-reported outcomes
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FUP
follow-up
g
gram
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GnRH(a)
gonadotropin-releasing hormone (agonist)
GOT
glutamic oxaloacetic transaminase (also known as AST)
GPT
glutamic pyruvic transaminase (also known as ALT)
HbA1c
glycosylated hemoglobin
HDL
high density lipoprotein
HMB
heavy menstrual bleeding
HPV
human papilloma virus
HRQoL
Health-related quality of life
IB
investigator’s brochure
ICH
International Council on Harmonisation
ie
id est, that is
IEC
Independent Ethics Committee
INN
international nonproprietary names


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INR
international normalized ratio
IRB
Institutional Review Board
IVRS/IWRS
interactive voice/web response system
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LDL
low density lipoprotein
LH
luteinizing hormone
MBL
menstrual blood loss
MCH
mean corpuscular hemoglobin
MCS
mental component summary
MCV
mean corpuscular volume
MD
doctor of medicine
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mL
milliliter
MP
menstrual pictogram
MRI
magnetic resonance imaging
M&S
Modeling and Simulation
NASH
non-alcoholic steatohepatitis
P
progesterone
PAEC
progesterone receptor modulator-associated endometrial changes
PASS
Power analysis and sample size
PCS
Physical component summary
PD
pharmacodynamic(s)
PGI-S
Patient Global Impression of Severity
pH
negative logarithm of proton concentration
PK
pharmacokinetic(s)
PPS
per protocol set
PRM
progesterone receptor modulator
PRO
patient-reported outcome
QA
Quality assurance
QC
quality control
RAVE
electronic data capturing system
RND
randomization
SAE
serious adverse event
SAF
safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SD 
standard deviation
SESAC
Site Electronic Source Assessment Checklist
SID
subject identification
SS
Symptom severity
SUSAR
suspected, unexpected serious adverse reaction
TEAE
Treatment emergent adverse event
THIN
The Health Improvement Network
TP
treatment period
TSH
thyroid-stimulating hormone
tT
Total testosterone
TVU
transvaginal ultrasound
UAE
uterine artery embolization
UF-DBD
Uterine Fibroid Daily Bleeding Diary
UF-DSD
Uterine Fibroid Daily Symptom Diary
UFS-QoL
Uterine Fibroid Symptom and Quality of Life questionnaire


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ULN
upper limit of normal
UPA
ulipristal acetate
UPP
uterus-preserving procedures
US/USA
United States of America
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
wk
week
Definition of terms
3/1 regimen
3 months (ie, 3 x 28 days) of treatment with 1 bleeding episode between 
treatment periods
month
equals 28 days when referring to treatment (ie, 28 tablets per drug pack); 
equals 30 days when referring to the number of days in a month


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3.
Introduction
With the implementation of the protocol amendment 5, Version 5.0 no new subjects will be 
enrolled in the study and no subjects will receive any further study drug treatment. Any 
subjects who have taken at least one dose of study medication (including the subjects who 
completed the study or were prematurely terminated) will be asked to undergo the safety 
monitoring procedures described in this document.
Based on findings in preclinical carcinogenicity studies in rats and mice all vilaprisan clinical 
studies were temporarily paused since December 2018. In those carcinogenicity studies, 
adenocarcinomas of the endometrium and tumors of the adrenal cortex (benign and 
malignant) were seen in female rats and mice. Furthermore, skin sarcomas were found in 
female mice at a high exposure, representing 100 times the human therapeutic dose of 2 mg. 
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018 (protocol amendment 4, Version 4.0) while pre-clinical toxicology 
findings and their relevance to humans were being further investigated. Although the outcome 
of this investigation revealed that the observed pre-clinical findings are regarded to be of 
limited relevance to the human situation (IB version 11.0 including the associated amendment
and Introduction section), Bayer will conduct a comprehensive safety follow up to confirm 
this. The protocol amendment 5, Version 5.0 introduced measures and processes to prepare 
this study for an orderly closure, including safety follow up measures in all study subjects
who received at least one dose of study drug.
The protocol amendment 5, Version 5.0 introduced endometrial, adrenal, and skin safety 
evaluations with the aim to confirm that the carcinogenicity study findings did not translate 
into an increased risk for subjects when treated with the regimens and doses tested in the 
current studies.
In conclusion, all ongoing clinical studies with vilaprisan will be closed after implementation 
of a structured safety follow-up in all exposed subjects which aims to: 

provide certainty to subjects that they leave the study without any concerning finding,

generate clinical data that will support a thorough analysis of human safety data to 
confirm the hypothesis that the animal findings are of limited relevance to humans.
While closing the current clinical studies for the reasons explained above, the newly collected 
safety data will be thoroughly evaluated in addition to the already collected efficacy data.
Further detailed information and assessment of the carcinogenicity study findings are 
described below and also in the current version (V 11.0) of the vilaprisan Investigator’s 
Brochure.
Results from chronic carcinogenicity studies with vilaprisan in rodents (rat and mice)
In preclinical chronic carcinogenicity studies in rats and mice, adenocarcinomas of the 
endometrium were found. Furthermore, in female rats, benign and malignant tumors of the 
adrenal cortex were seen. Such tumors were not seen in male rats or in mice. In addition, skin 
sarcoma (not otherwise specified) were found with increased incidence of statistical 
significance at the high dose of 60 mg/kg in female mice only. This corresponds to about 100 
fold of the daily dose of 2 mg administered in this study). The tumors were derived from 
various cell lineages and were seen at various anatomical locations. The cause and the 
relevance of these skin tumors in mice is unclear but based on the high margin of exposure at 


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which these tumors were found, the relevance for humans treated at the intended therapeutic 
dose is regarded as limited.
Bayer assessment of human relevance of the observed rodent tumors: 
The etiology of the observed endometrial and adrenal tumors is regarded as related to 
vilaprisan’s mode-of-action with species-specific consequences. There was no indication of 
any direct carcinogenic or direct tumor-promoting effect of vilaprisan, which is non-
genotoxic. Male animals did not show any findings and in female animals, effects were 
limited to reproductive and endocrine organs, with the exemption of the skin sarcomas, where 
the high margin of exposure suggested limited human relevance. Reasons why the 
endometrial and adrenal tumors are regarded as of limited relevance in the human setting are 
described in more detail below: 
In the course of these carcinogenicity studies, rats and mice were treated with life-long and 
uninterrupted doses of vilaprisan leading to much higher unbound exposures compared to the 
human dose of 2 mg/day. As a consequence, progesterone action was blocked in these 
animals during their whole life-span. Compatible with this are signs of estrogen dominance 
that were observed in the aging female rats and mice. Such signs have not been found in 
clinical trials of vilaprisan in humans. In the carcinogenicity study rodents entered into 
reproductive senescence during the treatment phase leading to rodent specific endocrine 
changes resulting under continuous blockade of the progesterone receptor in the formation of 
tumors in the endometrium and adrenal cortex. The rodent specific endocrinology does not 
resemble the situation in humans. 
Relevant differences between the treatment of humans with vilaprisan and the setting of the 
carcinogenicity studies in rodents are:

Female rodents undergo specific endocrine changes during reproductive senescence 
that do not resemble human menopause, human premenopausal endocrine status or the 
endocrine situation during vilaprisan treatment. 

Prolonged estrous periods with high estradiol levels occur in rodent reproductive 
senescence, or a pseudopregnancy state with moderately high estradiol levels. This 
process takes place due to neurodegeneration on the hypothalamus-pituitary gland and 
in the presence of follicles in the ovaries which are capable of producing hormones. In 
the presence of vilaprisan with its strong antagonistic effect on the progesterone 
receptor this leads to a prolonged, fully unopposed estradiol exposure in the animals. 
Specifically, in rats, life-long vilaprisan treatment seems to promote prolonged estrous 
periods with follicular cysts and reduce states of pseudopregnancy, thus further 
enhancing estrogen dominance.

Prolonged phases of unopposed estrogen are a recognized risk factor for development 
of endometrial adenocarcinoma in rodents as well as in humans. However, in contrast 
to the rodents in the pre-clinical carcinogenicity studies, available clinical data for 
vilaprisan do not indicate the occurrence of an unopposed estrogen effect on human 
endometrium. This is supported by the estrogen-lowering effect of vilaprisan shown in 
the Phase 1 and Phase 2 studies as well as by the morphological features of 
endometrial histology in humans under vilaprisan treatment which do not seem to 
indicate a relevant proliferative effect. There was no increased incidence of relevant 
endometrial pathology (hyperplasias, neoplasms) seen in biopsies taken after up to 12 
months of treatment with vilaprisan. 


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


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probably even at an earlier stage than it would have become apparent otherwise. Furthermore, 
the safety measures will generate important data allowing to examine whether vilaprisan has a 
role in the development of such tumors and diseases.
The safety of short-term treatment with vilaprisan is supported by the available pre-clinical 
and clinical data. Therefore, it is Bayer’s assessment that no acute or long-term risk is 
expected for the subjects who have been treated in any of the clinical studies performed with 
vilaprisan. 
With regards to efficacy vilaprisan has demonstrated in Phase 1 a dose-dependent ovulation 
inhibition and induction of amenorrhea in healthy women. Two Phase 2 studies (15788 –
ASTEROID 1 and 17541 – ASTEROID 2) with a treatment duration of up to 24 weeks were 
conducted in women with uterine fibroids. The results of both studies demonstrated a 
clinically meaningful reduction of symptoms associated with uterine fibroids, especially of 
HMB, improvements of subjects’ health-related quality of life (HRQoL) and a reduction of 
fibroid size.
4.
Study objectives
The primary objective of this study is to show superiority in treatment of HMB of vilaprisan 
in subjects with uterine fibroids compared to placebo. 
The secondary objectives of this study are to additionally evaluate the efficacy and safety of 
vilaprisan in subjects with uterine fibroids. With the implementation of protocol amendment 
5, Version 5.0 , additional focus was put on safety evaluations of the endometrium, adrenal 
glands and skin. 
The other objectives of this study are to evaluate the variability in exposure in relation to the 
efficacy and safety for vilaprisan and to collect patient-reported outcome (PRO) and clinician-
reported outcome (ClinRO) data. 
5.
Study design
This section was changed in Amendment 1, see Section 15.1.1
This is a randomized, parallel-group, double-blind, placebo-controlled, multicenter study. 
The study is conducted in the US, Japan and European countries. 
Overview of the study design before the temporary pause is shown in Figure 5–1.
With the implementation of the protocol amendment 5, Version 5.0, this study design is no 
longer valid. No subjects will receive further study drug. 


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Figure 5–1: Design overview - amended
Treatment 
Group A1
Screening 
up to120 days
Randomization
Vilaprisan 2 mg 
12 weeks
Bleeding 
episode
Vilaprisan 2 mg 
12 weeks
Follow-up
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT
Treatment 
Group B1
Screening 
up to120 days
Randomization
Placebo 
12 weeks
Bleeding 
episode
Vilaprisan 2 mg
12 weeks
Follow-up
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT
Treatment 
Group B2
Screening 
up to120 days
Randomization
Vilaprisan 2 mg 
12 weeks
Bleeding 
episode
Placebo
12 weeks
Follow-up
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT
EoT = end of treatment
During the screening period, subjects had to demonstrate eligibility including the presence of 
at least 1 uterine fibroid 30 mm and <120 mm in largest diameter based on ultrasound, HMB 
in at least 2 bleeding periods, each with menstrual blood loss (MBL) >80.00 mL documented 
by the alkaline hematin (AH) method, and endometrial biopsy results without significant 
histological disorder. 
Eligible subjects were randomized in 1:1:1 ratio to one of the three treatment groups (Group 
A1, B1, or B2) and stratified by country/region (US, Japan and other countries). Treatment 
was started as described in Section 7.1. 
After the end of the final treatment period, subjects were planned to be followed up for until 
day 7 to 15 of the 2nd menstrual cycle after end of treatment visit.
The primary efficacy variable is:

Amenorrhea (yes/no), defined as MBL <2 mL during the last 28 days of treatment. 
For secondary variables, see Section 10.3.1.2 and 10.3.2.2.
Justification of the design
Placebo control and blinding:
A double-blind placebo-controlled design was considered necessary to differentiate drug 
effects from the natural course of disease and background findings. To minimize subject 
burden due to randomization to placebo treatment, all subjects were planned to receive active 
treatment during a part of the study. 
Study design valid with the implementation of the protocol amendment 5, Version 5.0: 
The study was temporarily paused since December 2018. No further subjects will be recruited 
and none of the enrolled subjects will receive further study drug treatment. All subjects who 
were randomized and started treatment before the temporary pause will be asked to have a 
comprehensive safety evaluation (with particular focus on endometrial, adrenal and skin
safety) performed. This also applies to subjects who have completed or discontinued the study 


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before or during the temporary pause, provided they have taken at least one dose of study 
medication.
Efficacy / pharmacodynamic assessments:
Menstrual bleeding and the impact uterine fibroids symptoms have on the subjects’ daily life 
are determined as efficacy parameters.
Fibroid size, uterus size (by ultrasound), endocrine hormone levels, and bleeding are
determined as pharmacodynamic (PD) parameters.
Safety monitoring:
Safety parameters are regularly and closely monitored throughout the study (eg, questioning 
for AEs, measurement of laboratory values, close observation of subjects in case of increased 
liver parameters, a separate liver symptom questionnaire, i.e. the liver symptom inquiry, vital 
signs, endometrial thickness, abnormal menstrual bleeding, and size of follicle like structures
comprising follicles and functional ovarian cysts). A comprehensive screening program for 
adrenal tumors and a skin examination by a dermatology expert are implemented with the
protocol amendment 5, Version 5.0.
Endometrial monitoring
A careful endometrial safety monitoring assessment was applied in this study from the 
beginning, including regular ultrasound investigations during the treatment period, 
observation of bleeding patterns, and endometrial biopsies at defined time points. Clear 
decision trees were 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/abnormal menstrual bleeding pattern (see Section 9.7.2). Highly reliable 
diagnosis of any findings in the endometrial biopsies is ensured through the involvement of a 
panel of highly experienced and well renowned expert pathologists who will assess every 
biopsy sample taken from study participants.
With the protocol amendment 5, Version 5.0, additional requirements for endometrial safety 
screening are outlined for subjects who took at least one dose of study medication, see Section
9.6.3.2.  
Liver monitoring
A liver-related safety signal was observed with some selective progesterone receptor 
modulator (PRM) compounds which display differences in molecular structure compared to 
vilaprisan.
Monthly monitoring of liver parameters under treatment was introduced with an earlier 
version of this protocol (protocol amendment 2, Version 3.0). With the protocol amendment 
5, Version 5.0, subjects who remained in the study during the temporary pause will receive 
one further laboratory assessment, including liver parameters.
Adrenal monitoring
A comprehensive adrenal screening program was implemented with the protocol amendment 
5, Version 5.0. 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 adrenal cortex. Tumors of the adrenal glands 
(cortical or medullary in origin, benign as well as malignant) are known to occur in a certain 


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frequency (1) in the general population, independent of an exposure to the study drug 
vilaprisan. For adrenal tumors detected by the screening program in this study, a causal 
relationship to vilaprisan can therefore not be automatically assumed. However, it is expected 
that all subjects, irrespective of their exposure to vilaprisan, will benefit from detection of 
potential adrenal gland disorders through the study monitoring program. All study subjects 
who took at least one dose of study medication in any of the currently paused clinical studies 
will be asked to undergo adrenal monitoring in order to demonstrate adrenal safety of 
repeated intermittent treatment with vilaprisan.
Skin monitoring
In the above-mentioned carcinogenicity studies performed in mice and rats, skin sarcomas 
were found at a dose representing about 100 times the human therapeutic dose of 2 mg. The
tumors were derived from various cell lineages and were seen at various anatomical locations. 
The cause and the relevance of the skin tumors in mice is unclear but based on the high 
exposure at which these tumors were found, the relevance for humans treated at the intended 
therapeutic dose is regarded as limited. 
Nevertheless, all study subjects who took at least one dose of study medication in any of the 
currently paused clinical studies will be asked to undergo a thorough skin examination by a 
dermatology expert in order to demonstrate skin safety of repeated intermittent treatment with 
vilaprisan. 
Effects related to study conduct
In addition to drug-related side effects, symptoms caused by the study conduct (eg, due to 
blood sampling, endometrial biopsy) are possible. However, possible risks are regarded as 
acceptable because the planned methods are used routinely in clinical studies, clinical and/or 
gynecological practice.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).
Primary completion
The primary completion event for this study is the last visit of the last subject.
The primary completion date for this study according to the Food and Drug Administration 
(FDA) Amendment Act is specified in a separate document (not part of this study protocol).
6.
Study population
Eligibility
No longer valid, since no new subjects will be enrolled in this study with the 
implementation of the protocol amendment 5, Version 5.0. Originally the study 
population had to fulfill the following criteria:
Women with symptomatic uterine fibroids meeting all inclusion and presenting none of the 
exclusion criteria will be eligible for enrollment in the study.


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Inclusion criteria
6.1
1. Signed and dated informed consent 
2. Women, 18 years or older at the time of Visit 1 
3. Diagnosis of uterine fibroid(s) documented by ultrasound at screening with at least 1
fibroid with largest diameter ≥30 mm
4. The largest diameter of any uterine fibroid is <120 mm
5. Heavy menstrual bleeding (HMB) in at least 2 bleeding periods during the screening 
period each with blood loss volume of >80.00 mL documented by the alkaline hematin 
(AH) method
Women who did not suffer from perceived HMB during the 3 months prior to Visit 1 
due to any effective medical treatment (eg, with a hormonal contraceptive) are not 
considered appropriate candidates and should not undergo further screening 
procedures.
Women suffering from perceived HMB despite medical treatment (eg, with a 
hormonal contraceptive) are appropriate candidates for further screening, if rules on 
stopping prior medication (see exclusion criterion 7) are followed.
Heavy menstrual bleeding (HMB) >80.00 mL should be documented within 10 
consecutive days. As guidance, the duration of a bleeding episode should not exceed 
12 days.
6. Good general health (except for findings related to uterine fibroids) as proven by 
medical history, physical and gynecological examinations, and laboratory test results
7. Normal or clinically insignificant cervical smear not requiring further follow-up. The 
cervical smear may be waived if a normal result has been documented in the subject’s 
medical records within the previous 6 months.
Human papilloma virus (HPV) testing in subjects with atypical squamous cells of 
undetermined significance (ASCUS) can be used as an adjunctive test. Subjects with 
ASCUS can be included if they are negative for high-risk HPV strains.
8. An endometrial biopsy performed during the screening period without significant 
histological disorder such as endometrial hyperplasia (including simple hyperplasia) 
or other significant endometrial pathology. 
If the sample is inadequate, the biopsy can be repeated once within the screening 
period and must be repeated within 6 weeks from the first biopsy in order for the 
subject to continue. No further repeated biopsies for inadequate samples are permitted.
9. Use of an acceptable non-hormonal method of contraception (ie, either male condom, 
cap, diaphragm or sponge, each in combination with spermicide) starting at Visit 1 
until the end of the study. (Short-acting hormonal contraception [oral, vaginal, or 
transdermal] are allowed up until the start of the menstrual cycle that follows Visit 1.) 
This is not required if contraception is achieved by a permanent method, such as 
bilateral fallopian tube blockage of the subject (including Essure®) or vasectomy of 
the partner(s).


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Exclusion criteria
6.2
This section was changed in Amendment 1, see Section 15.1.1
1. Pregnancy or lactation (less than 3 months since delivery, abortion, or lactation before 
start of treatment) 
2. Hypersensitivity to any ingredient of the study drug
3. Hemoglobin values ≤6 g/dL or any condition requiring immediate blood transfusion 
(subjects with hemoglobin values ≤10.9 g/dL will be recommended to use iron 
supplementation).
4. Any diseases, conditions, or medications that can compromise the function of the body 
systems and could result in altered absorption, excessive accumulation, impaired 
metabolism, or altered excretion of the study drug including, but not limited to: 
o
Impaired function of the kidneys (laboratory values outside of inclusion 
range2) 
o
Abnormal liver parameters (presence of at least one of the following criteria,
please see also section 9.6.3.1 Laboratory evaluations)3: 

2 x upper limit of normal (ULN) for glutamic oxaloacetic transaminase 
(GOT) / aspartate aminotransferase (AST) 

2 x ULN for glutamic pyruvic transaminase (GPT) / alanine 
aminotransferase (ALT) 

2 x ULN for alkaline phosphatase (AP) 

Total bilirubin outside the upper limit of normal range4

International normalized ratio (INR) outside the upper limit of the 
normal
5
o
Diagnosis of hepatitis B infection, i.e., Hbs-antigen positive at Visit 16
o
Diagnosis of hepatitis C infection, i.e., hepatitis C-antibodies and HCV-RNA 
positive at Visit 17
o
Chronic bowel diseases, eg, M. Crohn and Colitis ulcerosa 
                                                
2 As specified in the laboratory manual and in the reports from the central laboratory
3 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 (see Section 
9.6.3.1).
4 As specified in the laboratory manual and in the reports from the central laboratory.
5 As specified in the laboratory manual and in the reports from the central laboratory.
6 This will be applied only to subjects newly enrolled into the study after protocol version 3.0 has become valid
7 This will be applied only to subjects newly enrolled into the study after protocol version 3.0 has become valid


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o
Intake of strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors within 
the last 2 weeks before the randomization visit and during the treatment period 
including: antivirals (eg, viekira pak, telaprevir, boceprevir), protease 
inhibitors (eg, ritonavir, lopinavir, indinavir, nelfinavir, saquinavir), 
antifungals (eg, itraconazole, voriconazole, posaconazole), antibiotics (eg, 
clarithromycin, telithromycin), grapefruit and any grapefruit containing food 
products (eg, grapefruit juice). Ketoconazole and other triazole antifungal 
drugs are allowed for topical/local use (including vaginal application). A 
detailed list is provided in Section 16.1
o
Intake of strong CYP3A4 inducers (eg, rifampicin, carbamazepine, 
oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St John´s 
wort [Hypericum], efavirenz, nevirapine, long term use of ritonavir) within the 
last 2 weeks before the randomization visit and during the treatment period. A 
detailed list is provided in Section 16.2.
5. Any diseases or conditions that might interfere with the conduct of the study or the 
interpretation of the results, including
o
Known severe coagulation disorder
o
Known anemia for reason other than HMB
o
Known hemoglobinopathy
o
History of or current uterine, cervical, ovarian, or breast cancer, except cervical 
cancers after curative treatment
o
One or more ovarian cysts >30 mm in diameter as measured by ultrasound
(except endometrioma)
o
Any ovarian tumors or pelvic masses of unclear etiology requiring further 
diagnostic procedures
o
Known or suspected uterine polyp >15 mm
6. Abuse of alcohol, drugs, or medicines (eg, laxatives) 
7. Use of other treatments that might interfere with the conduct of the study or the 
interpretation of the results including 
o
Short-acting hormonal contraception (oral, vaginal, or transdermal), if not 
stopped at the start of the menstrual cycle that follows Visit 1 
o
Long-acting hormonal contraception (injectable), if last application was 
performed less than 1 application interval before start of the menstrual cycle 
that follows Visit 1 
o
Contraceptive devices with or without hormone release (implant, intra-uterine 
device), if not removed at Visit 1 (not applicable in cases of bilateral fallopian 
tube blockage of the subject (including Essure®)
o
Other hormonal treatments for HMB or fibroids, if not stopped before the start 
of the menstrual cycle that follows Visit 1 (eg, androgens, estrogen receptor 
antagonists, selective estrogen receptor modulators). For progesterone receptor 
modulators see next bullet point


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o
Previous use of ulipristal acetate, if there were not at least two menstruations 
after the last intake before Visit 1
o
Gonadotropin-releasing hormone agonists (GnRHa), if not stopped at least one 
application interval before Visit 1 
o
Tranexamic acid, traditional Chinese medicine for uterine fibroids or HMB, or 
other treatments for HMB, if not stopped at Visit 1
o
Anticoagulants, if not stopped at Visit 1 
o
Previous use of vilaprisan (≥2 mg) without satisfactory result 
8. Undiagnosed abnormal genital bleeding 
9. Simultaneous participation in another clinical study with investigational medicinal 
product(s). Participation in another clinical trial prior to study entry (before Visit 1) 
that might have an impact on the study objectives.
10. Close affiliation with the investigational site (eg, a close relative of the investigator), 
dependent person (eg, employee or student of investigational site, or sponsor’s staff) 
11. Inability to cooperate with the study procedures for any reason, including the 
following examples: language comprehension, psychiatric illness, inability to get to 
the study site, eDiary compliance 
12. Previous enrollment to the study (ie, rescreening is only allowed as described in 
Section 6.4.1).
Justification of selection criteria
6.3
The exclusion criteria are valid for known or suspected conditions and were chosen to ensure 
that subjects with specific risks for administration of the study drugs and/or subjects with 
conditions that may have an effect on the aims of the study are excluded.


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Withdrawal of subjects from study
6.4
6.4.1
Withdrawal
No longer valid, since with the implementation of the protocol amendment 5, Version 5.0 
no subjects will start or continue treatment in this study. Originally, the criteria for 
withdrawal from the study or from the study treatment were the following:  
Withdrawal criteria
Subjects must be withdrawn from the study if any of the following occurs:
At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result. 
At the specific request of the sponsor and in liaison with the investigator (eg, obvious 
non-compliance, safety concerns). 
Pregnancy 
Surgical treatment of uterine fibroids 
Subjects must be withdrawn from study treatment if any of the following occurs:

If, in the investigator's opinion, continuation of the study treatment would be harmful 
to the subject's well-being 

GPT/ALT or GOT/AST >8 x ULN 

GPT/ALT or GOT/AST >5 x ULN for more than 2 weeks 

GPT/ALT or GOT/AST >3 x ULN and total bilirubin >2 x ULN or international 
normalized ratio (INR) >1.5 

GPT/ALT or GOT/AST >3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper abdominal quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

Atypical hyperplasia, endometrial intraepithelial neoplasia (EIN) or malignant 
neoplasm 
Subjects may be withdrawn from study treatment if any of the inclusion criteria are no longer 
fulfilled or if any of the exclusion criteria apply during treatment. 
Follow-up of subjects prematurely withdrawing from study treatment or during follow-
up
With the implementation of the protocol amendment 5, Version 5.0, subjects who do not 
consent to the updated study design and the additional safety measures will be regarded as 
“dropouts”.
Screening failure
A subject who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before randomization, is regarded a “screening failure”. 


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Dropout
A subject who discontinues study participation prematurely for any reason (including subjects 
who do not consent to this protocol amendment which defines safety measures before study 
closure) is defined as a “dropout” if the subject has already been randomized.
Those subjects who were randomized but never started the study medication will not need to 
consent to the safety follow up, but will be handled as drop outs after having been informed 
about the study closure.
Contacting of treated subjects who already left the study
The investigator or designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be documented 
in the subject’s source document.
General procedures
In all cases, the reason for withdrawal must be recorded in the electronic Case Report Form 
(eCRF) and in the subject's medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.4.2
Replacement
Dropouts will not be replaced. 
Subject identification
6.5
At screening upon signing the informed consent form and registering the subject in the 
interactive voice/web response system (IVRS/IWRS), each subject was assigned a unique 
multi-digit SID number by the site for unambiguous identification. The SID number 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); 6th digit will be “4” for 
this ASTEROID 4 study
Once allocated, the SID number identified the subject throughout the study.
On random assignment to treatment, each subject was assigned a unique randomization 
number.
7.
Treatments
Instructions in Sections 7.1 to 7.4 are no longer valid, since with the implementation of 
the protocol amendment 5, Version 5.0 no subjects will start or continue treatment in 
this study. 


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Originally, the instructions in Sections 7.1 to 7.4 were the following:
Treatments to be administered
7.1
Eligible subjects will be randomized to one of the following treatment groups: 
A1: vilaprisan (2 mg), 2 treatment periods of 12 weeks, separated by 1 bleeding episode 
B1: placebo, 1 treatment period of 12 weeks, and vilaprisan (2 mg), 1 treatment period of 12 
weeks, separated by 1 bleeding episode
B2: vilaprisan (2 mg), 1 treatment period of 12 weeks, and placebo, 1 treatment period of 12 
weeks, separated by 1 bleeding episode
Randomization will be 1:1:1 and stratified by country/region (US, Japan and other countries)
for Treatment Groups A1, B1, and B2.
Each treatment period will consist of 12 weeks (84 days). One tablet (oral) will be taken daily 
during the treatment periods.
The tablets should be taken at about the same time every day. Exceptions to this rule may
occur before visits with PK blood sampling (see Section 9.5.1).
Start of treatment
Treatment Period 1 for all subjects will start within Days 3 to 7 of the first bleeding episode 
following randomization visit. In case a bleeding episode is ongoing at randomization visit, 
the subject can already start with the intake of study medication during Days 3 to 7 of this 
bleeding episode. A negative pregnancy test is a prerequisite for starting the study drug
(applies to both treatment periods).
Treatment Period 2 will start within Days 3 to 7 of the first bleeding episode following the 
end of the Treatment Period 1. If no bleeding episode occurs within 7 weeks after end of the 
previous treatment period, proceed with the induction of bleeding according to Section 9.7.5. 
For the start of treatment, subjects will judge based on their experience whether their bleeding 
episode has started. In case of unusual patterns (eg, start with some days of spotting) subjects 
should consult with the investigator.
For the statistical analysis, a bleeding episode is characterized by the following entries in the
Uterine Fibroid Daily Bleeding Diary (UF-DBD):

day(s) with bleeding / spotting of which at least one day is of intensity “mild” or 
higher 

preceded and followed by at least 2 bleed-free days
(in case the first bleeding episode starts directly after Visit 1, the preceding 2 
bleed-free days may not be recorded for this first bleeding episode).
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.


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Diet
Subjects will be allowed to eat and drink as usual. However, grapefruit and grapefruit juice 
must be excluded from the subject's diet during treatment because these foods contain 
constituents that inhibit cytochrome P450 3A4. 
Identity of study treatment
7.2
The investigational medicinal product vilaprisan and matching placebo are round immediate-
release tablets, 6 mm in diameter and coated with a dark red coat (see Table 7–1).
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 
Composition
Active ingredient: Vilaprisan micronized
Other ingredients:
Lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, magnesium stearate, dark red 
lacquer (containing hypromellose, macrogol 3350, talc, titanium 
dioxide, and red ferric oxide)
Packaging
28 tablets per package 
Marketing Authorization Holder
Not applicable
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)
Packaging
28 tablets per package 
Marketing Authorization Holder
Not applicable
INN = International nonproprietary name.
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 QA group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
Study drugs need to be stored in accordance with the label text.


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Treatment assignment
7.3
At Visit 3 (randomization), eligible subjects will be randomized via the IVRS/IWRS to one of 
the treatment groups (see Section 7.1).
The site will receive confirmation on the completion of the randomization procedure from the 
IVRS/IWRS. The confirmation will be considered as source documentation and should be 
maintained in the subject files. For additional details, refer to the separate IVRS/IWRS
instructions.
Dosage and administration
7.4
See Section 7.1 for administration details.
Blinding
7.5
Forward looking instructions regarding blinding are no longer valid, since with the 
implementation of the protocol amendment 5, Version 5.0 no subjects will start or 
continue treatment in this study. However, for the subjects randomized in this study 
before the temporary pause, the blinding will be maintained until database lock. 
7.5.1
Blinding measures
Vilaprisan tablets and respective placebo tablets are identical in appearance (size, shape, 
color). The packaging and labeling will be designed to maintain the blinding of the 
investigator’s team and the subjects.
The study data will remain blinded until database lock and authorization of data release 
according to Sponsor’s standard operating procedures.
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).
Study responsible PK and bioanalytical personnel will remain unblinded.
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, unless safety findings required unblinding.
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.


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Drug logistics and accountability
7.6
No longer valid, since with the implementation of the protocol amendment 5, Version 5.0
no subjects will start or continue treatment in this study and therefore no study 
medication will be newly distributed. All unused study drug should have been returned 
during the temporary pause and this should have been documented in the drug 
accountability section of the eCRF and on the appropriate drug dispensing form by the 
investigator or designee.
Receipt, distribution, return and destruction (if any) of the study drug must be properly 
documented according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
Treatment compliance
7.7
To monitor compliance, the subjects were required to complete an electronic Diary (eDiary) 
daily throughout the study. The date of each study drug intake was tracked via the eDiary. 
The eDiary was dispensed at Visit 1 and the completeness of the eDiary data reviewed by the 
investigator or designee regularly between the visits, and together with the subject at every 
visit.
8.
Non-study therapy
Prior and concomitant therapy
8.1
All concomitant medications administered after signing of informed consent until the 
completion of study participation8, including topical (eg, vaginal) preparations and over the 
counter drugs are to be recorded in the eCRF (trade name, dose, unit, frequency, route, start
and stop dates, and indication). This applies with specific focus for medications that could 
interfere with the testing of adrenal parameters. 
Restrictions regarding forbidden concomitant medications were valid before and during the 
treatment phase of this study, but were lifted during the treatment-free safety FUP phase that 
started during the temporary pause and continued with protocol amendment 5, Version 5.0. 
Please see also Section 6.2.
Subjects who withdrew from study drug and subjects who withdrew during FUP were asked
to not take hormonal treatments before the first menstruation after EoT was completed and the 
end of treatment biopsy was performed.
Surgical and interventional treatment for fibroids must be documented in the eCRF if 
performed during the study period (ie, until the last visit of the subject) and should be 
regarded as AE if deemed appropriate by the investigator (see Section 9.6.1.1).
                                                
8 In subjects who have completed or discontinued the study before or during the temporary pause, who are asked 
to participate in the safety evaluation, the concomitant medication used during the off study period until re-
consenting to this protocol amendment should also be recorded in the eCRF.


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Reasonable efforts should be undertaken to capture such interventions also in subjects who 
had already left the study and are now returning.
8.1.1
Iron supplementation
In subjects with hemoglobin 10.9 g/dL in blood, iron supplementation should be offered in a 
standardized regimen (see Section 9.7.1) consistent with local standards of practice and at the 
investigator’s discretion. Iron supplementation will not be considered a study medication and 
will be documented as concomitant medication. 
8.1.2
Progestin therapy for induction of bleeding
If required, subjects were given an appropriate progestin therapy for induction of bleeding. 
Progestin therapy will not be considered as study medication and will be documented as 
concomitant medication.
Post-study therapy
8.2
Before the temporary pause, it was foreseen that subjects completing the treatment periods
will participate in the post treatment FUP without drug treatment. According to the rules of
the temporary pause, subjects were required to not start any new treatment period and thereby 
those subjects entered a study drug free FUP phase if they agreed to remain in the study.
Subjects completing the treatment periods will participate in the post-treatment FUP without 
study drug treatment.
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. 
9.
Procedures and variables
Tabular schedule of evaluations
9.1
No longer valid, since with the implementation of the protocol amendment 5, Version 5.0 
no subjects will be recruited and none of the enrolled subjects will receive further study 
drug treatment. All subjects who were randomized and started treatment before the 
temporary pause will be asked to have the comprehensive safety evaluation (with 
particular focus on endometrial, adrenal and skin safety) performed. This also applies to
subjects who have completed or discontinued the study before or during the temporary 
pause, provided they have taken at least one dose of study medication. All these subjects 
are asked to come to the site for the “Safety closeout visit” which was implemented with 
the protocol amendment 5, Version 5.0. 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 and implementation of the protocol amendment 5, Version 5.0. The 
following procedures are to be done:


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Table 9–1: Schedule of procedures
Visit
Safety closeout visit a
Safety result reporting 
visit
(can be a telephone visit)
Timing
After implementation of 
protocol amendment 5, 
Version 5.0
Once all safety results are 
available
Informed consent
X
Concomitant medications
→
→
AE assessments
→
→
Adrenal disorder signs and symptoms
incl. vital signs b
X
MRI of adrenal glands c
X
Dispense saliva test tubes
X
Collect saliva test tubes d
X
Referral to dermatology expert
X
Physical examination
X
Body weight
X
Gynecological/breast exam e
X
Urine pregnancy test
X
Cervical smear ff
X
Ultrasound examination g
X
Endometrial biopsy c,h
X
Laboratory (blood) i
X
Collection of unused study drug and 
empty drug packs/drug accountability
X
if applicable
Collection of eDiary device and 
review of bleeding data for unusual 
bleeding pattern
X
if applicable
Deactivation of the subject on the 
tablet computer without selecting a 
particular visit 
X
Communication of results from safety 
evaluations to the subject
X
a.
In most cases the procedures scheduled for this visit will not take place on the same day
b.
Blood pressure in triplicates and heart rate after 5 minutes of rest in a sitting position
c.
Negative pregnancy test is a prerequisite
d.
Saliva tests should be performed as soon as possible after dispense, to allow for a repeat in case of 
unevaluable results or for review by one of the adrenal experts in case of abnormal results. Saliva test 
tubes should be returned to site on the next day after samples have been taken on two consecutive days.
e.
Only to be performed if subject did not have these performed with normal result after end of treatment
f.
Only to be performed if subject did not have this performed with normal or clinically insignificant result after 
end of treatment
g.
The ultrasound must be done before the biopsy
h.
Only to be performed in subjects who did not have a post-treatment endometrial biopsy (defined as biopsy 
taken at the earliest 7 days before last study drug intake) with a normal result. For subjects with menstrual 
cycles the endometrial biopsy should be taken between Day 7 to 15 (inclusive) of a menstrual cycle. This 
is defined as diagnosis of safety read and of all 3 individual components of the multiread to be “benign 
endometrium” in Part II of the evaluation form. In addition, the majority diagnosis needs to be “PAEC no” in 
Part IV of the evaluation form. Furthermore, an endometrial biopsy may also be triggered by results of 
ultrasound examination or bleeding data (see Section 9.6.3.2.7). The biopsy CRF page needs to be 
completed for all subjects, including cases where according to protocol no biopsy is required.
i.
In subjects who take biotin, the last dose of biotin should be at least 72 hours prior to hormone testing.
AE = adverse event, MRI = magnetic resonance imaging, PAEC = progesterone receptor modulator-associated 
endometrial changes


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Visit description
9.2
No longer valid, since with the implementation of the protocol amendment 5, Version 5.0
all subjects will need to come to the site for the safety closeout visit. In most cases the 
procedures scheduled for this visit will not take place on the same day. 
The second scheduled visit, the “Safety result reporting visit” can be done as a telephone 
visit. During this visit the subject will be informed about the results of the safety 
investigations. In case follow-up assessments 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 the protocol amendment 5, Version 5.0 
no new subjects will be recruited.
9.2.3
Scheduled visits
With the implementation of the protocol amendment 5, Version 5.0 all subjects who took 
at least one dose of study medication will need to come to the site for the safety closeout
visit. For details regarding this safety closeout visit please see Section 9.1. The second 
scheduled visit, the “Safety result reporting visit” can be done as a telephone visit.
Population characteristics
9.3
With the implementation of the protocol amendment 5, Version 5.0 no new subjects will 
be recruited. This section describes the data collection performed in subjects enrolled 
before the temporary pause.
9.3.1
Demographic
Demographic data (eg, year of birth, age at Visit 1, race, ethnic group, educational level) and 
other population characteristics including smoking habits and alcohol consumption were 
collected consistent with the schedule of procedures in protocol amendment 3, Version 3.0.
9.3.2
Medical history
Medical history findings (ie, previous diagnoses, diseases or surgeries) meeting all criteria 
listed below were collected as available to the investigator:

Not pertaining to the study indication

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.
Any condition that was stabilized by medication at the time of signing the informed consent 
should also be documented in the eCRF. The medication being used had to be recorded in the 
prior and concomitant medication eCRF.


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All new or worsened findings after signing the informed consent had to be documented on the 
Adverse Event eCRF.
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 fibroids history
Reproductive and menstrual history includes information on menarche, births, other 
pregnancies, and inability to conceive.
Fibroids history includes information on family history, onset of symptoms, diagnosis, and 
previous medical treatments and procedures, if applicable.
9.3.4
Heavy menstrual bleeding questions
This set of questions has been developed as a tool to identify women with HMB. It could have
been used at Visit 1 and the responses could have been entered directly into electronic data 
capturing system RAVE, which is considered as primary source data. The questionnaire could 
also have been used as a pre-screening tool. Print outs of the questionnaire were provided to 
the sites as needed.
Efficacy
9.4
This section details the procedures for collecting efficacy variables. A concise listing of 
efficacy variables as collected before the temporary pause is given in Section 10.3.1. The 
complete list of variables to be analyzed for this study will be provided in the Statistical 
Analysis Plan (SAP).
9.4.1
Alkaline hematin method to assess HMB
This section was changed in Amendment 1, see Section 15.1.1
During the duration of the study, subjects were required to use selected types of sanitary 
products provided (pads and/or tampons). During the entire duration of the study, subjects 
were to collect their used sanitary products and return them to the study site as soon as the 
bleeding episode was completed to be sent to the central laboratory for analysis.
The AH method is applied to measure MBL from Screening onwards during the entire study.
The AH method measures hemoglobin in a fixed amount of alkaline solution with the use of a 
spectrophotometer (2). The fixed amount of solution is taken from the solution pool in which 
the materials (ie, used sanitary protection) to be tested have been macerated for hemoglobin 
extraction. The blood loss volume was to be reported by day and bleeding episode. This test 
was performed at the central laboratory. For details refer to the laboratory manual.
9.4.2
Ultrasound (efficacy) to assess uterine fibroids
This section was changed in Amendment 1, see Section 15.1.1
If possible, the same examiner should have conducted all examinations of a subject 
throughout the study and the same ultrasound machine (per site) should have been used 
throughout the study. For each subject, the most appropriate ultrasound method (transvaginal, 
abdominal or transrectal) had to be used depending on fibroid location and this method should 
have been used consistently throughout the study. 


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Ultrasound examinations were to be performed consistent with the original schedule of 
procedures. The 3 largest fibroids were to be identified during the screening period. The 
largest transverse, longitudinal, and antero-posterior diameters of these 3 fibroids were to be 
documented at each efficacy ultrasound examination for volume calculation.
The dimensions of the uterus were also to be documented at the same time points. This is of 
particular importance in subjects with multiple small fibroids.
The minimum source documentation included electronic or paper documentation from the 
ultrasound machine showing the 3 largest fibroids. The printouts had to be labeled 
unambiguously, containing at least the study number, SID number, time point, and longest 
diameter of 3 largest fibroids. It is also possible that the site has a CD with the ultrasound 
images available, when in the source the evaluation of the ultrasound images from the CD is 
available as well. The CRA has to be able to review the data on the CD and compare the 
images with the evaluations in the source during the onsite monitoring visits.
Furthermore, if the ultrasound machine is SESAC (Site Electronic Source Assessment 
Checklist) conform, ie, GCP conform electronic data storage is possible, then no print out is 
needed.
For safety ultrasound procedures, see Section 9.6.3.6.
Pharmacokinetics / pharmacodynamics
9.5
With the implementation of the protocol amendment 5, Version 5.0 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 in plasma for PK were to be collected at the 
time points given in the original schedule of procedures. At Visit 5, the PK sample was to be 
taken predose. At Visit 6, 3 PK samples were to be taken. The first sample was to be taken 
before intake of study drug. After the predose sample was taken at Visits 5 and 6, the subject 
should have taken her study drug under supervision at the site. The second sample at Visit 6 
was to be taken 0.5 to 1 hour after drug intake and the third sample was to be taken 2 to 4 
hours after drug intake. The date and time of the last 2 doses of the study drug prior to the 
first PK sample at Visits 5 and 6, the time of the supervised drug intake at the study site, and 
the time of all blood samples had to be documented in the eCRF. 
If, for any reason, PK samples were taken outside of the pre-specified time window, the exact 
time that the sample was taken should have been recorded and not the time of the time 
window. These time deviations were not to be considered as important deviations.
If a subject discontinued study treatment permanently, no blood sampling for PK was
required. Pharmacokinetic analyses are based on a population modeling approach (see Section 
9.5.2). Blood samples are considered valid for the population PK analysis under the following 
conditions:
1) The dose amount and time of drug intake prior to the blood sample is known
2) The time of the blood sample collection is known.


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The samples were to be collected and processed as described in detail in the respective 
Sample Handling Sheets as a part of a separate Laboratory manual. 
Plasma concentrations of vilaprisan are determined using a validated liquid chromatography-
tandem mass spectrometry (LC-MS/MS). Quality control (QC) and calibration samples are
analyzed concurrently with study samples. The results of calibration samples, QC samples, 
and study samples will be reported in the Bioanalytical Reports which will be included in the 
Clinical Study Report for this study. A re-opening of the database may become necessary in 
order to include the results of the PK measurements.
The bioanalyst will be unblinded for analysis of study samples. Placebo samples will not be 
analyzed.
9.5.2
Population pharmacokinetic analysis of vilaprisan
Based on the plasma concentrations, the variability in vilaprisan PK will be analyzed using
population PK modeling. This analysis might start prior to database lock (eg, at the moment 
that approximately 80% of the expected PK samples have been measured). Appropriate 
measures will be taken to maintain blinding of the study team (eg, data access will be 
restricted to specific people involved in the analysis and members of the study team will 
neither have access to the randomization list nor to individual data). The measures will be 
described in a Data Operations Plan, which will be provided to the study manager for 
adequate documentation. 
Population or nonlinear mixed effects PK models describe the relationship between dose, 
time, and the vilaprisan plasma drug concentration. A previously developed population PK 
model for vilaprisan based on Phase 1 and 2 data will be applied to all valid PK samples to 
evaluate the relationship between variability in PK and covariates, (ie, intrinsic [eg, body 
weight, race] and extrinsic factors [eg, concomitant medication]) that are of clinical relevance. 
If necessary, the population PK model will be adapted to adequately fit the data. Individual 
PK parameters of vilaprisan will be calculated. A separate Modeling and Simulation (M&S) 
Plan, providing details of the model development and evaluation will be provided before the 
start of the population PK analysis. Evaluation of the data will be presented in a separate 
M&S Report.
9.5.3
Pharmacokinetic/pharmacodynamic relationship of vilaprisan
Optionally, a population PK/PD model could be used to describe the effect of vilaprisan 
exposure on PD data related to efficacy and safety such as bleeding intensity and endocrine 
hormone levels. The final population PK model that will be applied to describe the PK of 
vilaprisan in the study population as outlined in Section 9.5.2 will be linked to relevant PD 
parameters (eg, fibroid size, uterus size, endocrine hormone levels, and bleeding) obtained in 
this study to investigate the relationship between vilaprisan exposure and response. Details of 
the model development and evaluation, if conducted, will be described in a separate M&S 
Analysis Plan and the results reported in a separate M&S Report.


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Safety
9.6
9.6.1
Adverse events
Definitions
9.6.1.1
Definition of AE
This section was changed in Amendment 1, see Section 15.1.1
In a clinical study, an AE is any untoward medical occurrence (ie, any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing 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. Treatment emergent adverse event (TEAE) is defined as 
any event that occurred after the first study drug intake until the end of FUP.
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 eg, physical examination findings, symptoms, diseases, and laboratory
findings.

Conditions that started before signing of the initial informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded as 
medical history (eg, seasonal allergy without acute complaints).

Conditions that started before signing of the initial informed consent and for which 
symptoms or treatment are present after signing of informed consent, at unchanged 
intensity, are recorded as medical history (eg, allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. This includes intercurrent illnesses (eg, increase in 
occurrences and/or severity of symptoms for seasonal allergy or allergic pollinosis).

In subjects who completed or discontinued before or during the temporary pause and 
now get reconsented conditions that newly occurred or worsened during the off-study 
period should be documented as AEs.
Definition of SAE
An 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.


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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
(eg, elective or scheduled surgery arranged prior to the start of the study)
- The admission is not associated with an AE 
(eg, social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may fulfill the 
criterion of ‘medically important’ and as such may be reportable as an SAE dependent on 
clinical judgment. In addition, where local regulatory authorities specifically require a more 
stringent definition, the local regulation takes precedence. Any fibroid surgery should always 
be reported as SAE, irrespective of associated hospitalization.
d. Results in persistent or significant disability / incapacity
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 as judged by the investigator and/or as 
defined below
All instances of liver parameter testing which meet the criteria for withdrawal defined in the 
original study protocol (see Section 6.4.1) of a subject from the study should be reported as 
SAEs.
Endometrial biopsies with a safety read diagnosis of “simple or complex atypical hyperplasia” 
(according to WHO 1994 criteria) or “EIN” (according to WHO 2014 criteria) (3) or with 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. 
An adrenal tumor needs to be reported as an SAE.
Any dermatology expert´s diagnosis of a malignant skin lesion, including cutaneous sarcoma 
confirmed by biopsy diagnosis, needs to be reported as an SAE.
The following types of events are excluded from SAE reporting:

Elective abortion is considered as an ‘abnormal pregnancy outcome’ but is not 
considered an SAE. (However, abortions are to be documented as SAEs if they match 
one of the following terms: spontaneous abortion, missed abortion, infected abortion, 


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or abortion induced incomplete. If no specification for the abortion is available, then 
one of these categories is assumed to have occurred and the ‘abortion’ is regarded as 
serious and must be recorded as an SAE.)

Hospitalizations for the evaluation or treatment of pre-existing conditions that do not 
worsen in severity or frequency during the subject’s participation in the study. Such 
conditions must have been present before the subject’s participation in the study and 
reported as such in the corresponding eCRF.

Elective surgery performed for cosmetic reasons or because of pre-existing conditions
as defined in Section 9.3.2.
Important medical event: Any AE may be considered serious because it may jeopardize the 
subject and may require intervention to prevent another serious condition. As guidance for
determination of important medical events, refer to the “World Health Organization (WHO) 
Adverse Reaction Terminology – Critical Terms List”. These terms either refer to or might be 
indicative of a serious disease state. Such reported events warrant special attention because of 
their possible association with a serious disease state and may lead to more decisive action 
than reports on other terms.
Classifications for AE assessment
9.6.1.2
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 eCRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”


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An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, eg, mechanical bleeding at 
surgical site.
or
2. Non-plausibility, eg, 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 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
- The pharmacology and PK of the study treatment: The PK properties (absorption, 
distribution, metabolism and excretion) of the study treatment, coupled with the 
individual subject’s pharmacodynamics should be considered.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”.
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.


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The study treatment action should be recorded as detailed in the eCRF.
- Drug withdrawn
- Drug interrupted
- Dose not changed
- Not applicable
- Unknown
9.6.1.2.5
Other specific treatment(s) of AEs
- 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
Assessments and documentation of AEs
9.6.1.3
Attention is to be paid to the occurrence of AEs at all stages of the examination. Thus, the 
subject should be closely observed by the investigator.
AEs observed, mentioned on open questioning by a member of the investigator team or 
spontaneously reported by the subject will be documented. The observation period for AEs 
will start with signing the informed consent and will end with the last visit. After the Safety 
result reporting visit there is no requirement to actively collect new AEs. 
The outcome of recorded non-serious AEs should be followed up between the signing of the 
informed consent and the end of the FUP phase. For adverse events of special safety interest,
efforts should be made to follow them up until resolution or stabilization (even after the
Safety result reporting visit, if applicable).
The investigator is responsible for the grading of each category listed in Section 9.6.1.2. An 
assessment of the seriousness of the event will be made by the investigator using the 
electronic reporting tool in RAVE. However, SAEs will also be recorded on the AE page of 
the eCRF.
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to study drug.
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s).


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For details on monitoring algorithms see Section 9.7.
Reporting of SAEs
9.6.1.4
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 using the electronic 
reporting tool in RAVE (see Section 11) according to the detailed instructions for SAE 
reporting included in the Investigator File. 
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the Independent Ethics Committees/Institutional Review Boards
Notification of the Independent Ethics Committees (IECs)/Institutional Review Boards
(IRBs) about all relevant events (eg, SAEs, suspected, unexpected, serious adverse reactions 
[SUSARs]) will be performed by the sponsor and/or by the investigator according to all 
applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (eg, SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (eg, SUSARs) 
according to all applicable regulations.
Expected AEs
9.6.1.5
For this study, the applicable reference document is the most current version of the IB.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
Adverse events of special safety interest
9.6.1.6
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: 


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
HMB (especially after EoT) should be recorded as an AE (and then it 
automatically qualifies as an AESI) only if one or more of the following applies:

Leads to study discontinuation

Leads to diagnostic procedures

Requires any treatment

Shows a clinically significant worsening during the study that, in the judg-
ment of the investigator, is not consistent with the expected clinical course

Meets any seriousness criterion and is to be recorded as an SAE.
HMB will be documented in detail throughout the study (see Section 9.7.3).

Liver disorders:

For all cases which qualified for “close observation” before 
implementation of the protocol amendment 5, Version 5.0 and/or qualify 
for “ruling out of alternative cause” after implementation of the protocol 
amendment 5, Version 5.0 (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 9.6.3.2.

Endometrial thickening >18 mm: If endometrial thickness (double layer) 
18 mm is detected after the start of treatment, the subject should undergo 
immediate evaluation by endometrial biopsy as described in Section 9.7.4.

Skin disorders:

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.


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Progesterone receptor modulator-associated endometrial changes (PAEC) will be assessed 
and documented in a systematic way (see Section 9.6.3.2.6). 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 HMB (see 
Section 9.7.3), endometrial hyperplasia and endometrial thickening (see Sections 9.7.2 and 
9.7.4), and liver parameters. 
9.6.2
Pregnancies
An acceptable nonhormonal contraceptive method has to be used starting at Screening Visit 1 
and continued until the end of the study. Barrier contraception (eg, condoms with spermicide)
will be dispensed as required by the subject. This is not required if contraception is achieved 
by a permanent method such as bilateral fallopian tube blockage (including Essure) of the 
subject or vasectomy of her partner(s). 
Pregnancy tests were to be performed at site visits and at home before the start of study drug 
in each treatment period. Home pregnancy tests should also have been performed in case the 
subject was concerned about being pregnant. All home pregnancy tests were to be
documented in the eDiary. In case of a positive pregnancy test, study drug had to be 
discontinued and the investigator had to be be informed immediately.
Any planned pregnancy should be postponed until the end of the study. This was to be 
discussed with the subject at screening. If an investigator became aware that a subject wished
to conceive or planned an insemination directly after EoT (thereby deviating from study 
protocol), subject should have been made aware that she is participating in a clinical study 
with a new drug in early clinical development. Therefore she should preferably have 
completed 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.
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 
was detected before initiation of study drug, the subject was not to be enrolled into the study 
(see Section 6.2).
The investigator must report to the sponsor any pregnancy occurring in a study subject during 
the subject’s participation in this study. The report should be submitted within the same 
timelines as an SAE (ie, no later than 24 hours of having gained knowledge of the event; see 
Section 9.6.1.4), although a pregnancy per se is not considered an AE or SAE. The subject 
was instructed to contact the study site immediately if a pregnancy is suspected or detected. In 
such a case, an unscheduled visit should be arranged for the subject as soon as possible and 
the investigator or designee should confirm the pregnancy by a valid method [eg, ultrasound, 
serum human chorionic gonadotropin (-HCG) test]. If such confirmation cannot be achieved 


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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 upon the first birthday of the child.
Any abnormal outcome of the mother or the child should also be reported as an SAE (eg,
spontaneous abortion, preterm birth, elective abortion triggered by medical concern).
For details on elective abortions, refer to Section 9.6.1.1.
For all reports, the forms provided are to be used. 
9.6.3
Further safety
Laboratory evaluations
9.6.3.1
This section was changed in Amendment 1, see Section 15.1.1
Only blood samples analyzed at the central laboratory will be considered for analysis. The 
name and address for the central lab service provider can be found in the documentation 
supplied by the vendor. 
The following parameters will be assessed at the safety closeout visit in subjects who 
remained in the study during the temporary pause:
Hematology: leukocytes, erythrocytes, hematocrit, mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), platelets, neutrophils, eosinophils, basophils, lymphocytes, 
and monocytes.
Hemoglobin (Hb concentration)
Serum chemistry: creatinine, chloride, potassium, sodium, calcium, total protein, albumin, 
total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) 
cholesterol, triglycerides, ALT, AST, AP, gamma-glutamyl transpeptidase (GT), and total 
bilirubin (in case the result is > 2xULN, conjugated and unconjugated bilirubin will be 
determined).
See Section 9.6.1.6 for procedure in case of elevated liver parameters.
Biochemistry: glycosylated hemoglobin (HbA1c) and ferritin.


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Additional parameters9: hormones (follicle-stimulating hormone [FSH], luteinizing 
hormone [LH], estradiol [E2], progesterone [P], prolactin, thyroid-stimulating hormone 
[TSH]), and vitamin D (serum 25-hydroxyvitamin D).
In case of elevated liver enzymes requiring investigation of alternative cause the 
following parameters will have to be determined (in earlier CSP versions this was 
summarized in a particular section “close observation”): 
Serum chemistry panel (see above), A1AT level, conjugated bilirubin, ceruloplasmin, 
cholinesterase, CK, ferritin, full blood count (incl. eosinophilia), hemoglobin, INR, iron, 
LDH, platelets, PT, total iron binding capacity (TIBC), testing to rule out Hepatitis A-, 
Hepatitis B-, Hepatitis C,  Hepatitis E-, Cytomegalie-, Epstein-Barr-, and Herpes simplex 
virus infection,  brucellosis, leptospirosis, and toxoplasmosis. ANA/ANCA screening with 
further tests depending on result and IgA, IgG, and IgM, potentially also testing to out 
Hepatitis 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 sampling if the cortisol measurement yields 
an abnormal value.

late night salivary cortisol (to be obtained between 11 PM and midnight)

Serum dehydroepiandrosterone sulfate (DHEA-S)
o
the age-specific DHEA-S ratio (derived by dividing the subject’s DHEA-S value 
by the lower limit of the age-specific reference range) will be calculated. In case of 
an abnormal DHEA-S ratio ACTH will be assessed from the sample taken for 
serum cortisol measurement.

serum total testosterone (tT)

serum glucose measurement under fasting conditions

serum potassium.
The following parameters will be assessed at the safety closeout visit in subjects who 
have completed or discontinued the study before or during the temporary pause:

estradiol

vitamin D (serum 25-hydroxyvitamin D)

Parameters measured for adrenal monitoring:

serum cortisol (to be measured between 6 am and 10 am)
                                                
9 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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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 subject’s DHEA-S 
value by the lower limit of the age-specific reference range) will be calculated.
In case of an abnormal DHEA-S ratio ACTH will be assessed from the sample 
taken for serum cortisol measurement.

serum total testosterone (tT)

serum glucose measurement under fasting conditions

serum potassium. 

glycosylated hemoglobin (HbA1c).
Endometrial biopsies
9.6.3.2
9.6.3.2.1
Algorithm for endometrial biopsy evaluation
Figure 9–1: Overview of the endometrial safety monitoring algorithm


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1 Normal is 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.
2 Post-treatment is defined as biopsy taken at the earliest 7 days before last study drug intake.
9.6.3.2.2
Timing of last endometrial biopsy
Each subject should have an endometrial biopsy with a normal10 result documented from a 
timepoint taken at the earliest 7 days before 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 TVU and/or bleeding pattern are required to undergo an endometrial 
biopsy at the safety closeout visit. 
This also applies to subjects who started treatment and have completed or discontinued the 
study before or during the temporary pause. At least three attempts and a certified letter 
should be made by the site to get in contact with such subjects. The attempts should be 
documented in the subject file.
The biopsy CRF page should be filled out for every subject at the safety closeout visit. This 
also applies to subjects who do not require a new biopsy according to the guidance above. The 
CRF page allows to capture the reason why a biopsy was not done.
Depending on the result of the last scheduled biopsy repeat unscheduled endometrial biopsies 
should be performed in addition. See Sections 9.6.3.2.5 and 9.7.3 for details.
9.6.3.2.3
Sampling of endometrial biopsies
All endometrial biopsies must be collected by a gynecologically well experienced physician.
A negative pregnancy test is a prerequisite for performing an endometrial biopsy. In addition, 
an ultrasound should be performed before each biopsy.
If a cervical smear sample is collected at the same visit, those procedures have to be 
performed before performing the biopsy.
The sterilized, disposable device Pipelle de Cornier will be used – a flexible and transparent 
polypropylene sheath with an internal plunger for aspiration. This device allows for gentle 
tissue sampling, without hysteroscopy, and generally requires no local anesthesia or cervical 
dilatation. 
The following contraindications have to be strictly adhered to: pregnancy (ie, positive urine 
pregnancy test), and local inflammation (eg, vaginitis, cervicitis). 
                                                
10 Normal is defined as: Diagnosis of safety read and of all 3 individual components of the multiread needs to be 
“benign endometrium” in Part II of the evaluation form. In addition, the majority diagnosis needs to be “PAEC 
no” in Part IV of the evaluation form.


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Any procedure-related complaints will be documented as AEs. If necessary for pain 
prophylaxis or relief relating to the endometrial biopsy procedure, the use of an analgesic is 
permitted and will be documented as concomitant medication (investigator’s choice; however, 
no intake of acetylsalicylic acid or any other medication substantially influencing bleeding). 
9.6.3.2.4
Assessment of endometrial biopsies
Blinding and distribution of biopsy samples will be organized by the central laboratory.
Central assessment of endometrial biopsies will be performed in 2 steps, i.e. safety assessment 
and multi-reader assessment. In cases where an abnormality, e.g. atypia or malignancy, cannot 
be ruled out, readers will select the most severe diagnosis:
Safety assessment
The safety assessment will be performed by one pathologist who will be blinded regarding 
treatment group. The results of the safety assessment need to be available in time to 
document:

Any relevant pathology that requires further diagnostic or therapeutic measures 
according to local medical practice

Absence of clinically relevant endometrial pathology before the subject leaves the 
study 

A repeat endometrial biopsy will be requested, if sample is inadequate for evaluation 
in the safety assessment.

For follow-up of biopsies with abnormalities see Section 9.6.3.2.5.
Multi-reader assessment
The multi-reader assessment will be performed by a panel of pathologists who will be blinded 
regarding treatment group and time point of sample. 
A majority consensus diagnosis of the multi-reader assessment is derived from the individual 
diagnoses of the pathologist panel (single-reader diagnoses), according to pre-specified rules.
In the absence of a majority consensus, the most severe diagnosis is used. The derived 
diagnosis resulting from these rules will be used for primary analysis of endometrial biopsy 
data. The individual diagnoses of each reader will be captured in addition.  
Starting with the protocol amendment 5, Version 5.0 the majority diagnosis of the multi-
reader assessment including the single reader assessments (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 9.6.3.2.5.
Besides standard safety criteria (e.g., proliferative/secretory/atrophic endometrium, 
endometrial hyperplasia, malignant neoplasm) the pathologists will document the presence of 
PAEC (see Section 9.6.3.2.6). The results of the PAEC assessment are not reported back to 
the investigators except if in the last biopsy within the study, PAEC is still present and further 
biopsy sampling is needed.


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The main study evaluation will be based on the majority diagnosis of the multi-reader 
assessment. An analysis of single-reader diagnoses that is more severe than the majority 
diagnosis will be provided in the Study Report. 
While the relevant diagnosis for study purposes is the majority result of the multi-reader 
assessment, any single reader diagnosis that is more severe than the majority diagnosis, 
should be evaluated by the investigator (or by a gynecologist in case the investigator or sub-
investigator is not specifically trained in gynecology) for the necessity of therapeutic 
interventions. The minimal requirement for those cases is a follow up biopsy. For all follow-
up examinations and/or therapeutic interventions all efforts should be taken that these 
examinations are conducted according to the standards of this protocol (e.g. biopsies should 
undergo multi-reader assessment) and are documented within the study framework.
9.6.3.2.5
Follow-up of endometrial biopsies with abnormalities
Endometrial biopsies with a safety-reader diagnosis (Part II of the evaluation form) other than 
“benign endometrium” (i.e. “Malignant neoplasm”, “Endometrial Hyperplasia” with or 
without atypia) should undergo an expedited multi-reader assessment. If an expedited multi-
reader assessment is not possible (e.g. due to sample export regulations), follow-up 
procedures will be decided based on the safety-reader diagnosis.
Endometrial biopsies with a multi-reader majority diagnosis (Part II of the evaluation form) 
other than “benign endometrium” (i.e. “Malignant neoplasm”, “Endometrial Hyperplasia” 
with or without atypia) should be followed-up according to investigator11 assessment, i.e., 
either by performing endometrial biopsies, until resolution (i.e. until a follow-up biopsy
shows a majority diagnosis of “Benign endometrium”) and/or by performing a therapeutic 
intervention as per local standard of care.
The timing of follow-up biopsies and/or possible therapeutic interventions according to local 
standard of care will be determined by the investigator (or by a gynecologist in case the 
investigator or sub-investigator is not specifically trained in gynecology) according to the 
observed abnormality. Typically, at least one endometrial shedding should have occurred 
before a follow-up biopsy is performed.
The follow-up biopsies should be performed within the study framework and analyzed by 
blinded multi-reader assessment. In case follow-up biopsies and/or other interventions are 
conducted at non-study sites, all efforts should be taken that results are obtained and 
documented appropriately.
For FUP of a majority diagnosis of “Benign endometrium – PAEC yes” please see Section 
9.6.3.2.6.
For reporting of abnormal biopsy results as adverse event of special interest or SAE, please 
see Sections 9.6.1.1 and 9.6.1.6.
                                                
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9.6.3.2.6
Follow-up of PAEC
Besides standard criteria (i.e., proliferative/secretory/atrophic endometrium, endometrial 
hyperplasia) presence of PAEC will be analyzed in all endometrial biopsy samples as part of 
the multi-reader assessment. The diagnosis of PAEC is based on a constellation of histologic 
features that, taken together, are characteristic. None of the features is unique, and to some 
extent any may be seen in subjects 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 according 
to the majority diagnosis resulting from the multi-reader assessment, the site will be informed 
and an additional biopsy should be scheduled. In case PAEC findings are still present, the 
study site will be informed and an additional biopsy is to be taken to evaluate resolution, with 
the timepoint of this additional biopsy to be determined case-by-case. If needed, more than 
one repeated biopsy may be taken and analyzed, except for cases with PAEC already present 
in the pre-treatment biopsy.
9.6.3.2.7
Heavy menstrual bleeding / suspicious bleeding pattern
The study drug was administered in a study population with symptomatic heavy menstrual 
bleeding. The study drug itself leads to changes in bleeding pattern, mostly amenorrhea 
during treatment, but can also be associated with intermittent spotting or mild intermittent 
bleeding of short duration. Heavy menstrual bleeding is expected to return in the FUP phase 
after cessation of treatment.
Because unusual bleeding patterns or unusually heavy menstrual bleeding can also be a sign 
of endometrial pathology, the subject should be instructed to report changes in bleeding 
pattern or bleeding volume that seem unusual to her (and does not resemble the subject´s 
natural cycle or bleeding pattern). In case such unusual bleeding events are reported or are 
detected from the AH, MP or UF-DBD the subject should undergo immediate evaluation by 
the investigator. With the safety closeout a review of the bleeding data entered during the 
temporary pause should rule out any suspicious bleeding that would need immediate 
evaluation.
Standard criteria for evaluation of unusual HMB or bleeding pattern identified from 
review of bleeding data or reports by the subject during the temporary pause
As guidance the following occurrences should be considered for further evaluation in the 
context of unusual bleeding: 

Prolonged bleeding:
Evaluation should be initiated if

Prolonged bleeding is reported by the subject and/or

the subject entered more than 10 consecutive days of bleeding in the e-diary 
(intensity of “mild” or more) with a maximum of 2 non-bleeding days in 
between. 

Continuous spotting:
Evaluation should be initiated if


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


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should be performed according to local medical practice and as defined in Section 
9.6.3.2.7.

For procedures in case of an abnormal result of the unscheduled biopsy, please see 
Section 9.6.3.2.5.
Cervical smear
9.6.3.3
This section was changed in Amendment 1, see Section 15.1.1
The cervical smear should be obtained with the gynecological examination at the safety 
closeout visit in subjects who did not have this performed with normal result after end of 
treatment. As a guidance, cervical smear should only be repeated once in case of insufficient 
material.
Physical and gynecological examinations
9.6.3.4
Complete physical examination will be done for all subjects. Gynecological examination, 
including breast palpation, will be performed in subjects who did not have this performed 
with normal result after end of treatment. In case of any suspicious finding, further diagnostic 
investigations will be performed at the discretion of the investigator.
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1).
Vital signs, weight, and height
9.6.3.5
Vital signs (blood pressure in triplicates and heart rate) should be documented at the safety 
closeout visit. Blood pressure should be measured in triplicates after 5 minutes of rest, while 
the subject is sitting. Measurements should be made at least 1 minute apart using the same 
arm at each visit and should be recorded on the eCRF. Body weight will be determined once 
again at the safety closeout visit.
Ultrasound (safety)
9.6.3.6
If possible, the same examiner should conduct all ultrasound examinations of a subject 
throughout the study and the same ultrasound machine (per site) should be used throughout 
the study. Preferably the safety evaluation should be performed by transvaginal ultrasound
(TVU). However, if deemed appropriate, transabdominal or transrectal ultrasound
examinations can be performed instead. The chosen method should be used consistently 
throughout the study.
The following safety parameters will be documented at the safety closeout visit: 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 as described in Section 9.7.4.
If cyst like structures >30 mm without suspicious appearance (ie, functional cysts) are 
visualized in the ovaries, unscheduled ultrasound examinations to document 
regression/outcome of these findings should be performed as described in Section 9.7.5.
In case of any suspicious finding, further diagnostic investigations will be performed at the 
discretion of the investigator.


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The minimum documentation at the site will include printouts from the ultrasound machine
showing the endometrium in sagittal section and both ovaries. The printouts have to be 
labeled unambiguously, containing at least the study number, SID number, time point, 
endometrial thickness, and side (left/right) for ovaries.
For efficacy ultrasound procedures, see Section 9.4.2. 
Contraception and pregnancy test
9.6.3.7
With the implementation of the protocol amendment 5, Version 5.0 no further restrictions
were applied to the use of contraception. New placement of intrauterine devices should only 
happen one it is clear that no further biopsies are needed.
At the safety closeout visit a urine pregnancy tests will be performed at the study site. A 
pregnancy test must also be performed in case of any further repeat of an endometrial biopsy. 
Any pregnancies during the study and during the off study period in subjects who return for 
the safety closeout visit must be reported as detailed in Section 9.6.2.
Adrenal monitoring
9.6.3.8
A robust adrenal safety monitoring program is implemented in all ongoing vilaprisan studies 
with this protocol amendment.
A plan for subjects showing adrenal neoplasms or hormonal abnormalities has been 
developed with the input of external endocrinology experts, see Adrenal monitoring algorithm 
below. 
A panel of three external clinical adrenal gland experts has been set up, that will support and 
guide further evaluations and/or referral to local specialists in case an abnormality is detected 
in a study subject. The assessment by the experts will be performed in 2 steps: 

A safety assessment of cases showing abnormalities will be performed by one of these 
experts. The results of this assessment will be available in time to document
-
Any relevant finding that requires further diagnostic or therapeutic 
measures according to local medical practice
-
Absence of clinically relevant adrenal findings before the subject 
discontinues from the study.
In case of a local specialist consult, the work-up and results will be captured in a dedicated 
CRF page.

In addition, the expert panel will perform a central evaluation of all cases after the 
outcome of the local specialist referral or other evaluations is available. The panel will 
meet once a sufficient number of cases is available to perform a comprehensive data 
analysis by using uniform diagnostic standards and classifications (see also Adrenal 
Monitoring Manual).
The further details of adrenal monitoring are described in the Adrenal Monitoring Manual.


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Figure 9–2: Adrenal monitoring algorithm
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 
completed or discontinued the study before or during the temporary pause. After re-


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consenting, data related to adrenal monitoring and their results are to be documented in the 
CRFs, and if applicable, same applies to 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 subject 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 
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 


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DHEA-s value by the lower limit of the age-specific reference range) will be 
calculated12.
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 eCRF13. 
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.
Liver monitoring
9.6.3.9
In the past, investigators, subjects and their family members were instructed to be alert for 
nonspecific symptoms which may be associated with liver dysfunction. In addition, the liver 
inquiry had to be completed at regular intervals. Based on the long interval between the 
implementation of the protocol amendment 5, Version 5.0 and last intake of study drug this 
was no longer needed on a routine basis.
Investigation of potential causes (which replaces the close observation procedures applied 
before this protocol amendment) has to be initiated and recorded in the dedicated liver case 
report form if at least one of the options below applies:

GPT/ALT or GOT/AST value increases to 3 x ULN
or

GPT/ALT or GOT/AST value 2-fold increases above the lowest baseline value for 
subjects with elevated values before drug exposure
or

AP (alkaline phosphatase) value increases to > 2x ULN and irrespective of the level of 
transaminase (GPT/ALT or GOT/AST) values
o
in cases with baseline showing normal AP
o
in cases of at least 2 times the baseline values if slightly above the upper 
limit of normal at baseline
In those cases, a search for underlying cause should be performed including:
                                                
12 High levels of tT and/or DHEA-s may be indicators of an androgen-producing adrenal cortical tumor and are 
measured in this study in conjunction with adrenal imaging to support their early detection. Therefore, despite 
the fact that many confounders are present in the female study population (e.g., PCOS, influence of Vilaprisan 
or other concomitant medications on hormone levels), tT and DHEA-s concentrations will be measured to 
screen for androgen-producing tumors. Highly abnormal values of one or both parameters, i.e., tT >150 ng/dL 
and/or DHEA-s > 600 µg/dL, will trigger an assessment by one of the external adrenal panel experts.
132018 Draft Guidance for Industry: Assessment of Pressor Effects of Drugs 
(https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm609185.pdf


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
Repeating a serum chemistry panel (including liver parameters and bilirubin).

Obtaining a more detailed history of the symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Ruling out acute viral hepatitis; autoimmune or alcoholic hepatitis; non-alcoholic 
steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and biliary tract disease. This 
may require performing additional procedures, e.g. ultrasound examinations.

Obtaining a history of exposure to environmental chemical agents. 

Obtaining additional tests to evaluate liver function as appropriate, (eg, international 
normalized ratio [INR], total bilirubin measurements). 

Referral for a liver ultrasound.
Any of these additional findings is to be recorded on the corresponding eCRF pages in 
RAVE.
Liver symptom inquiry
9.6.3.10
Investigators, subjects and their family members should be alert for non-specific symptoms 
which may be associated with liver dysfunction including anorexia, nausea, fatigue, right 
upper abdominal discomfort, vomiting, malaise, jaundice, fever, and rash. 
Before the implementation of protocol amendment 5 (version 5.0), investigators were asked to 
regularly inquire about symptoms that according to their medical judgement may indicate 
liver disturbance and document the result of this inquiry in the respective eCRF page. This 
structured inquiry was used to determine withdrawal criteria and is therefore not needed at the 
safety closeout visit.
Skin monitoring
9.6.3.11
All subjects who have taken at least one dose of the study medication will undergo a thorough
skin examination by a dermatology expert.
The outcome of the dermatology expert’s examinations will be reported in the CRF. Any 
dermatology expert´s diagnosis of a pre-cancerous or malignant skin lesion, including 
cutaneous sarcoma confirmed by biopsy diagnosis, qualify as an AESI. Any dermatology 
expert´s diagnosis of a malignant skin lesion, including cutaneous sarcoma confirmed by 
biopsy diagnosis, needs to be reported as an SAE to ensure timely reporting to regulatory 
agencies. (see Section 9.6.1.6).
Subjects who were randomized, started treatment, and have completed or discontinued the 
study before or during the temporary pause should be contacted by the site and asked to have 
the skin monitoring performed. After re-consenting, data related to the skin exam by a 
dermatology expert and the results are to be captured and if applicable any related AEs and 
respective concomitant medications. 
At least three attempts should be made by the site to get in contact with such subjects. The 
attempts should be documented in the subject file.


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Reporting of medical device failures (Japan only)
9.6.3.12
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.
Other procedures and variables
9.7
9.7.1
Iron supplementation
This section was changed in Amendment 1, see Section 15.1.1
Subjects in whom causes for anemia unrelated to HMB are suspected should not have been
enrolled. 
Moderate anemia is defined as hemoglobin 10.9 g/dL. Iron supplementation should be 
offered to subjects with hemoglobin 10.9 g/dL consistent with local standards of practice 
and at the investigator’s discretion. Iron supplementation will not be considered as study drug 
and should be documented as concomitant medication. 
9.7.2
Algorithm for monitoring of endometrial safety
See Section 9.6.3.2.1.
9.7.3
Heavy menstrual bleeding / suspicious bleeding pattern
See Section 9.6.3.2.7.
9.7.4
Unscheduled endometrial biopsy
See Section 9.6.3.2.8.
9.7.5
Monitoring of ovarian cysts
If cyst like structures >30 mm without suspicious appearance (ie, functional ovarian cysts) are 
visualized in the ovaries, unscheduled ultrasound examinations should be performed every 4 
weeks or more frequently, if required due to symptoms, to document the regression/outcome.
If the subject demonstrates menstrual cyclicity, the ultrasound should be performed after 
menstruation as soon as possible, preferably in the early follicular phase. The monitoring will 
be continued until resolution, ie, until cyst can no longer be distinguished from functional 
follicles. If the cysts persist after 3 months or grow, decision 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.
Appropriateness of procedures / measurements
9.8
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.


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10.
Statistical methods and determination of sample size
General considerations
10.1
Statistical analyses will be conducted by or under the supervision of the sponsor’s study 
statistician, except for the analysis of PK/PD data, which will be performed and reported 
under the supervision of the sponsor´s pharmacometrics group. 
Statistical analyses will be performed using Statistical Analysis Software (SAS Institute Inc., 
Cary, North Carolina, USA). The SAS version and further details on the statistical analyses 
will be provided in the SAP that will be approved before database release.
All target variables will be described according to their type using descriptive statistics 
frequencies or mean, standard deviation (SD), minimum, maximum, median, first and third
quartiles. Where appropriate, the individual change from baseline to end of treatment will also 
be analyzed. 
Analysis sets
10.2
The documentation of important deviations from the protocol and validity findings and the 
assignment of subject data to analysis sets will be performed according to the sponsor’s 
applicable Standard Operating Procedures and/or Instruction Manuals. The definition of 
important deviations and validity findings will be provided in the Specification of assessment 
criteria and identification requirements before unblinding the data.
The following statistical analysis sets will be defined:
Full analysis set (FAS): All randomized subjects, excluding randomized subjects who did 
not start Treatment Period 1 due to the study being temporarily on hold. Subjects will be 
analyzed as randomized. 
Per protocol set (PPS):  All subjects in the FAS without any validity findings impacting the 
primary efficacy variable in Treatment Period 1. 
Safety analysis set (SAF):  All subjects who took at least 1 dose of study drug. Subjects will 
be analyzed as treated.
The primary efficacy variable will be analyzed on the FAS and PPS, where the analysis on the 
FAS is considered to be the primary one. Safety analyses will be performed on the SAF. The 
FAS will be used for the display of all other variables.
Variables and planned statistical analyses
10.3
10.3.1
Variables
This section was changed in Amendment 1, see Section 15.1.1
The primary efficacy variable and secondary efficacy variables will be calculated based on the 
alkaline hematin method (unless otherwise specified). Other efficacy variables related to 
menstrual blood loss will be calculated for the two methods, the alkaline hematin method and 
the menstrual pictogram.
Primary efficacy variable
10.3.1.1
This section was changed in Amendment 1, see Section 15.1.1


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The primary efficacy variable is amenorrhea (yes/no), defined as MBL < 2 mL during the last 
28 days of treatment. 
If an endometrial biopsy was conducted during this time period, bleeding on the day of biopsy 
and the 3 days thereafter will not be considered in this evaluation.
For the primary analysis, the amenorrhea rates at the end of Treatment Period 1 of all 
Treatment Groups will be used.
Subjects who discontinue treatment prior to completion of treatment Week 8 of the respective 
treatment period will be considered not having amenorrhea.
Secondary efficacy variables
10.3.1.2
This section was changed in Amendment 1, see Section 15.1.1
The secondary efficacy variables are:

HMB response defined as blood loss <80.00 mL during the last 28 days of treatment 
and >50% reduction compared to baseline

Time to onset of amenorrhea. Onset of amenorrhea is defined by the first day for which 
the menstrual blood loss for all subsequent 28-day periods up to the end of the 
treatment period is <2 mL.

Time to onset of controlled bleeding. Onset of controlled bleeding is defined by the 
first day for which the menstrual blood loss for all subsequent 28-day periods up to the 
end of the treatment period is <80.00 mL.

Absence of bleeding (spotting allowed) during the last 28 days of the treatment; based 
on the UF-DBD
Other efficacy variables
10.3.1.3
This section was changed in Amendment 1, see Section 15.1.1

Treatment success rate defined as percentage of subjects who fulfill the criteria of 
HMB response (<80 mL, >50% reduction in menstrual blood loss as compared to 
baseline) and who have not been withdrawn from the study due to AEs, due to non-
fulfillment of selection criteria (related to fibroid size or HMB at baseline) or due to 
fibroid surgery having been performed during the study. 

Amenorrhea (yes/no), defined as MBL < 2 mL per 28 days of treatment (for treatment 
time/method not considered as primary variable)

HMB response defined as blood loss <80.00 mL and >50% reduction compared to 
baseline per 28 days of treatment (for treatment time/method not considered as 
secondary variable) 

Time to onset of amenorrhea. Onset of amenorrhea is defined by the first day for which 
the menstrual blood loss for all subsequent 28-day periods up to the end of the 
treatment period is <2 mL (for treatment time/method not considered as secondary 
variable) 

Time to onset of controlled bleeding. Onset of controlled bleeding is defined by the 
first day for which the menstrual blood loss for all subsequent 28-day periods up to the 


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end of the treatment period is <80.00 mL (for treatment time/method not considered as 
secondary variable) 

Volume of menstrual blood loss per 28 days

Volume of menstrual blood loss per bleeding episode for first, second, and if applicable 
third bleeding episode after the EoT 

Volume of menstrual blood loss per bleeding episode within the treatment break. All 
days of the bleeding episodes will be used even if some days of the episode lie outside 
the treatment break.

Percentage of subjects with ≥50% reduction in menstrual bleeding per 28 days 
compared to baseline

Time to start of bleeding after last study drug intake (assessed by the UF-DBD in 
addition to the other two measurement methods). If bleeding has to be induced, the 
subject´s data will be censored at that time point for the induction. 

Percent change in volume of 3 largest fibroids compared to baseline (measured by 
ultrasound) 

Percent change in volume of uterus compared to baseline (measured by ultrasound) 

Percentage of subjects with a volume reduction of ≥25% of the 3 largest fibroids 
(measured by ultrasound) 

Percentage of subjects with a reduction of ≥25% of uterine volume (measured by 
ultrasound) 

Percentage of subjects undergoing surgical treatment for uterine fibroids

Change in UF-DSD individual items compared to baseline 

Change in UFS-QoL scores compared to baseline 

Change in CGI_I scores compared to baseline. 

Change from baseline in hemoglobin, hematocrit, and ferritin 

Percentage of subjects with normal hemoglobin >12 g/dL and normal hematocrit >36% 
Pharmacokinetics (PK)
10.3.1.4
For details, see Section 9.5.2 and 9.5.3 and the separate M&S Analysis plan. 
Secondary safety variables
10.3.1.5

Endometrial histology (eg, benign endometrium, presence or absence of hyperplasia or 
malignancy)


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
Endometrial thickness
Other safety variables
10.3.1.6
This section was changed in Amendment 1, see Section 15.1.1

Endometrial histology (diagnosis of PAEC, individual features of PAEC)

Ovarian cysts (number, size)

Laboratory parameters 

AEs

Cervical Smear

Vital signs

Percentage of subjects with moderate to severe anemia, ie, hemoglobin 10.9 g/dL

Findings resulting from liver monitoring

Findings resulting from adrenal monitoring

Findings resulting from skin monitoring
10.3.2
Statistical and analytical plans
Demographic and other baseline characteristics
10.3.2.1
Demographic variables and baseline characteristics will be summarized overall by means of 
descriptive statistics and/or frequency tables as appropriate.
Medical history findings and AEs will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA) codes and medications by Anatomical Therapeutic Chemical (ATC) 
codes (World Health Organization Drug Dictionary [WHO-DD]).
Efficacy analysis
10.3.2.2
This section was changed in Amendment 1, see Section 15.1.1


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For the confirmatory efficacy analysis, a hierarchical testing approach will be applied, 
involving the primary efficacy variable amenorrhea (yes/no) and the first three secondary 
efficacy variables HMB response, time to onset of amenorrhea and time to onset of controlled 
bleeding. These tests always include a comparison of vilaprisan 2 mg versus placebo:
After 12 weeks of treatment in Treatment Period 1: 
Comparison of vilaprisan 2 mg in pooled Treatment Groups A1 and B2 (as the treatments are 
the same and pooling increases the power) vs. placebo in Treatment Group B1
In total, four tests will be carried out each to an alpha level of 0.05: First, the test for the 
primary efficacy variable amenorrhea (yes/no) will be carried out followed by the test for 
HMB response (yes/no), the test for time to onset of amenorrhea, and finally, the test for onset 
of controlled bleeding. As the hierarchical testing procedure follows a fixed sequence, it stops 
as soon as any of these tests cannot be rejected to an alpha level of 0.05 and all further tests 
after failing to reject one null hypothesis in the testing sequence will be considered 
exploratory. This fixed sequence procedure accounts for the multiplicity created by carrying 
out multiple tests. 
Amenorrhea (yes/no), defined as MBL <2 mL during the last 28 days of treatment
The primary efficacy variable amenorrhea (yes/no) will be analyzed by means of a two-sided 
Cochran-Mantel-Haenszel test stratified by region/country at a local 0.05 significance level. 
The number of subjects with amenorrhea (yes/no) is assumed to be binomial distributed. 
Thus, the Cochran-Mantel-Haenszel test is applied to test the null hypothesis  that the 
amenorrhea rates in the vilaprisan 2 mg group () and in the placebo group () in Treatment 
Period 1 are equal versus the alternative hypothesis 	 that they are not:
:  =    vs.   	:  ≠.
HMB response defined as blood loss <80.00 mL during the last 28 days and >50% 
reduction compared to baseline
The first secondary efficacy variable HMB response (yes/no) will be analyzed analogously to 
the primary efficacy variable amenorrhea. 
Time to onset of amenorrhea 
Onset of amenorrhea is defined by the first day for which the menstrual blood loss for all 
subsequent 28-day periods up to the end of Treatment Period 1 is <2 mL. Subjects are treated 
as censored if they did not experience an onset of amenorrhea during Treatment Period 1.
Censoring rules will be described in more detail in the SAP.
In order to investigate the null hypothesis that there is no difference in time to onset of 
amenorrhea between vilaprisan 2 mg and placebo versus the alternative hypothesis that there 
is a difference, a logrank test stratified by region/country is conducted at a local 0.05 
significance level. 
Time to onset of controlled bleeding
Onset of controlled bleeding is defined by the first day for which the menstrual blood loss for 
all subsequent 28-day periods up to the end of Treatment Period 1 is <80.00 mL. Subjects are 
treated as censored if they did not experience an onset of controlled bleeding during 
Treatment Period 1. Censoring rules will be described in more detail in the SAP.


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Time to onset of controlled bleeding will be analyzed analogously to the secondary efficacy 
variable time to onset of amenorrhea.
The study will be considered successful if at least superiority of vilaprisan 2 mg vs. placebo 
after Treatment Period 1 based on the primary variable could be demonstrated. 
Sensitivity analyses will be conducted for the primary efficacy variable and the first three 
secondary efficacy variables as applicable. These will be described in the SAP.
All primary and secondary efficacy variables will also be analyzed descriptively in frequency 
tables by treatment period within each treatment group, except for time to event variables 
which will be analyzed by treatment group using the Kaplan-Meier estimates. 
Other efficacy variables will be evaluated and presented by means of descriptive statistics.
Pharmacokinetic analysis
10.3.2.3
For details, see Sections 9.5.1 and 9.5.3 and the separate M&S Analysis Plan. Results will be 
reported in a separate M&S report, if applicable. 
Safety analysis
10.3.2.4
Safety analyses will be performed on the SAF. AEs and other safety variables will be 
summarized descriptively by treatment group.
The incidence of treatment-emergent AEs and drug-related AEs will be summarized using 
MedDRA preferred term and the primary system organ class. 
Subgroup analysis
10.3.2.5
This section was changed in Amendment 1, see Section 15.1.1
Subgroup analyses are planned using descriptive statistics for the primary and secondary 
efficacy variables separately for each country (the US and Japan), race and ethnicity. Further 
subgroup analyses will be described in the SAP.
10.3.3
Missing data/drop outs
This section was changed in Amendment 1, see Section 15.1.1
For the primary efficacy variable and secondary efficacy variables included in the testing 
strategy described in Section 10.3.2.2, it is assumed that data measured with the AH method 
will be only available on days when vaginal bleeding occurred. To differentiate missing AH 
data and days without vaginal bleeding the bleeding intensity collected in the UF-DBD will 
be used. 
Missing bleeding data in the subject diaries will be imputed. For the UF-DBD, the worst case 
approach will be used for missing bleeding intensity for the single or two consecutive missing 
days (i e, the maximum of the bleeding intensities of the day before and the day after the 
missing day[s] will be assumed).
If an endometrial biopsy was conducted during the time period under treatment, bleeding on 
the day of biopsy and the 3 days thereafter will not be considered as day(s) with 
bleeding/spotting and the AH value will be set to 0 mL. For the primary efficacy variable 
amenorrhea and the secondary efficacy variable HMB response, subjects will be defined as 
not having amenorrhea/not being a HMB responder if they did not complete at least 8 weeks 


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of treatment. Generally, in case a daily bleeding intensity is recorded with the UF-DBD as “no 
vaginal bleeding” or “spotting”, the missing AH value for this day will be set to 0 mL. 
For days with bleeding intensity of “mild” or higher in the UF-DBD, missing AH values will 
be replaced by the mean value of AH values of the days with the same bleeding intensity. In 
case there are no AH values with the same bleeding intensity, the mean of the AH values of 
next higher intensity will be used. In case there is no intensity higher than the bleeding 
intensity of the missing AH values available, either, no replacement for the missing AH 
values will be done for such days; but if at least one such day occurs within the respective 28 
days of treatment for a subject, the subject will be considered as not having amenorrhea/not 
being a HMB responder.
Furthermore, the last days under treatment with at least 28 days with non-missing bleeding 
intensity/AH values under treatment until the initial bleeding episode when the treatment 
started (after the imputations above) (without missing information: Days 57 to 84 under 
treatment) will be used to calculate the primary efficacy variable and the secondary efficacy 
variable HMB response. After these imputations a subject will be considered as not having 
amenorrhea in the presence of missing AH values if the sum of all non-missing AH values is 
not lower than 2 mL or if for missing AH values the bleeding intensity in the UF-DBD is 
“mild” or higher, otherwise the subject will be considered as having amenorrhea. An 
equivalent approach as described for the amenorrhea rate will be applied for the secondary 
variable HMB response, ie, after the imputations as described above a subject will be 
considered as not being a HMB responder in the presence of missing AH values if the sum of 
all non-missing AH values is ≥80 ml or the reduction of blood loss is ≤50% as compared to 
baseline or if for missing AH values the bleeding intensity in the UF-DBD is “mild” or 
higher, otherwise the subject will be considered as a HMB responder.
For the secondary variables onset of amenorrhea and onset of controlled bleeding the first 28 
days with non-missing bleeding/AH values until the last 28 days with non-missing
bleeding/AH values under treatment will be considered. An analogous approach as described 
above for the primary efficacy variable and the secondary efficacy variable HMB response 
will be applied to assess the bleeding status for each of these 28-day windows in terms of 
amenorrhea and controlled bleeding. If a subject does not achieve amenorrhea or controlled 
bleeding until end of treatment the subject will be considered as censored for the respective
endpoint.
Sensitivity analyses will be conducted to evaluate the impact of missing data. These will be 
described in the SAP.
Determination of sample size
10.4
This section was changed in Amendment 1, see Section 15.1.1
No longer valid, since with implementation of the protocol amendment 5, Version 5.0 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. 


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Assumptions for sample size calculations were based on the ASTEROID 1 study (Study 
15788) and the ASTEROID 2 study (Study 17541) with treatment durations of 12 and 24 
weeks respectively. 
In ASTEROID 1, amenorrhea rates (defined as MBL <2 mL during last 28 days of treatment) 
of about 0.7, 0.9, and 0.9 for vilaprisan 2 mg and of about 0.2, 0.0, and 0.1 for placebo for the 
regions US/Japan/European Union and Canada, respectively, were observed with differences 
between vilaprisan 2 mg and placebo of about 0.5 to 0.9. In ASTEROID 2, similar 
amenorrhea rates were observed with numerical variation between the treatment periods. 
HMB response rates in the last 28 days amounted to percentages above 90% for vilaprisan 2 
mg and 33% or lower for placebo. Median onset of amenorrhea was reached on day 6 after 
start of treatment for vilaprisan 2 mg. Due to the low number of subjects achieving
amenorrhea until end of placebo treatment no median onset of amenorrhea could be calculated 
for placebo. Onset of controlled bleeding was reached on day 2 after start of treatment for 
vilaprisan 2 mg. Again, as for onset of amenorrhea, no median onset of controlled bleeding 
could be calculated for placebo due to the low number of subjects achieving controlled 
bleeding until the end of placebo treatment. At the end of treatment controlled bleeding was
reported for about 97% of subjects for vilaprisan 2 mg and for 49% of subjects for placebo, 
respectively. 
Taking these aspects into account, a difference in amenorrhea rates of at least 0.4 between 
vilaprisan 2 mg and placebo is assumed after 12 weeks and 24 weeks. Sample size calculation 
was further based on a balanced randomization scheme of 1:1:1 (A1:B1:B2), an overall power 
of 0.9 for the study (ie, higher for each individual test), and the application of the two-sided 
Cochran–Mantel–Haenszel test for the primary variable and the secondary variable HMB 
response as well as the logrank test for the secondary variables Onset of amenorrhea and 
Onset of controlled bleeding (stratified by region/country), each to a local 0.05 significance
level.
Assuming a dropout rate of about 20%, the number of subjects to be randomized into the 
study was planned to be 156 (78, 39, 39 subjects in the US, Japan, other countries, 
respectively); 52 subjects in each treatment group (26, 13, and 13 subjects in the US, Japan, 
and other countries, respectively). 
Approximately 50% of the subjects were planned to be randomized from the US (based on the 
feedback from the FDA) and 25% from the subjects were planned to be randomized from 
Japan and other countries, respectively.   
Based upon the anticipated screen failures rates (60% in the US, 30% in Japan, and 50% in 
other countries), about 329 subjects were planned to be enrolled to achieve the planned 
number of randomized subjects.
PASS version 13.0.11 was used for sample size calculation.
Interim analysis
10.5
With the implementation of the protocol amendment 5, Version 5.0 a safety and efficacy 
analysis was planned after all subjects have completed their treatment period. Data of the 
follow-up period available at that time point will also be included in the analysis. Remaining 
data of the follow-up phase will be analyzed after all subjects have completed the follow-up 
period. For all other data this safety and efficacy analysis is considered the final analysis. 


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11.
Data handling and quality assurance
Data recording
11.1
The data collection tool for this study is a validated, internet-based, electronic data capture 
(EDC) software system called RAVE. Subject data necessary for analysis and reporting will 
be entered/transmitted into a validated database or data system (Clinical Information 
Environment). 
RAVE, which Bayer has licensed from Medidata Solutions Worldwide, has been validated by 
Medidata Solutions Worldwide and Bayer for use in its clinical studies. RAVE allows for the 
application of software logic to set-up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel. Bayer extensively 
applies the logic to ensure data are complete and reflect the clinical data requirements of the 
study. Data queries resulting from the application of the software logic are resolved by the site 
personnel. The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred on a periodic basis to Bayer's internal computer system via a 
secure Virtual Private Network.
Access to RAVE is through a password-protected security system that is part of the RAVE 
software. All Bayer and investigator site personnel must be trained before they are granted 
access. Training records are maintained.
All personnel with access to RAVE are supported by a Service Desk staffed with trained 
personnel to answer questions and ensure access is maintained so data entry can proceed in a 
timely manner.
RAVE contains a system-generated audit trail that captures any changes made to a data field, 
including who made the change, why the change was made, and the date and time it was 
made. This information is available both at the investigator’s site and at Bayer. Data entries 
made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this.
It is the expectation of the sponsor that all data have source documentation available at the 
site except for the data entered directly into the eCRF (eg, HMB questions, ClinRO) and 
ePRO data; these data will be the source and no additional source documentation will be 
available. The data entered directly into the eCRF/ePRO are not needed for the subject’s 
routine medical care. 


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Data recorded from screening failures (screening failure confirmed at Visit 1)
At a minimum, the following data should have been recorded in the eCRF, which will be 
transferred to the respective database:

Demographic information (SID number, year of birth, age, race, ethnicity)

Date of informed consent

Date of Visit 1

Relevant inclusion/exclusion criteria

Reason for screening failure

Date of last visit.
For all subjects continuing after Visit 1, all data had to be reported until screen failure was 
declared or randomization occurred. Additionally, to the above mentioned data these include:

All available data from Visit 1, Visit 2, and Visit 3 including visit independent folder 
data, if applicable (AE, concomitant medication, and medical history data)

Endometrial biopsy results (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).
Monitoring
11.2
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors  
contacted 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 also included
identification and documentation of source data items.
The sponsor/designee is monitoring the site activity to verify that the:

Data are authentic, accurate and complete

Safety and rights of subjects are being protected

Study is conducted 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.


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Data processing
11.3
Data management is performed consistent with applicable sponsor’s standards and data 
cleaning procedures. This is applicable for data recorded in the eCRF as well as for data from 
other sources (eg, IVRS/IWRS, laboratory, ePRO).
For data coding (eg, AEs, medication), internationally recognized and accepted dictionaries 
are used. MedDRA is used for AEs and medical history and WHO Drug Dictionary for prior 
and concomitant medication.
The results of endometrial biopsies taken after the FUP Visit will be entered into the clinical 
database at a pre-planned database re-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 measurements.
Missing data 
11.4
Most important is to avoid missing data, eg, by monitoring in time for completeness (see 
Section 11.2) and by training the investigators, especially instructing them to motivate 
subjects to be compliant with the study protocol. Study site personnel has been trained to 
monitor the completeness of the eDiary data using the web portal, and the importance of the 
regular checks throughout the study for all subjects were emphasized in the training and by 
the clinical research associate (CRA) during the study. The subjects were informed on use of 
the dispensed sanitary products, and the reasons for adhering to these practices were
emphasized at the beginning of the study and reviewed with them during the site visits.
Audit and inspection
11.5
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.
Archiving
11.6
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Subject (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.


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The investigator/institution notifies the sponsor if the archival arrangements change (eg, 
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[eg, treatment 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 (eg, SAEs)

Results of parallel clinical studies

Results of parallel animal studies (on eg, toxicity, teratogenicity, 
carcinogenicity or reproduction toxicity).

If the study conduct (eg, 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 (eg, IECs/IRBs; 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 6.4.1.
13.
Ethical and legal aspects
Investigators and other study personnel
13.1
Study Medical Expert is identified on the Title Page of this protocol (see Section 1). From 
among the participating investigators, the Global Clinical Leader will select the coordinating 
investigator, who will be responsible for signing the clinical study report. All other study 
personnel not included in this section are identified in a separate personnel list (not part of this 
clinical study protocol) as appropriate. This list will be updated as needed; an abbreviated 


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version with personnel relevant for the centers will be available in each center’s investigator 
site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (eg, health authority, ethics committee, sponsor) before 
subject recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
Funding and financial disclosure
13.2
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.
Ethical and legal conduct of the study
13.3
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 
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 IECs/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 (eg, 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 


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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.
Subject information and consent
13.4
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent provided by the sponsor or the study center. A sample subject 
information and informed consent 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 her entry into the study (ie, before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2.4 in protocol amendment 3, Version 3.0 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 (eg, image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the 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 and will be informed 
about the right to withdraw from the study at any time without any disadvantage and without 
having to provide reasons for this decision.
Only if the subject voluntarily agrees to sign the informed consent and has done so, may she 
enter the study. Additionally, the investigator will personally sign and date the form. The 
subject will receive a copy of the signed and dated form.
The signed informed consent is to remain in the investigator site file or, if locally required, in 
the subject’s note/file of the medical institution.
If the informed consent is obtained on the date that baseline study procedures are performed, 
the study record or subject´s clinical record must clearly show that informed consent was 
obtained prior to these procedures.


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The informed consent and any other written information provided to subjects will be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent, or there is an amendment to the protocol that necessitates a change to the content of 
the subject information and/or the written informed consent. The investigator will inform the 
subject of changes in a timely manner and will ask the subject to confirm her participation in 
the study by signing the revised informed consent. Any revised informed consent text and 
other information must receive the IEC/IRB’s approval/favorable opinion in advance of use.
Publication policy and use of data
13.5
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs. 
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
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. 
Compensation for health damage of subjects / insurance
13.6
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.
Confidentiality
13.7
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 SID number will be recorded in 
the eCRF, and if the subject name appears on any other document (eg, pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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14.
Reference list 
1.
Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered 
adrenal masses. Endocr Rev. 1995;16(4):460-84.
2.
Hallberg L, Nilsson L. Determination of Menstrual Blood Loss. Scand J Clin Lab 
Invest. 1964;16:244-8.
3.
Emons G, Beckmann MW, Schmidt D, Mallmann P, for the Uterus commission of the 
Gynecological Oncology Working G. New WHO Classification of Endometrial 
Hyperplasias. GebFra - DGGG-Gesellschaftsausgaben. 2015(01):135-6.
15.
Protocol amendments
Amendment 1 – Dated 15 NOV 2017
15.1
Amendment 1 is the first global amendment. The following is an overview of the changes 
made to the original protocol Version 1.0.
15.1.1
Overview of the changes to the study
The protocol was amended to maintain consistency across Vilaprisan Phase 3 studies and to 
modify the collection period of the sanitary products.
Change 1: Modification of the collection periods of sanitary products
15.1.1.1
The collection period for sanitary products was extended to cover the whole treatment period.
Rationale
Currently, the alkaline hematin method is the only validated method to collect information on 
menstrual blood loss volume accepted by the FDA. In order not to jeopardize the data 
collection in the two pivotal studies, Asteroid 3 and 4, by using a non-validated method, ie, 
the menstrual pictogram, the decision was made to use both, AH and MP, throughout the 
entire study.
Affected sections:

Section 9.1 Tabular schedule of evaluations

Section 9.2.3.1 Visit 1 Screening

Section 9.2.3.2 Visit 2 Screening

Section 9.2.3.3 Visit 3 Randomization

Section 9.2.3.4 Visits 4 and 5

Section 9.2.3.5 Visit 6

Section 9.2.3.6 EoT visit

Section 9.4.3 Alkaline hematin method to assess HMB
Change 2: changes in the statistical analysis
15.1.1.2
The statistical sections of the protocol were updated.


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Rationale:
In order to consider feedback from Authorities and to support label claims on the endpoints 
HMB response, time to onset of amenorrhea and time to onset of controlled bleeding, time to 
onset of amenorrhea was elevated to a secondary endpoint and all of these above-mentioned 
endpoints were included in the hierarchical testing strategy. Description of analyses and 
missing data considerations were added for these endpoints and the rationale for the study 
sample size was modified with respect to these changes in the testing strategy. Furthermore, 
the calculation of the primary efficacy variable was adapted and further efficacy variables 
were added to ‘other’ efficacy variables. 
Affected sections:

Section 9.6.3.1 Laboratory evaluations

Section 10.3.1 Variables

Section 10.3.1.1 Primary efficacy variable

Section 10.3.1.2 Secondary efficacy variables

Section 10.3.1.3 Other efficacy variables

Section 10.3.1.6 Other safety variables

Section 10.3.2.2 Efficacy analysis, Section 10.3.2.3 Secondary efficacy analysis and 
Section 10.3.2.4 Other efficacy

Section 10.3.2.5 Subgroup analysis

Section 10.3.3 Missing data/drop-outs

Section 10.4 Determination of sample size
Change 3: Modifications of the tabular schedule of evaluations
15.1.1.3
Footnotes were modified.
Rationale:
Footnotes were revised to reflect the actual requirements correctly.
Affected sections:

Section 9.1 Tabular schedule of evaluations
Change 4: Minor clarifications for consistency
15.1.1.4
Clarifications were made throughout the document to ensure readability, logic and 
consistency of the protocol and across studies.
Affected sections:

Section 5 Study design

Section 6.2 Exclusion criteria

Section 9.1 Tabular schedule of evaluations

Section 9.2.2 Optional pre-screening phone contact


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
Section 9.4.4 Ultrasound (efficacy) to assess uterine fibroids

Section 9.6.1.1 Definitions

Section 9.6.3.3 Cervical smear

Section 9.7.1 Iron supplementation

Section 9.7.3 Heavy menstrual bleeding / suspicious bleeding pattern
15.1.2
Changes to the protocol text
In this section, all changes are detailed by presenting the “old text” and the “new text”, and 
the sequence of the sections follows the structure of the protocol. Deletions are crossed out 
and additions are underlined. Corrections of typos or omissions, as well as automatic update 
of referenced numbers, are not highlighted. 
Section 2 Synopsis
15.1.2.1
Old text:
[…]
Methodology
Subjects will document the intensity of their daily menstrual bleeding in the 
Uterine Fibroid Daily Bleeding Diary (UF-DBD) and assess the intensity of 
their menstrual blood loss daily using a visual scoring system (MP) in an 
electronic diary (eDiary). Subjects will collect the sanitary products used 
during specified periods of the study to analyze the volume of blood loss 
using the AH method.
[…]
[…]
Plan for statistical analysis
The primary efficacy will be assessed by testing the amenorrhea rates of 
vilaprisan after 12 weeks of treatment in Treatment Period 1 and after 
24 weeks of treatment in Treatment Period 2 versus placebo after 12 weeks 
of treatment using two-sided Cochran-Mantel-Haenszel test at a 0.05 
significance level. A hierarchical (fixed sequence) testing procedure will be 
used.
In addition, efficacy and safety variables will be summarized by descriptive 
statistics.


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New text:
[…]
[…]
Methodology
Subjects will document the intensity of their daily menstrual bleeding in the 
Uterine Fibroid Daily Bleeding Diary (UF-DBD) and assess the intensity of 
their menstrual blood loss daily using a visual scoring system (MP) in an 
electronic diary (eDiary). Subjects will collect the sanitary products used 
during the study to analyze the volume of blood loss using the AH method.
[…]
[…]
Plan for statistical analysis
The primary efficacy will be assessed by testing the amenorrhea rates of 
vilaprisan after 12 weeks of treatment in Treatment Period 1 and after 24 
weeks of treatment in Treatment Period 2 versus placebo after 12 weeks of 
treatment using two-sided Cochran-Mantel-Haenszel test at a 0.05 
significance level. A hierarchical (fixed sequence) testing procedure will be 
used, involving the primary efficacy variable amenorrhea and key 
secondary efficacy variables HMB response, time to onset of amenorrhea 
and time to onset of controlled bleeding.
In addition, efficacy and safety variables will be summarized by descriptive 
statistics.
Section 5 Study design
15.1.2.2
Old text:
[…]
Overview of the study design is shown in Figure 5–1.
Figure 5–1: Design overview
Treatment 
Group A1
Screening 
about 120
days
Randomization
Vilaprisan 2 mg 
12 weeks
Bleeding 
episode
Vilaprisan 2 mg 
12 weeks
12-week
follow-up
Treatment 
Group B1
Screening 
about 120 
days
Randomization
Placebo 
12 weeks
Bleeding 
episode
Vilaprisan 2 mg
12 weeks
12-week 
follow-up
Treatment 
Group B2
Screening 
about 120 
days
Randomization
Vilaprisan 2 mg 
12 weeks
Bleeding 
episode
Placebo
12 weeks
12-week 
follow-up
During the screening period, subjects will have to demonstrate eligibility including presence 
of at least 1 uterine fibroid 30 mm and <120 mm in largest diameter based on ultrasound, 
HMB in at least 2 bleeding periods, each with menstrual blood loss (MBL) >80.00 mL 
documented by the alkaline hematin (AH) method, and endometrial biopsy results without 
significant histological disorder. The duration of the screening period should be kept to a 
minimum (about 120 days). In the event that the screening endometrial biopsy yielded an 


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inadequate sample and needs to be repeated before randomization, the screening period 
interval is allowed to be extended in order to accommodate the endometrial sample analysis. 
In this case, the randomization visit (Visit 3) should take place: 1) after the biopsy results are 
available, 2) when all the eligibility criteria are confirmed, and 3) as close to the screening 
period interval as possible.
[…]
After the end of the final treatment period, subjects will be followed up for 12 weeks.
[…]
Dose and regimen:
Nine Phase 1 studies with vilaprisan have been completed. Vilaprisan has been tested at a 
maximum oral dose of 30 mg for up to 28 days (Study 14721, Report A52153) in 
postmenopausal women and at oral doses of 0.1, 0.5, 1.0, 2.0 and 5.0 mg for up to 12 weeks 
(Study 14723, Report A56310) in healthy young women.
[…]
New text:
[…]
Overview of the study design is shown in Figure 5–1.
Figure 5–1: Design overview 
Treatment 
Group A1
Screening 
up to120 days
Randomization
Vilaprisan 2 mg 
12 weeks
Bleeding 
episode
Vilaprisan 2 mg 
12 weeks
Follow-up
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT
Treatment 
Group B1
Screening 
up to120 days
Randomization
Placebo 
12 weeks
Bleeding 
episode
Vilaprisan 2 mg
12 weeks
Follow-up
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT
Treatment 
Group B2
Screening 
up to120 days
Randomization
Vilaprisan 2 mg 
12 weeks
Bleeding 
episode
Placebo
12 weeks
Follow-up
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT
During the screening period, subjects will have to demonstrate eligibility including the
presence of at least 1 uterine fibroid 30 mm and <120 mm in largest diameter based on 
ultrasound, HMB in at least 2 bleeding periods, each with menstrual blood loss (MBL) >80.00 
mL documented by the alkaline hematin (AH) method, and endometrial biopsy results 
without significant histological disorder. The duration of the screening period should be kept 
to a minimum (maximum up to 120 days). In the event that the screening endometrial biopsy 
yielded an inadequate sample and needs to be repeated before randomization, the screening 
period interval is allowed to be extended in order to accommodate the endometrial sample 
analysis. In this case, the randomization visit (Visit 3) should take place: 1) after the biopsy 


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results are available, 2) when all the eligibility criteria are confirmed, and 3) as close to the 
screening period interval as possible.
[…]
After the end of the final treatment period, subjects will be followed up for until day 7 to 15 
of the 2nd menstrual cycle after end of treatment visit.
[…]
Dose and regimen:
Ten Phase 1 studies with vilaprisan have been completed. Vilaprisan has been tested at a 
maximum oral dose of 30 mg for up to 28 days (Study 14721, Report A52153) in 
postmenopausal women and at oral doses of 0.1, 0.5, 1.0, 2.0 and 5.0 mg for up to 12 weeks 
(Study 14723, Report A56310) in healthy young women.
[…]
Section 6.2 Exclusion criteria
15.1.2.3
Old text:
[…]
7. Use of other treatments that might interfere with the conduct of the study or the 
interpretation of the results including 

Short-acting hormonal contraception (oral, vaginal, or transdermal), if not 
stopped at the start of the menstrual cycle that follows Visit 1.

Long-acting hormonal contraception (injectable), if last application was 
performed less than 1 application interval before start of the menstrual cycle 
that follows Visit 1.

Contraceptive devices with or without hormone release (implant, intra-uterine 
device), if not removed at Visit 1.
[…]
New text:
[…]
7. Use of other treatments that might interfere with the conduct of the study or the 
interpretation of the results including 

Short-acting hormonal contraception (oral, vaginal, or transdermal), if not 
stopped at the start of the menstrual cycle that follows Visit 1 

Long-acting hormonal contraception (injectable), if last application was 
performed less than 1 application interval before start of the menstrual cycle 
that follows Visit 1 

Contraceptive devices with or without hormone release (implant, intra-uterine 
device), if not removed at Visit 1 (not applicable in cases of bilateral fallopian 
tube blockage of the subject (including Essure®)
[…]


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Section 9.1 Tabular schedule of evaluations
15.1.2.4
Old text:
[…]
Table 9–1: Schedule of procedures
Study Phase
Screening
Treatment period 1 a
Treatment period 2 b
FUP
Visit
1
2
3
4 c
5
6 d
EoT 
visite
FUP 
visit f
Timing 
Day 7-15 
(inclusive) of 
the 1st or 
2nd 
menstrual 
cycle after 
Visit 1
RND
Day 22-42/  
Wk 4-6 after 
start of TP1
Day 78-84/ 
Wk 12 after 
start of TP1
Day 22-42/ 
Wk 4-6 after 
start of TP2
Day 78-84/ 
Wk 12 after 
start of TP2
Day 7-15 
(inclusive) of 
the 2nd 
menstrual 
cycle after 
EoT 
Informed consent
X
In-/exclusion criteria
X
X
X
Demographics/smoking/alcohol 
consumption
X
Medical/reproductive/menstrual/ 
fibroids histories
X
HMB questions
X
Prior /concomitant medications
X
X
X
X
X
X
X
X
AE assessments
X
X
X
X
X
X
X
X
Physical examination
X
X
X
Vital signs g / body 
weight/BMI/height at Visit 1 only
X
X
X
X
Gynecological/breast exam
X
X
Urine pregnancy testh
X
X
X
X
X
X
X
X
Cervical smear
X i
X
Ultrasound examination j
X
X k
X
X
X
X
X
Xb
Endometrial biopsy l
X m
X n
Xb
Laboratory (blood) o
X
X
X
X
Instruct subject to call site at start of 
next menstrual bleed
X
X
X
at the 2nd 
bleed
PK sampling p
X
X
Supervised study drug intake at site
X
X
Urinalysis
X
Barrier contraception/sanitary 
protection/home pregnancy test 
dispensed
X
X
X
X
X
X
X
Alkaline hematin kit dispensed (as 
needed)
X
X
X
X
X
X
Collect pads & tampons (as needed)
→
→
→
→
→
→
Randomization
X
Study drug dispensed
X
X
X
X
Unused study drug and empty drug 
packs collected/drug accountability 
X
X
X
X
X
if applicable
Return unused study drug to subject
X
X q
X
X q
Assess subject's study drug 
compliance
→
→
→
→
→ 
if applicable
eDiary dispensed/collected
X
X
eDiary checked via web-report
→
→
→
→
→
→
→
→
PROs (eDiary/hand-held device) r:
UF-DSD
→
→
→
→
→
→
→
→
UF-DBD s
→
→
→
→
→
→
→
→
Menstrual pictogram
→
→
→
→
→
→
→
→
PROs (tablet computer) completed at the site t
UFS-QoL
X
X
X
X
ClinRO (RAVE): CGI_I
X
X
X


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Treatment Day 1 is defined as the first day of study drug intake (ie, start of treatment).
a
If no bleeding episode occurs within 7 weeks after the end of the treatment period, an ultrasound will be 
performed after which bleeding will be induced. 
b
If spontaneous menstrual bleeding does not occur within 7 weeks after the EoT, the scheduled ultrasound 
will be performed as planned after which bleeding will be induced. The scheduled endometrial biopsy (ie, at 
FUP visit) will be performed thereafter at Day 7 to 15 (inclusive) of the first menstrual cycle after the induced 
bleeding episode. Ultrasound and pregnancy test will be performed before the endometrial biopsy as 
described in Section 9.6.3.2.2.
c
Remind subjects to start collecting sanitary items on Day 50 of the TP1.
d
Remind subjects to start collecting sanitary items on Day 50 of the TP2.
e
EoT visit is also to be performed if a subject is prematurely withdrawn from the study during treatment 
phase.
f
FUP visit is also to be performed, if a subject is prematurely withdrawn from the study during FUP phase.
g
Vital signs after 5 minutes of rest in a sitting position.
h
Instruct the subject to perform a home pregnancy test before the start of study drug treatment (Treatment 
Periods 1 and 2), document it in the eDiary and only start study drug if the test is negative.
i
The cervical smear may be waived if a normal result has been documented in the subject’s medical records 
within the previous 6 months.
j
Ultrasound for safety only.
k
If spontaneous menstrual bleeding does not occur within 7 weeks after the EoT, the scheduled ultrasound 
will be performed as planned after which bleeding will be induced. The scheduled endometrial biopsy (ie, at 
FUP visit) will be performed thereafter at Day 7 to 15 (inclusive) of the first menstrual cycle after the induced 
bleeding episode. Ultrasound and pregnancy test will be performed before the endometrial biopsy as 
described in Section 9.6.3.2.2.
l
For scheduling the visits, consider for subjects with menstrual cycles that biopsies should be taken between 
Day 7-15 (inclusive) of a menstrual cycle, which may require scheduling an additional visit. The EoT biopsy 
should be taken while under treatment; this biopsy may require to be scheduled before the EoT visit. A 
pregnancy test and ultrasound have to be performed before an endometrial biopsy is taken. See Section 
9.6.3.2 for details.
m
Check laboratory results prior to the biopsy at Visit 2 to ensure subject is still eligible for the study.
n
For subjects with amenorrhea, biopsies are to be taken without considering any day in a cycle.
o
Coagulation parameters will be determined at Visit 1 only.
p
PK sampling. At Visit 5, one sample is to be taken pre-dose. At Visit 6, 1 sample is to be taken pre-dose, 
and 2 samples are to be taken after supervised study drug intake at the site (one between 0.5 – 1 hour 
after, and one between 2 - 4 hours after study drug intake). Document the following in the eCRF: the date 
and time of the last 2 study drug doses prior to the first PK sample, the time of the supervised drug intake at 
the study site, and the time of all blood samples, see Section 9.5.1.
q
For subjects who have completed the treatment period, collect unused study drug and empty packaging. 
For subjects who have not completed the treatment period, collect empty packaging and provide unused 
study drug back to the subject. Instruct the subject to complete the treatment period.
r
PROs on the eDiary/electronic hand-held device will be responded by the subjects until the next visit at 
home as required.
s
Check for any suspicious bleeding pattern and/or HMB at each visit except Visit 1.
t
The PRO on the tablet computer will be responded by the subjects at scheduled visits under standardized 
conditions in the same visit-relevant sequence and prior to other activities and evaluations.
= continuous collection of data (eg, daily or weekly questionnaire) or collection of data in a schedule different 
to the visit time point; AE = adverse event; BMI = body mass index; CGI_I = Clinical Global Impression -
Investigator; ClinRO= Clinician-reported outcome; EoT = end of treatment; FUP = follow-up; HMB = heavy 
menstrual bleeding; PK = pharmacokinetics; PRO = patient-reported outcome; RND = randomization; TP1, 2 = 
Treatment Period 1, 2; UF-DBD = Uterine Fibroid Daily Bleeding Diary; UF-DSD = Uterine Fibroid Daily 
Symptom Diary; UFS-QoL = Uterine Fibroid Symptom and Quality of Life questionnaire; Wk = week.


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New text:
[…]
Table 9–1: Schedule of procedures 
Study Phase
Screening
Treatment period 1 a
Treatment period 2 b
FUP
Visit
1
2
3
4 
5
6 
EoT 
visitc
FUP 
visit d
Timing 
Day 7-15 
(inclusive) of 
the 1st or 
2nd 
menstrual 
cycle after 
Visit 1
RND
Day 22-42/  
Wk 4-6 after 
start of TP1
Day 78-84/ 
Wk 12 after 
start of TP1
Day 22-42/ 
Wk 4-6 after 
start of TP2
Day 78-84/ 
Wk 12 after 
start of TP2
Day 7-15 
(inclusive) of 
the 2nd 
menstrual 
cycle after 
EoT 
Informed consent
X
In-/exclusion criteria
X
X
X
Demographics/smoking/alcohol 
consumption
X
Medical/reproductive/menstrual/ 
fibroids histories
X
HMB questions
X
Prior /concomitant medications
X
X
X
X
X
X
X
X
AE assessments
X
X
X
X
X
X
X
X
Physical examination
X
X
X
Vital signs e / body 
weight/BMI/height at Visit 1 only
X
X
X
X
Gynecological/breast exam
X
X
Urine pregnancy testf
X
X
X
X
X
X
X
X
Cervical smear
X g
X
Ultrasound examination h
X
Xi
X
X
X
X
X
Xb
Endometrial biopsy j
X k
X l
Xb
Laboratory (blood) m
X
X
X
X
Instruct subject to contact site at 
start of next menstrual bleed
X
X
at the 2nd 
bleed
PK sampling n
X
X
Supervised study drug intake at site
X
X
Urinalysis
X
Barrier contraception/sanitary 
protection/home pregnancy test 
dispensed
X
X
X
X
X
X
X
Alkaline hematin kit dispensed (as 
needed)
X
X
X
X
X
X
X
Collect pads & tampons (as needed)
→
→
→
→
→
→
→
Randomization
X
Study drug dispensed
X
X
X
X
Unused study drug and empty drug 
packs collected/drug accountability 
X
X
X
X
X
if applicable
Return unused study drug to subject
X
X o
X
X o
Assess subject's study drug 
compliance
→
→
→
→
→ 
if applicable
eDiary dispensed/collected
X
X
eDiary checked via web-report
→
→
→
→
→
→
→
→
PROs (eDiary/hand-held device) p:
UF-DSD
→
→
→
→
→
→
→
→
UF-DBD q
→
→
→
→
→
→
→
→
Menstrual pictogram
→
→
→
→
→
→
→
→
PROs (tablet computer) completed at the site r
UFS-QoL
X
X
X
X
ClinRO (RAVE): CGI_I
X
X
X


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Treatment Day 1 is defined as the first day of study drug intake (ie, start of treatment).
a
If no bleeding episode occurs within 7 weeks after the end of the treatment period, an ultrasound will be 
performed after which bleeding will be induced. 
b
If spontaneous menstrual bleeding does not occur within 7 weeks after the EoT, the scheduled ultrasound 
will be performed as planned after which bleeding will be induced. The scheduled endometrial biopsy (ie, at 
FUP visit) will be performed thereafter at Day 7 to 15 (inclusive) of the first menstrual cycle after the induced 
bleeding episode. Ultrasound and pregnancy test will be performed before the endometrial biopsy as 
described in Section 9.6.3.2.2.
c
EoT visit is also to be performed if a subject is prematurely withdrawn from the study during treatment 
phase.
d
FUP visit is also to be performed, if a subject is prematurely withdrawn from the study during FUP phase.
e
Vital signs after 5 minutes of rest in a sitting position.
f
Instruct the subject to perform a home pregnancy test before the start of study drug treatment (Treatment 
Periods 1 and 2), document it in the eDiary and only start study drug if the test is negative.
g
The cervical smear may be waived if a normal result has been documented in the subject’s medical records 
within the previous 6 months.
h
1. Ultrasound measurements do not have to be done on the same day as other assessment on that visit, but have 
to be performed as close to the specified visit as possible. On visits where a biopsy will be taken, the ultrasound 
must be done before the biopsy.
2. If endometrial thickness (double layer) >18 mm is detected after the start of treatment, the subject should 
undergo immediate evaluation by endometrial biopsy as described in Section 9.6.3.2. 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 finding should be performed every 4 
weeks or more frequently, if required due to symptoms
i
Ultrasound for safety only.
j
For scheduling the visits, consider for subjects with menstrual cycles that biopsies should be taken between 
Day 7-15 (inclusive) of a menstrual cycle, which may require scheduling an additional visit. The EoT biopsy 
should be taken while under treatment; this biopsy may require to be scheduled before the EoT visit. A 
pregnancy test and ultrasound have to be performed before an endometrial biopsy is taken. See Section 
9.6.3.2 for details.
k
Check laboratory results prior to the biopsy at Visit 2 to ensure subject is still eligible for the study.
l
For subjects with amenorrhea, biopsies are to be taken without considering any day in a cycle.
m
Coagulation parameters will be determined at Visit 1 only.
n
PK sampling. At Visit 5, one sample is to be taken pre-dose. At Visit 6, 1 sample is to be taken pre-dose, 
and 2 samples are to be taken after supervised study drug intake at the site (one between 0.5 – 1 hour 
after, and one between 2 - 4 hours after study drug intake). Document the following in the eCRF: the date 
and time of the last 2 study drug doses prior to the first PK sample, the time of the supervised drug intake at 
the study site, and the time of all blood samples, see Section 9.5.1.
o
For subjects who have completed the treatment period, collect unused study drug and empty packaging.  
For subjects who have not completed the treatment period, collect empty packaging and provide unused 
study drug back to the subject. Instruct the subject to complete the treatment period.
p
PROs on the eDiary/electronic hand-held device will be responded by the subjects until the next visit at 
home as required.
q
Check for any suspicious bleeding pattern and/or HMB at each visit except Visit 1.
r
The PRO on the tablet computer will be responded by the subjects at scheduled visits under standardized 
conditions in the same visit-relevant sequence and prior to other activities and evaluations.
= continuous collection of used sanitary products (pads or tampons), data (eg, daily or weekly questionnaire) 
or collection of data and used sanitary products in a schedule different to the visit time point; AE = adverse 
event; BMI = body mass index; CGI_I = Clinical Global Impression - Investigator; ClinRO= Clinician-reported 
outcome; EoT = end of treatment; FUP = follow-up; HMB = heavy menstrual bleeding; PK = pharmacokinetics; 
PRO = patient-reported outcome; RND = randomization; TP1, 2 = Treatment Period 1, 2; UF-DBD = Uterine 
Fibroid Daily Bleeding Diary; UF-DSD = Uterine Fibroid Daily Symptom Diary; UFS-QoL = Uterine Fibroid 
Symptom and Quality of Life questionnaire; Wk = week.


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Section 9.2.2 Optional pre-screening phone contact
15.1.2.5
Old text:
[…]
After the telephone discussion, the patient information and informed consent form may be 
sent to the subject for further information. Regardless of whether the patient information and 
informed consent form is sent to the subject, it must be thoroughly discussed and reviewed 
with her at the Screening Visit 1 before obtaining the signed informed consent form.
[…]
New text:
[…]
After the telephone discussion, the patient information and informed consent form may be 
sent to the subject for further information. Regardless of whether the patient information and 
informed consent form is sent to the subject, it must be thoroughly discussed and reviewed 
with her in person before obtaining the signed informed consent form.
[…]
Section 9.2.3.1 Visit 1 Screening
15.1.2.6
Old text:
[…]

Obtain signed and dated informed consent
[…]

Dispense alkaline hematin kit

Dispense sanitary protection. Explain procedure for collection of sanitary protection 
items for measurement of menstrual blood loss.

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed 

[…]
New text:
[…]

Obtain signed and dated informed consent. Consent form can be signed and dated also 
at an earlier timepoint.
[…]

Dispense alkaline hematin kit and sanitary protection. Explain procedure for collection 
of sanitary protection items for measurement of menstrual blood loss.

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed (but no later than 12 days from the start of the collection 
of the first item).

[…]


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Section 9.2.3.2 Visit 2 Screening
15.1.2.7
Old text:
[…]

Dispense sanitary protection

[…]

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed 
[…]
New text:
[…]

Dispense AH kit and sanitary protection. Explain procedure for collection of sanitary 
protection items for measurement of menstrual blood loss.

[…]

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed (but no later than 12 days from the start of the collection 
of the first item).
[…]
Section 9.2.3.3 Visit 3 Randomization
15.1.2.8
Old text:
[…]

Dispense alkaline hematin kit

Dispense sanitary protection

[…]

Complete ClinRO (RAVE): CGI_I (see Section 9.4.2)
New text:
[…]

Dispense AH kit and sanitary protection. Explain procedure for collection of sanitary 
protection items for measurement of menstrual blood loss.

[…]

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed (but no later than 12 days from the start of the collection 
of the first item).

Complete ClinRO (RAVE): CGI_I (see Section 9.4.2)


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Section 9.2.3.4 Visits 4 and 5
15.1.2.9
Old text:
[…]

Dispense alkaline hematin kit

Dispense sanitary protection

Visit 4: Remind subjects randomized to start collecting sanitary items on Day 50 of 
the TP1; collection to be continued until the end of this TP.
Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed.

Visit 5: Collect used sanitary protection items, if they have not yet been provided to 
the site. If a subject is continuing her treatment after the visit, remind her to continue 
collecting the used sanitary items until the end of their treatment and advise the 
subject to return them to the site as soon as bleeding episode has been completed.

[…]

Dispense study drug according to IVRS/IWRS assignment

Visit 5 only: Instruct the subject to start study drug within Days 3 to 7 of the next 
menstrual cycle following the end of Treatment Period 1

Drug accountability and assessment of subject compliance; remind the subject to bring 
unused study drug and empty drug packs to the next visit

Visit 4 only: Collect unused study drug and empty drug packs and provide unused 
study drug back to subject

Visit 5 only: For subjects who have completed Treatment Period 1, collect unused 
study drug and empty packaging. For subjects who have not completed Treatment 
Period 1, collect empty packaging and provide unused study drug back to the subject 
and instruct the subject to complete Treatment Period 1.

Remind the subject to complete eDiary-based questionnaires until the next visit as 
required (UF-DSD, UF-DBD, MP) (see Sections 9.4.1.1 and 9.4.1.2.1)

[…]
New text:
[…]

Dispense AH kit and sanitary protection. Explain procedure for collection of sanitary 
protection items for measurement of menstrual blood loss.

Collect used sanitary protection items, if they have not yet been provided to the site.

[…]

Dispense study drug according to IVRS/IWRS assignment

Drug accountability and assessment of subject compliance; remind the subject to bring 
unused study drug and empty drug packs to the next visit


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
Visit 4 only: Collect unused study drug and empty drug packs and provide unused 
study drug back to subject

Visit 5 only: For subjects who have completed Treatment Period 1, collect unused 
study drug and empty packaging. For subjects who have not completed Treatment 
Period 1, collect empty packaging and provide unused study drug back to the subject 
and instruct the subject to complete Treatment Period 1.

Visit 5 only: Instruct the subject to start study drug within Days 3 to 7 of the next 
menstrual cycle following the end of Treatment Period 1

Remind the subject to complete eDiary-based questionnaires until the next visit as 
required (UF-DSD, UF-DBD, MP) (see Sections 9.4.1.1 and 9.4.1.2.1)

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed (but no later than 12 days from the start of the collection 
of the first item).

[…]
Section 9.2.3.5 Visit 6
15.1.2.10
Old text:
[…]

Dispense alkaline hematin kit 

Dispense sanitary protection

Remind subjects to start collecting sanitary items on Day 50 of the TP2; collection to 
be continued until the end of this TP. 
Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed.

[…]

Remind the subject to complete eDiary-based questionnaires until the next visit at 
home as required (UF-DSD, UF-DBD, MP) (see Sections 9.4.1 and 9.4.1.2.1)

[…]
New text:
[…]

Dispense AH kit and sanitary protection. Explain procedure for collection of sanitary 
protection items for measurement of menstrual blood loss.

[…]

Remind the subject to complete eDiary-based questionnaires until the next visit at 
home as required (UF-DSD, UF-DBD, MP) (see Sections 9.4.1 and 9.4.1.2.1)

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed (but no later than 12 days from the start of the collection 
of the first item).

[…]


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Section 9.2.3.6 EoT visit
15.1.2.11
Old text:
[…]

Dispense alkaline hematin kit 

Dispense sanitary protection

Collect used sanitary protection items, if they have not yet been provided to the site. If 
a subject is continuing her treatment after the visit, remind her to continue collecting 
the used sanitary items until the end of her treatment and remind the subject to return 
them to the site as soon as bleeding episode has been completed.

Remind the subject to return all used sanitary protection items as soon as a bleeding 
episode has been completed

[…]
New text:
[…]

[…]

Dispense AH kit and sanitary protection. Explain procedure for collection of sanitary 
protection items for measurement of menstrual blood loss.

Collect used sanitary protection items, if they have not yet been provided to the site. 

Remind the subject to continue collecting the used sanitary products during the 
follow-up 

Remind the subject to return all used sanitary protection items as soon as the bleeding 
episode has been completed (but no later than 12 days from the start of the collection 
of the first item).

[…]
Section 9.4.3 Alkaline hematin method to assess HMB
15.1.2.12
Old text:
During the duration of the study, subjects will be required to use selected types of sanitary 
products provided (pads and/or tampons). During specified periods of the study, subjects need 
to collect their used sanitary products and return them to the study site as soon as the episode 
is completed to be sent to the central laboratory for analysis. 
The AH method will be applied to measure MBL during Screening and during the last 35 
days of each treatment period. Collection for 35 days at the end of each treatment period is 
chosen to avoid missing data for calculation of the primary endpoint (last 28 days of 
treatment) in cases where subjects stop treatment prematurely.
[…]


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New text:
During the duration of the study, subjects will be required to use selected types of sanitary 
products provided (pads and/or tampons). During the entire duration of the study, subjects 
need to collect their used sanitary products and return them to the study site as soon as the 
bleeding episode is completed to be sent to the central laboratory for analysis. 
The AH method will be applied to measure MBL from Screening onwards during the entire 
study.
[…]
Section 9.4.4 Ultrasound (efficacy) to assess uterine fibroids
15.1.2.13
Old text:
[…]
The minimum source documentation will include printouts from the ultrasound machine 
showing the 3 largest fibroids. The printouts have to be labeled unambiguously, containing at 
least the study number, SID number, time point, and longest diameter of 3 largest fibroids.
For safety ultrasound procedures, see Section 9.6.3.6.
New text:
[…]
The minimum source documentation will include printouts from the ultrasound machine 
showing the 3 largest fibroids. The printouts have to be labeled unambiguously, containing at 
least the study number, SID number, time point, and longest diameter of 3 largest fibroids. It 
is also possible that the site has a CD with the ultrasound images available, when in the source 
the evaluation of the US images from the CD is available as well. The CRA should be able to 
review the data on the CD and compare the images with the evaluations in the source during 
the onsite monitoring visits.
Furthermore, if the ultrasound machine machine is SESAC (Site Electronic Source 
Assessment Checklist) conform, ie, GCP conform electronic data storage is possible, then no 
print out is needed.
For safety ultrasound procedures, see Section 9.6.3.6.
Section 9.6.1.1 Definitions
15.1.2.14
Old text:
In a clinical study, an AE is any untoward medical occurrence (ie, any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing 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.
[…]


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In a clinical study, an AE is any untoward medical occurrence (ie, any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing 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. Treatment emergent adverse event (TEAE) is defined as 
any event that occurred after the first study drug intake until the end of FUP.
[…]
Section 9.6.3.1 Laboratory evaluations
15.1.2.15
A footnote was added to Laboratory evaluations of hematocrit, hemoglobin, and ferritin 
stating that hemoglobin, hematocrit and ferritin are also efficacy variables.
Section 9.6.3.3 Cervical smear
15.1.2.16
Old text:
The cervical smear should be obtained with the gynecological examination at the visits shown 
in Table 9–1. It may be repeated once during the screening period if the results are abnormal 
(this repeat is not considered rescreening). If the cervical smear is repeated at Visit 2 
(screening), it should be performed before the endometrial biopsy. The cervical smear at 
screening may be waived if a normal result has been documented in the subject’s medical 
records within the previous 6 months. Subjects with ASCUS can be included in the study if 
they have an HPV deoxyribonucleic acid test that is negative for high-risk HPV.
New text:
The cervical smear should be obtained with the gynecological examination at the visits shown 
in Table 9–1. It may be repeated once during the screening period if the results are abnormal 
(this repeat is not considered rescreening). If the cervical smear is repeated at Visit 2 
(screening), it should be performed before the endometrial biopsy. The cervical smear at 
screening may be waived if a normal result has been documented in the subject’s medical 
records within the previous 6 months. Subjects with ASCUS can be included in the study if 
they have an HPV deoxyribonucleic acid test that is negative for high-risk HPV. As a 
guidance, cervical smear should only be repeated once in case of insufficient material.
Section 9.7.1 Iron supplementation
15.1.2.17
Old text:
If causes for anemia unrelated to HMB are suspected these subjects should not be enrolled. 
Moderate anemia is defined as hemoglobin 10.9 g/dL (11). Iron supplementation should be 
offered to subjects with hemoglobin 10.9 g/dL consistent with local standards of practice 
and the Centers for Disease Control and Prevention recommendation, ie, 50 to 60 mg of oral 
elemental iron (the approximate amount of elemental iron in one 325 mg tablet of ferrous 
sulfate) twice daily for 3 months for the treatment of iron deficiency anemia. Iron 
supplementation will not be considered as study drug and should be documented as 
concomitant medication.


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New text:
If causes for anemia unrelated to HMB are suspected these subjects should not be enrolled. 
Moderate anemia is defined as hemoglobin 10.9 g/dL (11). Iron supplementation should be 
offered to subjects with hemoglobin 10.9 g/dL consistent with local standards of practice 
and at the investigator’s discretion. Iron supplementation will not be considered as study drug 
and should be documented as concomitant medication.
Section 9.7.3 Heavy menstrual bleeding / suspicious bleeding pattern
15.1.2.18
Old text:
[…]
In case of suspicious bleeding pattern (eg, continuous spotting, unusually heavy bleeding) 
after the start of treatment, which does not resemble the subject’s natural cycle or bleeding 
pattern, detected from the MP or UF-DBD, the subject should undergo immediate evaluation 
by the investigator. 
Especially if during intake of the study drug and after the initial reduction of bleeding and/or 
onset of amenorrhea, any recording in the MP, or bleeding of an intensity of “mild” or worse 
occurs continuously for 10 days or more the subject should be instructed to contact the site for 
immediate evaluation.
[…]
New text:
[…]
In case of suspicious bleeding pattern (eg, continuous spotting, unusually heavy bleeding) 
after the start of treatment, which does not resemble the subject’s natural cycle or bleeding 
pattern, detected from the AH, MP or UF-DBD, the subject should undergo immediate 
evaluation by the investigator. 
Especially if during intake of the study drug and after the initial reduction of bleeding and/or 
onset of amenorrhea, any recording in the MP, worsened bleeding detected from the AH 
analysis, or bleeding of an intensity of “mild” or worse occurs continuously for 10 days or 
more the subject should be instructed to contact the site for immediate evaluation.
[…]
Section 10.3.1 Variables
15.1.2.19
Old text:
The primary efficacy variable will be calculated based on the alkaline hematin method. 
Secondary and other variables related to menstrual blood loss will be calculated for the two 
methods, the alkaline hematin method and the menstrual pictogram, depending on the planned 
application of the methods.
New text:
The primary efficacy variable and secondary efficacy variables will be calculated based on the 
alkaline hematin method (unless otherwise specified). Other efficacy variables related to 
menstrual blood loss will be calculated based on the two methods, the alkaline hematin 
method and the menstrual pictogram.


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Section 10.3.1.1 Primary efficacy variable
15.1.2.20
Old text:
[…]
Subjects who discontinue treatment due to lack of efficacy, AEs, or prior to completion of 
treatment Week 8 of the respective treatment period will be considered not having 
amenorrhea.
Further, based on scientific advice by FDA, subjects who did not adequately fulfill selection 
criteria or require fibroid surgery during study participation will be considered not having 
amenorrhea.
New text:
[…]
Subjects who discontinue treatment prior to completion of treatment Week 8 of the respective 
treatment period will be considered not having amenorrhea.
Section 10.3.1.2 Secondary efficacy variables
15.1.2.21
Old text:
The secondary efficacy variables are:

Absence of bleeding (spotting allowed) during the last 28 days of the treatment; based 
on the UF-DBD

Time to onset of controlled bleeding. Onset of controlled bleeding is defined by the 
first day, for which the menstrual blood loss for all subsequent 28-day periods up to the 
end of the treatment period is <80.00 mL

HMB responder rate (percentage of subjects with blood loss <80.00 mL per 28 days 
and 50% reduction compared to baseline)
New text:
The secondary efficacy variables are:

HMB response defined as blood loss <80.00 mL during the last 28 days of treatment 
and >50% reduction compared to baseline

Time to onset of amenorrhea. Onset of amenorrhea is defined by the first day for which 
the menstrual blood loss for all subsequent 28-day periods up to the end of the 
treatment period is <2 mL.

Time to onset of controlled bleeding. Onset of controlled bleeding is defined by the 
first day for which the menstrual blood loss for all subsequent 28-day periods up to the 
end of the treatment period is <80.00 mL.

Absence of bleeding (spotting allowed) during the last 28 days of the treatment; based 
on the UF-DBD


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Section 10.3.1.3 Other efficacy variables
15.1.2.22
Old text:

Amenorrhea (yes/no), defined as MBL < 2 mL during the last 28 days of treatment 
(for treatment time/method not considered as primary variable) 

Volume of menstrual blood loss per 28 days 

Volume of menstrual blood loss per bleeding episode for the first, second, and if 
applicable third bleeding episode after the EoT 

Percentage of subjects with 50% reduction in menstrual bleeding per 28 days 
compared to baseline 

Time to onset of amenorrhea. Onset of amenorrhea is defined by the first day for 
which the menstrual blood loss for all subsequent 28-day periods up to the end of the 
treatment period is less than 2 mL.

Time to start of bleeding after last study drug intake (assessed by the UF-DBD). If 
bleeding has to be induced, the subject´s data will be censored at that time point for 
the induction. 
[…]

Change in CGI_I scores compared to baseline.
New text:
[…]

Treatment success rate defined as percentage of subjects who fulfill the criteria of 
HMB response (<80 mL, >50% reduction in menstrual blood loss as compared to 
baseline) and who have not been withdrawn from the study due to AEs, due to non-
fulfillment of selection criteria (related to fibroid size or HMB at baseline) or due to 
fibroid surgery having been performed during the study.

Amenorrhea (yes/no), defined as MBL < 2 mL per 28 days of treatment (for treatment 
time/method not considered as primary variable) HMB response defined as blood loss 
<80.00 mL and >50% reduction compared to baseline per 28 days of treatment (for 
treatment time/method not considered as secondary variable)

Time to onset of amenorrhea. Onset of amenorrhea is defined by the first day for 
which the menstrual blood loss for all subsequent 28-day periods up to the end of the 
treatment period is <2 mL (for treatment time/method not considered as secondary 
variable)

Time to onset of controlled bleeding. Onset of controlled bleeding is defined by the 
first day for which the menstrual blood loss for all subsequent 28-day periods up to the 
end of the treatment period is <80.00 mL (for treatment time/method not considered as 
secondary variable)


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
Volume of menstrual blood loss per 28 days 

Volume of menstrual blood loss per bleeding episode for the first, second, and if 
applicable third bleeding episode after the EoT 

Volume of menstrual blood loss per bleeding episode within the treatment break. All 
days of the bleeding episodes will be used even if some days of the episode lie outside 
the treatment break. 

Percentage of subjects with 50% reduction in menstrual bleeding per 28 days 
compared to baseline 

Time to start of bleeding after last study drug intake (assessed by the UF-DBD in 
addition to the other two measurement methods). If bleeding has to be induced, the 
subject´s data will be censored at that time point for the induction. 
[…]

Change in CGI_I scores compared to baseline

Change from baseline in hemoglobin, hematocrit, and ferritin

Percentage of subjects with normal hemoglobin >12 g/dL and normal hematocrit 
>36% 
Section 10.3.1.6 Other safety variables
15.1.2.23
Old text:
[…]

Vital signs 

Change from baseline in hemoglobin, hematocrit, and ferritin 

Percentage of subjects with normal hemoglobin >12 g/dL and normal hematocrit >36% 

Percentage of subjects with moderate to severe anemia, ie, hemoglobin 10.9 g/dL
New text:
[…]

Vital signs 

Percentage of subjects with moderate to severe anemia, ie, hemoglobin 10.9 g/dL


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Section 10.3.2.2 Efficacy analysis, Section 10.3.2.3 Secondary efficacy 
15.1.2.24
analysis and Section 10.3.2.4 Other efficacy
Old text:
10.3.2.2 Primary efficacy analysis
The primary efficacy will be assessed by testing the amenorrhea (yes/no) for superiority of 
vilaprisan 2 mg after 12 weeks of treatment in Treatment period 1 and 24 weeks of treatment 
in Treatment Period 2 against placebo after 12 weeks of treatment using two-sided Cochran-
Mantel-Haenszel test stratified by country/region at a 0.05 significance level. The number of 
subjects with amenorrhea (yes/no) is assumed to be binomial distributed.
In order to adjust for multiple testing problem a fixed sequence procedure is applied:
,		: 		, = 		,vs. 	,		: 		, ≠		,
,	: 	, = 	, vs. 	,	: 	, ≠	,
where 		, and 		, are the amenorrhea rate during the last 28 days of vilaprisan 
treatment after 12 weeks of treatment (in pooled Treatment Groups A1 and B2, as the 
treatments are the same and pooling increases the power) and the amenorrhea rate during the 
last 28 days of placebo treatment after 12 weeks of treatment (in Treatment Group B1), 
respectively. Similarly, 	, and 	, represent the amenorrhea rate during the last 28 
days of vilaprisan treatment after 2x12 weeks of treatment (in Treatment Group A1) and the 
amenorrhea rate during the last 28 days of placebo treatment after 2x12 weeks of treatment (in 
Treatment Group B2). 
First ,		 is tested to the significance level of 0.05. If ,		 is rejected, the procedure 
moves on to test the second hypothesis ,	 to the same alpha level, otherwise the 
procedure stops at ,		. 
10.3.2.3 Secondary efficacy analysis
The secondary efficacy variables will be analyzed descriptively in frequency tables by 
treatment period within each treatment group, except for time to event variables which will be 
analyzed by treatment group using the Kaplan-Meier estimates.
10.3.2.4 Other efficacy
Other variables will be evaluated and presented by means of descriptive statistics.
New text:
10.3.2.2 Efficacy analysis
For the confirmatory efficacy analysis, a hierarchical testing approach will be applied, 
involving the primary efficacy variable amenorrhea (yes/no) and the first three secondary 
efficacy variables HMB response, time to onset of amenorrhea and time to onset of controlled 
bleeding. These tests always include a comparison of vilaprisan 2 mg versus placebo and can 
be applied in two different situations:


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1
After 12 weeks of treatment in Treatment Period 1: 
Comparison of vilaprisan 2 mg in pooled Treatment Groups A1 and B2 (as the 
treatments are the same and pooling increases the power) vs. placebo in 
Treatment Group B1
2
After 12 weeks of treatment in Treatment Period 2:
Comparison of vilaprisan 2 mg in Treatment Group A1 vs. placebo in 
Treatment Group B2
In total, eight tests will be carried out each to an alpha level of 0.05: First, the tests for the 
primary efficacy variable amenorrhea (yes/no) will be carried out in scenarios 1 and 2 in this 
order, followed by the tests for HMB response (yes/no) in scenarios 1 and 2, the tests for time 
to onset of amenorrhea in scenarios 1 and 2, and finally, the tests for onset of controlled 
bleeding again in scenarios 1 and 2. As the hierarchical testing procedure follows a fixed 
sequence, it stops as soon as any of these tests cannot be rejected to an alpha level of 0.05 and 
all further tests after failing to reject one null hypothesis in the testing sequence will be 
considered exploratory. This fixed sequence procedure accounts for the multiplicity created 
by carrying out multiple tests. 
Amenorrhea (yes/no), defined as MBL <2 mL during the last 28 days of treatment
The primary efficacy variable amenorrhea (yes/no) will be analyzed by means of a two-sided 
Cochran-Mantel-Haenszel test stratified by region/country at a local 0.05 significance level. 
The number of subjects with amenorrhea (yes/no) is assumed to be binomial distributed. 
Thus, the Cochran-Mantel-Haenszel test is applied to test the null hypothesis , that the 
amenorrhea rates in the vilaprisan 2 mg group (,) and in the placebo group (,) in the 
respective situations  =1 and 2 are equal versus the alternative hypothesis 	, that they are 
not:
,: , = ,   vs.   	,: , ≠,.
__________________________________________________________________________________________________________________
HMB response defined as blood loss <80.00 mL during the last 28 days and >50% 
reduction compared to baseline
The first secondary efficacy variable HMB response (yes/no) will be analyzed analogously to 
the primary efficacy variable amenorrhea. 
Time to onset of amenorrhea 
Onset of amenorrhea is defined by the first day for which the menstrual blood loss for all 
subsequent 28-day periods up to the end of the treatment period is <2 mL. Subjects are treated 
as censored if they did not experience an onset of amenorrhea during the respective treatment 
period. Censoring rules will be described in more detail in the SAP.
In order to investigate the null hypothesis that there is no difference in time to onset of 
amenorrhea between vilaprisan 2mg and placebo versus the alternative hypothesis that there is 
a difference, a logrank test stratified by region/country is conducted at a local 0.05 
significance level. 


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Time to onset of controlled bleeding
Onset of controlled bleeding is defined by the first day for which the menstrual blood loss for 
all subsequent 28-day periods up to the end of the treatment period is <80.00 mL. Subjects are 
treated as censored if they did not experience an onset of controlled bleeding during the 
respective treatment period. Censoring rules will be described in more detail in the SAP.
Time to onset of controlled bleeding will be analyzed analogously to the secondary efficacy 
variable time to onset of amenorrhea.
The study will be considered successful if at least superiority of vilaprisan 2 mg vs. placebo 
after Treatment Period 1 based on the primary variable could be demonstrated. 
Sensitivity analyses will be conducted for the primary efficacy variable and the first three 
secondary efficacy variables as applicable. These will be described in the SAP.
All primary and secondary efficacy variables will also be analyzed descriptively in frequency 
tables by treatment period within each treatment group, except for time to event variables 
which will be analyzed by treatment group using the Kaplan-Meier estimates.
Other efficacy variables will be evaluated and presented by means of descriptive statistics.
Sections 10.3.2.3 (Secondary efficacy analysis) and 10.3.2.4 (Other efficacy) have been 
incorporated into Section 10.3.2.2 Efficacy analysis. Due to this section numbering of
sections 10.3.2.3 Pharmacokinetic analysis, 10.3.2.4 Safety analysis and 10.3.2.5 
Subgroup analysis have changed.
Section 10.3.2.5 Subgroup analysis
15.1.2.25
Old text:
Subgroup analyses are planned using descriptive statistics for the primary and secondary 
efficacy variables separately for each country (the US and Japan), race and ethnicity. 
New text:
Subgroup analyses are planned using descriptive statistics for the primary and secondary 
efficacy variables separately for each country (the US and Japan), race and ethnicity. Further 
subgroup analyses will be described in the SAP. 
Section 10.3.3 Missing data/drop-outs
15.1.2.26
Old text:
For the primary efficacy variable it is planned to collect the AH data only on days when 
vaginal bleeding occurred. To differentiate missing AH data and days without vaginal 
bleeding the bleeding intensity collected in the UF-DBD will be used. 
Missing bleeding data in the subject diaries will be imputed. For the UF-DBD, the worst case 
approach will be used for missing bleeding intensity for the single or two consecutive missing 
days (ie, the maximum of the bleeding intensities of the day before and the day after the 
missing day[s] will be assumed).


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If an endometrial biopsy was conducted during the time period under treatment, bleeding on 
the day of biopsy and the 3 days thereafter will not be considered as day(s) with 
bleeding/spotting and AH value will be set to 0 mL. For the primary efficacy analysis, 
subjects will be defined as not having amenorrhea if they did not complete at least 8 weeks of 
treatment. Generally, in case a daily bleeding intensity is recorded as “no vaginal bleeding” or 
“spotting”, the missing AH value for this day will be set to 0 mL. 
For days with bleeding intensity of light bleeding or higher in the UF-DBD, missing AH 
values will be replaced by the mean value of AH values of the days with the same bleeding 
intensity. In case there are no AH values with the same bleeding intensity, the arithmetic
mean of the AH values of next higher intensity will be used. In case there is no intensity 
higher than bleeding intensity of the missing AH values available, either, no replacement for 
the missing AH values will be done for such days; but if at least one such day occurs within 
the respective 28 days of treatment for a subject, the subject will be considered as not having 
amenorrhea.
Furthermore, the last days under treatment with at least 28 days with non-missing bleeding 
intensity/AH values under treatment until the initial bleeding episode when the treatment 
started (after the imputations above) (without missing information: Days 57 to 84 under 
treatment) will be used to calculate the primary variable. After these imputations a subject 
will be considered as not having amenorrhea in the presence of missing AH values if the sum 
of all non-missing AH values is not lower than 2 mL or if for missing AH values the bleeding 
intensity in the UF-DBD is light or higher, otherwise the subject will be considered as having 
amenorrhea.
Sensitivity analyses will be conducted to evaluate the impact of missing data. These will be 
described in the SAP.
New text:
For the primary efficacy variable and secondary efficacy variables included in the testing 
strategy described in section 10.3.2.2 it is assumed that data measured with the AH method 
will be only available on days when vaginal bleeding occurred. To differentiate missing AH 
data and days without vaginal bleeding the bleeding intensity collected in the UF-DBD will 
be used. 
Missing bleeding data in the subject diaries will be imputed. For the UF-DBD, the worst case 
approach will be used for missing bleeding intensity for the single or two consecutive missing 
days (ie, the maximum of the bleeding intensities of the day before and the day after the 
missing day[s] will be assumed).
If an endometrial biopsy was conducted during the time period under treatment, bleeding on 
the day of biopsy and the 3 days thereafter will not be considered as day(s) with 
bleeding/spotting and the AH value will be set to 0 mL. For the primary efficacy variable 
amenorrhea and the secondary efficacy variable HMB response, subjects will be defined as 
not having amenorrhea/ not being a HMB responder if they did not complete at least 8 weeks 
of treatment. Generally, in case a daily bleeding intensity is recorded with the UF-DBD as “no 
vaginal bleeding” or “spotting”, the missing AH value for this day will be set to 0 mL. 
For days with bleeding intensity of light bleeding or higher in the UF-DBD, missing AH 
values will be replaced by the mean value of AH values of the days with the same bleeding 
intensity. In case there are no AH values with the same bleeding intensity, the mean of the AH 


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values of next higher intensity will be used. In case there is no intensity higher than the 
bleeding intensity of the missing AH values available, either, no replacement for the missing 
AH values will be done for such days; but if at least one such day occurs within the respective 
28 days of treatment for a subject, the subject will be considered as not having amenorrhea/ 
not being a HMB responder.
Furthermore, the last days under treatment with at least 28 days with non-missing bleeding 
intensity/AH values under treatment until the initial bleeding episode when the treatment 
started (after the imputations above) (without missing information: Days 57 to 84 under 
treatment) will be used to calculate the primary efficacy variable and the secondary efficacy 
variable HMB response. After these imputations a subject will be considered as not having 
amenorrhea in the presence of missing AH values if the sum of all non-missing AH values is 
not lower than 2 mL or if for missing AH values the bleeding intensity in the UF-DBD is light 
or higher, otherwise the subject will be considered as having amenorrhea. An equivalent 
approach as described for the amenorrhea rate will be applied for the secondary variable 
HMB response, ie, after the imputations as described above a subject will be considered as not 
being a HMB responder in the presence of missing AH values if the sum of all non-missing 
AH values is ≥80 mL or the reduction of blood loss is ≤50% as compared to baseline or if for 
missing AH values the bleeding intensity in the UF-DBD is light or higher, otherwise the 
subject will be considered as a HMB responder.
For the secondary variables onset of amenorrhea and onset of controlled bleeding the first 28 
days with non-missing bleeding/AH values until the last 28 days with non-missing 
bleeding/AH values under treatment will be considered. An analogous approach as described 
above for the primary efficacy variable and the secondary efficacy variable HMB response 
will be applied to assess the bleeding status for each of these 28-day windows in terms of 
amenorrhea and controlled bleeding. If a subject does not achieve amenorrhea or controlled 
bleeding until end of treatment the subject will be considered as censored for the respective 
endpoint. 
Sensitivity analyses will be conducted to evaluate the impact of missing data. These will be 
described in the SAP.
Section 10.4 Determination of sample size
15.1.2.27
Old text:
Assumptions for sample size calculations are based on the ASTEROID 1 study (Study 15788) 
with treatment duration of 12 weeks and take into account scientific advice from Health 
Authorities. 
In ASTEROID 1, amenorrhea rates (defined as MBL <2 mL during last 28 days of treatment) 
of about 0.7, 0.9, and 0.9 for vilaprisan 2 mg and of about 0.2, 0.0, and 0.1 for placebo for the 
regions US/Japan/European Union and Canada were observed with differences between 
vilaprisan 2 mg and placebo of about 0.5 to 0.9. 
Based on scientific advice by FDA an analysis will be required in which certain groups of 
patients are counted as treatment failures (patients who did not adequately fulfill selection 
criteria; patients who require fibroid surgery during study participation).
Taking these aspects into account, a difference of at least 0.4 between vilaprisan and placebo 
is assumed after 12 weeks and 24 weeks. Sample size calculation is further based on a 


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balanced randomization scheme of 1:1:1 (A1:B1:B2), a power of 0.9 for the study (ie, higher 
for each individual test), and the application of the two-sided Cochran-Mantel-Haenszel test 
to a 0.05 significance level.
Assuming a dropout rate of about 20%, the number of subjects to be randomized into the 
study is planned to be 156 (78, 39, 39 subjects in the US, Japan, other countries, respectively); 
52 subjects in each treatment group (26, 13, and 13 subjects in the US, Japan, and other 
countries, respectively).
Approximately 50% of subjects are planned to be enrolled from the US and 25% from the 
subjects are planned to be randomized from Japan and other countries, respectively.
Based upon the anticipated screen failures rates (60% in the US, 30% in Japan, and 50% in 
the other countries), about 329 subjects will be enrolled to achieve the planned number of 
randomized subjects.
PASS version 13.0.11 was used for sample size calculation.
New text:
Assumptions for sample size calculations are based on the ASTEROID 1 study (Study 15788) 
and the ASTEROID 2 study (Study 17541) with treatment durations of 12 and 24 weeks, 
respectively. 
In ASTEROID 1, amenorrhea rates (defined as MBL <2 mL during last 28 days of treatment) 
of about 0.7, 0.9, and 0.9 for vilaprisan 2 mg and of about 0.2, 0.0, and 0.1 for placebo for the 
regions US/Japan/European Union and Canada, respectively, were observed with differences 
between vilaprisan 2 mg and placebo of about 0.5 to 0.9. In ASTEROID 2, similar 
amenorrhea rates were observed with numerical variation between the treatment periods. 
HMB response rates in the last 28 days amounted to percentages above 90% for vilaprisan 2 
mg and 33% or lower for placebo. Median onset of amenorrhea was reached on day 6 after 
start of treatment for vilaprisan 2 mg. Due to the low number of subjects achieving
amenorrhea until end of placebo treatment, no median onset of amenorrhea could be 
calculated for placebo. Onset of controlled bleeding was reached on day 2 after start of 
treatment for vilaprisan 2 mg. Again, as for onset of amenorrhea, no median onset of
controlled bleeding could be calculated for placebo due to the low number of subjects 
achieving controlled bleeding until the end of placebo treatment. At the end of treatment 
controlled bleeding was reported for about 97% of subjects for vilaprisan 2 mg and for 49% 
of subjects for placebo, respectively. 
Taking these aspects into account, a difference in amenorrhea rates of at least 0.4 between 
vilaprisan 2 mg and placebo is assumed after 12 weeks and 24 weeks. Sample size calculation 
is further based on a balanced randomization scheme of 1:1:1 (A1: B1:B2), an overall power 
of 0.9 for the study (ie, higher for each individual test), and the application of the two-sided 
Cochran-Mantel-Haenszel test for the primary variable and the secondary variable HMB 
response as well as the logrank test for the secondary variables onset of amenorrhea and onset 
of controlled bleeding (stratified by region/country), each to a local 0.05 significance level.
Assuming a dropout rate of about 20%, the number of subjects to be randomized into the 
study is planned to be 156 (78, 39, 39 subjects in the US, Japan, other countries, respectively); 
52 subjects in each treatment group (26, 13, and 13 subjects in the US, Japan, and other 
countries, respectively).


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Approximately 50% of subjects are planned to be enrolled from the US (based on feedback 
from the FDA) and 25% from the subjects are planned to be randomized from Japan and other 
countries, respectively.
Based upon the anticipated screen failures rates (60% in the US and 30% in Japan, and 50% 
in the other countries), about 329 subjects will be enrolled to achieve the planned number of 
randomized subjects.
PASS version 13.0.11 was used for sample size calculation.
Amendment 2
15.2
Amendment 2 is presented using a different approach compared with previous amendments to 
this protocol. 
Amendment 2 (04 JUL 2018)
Overall Rationale for the Amendment:
This amendment is based on recommendations provided for ulipristal acetate on 18 May 2018 
from the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines 
Agency (EMA) and guidance from Health Authorities regarding hepatic monitoring to 
provide a robust data base for evaluation of hepatic safety of vilaprisan. In addition to health 
authority triggered changes additional updates had to be performed, which are listed below, 
together with the respective reasons for the updates.
Section # and 
Name
Description of Major Changes
Brief Rationale
3 Introduction
1) Text added describing hepatic safety 
signal with Esmya® (ulipristal acetate), a 
compound that belongs to the compound 
group of selective PRMs, and the result of 
the respective PRAC review procedure 
including risk minimization measures. 
2) Provided rationale that vilaprisan is 
structurally different from other selective 
PRMs.
1) EMA 
Pharmacovigilance Risk 
Assessment Committee 
(PRAC) review 
procedure concluded in
May 2018
2) For clarification
5. Study design
1) Description of increased frequency of 
liver monitoring and its background in 
subsection “safety monitoring”
2) Creation of a separate section on Benefit 
Risk Assessment 
1) FDA feedback in 
January and May 2018; 
FDA Guidance for 
Industry Drug-Induced 
Liver Injury (July 2009)
2) Feedback received 
from health authorities in 
the initial submission of 
Asteroid protocols
6.2 Exclusion 
criteria
1) The criterion about abnormal liver parameters 
was revised.
1) + 2) To address FDA’ 
requirement on more robust 


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2) The diagnosis of chronic hepatitis B / C 
infection was added to exclusion criteria.
3) The criterion about intake of strong CYP 
inducer was updated, correcting information 
about metronidazole. 
4) A clarification that endometrioma are exempt 
was added to the criterion regarding ovarian 
cysts.
liver safety data and to 
closely align with specific 
feedback received in Jan 
and May 2018 and the 
2009 FDA DILI guideline.
3) correction
4) clarification
9.1 Tabular 
schedule of 
evaluations
9.2.2 Scheduled 
visits
Added additional visits (e. Visits 4.1, 5.1 and 
6.1); added liver symptom inquiry for all visits
To address FDA 
requirement on more robust 
liver safety data, and to 
closely align with specific 
feedback received in Jan 
and May, 2018 and the 
2009 FDA DILI guideline
9.6.1.1 
Definition
1) Newly included sentences “Any fibroid 
surgery should always be reported as serious 
adverse event (SAE), irrespective of 
associated hospitalization” and “All 
instances of liver parameter testing which 
meet criteria for withdrawal of a subject 
from the study treatment should be reported 
as SAE.”
2) Added definition of TEAE
1) To address FDA 
recommendation in 
response to  SPA for 
Asteroid 3 received 
in Jul 2017 and to 
align with FDA 2009 
DILI guidance
For clarity
9.6.1.3 
Assessments 
and 
documentation 
of adverse 
events
Added details about follow up of AEs of 
special safety interest.
For clarity
9.6.1.6 AEs of 
special interest
Added more detailed instructions for the 
monitoring of liver parameters and liver 
disorders and for close observation in cases 
with increased liver parameters and liver 
disorders; added a flow chart aiding the 
understanding of the intended processes for 
liver function monitoring
FDA feedback in Jan and 
May 2018 regarding 
improved liver 
monitoring
9.6.3.2 Further 
safety
Added description for liver symptom inquiry.
To address FDA require-
ment on more robust liver 
safety data received in Jan  
and May 2018 
9.6.3.1 
Laboratory 
Added more details on laboratory parameters 
including liver related parameters, screening 
tests for hepatitis A, B, and C, hemoglobin, and 
To address FDA’ 
requirement on more robust 
liver safety data received in 


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evaluations
additional parameters.  Added parameters 
measured under close observation in cases of 
increased liver parameters after start of 
treatment
Jan and May 2018
9.6.3.2.3 
Sampling of 
endometrial 
biopsies
A repeat endometrial biopsy will be requested, if 
sample is inadequate for evaluation
To address FDA 
recommendation received 
in May 2018
9.7.6 Monitoring 
of ovarian cysts
The monitoring will be continued until 
resolution, ie, until cyst can no longer be 
distinguished from functional follicles.
To address FDA 
recommendation  received 
in May 2018
9.7.4 
Unscheduled 
endometrial 
biopsy
Following procedures regarding the case of a 
diagnosis that does not fall into the categories 
that require immediate stop of study drug (e.g. 
simple hyperplasia) were added.
For clarity
8.1.1 Iron 
supplementation
Addition of “consistent with local standards of 
practice and at the investigator’s discretion”
Clarification needed 
because of regional 
differences in medical 
practice
9.1 Tabular 
schedule of 
evaluations, 9.2.3 
Scheduled visits, 
9.3.4 HMB 
questions
Addition of “not mandatory” for HMB- related 
pre-screening questions
For clarity, to avoid 
unnecessary burden to 
investigators and subjects
10.3.1.6 Other 
safety variables
Details for laboratory parameters were added
To address FDA re-
quirement on more robust 
liver safety data received in 
Jan and May 2018
16.1 Strong 
CYP3A4 
inhibitors
Added delavirdine and troleandomycin to the 
listing of strong CYP3A4 inhibitors
New compounds which 
need to be added to the list 
of excluded concomitant 
medications
Amendment 5
15.3
Amendment 5 was presented using the same approach as Amendment 4. The rationale for 
changes in Amendment 5 and all affected sections are provided as follows.
Overall Rationale for the Amendment:
Bayer has decided to close all clinical studies with vilaprisan, which were put on temporary 
pause in December 2018 (protocol amendment 4, Version 4.0) while pre-clinical toxicology 
findings and their relevance to humans were being further investigated. Although the outcome 
of Bayer’s investigation revealed that the observed pre-clinical findings are regarded to be of 
limited relevance to the human situation (refer to IB version 11.0 and Introduction section), a 


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comprehensive safety follow up will be conducted to provide additional confirmatory 
evidence. This amendment introduces measures and processes to prepare this study for an 
orderly closure, including safety follow up measures in all study subjects who received at 
least one dose of study drug.
15.3.1
Overview of the changes
3 Introduction
Information on carcinogenicity studies with 
vilaprisan in rodents as well as details 
regarding the additional safety measures 
were added to the section, included adrenal 
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
4. Study 
objectives
Added additional focus on safety 
evaluations of the endometrium, adrenal 
glands and skin
To address FDA requests
5. Study design
Updated study design; information deleted
To address FDA requests
With the implementation
of this amendment
(protocol amendment 5, 
Version 5.0) no new 
subjects will be recruited 
and no study medication 
will be given to the 
subjects who have been 
enrolled in the study
6 Study 
population
7. Treatments
8. Non-study 
therapy
9.3 Population 
characteristics
9.4 Efficacy
9.5 
Pharmacokineti
Updated based on new study design; 
information deleted  
To address FDA requests


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cs/pharmacodyn
amics
11. Data 
handling and 
quality 
assurance
9.1 Tabular 
schedule of 
evaluations
9.2 Visit 
description
Irrelevant information deleted that is no 
longer relevant; added “Safety closeout
visit” and “Safety result reporting visit” 
To depict the procedures 
of the “Safety closeout 
visit” and the “Safety 
result reporting visit” 
9.6.1.1 
Definition
New criteria for SAE reporting for 
endometrial biopsies, adrenal tumors, and 
malignant skin tumors
To address FDA requests 
9.6.1.6 AEs of 
special interest
New AESIs added for adrenal and skin 
disorders.
To address FDA requests
9.6.3 Further 
safety
Deleted “In addition, the subjects should be 
reminded regularly to contact the study site 
immediately, if they are concerned about 
such symptoms and testing for unscheduled 
liver parameters should be considered.”
No longer required as no 
further treatment will be 
administered
9.6.3.1 
Laboratory 
evaluations
Added more details on laboratory 
parameters associated with adrenal 
disorders. Added requirement for Vit D 
measurement
To address FDA 
requirement on adrenal 
monitoring; Vit D 
measurement for 
harmonization of data 
across all studies
9.6.3.2
Endometrial 
biopsies
Added more details on endometrial biopsies
To address FDA requests
9.6.3.3 Cervical 
smear
9.6.3.4 Physical 
and 
gynecological 
examinations
9.6.3.5 Vital 
signs, weight, 
and height
9.6.3.6
Revised to reflect the collection of the 
parameters at the Safety closeout visit.
Update necessary due to new 
visit structure


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Ultrasound 
(safety)
9.6.3.7
Contraception 
and pregnancy 
test
9.6.3.8 Adrenal 
monitoring
Added description for adrenal monitoring 
(MRI, laboratory investigations and inquiry)
To address FDA requests
9.6.3.9 Liver 
monitoring
Content shifted from previous Section 
9.6.1.6 and added alkaline phosphatase (AP) 
value increasing to > 2x ULN in cases with 
normal baseline AP as a close observation 
criterion
To address FDA requests
9.6.3.11 Skin 
monitoring
New section added on skin monitoring
To address FDA requests
9.7.2 Algorithm 
for monitoring 
of endometrial 
safety
9.7.3 Heavy 
menstrual 
bleeding / 
suspicious 
bleeding pattern
9.7.4 
Unscheduled 
endometrial 
biopsy
Content shifted to Sections 9.6.3.2.1, 
9.6.3.2.7, and 9.6.3.2.8
To address FDA requests
10.2 Analysis 
sets
Adapted FAS and PPS definitions
FAS needed to be newly 
defined to take the 
handling of subjects into 
account who were not 
allowed to start TP1 due 
to the clinical hold. 
PPS needed to be newly 
defined in order to 
account for the changed 
analysis (only evaluation 
of Treatment Period 1).
10.3.1.1 
Primary 
Changed text since primary efficacy 
analysis will only be performed for 
Data for Treatment Period 
2 is not sufficient to draw 


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Amendment 6 - dated 17 FEB 2020
15.4
Amendment 6 is presented using the same approach as Amendment 5. The rationale for this 
amendment and all affected sections are provided in the “Protocol Amendment Summary of 
Changes Table” directly before the Table of Contents in this document. Changes are made 
directly in the protocol body without annotations. A separate file with tracked changes against 
the last integrated protocol version is available upon request.
efficacy 
variable
Treatment Period 1
valid conclusions.
10.3.1.6 Other 
safety variables
Added adrenal monitoring and skin safety
To address FDA requests
10.3.2.2 
Efficacy 
analysis
Changed text and hypothesis since primary 
efficacy analysis will only be performed for 
Treatment Period 1
Data for Treatment Period 
2 is not sufficient to draw 
valid conclusions.
10.4 Sample 
size
Added text to clarify that the sample size 
calculation described is not valid anymore.
No new subjects will be 
included in the study. 
10.5 Planned 
interim analysis
Added text on additional analysis planned 
before the end of the study
Added to reflect new 
analysis strategy


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16.
Appendices
Strong CYP3A4 inhibitors
16.1
Table 16–1: Strong CYP3A4 inhibitors
Substance name
Inhibitor strength
Boceprevir
Strong
Clarithromycin
Strong
Cobicistat
Strong
Conivaptan
Strong
Delavirdine
Strong
Grapefruit juice
Depending on dose: Moderate or 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
Strong CYP3A4 inducers
16.2
Table 16–2: Strong CYP3A4 inducers
Substance name
Inducer strength
Phenobarbital
Strong
Avasimibe
Strong
Carbamazepine
Strong
Enzalutamide
Strong
St. Johns Wort (Hypericum)
Strong
Lumacaftor
Strong
Methylphenobarbital
Strong
Mitotane
Strong
Phenytoin
Strong
Rifampicin
Strong
Rifamycin
Strong

SAP_001.pdf: 
 
Document Type: 
Study Analysis Plan 
Official Title: 
A randomized, parallel-group, double-blind and placebo-
controlled, multicenter study to assess the efficacy and safety of 
vilaprisan in subjects with uterine fibroids 
NCT Number: 
NCT03400956 
Document Date: 
20 MAY 2020 
 
 


Statistical Analysis Plan 
BAY 1002670 / 15790 
Page: 1 of 58
 
 
Title page 
A randomized, parallel-group, double-blind and placebo-
controlled, multicenter study to assess the efficacy and safety of 
Vilaprisan in subjects with uterine fibroids 
Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids  
Acronym: ASTEROID 4 
Bayer study drug 
BAY 1002670 / Vilaprisan 
Study purpose: 
Assessment of safety and efficacy 
Clinical study 
phase: 
III 
Date: 
20 MAY 2020 
Study No.: 
 
15790  
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 
BAY 1002670 / 15790 
Page: 2 of 58
 
 
Table of Contents 
 
Title page ................................................................................................................................... 1 
Abbreviations ............................................................................................................................ 4 
1. 
Introduction ....................................................................................................................... 6 
2. 
Study Objectives ................................................................................................................ 6 
3. 
Study Design ...................................................................................................................... 7 
4. 
General Statistical Considerations .................................................................................. 8 
4.1 
General Principles ............................................................................................................ 8 
4.2 
Handling of Dropouts ...................................................................................................... 9 
4.3 
Handling of Missing Data ................................................................................................ 9 
4.3.1 
Bleeding data ................................................................................................................ 9 
4.3.2 
Dates for MBL assessed by AH method .................................................................... 10 
4.3.3 
Ultrasound-related volume measurements ................................................................. 10 
4.3.4 
Last study drug intake on eCRF Study Drug Exposure page ..................................... 10 
4.4 
Interim Analyses and Data Monitoring ......................................................................... 11 
4.5 
Data Rules ...................................................................................................................... 11 
4.6 
Blind Review ................................................................................................................. 15 
5. 
Analysis Sets .................................................................................................................... 16 
5.1 
Assignment of analysis sets ........................................................................................... 16 
6. 
Statistical Methodology .................................................................................................. 16 
6.1 
Population characteristics .............................................................................................. 16 
6.1.1 
Subject validity and disposition .................................................................................. 16 
6.1.2 
Demographics and baseline characteristics ................................................................ 17 
6.1.3 
Medical history ........................................................................................................... 18 
6.1.4 
Reproductive, menstrual, and fibroid history ............................................................. 18 
6.1.5 
Heavy menstrual bleeding questions .......................................................................... 18 
6.1.6 
Exposure and compliance to study drug ..................................................................... 18 
6.1.7 
Prior, concomitant and post-treatment medication ..................................................... 19 
6.2 
Efficacy .......................................................................................................................... 20 
6.2.1 
Primary efficacy variable............................................................................................ 22 
6.2.2 
Secondary efficacy variables ...................................................................................... 27 
6.2.3 
Further efficacy variables and analyses ...................................................................... 31 
6.2.4 
Subgroup analyses ...................................................................................................... 36 
6.3 
Pharmacokinetics/pharmacodynamics ........................................................................... 36 
6.4 
Safety ............................................................................................................................. 37 
6.4.1 
Secondary safety variables ......................................................................................... 37 
6.4.2 
Other safety variables ................................................................................................. 40 
7. 
Document history and changes in the planned statistical analysis ............................. 50 
8. 
References ........................................................................................................................ 52 
9. 
Appendices ....................................................................................................................... 53 
Appendix 1: Menstrual pictogram (MP) mapping to menstrual blood loss volume (in mL) ... 53 
Appendix 2: Uterine Fibroid Daily Bleeding Diary (UF-DBD) .............................................. 54 
Appendix 3: Uterine Fibroid Daily Symptoms Diary (UF-DSD) ............................................ 54 


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Appendix 4: Uterine Fibroid Symptom and Quality of Life questionnaire (UFS-QoL) .......... 55 
Appendix 5: List of laboratory parameters .............................................................................. 57 
 
Table of Tables 
Table 6–1: Overview of biopsy endpoints including majority result handling and worst case 39 
Table 6–2: List of AESIs in current expert statement based on MedDRA Version 22.1 
(version 5.0, status 19FEB2020) ........................................................................... 44 
Table 9–1: Mapping of the menstrual pictogram (MP) to menstrual blood loss ..................... 53 
Table 9–2: Uterine Fibroid Daily Symptoms Diary questionnaire .......................................... 54 
Table 9–3: Description of the UFS-QoL scoring system for assessing symptom severity. ..... 55 
Table 9–4: Description of the UFS-QoL scoring system. ........................................................ 56 
Table 9–5: List of laboratory parameters ................................................................................. 57 
 
Table of Figures 
Figure 3–1: Study design as originally planned prior to Global Protocol Amendment, version 
4.0 ............................................................................................................................ 7 
Figure 4–1: Overview of time intervals used for the statistical analysis. ................................ 13 
Figure 6–1: Categories of medication (example) ..................................................................... 20 
Figure 6–2: Hierarchical testing strategy for the confirmatory efficacy analysis .................... 21 
Figure 6–3: Illustration of censoring rules for subjects prematurely discontinuing a treatment 
period. .................................................................................................................... 29 
 
 
 


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Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH 
Alkalin hematin 
ALT 
Alanine aminotransferase (also known as GPT) 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase (also known as GOT) 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BMQ 
Bayer MedDRA query 
BR 
Treatment break 
BRM 
Blind review meeting 
CGI-I 
Clinician Global Impression Investigator 
CMH 
Continuity-corrected Cochran-Mantel-Haenszel 
DSMB 
Data safety monitoring board 
E2 
Estradiol 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
EIN 
Endometrioid Intraepithelial Neoplasia 
ePRO 
Electronic patient-reported outcome 
EoT 
End of treatment 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
FUP 
Follow-up period 
HbA1c 
Glycated hemoglobin 
HDL 
High density lipoprotein 
HMB 
Heavy menstrual bleeding 
HRQoL 
Health Related Quality of Life 
LH 
Luteinizing hormone 
LDL 
Low density lipoprotein  
LKF 
Laboratorium für Klinische Forschung 
LLOQ 
Lower limit of quantification 
MAR 
Missing at random 
MNAR 
Missing not at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MBL 
Menstrual blood loss 
MP 
Menstrual pictogram 
M&S plan 
Modelling and Simulation plan 
NRC 
National Research Council 
P 
Progesterone 
PAEC 
Progesterone receptor modulator-associated endometrial changes 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
pH 
Potential of hydrogen  
PPS 
Per-protocol set 
PRO 
Patient-reported outcome 
RAVE 
Electronic data capturing system 
RND 
Randomization 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TP𝑥𝑥 
Treatment Period 𝑥𝑥, 𝑥𝑥= 1,2 
TSH 
Thyroid-stimulating hormone 
UF-DBD 
Uterine Fibroid Daily Bleeding Diary 


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UF-DSD 
Uterine Fibroid Daily Symptom Diary 
UFS-QoL 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
WHO (-DD) 
World Health Organization (-Drug Dictionary) 


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1. 
Introduction 
Uterine fibroids are benign tumors originating from smooth muscle cells of the myometrium. 
The pathophysiology of fibroids is not well understood. Genetic predisposition, exposure to 
steroid hormones, and growth factors play a role in formation and growth. 
Uterine fibroids typically appear and grow during reproductive years, but stabilize or regress 
after menopause. Therefore, they rarely require treatment after menopause. Clinically, 
fibroids and associated symptoms are most prominent in the late reproductive years. The most 
common symptoms of uterine fibroids are heavy menstrual bleeding (HMB) and pelvic 
discomfort. 
Uterine fibroids are the leading cause for hysterectomy. Hysterectomy is the only definitive 
treatment so far and eliminates the possibility of recurrence. The hysterectomy rate has 
decreased recently but still accounts for almost three quarters of all fibroid related surgical 
procedures. Increasingly more women desire to avoid hysterectomy, electing for a uterine 
preserving procedure, regardless of whether they desire to retain their fertility. The surgical 
treatment options are numerous, and each carries both the risks for surgery itself, as well as 
the possibility that the woman may require subsequent surgery as new fibroids often develop 
over time and become symptomatic.  
The development of selective progesterone receptor modulators offers the potential for a 
novel, well tolerated medical treatment approach for women who are experiencing symptoms 
caused by their fibroids. Various studies have demonstrated the steroid-dependence of fibroid 
growth and that progesterone has a critical role.  
This clinical study is part of a development program for vilaprisan. The rationale of the study 
is to assess the efficacy and the safety of vilaprisan in subjects with uterine fibroids. 
The statistical analysis plan (SAP) is based on the following study protocol documents:  
• Integrated Clinical Study Protocol, version 6.0, dated 17 FEB 2020 
• Integrated Clinical Study Protocol, version 5.0, dated 21 NOV 2019 
• Global Protocol Amendment, version 4.0, dated 11 DEC 2018 
• Integrated Clinical Study Protocol, version 3.0, dated 04 JUL 2018 
• Integrated Clinical Study Protocol, version 2.0, dated 15 NOV 2017 
• Clinical Study Protocol, version 1.0, dated 01 SEP 2017 
 
2. 
Study Objectives 
The primary objective of this study is to show superiority in treatment of HMB of vilaprisan 
in subjects with uterine fibroids compared to placebo.  
The secondary objectives of this study are to additionally evaluate the efficacy and safety of 
vilaprisan in subjects with uterine fibroids. With the implementation of Integrated Clinical 
Study Protocol, version 5.0, additional focus will be put on safety evaluations of the 
endometrium, adrenal glands and skin. 


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The other objectives of this study are to evaluate the variability in exposure in relation to the 
efficacy and safety for vilaprisan and to collect patient-reported outcome (PRO) and clinician-
reported outcome data. 
 
3. 
Study Design 
This is a randomized, parallel-group, double-blind, placebo-controlled, multicenter study. The 
study was conducted in the US, Japan and other countries in Europe. 
An overview of the study design before the temporary pause is shown in Figure 3–1. 
Figure 3–1: Study design as originally planned prior to Global Protocol 
Amendment, version 4.0 
 
 
 
Treatment 
Period 1 
(TP1) 
Treat-
ment 
break 
(BR) 
 
Treatment 
Period 2 
(TP2) 
 
Treatment  
group A1 
Screening  
Randomization 
Vilaprisan 2 mg 
Bleeding 
episode 
Vilaprisan 2 mg 
Follow-up 
 
 
 
 
 
Treatment  
group B1 
Screening  
Randomization 
Placebo 
Bleeding 
episode 
Vilaprisan 2 mg 
Follow-up 
 
 
 
 
 
 
 
Treatment  
group B2 
Screening  
Randomization 
Vilaprisan 2 mg  
Bleeding 
episode 
Placebo 
Follow-up 
 
Duration 
 
up to120 
days 
 
 
12 weeks 
 
 
12 weeks 
Day 7 to 15 
of the 2nd 
menstrual 
cycle after 
EoT 
Abbreviations: EoT: End of treatment 
 
The following procedures were implemented prior to the Global Protocol Amendment, 
version 4.0: 
• During the screening period, subjects needed to demonstrate eligibility including the 
presence of at least 1 uterine fibroid ≥ 30 mm and < 120 mm in largest diameter based 
on ultrasound, HMB in at least 2 bleeding periods, each with menstrual blood loss 
(MBL) > 80.00 mL documented by the alkaline hematin (AH) method, and 
endometrial biopsy results without significant histological disorder.  
• Eligible subjects were randomized in 1:1:1 ratio to one of the three treatment groups 
(A1, B1, or B2) and stratified by country/region (US, Japan and other countries). The 
time between randomization and start of treatment should not have exceeded 40 days. 
• After the end of the final treatment period, subjects were followed up until Day 7 to 
Day 15 of the 2nd menstrual cycle after end of treatment.  
 
With the implementation of the Global Protocol Amendment, version 4.0, no further subjects 
were recruited. Patients who were randomized but had not yet started treatment were 
instructed to not start TP1. Patients already in a treatment period were instructed to complete 
the current treatment period but to not start a new treatment period. Thus, with the 
implementation of the Global Protocol Amendment, version 4.0, the originally foreseen study 


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design outlined in Figure 3–1 is not applicable anymore. With the Integrated Clinical Study 
Protocol version 5.0 the confirmatory analysis was modified accordingly: The confirmatory 
analysis (originally including TP1 and TP2) will only be based on results of TP1 as the 
number of patients who start TP2 is not sufficient for drawing valid conclusions.   
All subjects who were randomized and started treatment before the temporary pause were 
asked to have a comprehensive safety evaluation (with particular focus on endometrial, 
adrenal and skin safety) performed. This also applies to subjects who have completed or 
discontinued the study before or during the temporary pause, provided they have taken at least 
one dose of study medication. 
 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical analysis will be performed using the software package SAS release 9.4 (SAS 
Institute Inc., Cary, NC, USA). 
The following Bayer standards are applied: RD-OI-0119 ‘Prepare statistical documents and 
programs’, RD-SOP-1107 ‘Recording and Evaluation of Bleeding Data’ together with 
corresponding Bayer standard SAS macro BCycle (version 6.0). Furthermore, global 
standards for tables and data displays are available and will be specified in the tables, listings 
and figures (TLF) specification document, which will be approved in parallel with this SAP. 
All variables will be analyzed by descriptive statistical methods according to their data type. 
The number of data available, mean, standard deviation (SD), minimum, median and 
maximum will be calculated for metric data as appropriate. The number of significant digits 
for minimum and maximum will correspond to that of the original data. The mean and median 
will be rounded to one more decimal place than the original data, and the SD it will be 
rounded to two more decimal places than the original data.  Frequency tables will be 
generated for categorical data including percentages with 1 decimal place. In general, the data 
will be presented by treatment group (see Figure 3–1) or by treatment period within treatment 
group, and overall, that is, based on the total study population of the respective analysis set. 
Tables, figures and listings will show the treatment groups, A1, B1 and B2. Additionally, for 
selected variables the treatment of vilaprisan in TP1 of the treatment groups A1 and B2 will 
be presented also as pooled.  
Variables recorded in the electronic case report form (eCRF) and relevant derived variables 
will be shown in subject data listings, whereby only randomized patients will be included. 
Data from screening failures will only be shown in the ‘Screening failure’ listing.  
Analyses will be performed based on either visits or time intervals as specified in the 
respective sections. For visit-based analyses the EoT visit will include also (scheduled or 
unscheduled) EoT visits for subjects who did not start TP2 for any reason, for example, due to 
the temporary pause of the studies or due to premature discontinuation at the subject’s wish. 
For time interval-based analyses of efficacy variables (except for fibroid surgeries), including 
analyses for the treatment break and FUP, analyses for the FUP will be based on data from 
patients who have started TP2. Data from FUP for patients who did not start TP2 for any 
reason will be included in the analysis of the break period. For those patients only efficacy-
related data up to a theoretical end of the break will be considered (see ‘break period’ in 
Section 4.5 for details). In contrast to that, for time interval-based analyses of safety variables 


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(except for bleeding patterns per 28 or 84 days based on UF-DBD), data from FUP for patient 
who did not start TP2 for any reason will be included in the analysis of the FUP. 
 
4.2 
Handling of Dropouts 
A subject who has been randomized and discontinues study participation prematurely for any 
reason is defined to be a dropout even if no study drug has been taken. Dropouts will not be 
replaced.  
The number of subjects, who prematurely discontinue the study, as well as the reasons for 
premature discontinuations, will be reported. 
The handling of missing data is described in Section 4.3.  
 
4.3 
Handling of Missing Data 
Missing data introduce ambiguity into the analysis, beyond the familiar sampling imprecision. 
Even with the best planning and despite best efforts, data may be missing at the end of the 
clinical trial. All missing or partial data will be presented in the subject data listing as they are 
recorded in the eCRF, electronic diary (eDiary) or tablet computer.  
When appropriate and for a limited number of variables, specific rules will be implemented so 
as not to exclude subjects or observations from statistical analyses due to missing or 
incomplete data. The rules are outlined in the following subsections. 
 
4.3.1 
Bleeding data 
The following rules for the handling of missing vaginal bleeding data pertains to bleeding 
data assessed by the AH method, the menstrual pictogram (MP, see Appendix 1) or the item 
“Rate the severity of any vaginal bleeding in the past 24 hours” (on a 6-point Likert scale) in 
the Uterine Fibroid Daily Bleeding Diary (UF-DBD, see Appendix 2). The resulting data 
forms the basis for the primary, the secondary and bleeding-related other efficacy variables 
(see Section 6.2). 
On days without bleeding, no collection of sanitary products for the AH value determination 
was asked for. The UF-DBD is used for the identification of these non-bleeding days. Thus, 
missing AH/MP values on days where the UF-DBD recorded the bleeding intensity as “No 
vaginal bleeding” or “Spotting” will be set to 0 mL. 
Missing bleeding data in the subjects’ diaries will be imputed. First, missing bleeding 
intensities in the UF-DBD will be imputed. Missing bleeding intensities will only be imputed 
if values are missing for a single or for two consecutive days. For the UF-DBD, a type of 
‘worst case approach’ will be used for imputing missing bleeding intensities. The approach 
consists in replacing the missing value(s) by the maximum of the bleeding intensities of the 
day before and the day after the day(s) with missing value(s).  
 
After having imputed missing values in the UF-DBD, missing AH/MP values are imputed in 
the next step.  


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For days with bleeding intensity of ‘mild’ or higher in the UF-DBD, missing AH/MP values 
will be replaced by the mean value of AH/MP values of the days with the same bleeding 
intensity. In case there are no AH/MP values with the same bleeding intensity, the mean of 
the AH/MP values of next higher intensity will be used. In case there is no intensity higher 
than the bleeding intensity of the missing AH/MP values available, no replacement for the 
missing AH/MP values will be done for such days, but if at least one such day occurs within 
the respective 28 days of treatment for a subject, the subject will be considered as not having 
amenorrhea. 
 
In case blood loss could not be measured by the vendor for a sanitary product, the missing 
value will be replaced by the mean blood loss measured for the same type of sanitary product 
for this specific subject. 
 
4.3.2 
Dates for MBL assessed by AH method 
If there is no information on the dates of reported AH values, the AH values will not be 
discarded from the analysis. Those AH values will be attributed to the subject’s last bleeding 
episode prior to the date of receipt of the sample at vendor “Laboratorium für Klinische 
Forschung” (LKF). For this purpose, the total MBL for each date of receipt will be derived 
using the AH values with missing date. The total MBL will then be added to equal amounts to 
the AH values of the subject’s last bleeding episode prior to receipt of the sample at LKF.  
The concrete steps are outlined below: 
(1) The number of days of the bleeding episode with at least ‘mild’ bleeding will be 
derived. 
(2) The total MBL will be divided by the number derived in (1). 
(3) The ‘mean’ MBL derived in (2) will be added to the AH values of all days of the 
bleeding episode with at least ‘mild’ bleeding. This step will be performed after 
having imputed missing bleeding intensities but before having imputed missing AH 
values (cf. Section 4.3.1). The resulting AH values will not be used for the imputation 
strategy of missing AH values described in Section 4.3.1. 
 
4.3.3 
Ultrasound-related volume measurements 
Partially missing data in ultrasound measurements for determining fibroid volume, uterine 
volume and cyst volume will be handled as described in Section 4.5.  
 
4.3.4 
Last study drug intake on eCRF Study Drug Exposure page 
Missing dates of last study drug intake on eCRF study drug exposure page used for defining  
• the end of a treatment period and the reference end date of treatment phase will be 
imputed by the date of last study drug intake in the same treatment period reported in 
the eDiary; 
• treatment duration and compliance to study drug will not be imputed (cf. Section 
6.1.6). 


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4.4 
Interim Analyses and Data Monitoring 
With the implementation of the Integrated Clinical Study Protocol, version 6.0 a safety and 
efficacy analysis is planned after all subjects have completed their treatment period. All data 
until 31 DEC 2019 will be cleaned and included in the analysis. The complete efficacy data 
used for the confirmatory analysis has been collected until this point in time and will be used 
for the efficacy analysis. Therefore, the confirmatory analysis will be final at this point in 
time. Additionally, available data up to the time point of analysis will be included in this 
analysis.  
Following this analysis neither the sample size nor the study design will be adjusted. The 
reason for this is that the confirmatory efficacy analysis will only be performed once and none 
of the analysis results will trigger decisions on the further conduct of the study, such as an 
early termination. Therefore, no alpha adjustment or power consideration are required. In 
addition, no Data Safety Monitoring Board (DSMB) will be required. 
The final analysis will follow the end of the study safety closeout visit.  
 
4.5 
Data Rules 
This section outlines definitions of relevant variables as well as rules for deriving variables. 
Variables are sorted alphabetically. 
 
Baseline cycle: First day of the baseline cycle is day one of the bleeding episode following 
Visit 1. The last day of the baseline cycle is the day preceding the next bleeding episode. The 
baseline cycle length is defined as the number of days from the first day of cycle until the last 
day of cycle. These definitions will apply if during this cycle the inclusion criterion of HMB 
diagnosis is fulfilled (MBL >80.00 mL). If HMB is not confirmed in the first bleeding 
episode following Visit 1 then the second bleeding episode recorded during screening will be 
considered. Similarly, the first day of the second cycle is the day one of the second bleeding 
episode following Visit 1 and the day preceding the next bleeding episode will be considered 
the last day of the cycle. Again, this second bleeding episode will be considered the baseline 
cycle only if the HMB criterion is fulfilled, otherwise the next bleeding episode, if recorded, 
will be inspected for the diagnosis of HMB. If none of the bleeding episodes preceding the 
first drug administration fulfills the HMB inclusion criterion the first bleeding episode 
following Visit 1 will be considered for the baseline cycle. If no such bleeding episode exists, 
then the bleeding episode already ongoing at Visit 1, if recorded, will be considered for the 
baseline cycle, starting with Day 1. 
Note that during the screening period the diagnosis of HMB will be inspected using the 
definition of bleeding episode based on the AH method, as explained in this section and in the 
protocol. In contrast, during the analysis only the definition of bleeding episode based on the 
UF-DBD will be used. Therefore, the baseline cycle defined during the analysis here 
described is independently derived and may differ from the bleeding episode used to assess 
the HMB diagnosis during the screening period. 
Baseline menstrual blood loss (MBL): The baseline MBL is defined as the sum of MBL 
volume from all days included in the baseline cycle. If baseline cycle length is more than 28 


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days, only data from the first day of cycle to the 28th day of cycle will be used. If baseline 
cycle length is less than 28 days or equal to 28 days, data from the first day of cycle to the last 
day of cycle will be used.  
Baseline values and changes from baseline: If an analysis is performed by visits or by 
Intervals ‘Exit Examination’ (see Time Intervals), the last valid, non-missing value prior to 
the Reference start date will be considered as baseline value. If the analysis is performed by 
any time interval different than Intervals ‘Exit Examination’, the ‘worst’ measurement will be 
used, whereby ‘worst’ is defined for the considered parameter within the specific section.  
(Absolute) changes from baseline will be calculated as the difference between the 
post-baseline value and the baseline value: 
Absolute change = post baseline value – baseline value. 
Relative changes from baseline, also referred to as percent change from baseline, are derived 
for some variables. It is defined as  
Relative change = 100 × [post baseline value – baseline value] / baseline value. 
Those baseline definitions apply to the analysis of all TPs. For variables analyzed by 28-day 
periods, the baseline period corresponds to the last 28 days before Reference start date. This 
definition does not apply to baseline MBL volume where a specific definition is provided in 
this section (see Baseline menstrual blood loss). 
Bleeding episode (assessed by the UF-DBD): A bleeding episode is defined as day(s) with 
bleeding/‘spotting’ of which at least one day is of intensity ‘mild’ or higher, preceded and 
followed by at least 2 consecutive days with eDiary entry ‘no vaginal bleeding’. The 
preceding 2 bleeding-free days may not be recorded for the first bleeding episode at study 
entry [1]. 
This definition of bleeding episode, based on the UF-DBD, will be implemented in the 
analysis to identify bleeding episodes. The protocol includes a definition of bleeding episode 
based on the AH method, which will be implemented during the screening period to facilitate 
the assessment of the HMB inclusion criterion (criterion 5, MBL >80 mL) by clinical sites. 
This latter definition of bleeding period will not be used in the statistical analysis. 
Break period: The break period is defined as the treatment-free period between TP1 and 
TP2. The break period starts the day following the date of stop date of study drug 
administration in TP1, and ends the day before the study drug administration starts in TP2. 
Prior to the Global Protocol Amendment, version 4.0, subjects were instructed to start TP2 
within Days 3 to 7 of the first bleeding episode following the end of TP1. If a subject did not 
start TP2 (due to the temporary pause or for any other reason), the subject does not have any 
break period but only a follow up period which starts at the first day after the end of TP1. For 
efficacy variables evaluated within the break period, part of the data from the follow-up 
period of those patients will be included in the analysis of the break as well. In this case a 
theoretical end date which reflects the assumed end date of the break period if the subject had 
started TP2 will be generated. For this purpose information on the start of TP1 will be used: If 
a subject started TP1 at the i-th Day of her bleeding episode, the theoretical start date of TP2 
will be assumed as the i-th Day of her first bleeding episode during treatment break. The 
theoretical end date of the break period will then be assumed as the day before the theoretical 
start date of TP2.  


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Endometrial biopsy conducted: A biopsy will be regarded as conducted if the intervention 
was attempted, either successfully or unsuccessfully. Successful means that the date of biopsy 
is given and ‘Biopsy sample obtained - Not done’ is not ticked in the eCRF. Unsuccessful 
means that the date of biopsy is given, ‘Biopsy sample obtained - Not done’ is ticked in the 
eCRF, and the reason ‘Unsuccessful attempt’ is selected. 
Largest fibroid: The largest fibroid is defined as the fibroid with the largest volume at 
baseline (measured by ultrasound). The fibroid identified at baseline as the largest will be 
followed up at subsequent visits. 
Menstrual blood loss (MBL) for 28-day periods: The MBL for a 28-day period is defined 
as the sum of MBL (in mL) assessed by AH/MP method in a 28-day period. Non-overlapping, 
consecutive 28-day periods will be created along the different study periods: screening, 
treatment periods, break period and FUP. For details about the volume of MBL assigned to 
MP, see Appendix 1. 
Reference start/end dates of treatment phase: The reference start and end dates of 
treatment phase refer to the first and last study drug intake and will be identified based on the 
eCRF entry (EXCATN=1). Missing eCRF end dates will be replaced by the date of the last 
study drug intake according to the eDiary. In case there is no study drug intake recorded in the 
eDiary, the date of the last available visit will be used, which is the maximum of the last date 
at which a visit took place (visit end date), and the “last visit” as collected on the eCRF page. 
Repeated measurements at the same visit: If more than one post-randomization 
measurement is available for a given visit, the first observation will be used in the analysis if 
no special reason for the additional observation was provided in the eCRF.  
All observations will be presented in data listings. 
Time intervals: Due to the complex visit schedule of the studies, a time-interval based 
approach is chosen to present data over time. Several time intervals are defined which are 
used for different analysis topics (‘BL/Post baseline’, ‘Intervals A’, ‘Intervals B’, ‘Intervals 
C’, ‘Intervals D’, ‘AE Intervals’, ‘Exit Examination’). Those are depicted in Figure 4–1. The 
selection of time intervals used for a certain analysis topic will be described within each 
section. 
 
Figure 4–1: Overview of time intervals used for the statistical analysis. 
 
Abbreviations: BL: Baseline, TP: Treatment Period, BR: Break, FUP: Follow-up, EoT: End of 
treatment, d: days.  
 


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Treatment periods and breaks will be identified as described above. Baseline/Pre-treatment 
starts with the date of informed consent and ends on the day before the start of the treatment 
phase. The treatment phase starts and ends with the reference start and end date. The FUP 
phase starts on the day after the end of the treatment phase and ends on the maximum of the 
last date at which a visit took place (visit end date), and the “last visit” as collected on the 
eCRF page. Baseline, treatment phase, FUP phase, treatment periods and breaks are 
subdivided into subsequent periods of different lengths. “Exit examination” intervals include 
the baseline measurement, i.e. the last non-missing value before reference start date, and the 
exit examination which is defined as the last non-missing value at or after the reference end 
date minus 7 days. It is per definition the safety closeout visit for subjects who perform this 
visit. 
Treatment period: Each treatment period is planned to consist of three subsequent 28-day 
periods. In case of premature discontinuation of study drug the subject’s respective treatment 
period might be shorter than 84 days. If a subject took the study drug for more than 84 days of 
a treatment period, the respective treatment period will be longer than 84 days, in contrast. 
Treatment periods will be numbered sequentially.  
Start and end of a treatment period will be identified based on eCRF entries (EXCATN=1). 
The start of TP1 will be the reference start date (i.e. the day of the first study drug intake). 
The end of TP1 will be the date of the last study drug intake for this treatment period. The 
start of TP2 will be the date of the first study drug intake in TP2. The end of TP2 will be the 
date of the last study drug intake in TP2. This coincides with the reference end date if the 
subject has started TP2. 
  
If the last study drug intake within TP1 is missing in the eCRF, then the date of the last study 
drug intake within the respective treatment period according to the eDiary (EXCATN=5 and 
EXMEDN≥1) will be used for defining the end date of the treatment period.  
Replacement rules for missing end date of the last treatment period are analogue to those 
described for reference end dates. 
Ultrasound-related measurements: The derivation of fibroid volume, uterine volume and 
cyst volume based on ultrasound measurements is described in the following. 
• Fibroid volume  
A fibroid's volume will be calculated by  
𝜋𝜋×𝑎𝑎×𝑏𝑏×𝑐𝑐
6
 (cf. [2]), where 
a = largest diameter of the fibroid (cm), 
b = largest diameter perpendicular to the largest diameter, a, (cm), 
c = largest diameter perpendicular to first and second largest diameters, a and b,  
(cm), 
with a, b and c measured by ultrasound. 
If only two diameters are available, the missing diameter will be replaced by the 
mean of the available two diameters and the fibroid's volume will be calculated as 
described above.  
If only one diameter is available, the fibroid's volume will be calculated by  
4×𝜋𝜋×𝑟𝑟3
3
, 
where 


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𝑟𝑟=
𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 (𝑐𝑐𝑐𝑐)
2
. 
• Uterine volume  
The uterine volume (mL) will be calculated by 
𝜋𝜋×𝑎𝑎×𝑏𝑏×𝑐𝑐
6
, where  
a = maximum width anteroposterior of uterus (cm), 
b = maximum width transverse of uterus (cm), 
c = corpus length + cervix length (cm),  
with a, b and c measured by ultrasound.  
If only two or one of a, b, and c is available, the uterine volume will be derived 
based on only the available measurements as has been described for the fibroid 
volume.  
• Cyst volume  
The volume of a cyst will be calculated by  
𝜋𝜋×𝑎𝑎×𝑏𝑏×𝑐𝑐
6
, where  
a = largest diameter of the cyst (cm),  
b = largest diameter perpendicular to the largest diameter of the cyst (cm), 
c = 
(𝑎𝑎+𝑏𝑏)
2  (cm), 
with a and b measured by ultrasound. 
If only one diameter is available, the volume of the cyst will be calculated by  
4×𝜋𝜋×𝑟𝑟3
3
, where 
𝑟𝑟=
𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑐𝑐𝑐𝑐)
2
. 
 
4.6 
Blind Review 
Important deviations from the protocol and validity findings and the resulting assignment of 
subjects to the analysis sets (see Section 5.1) are agreed upon in the blind review meeting 
(BRM). The documentation of important deviations, validity findings and the assignment of 
subject data to analysis sets will be performed according to the sponsor’s applicable Standard 
Operating Procedures and/or Instruction Manuals. The definition for important deviations and 
validity findings will be provided in the ‘Specification of assessment criteria and 
identification requirements’ before unblinding the data. 
Identification of important deviations and validity findings will be done periodically while the 
study is running, concluding with the completion of the final list during the BRM. Any 
changes to the statistical analysis prompted by the results of BRM will be documented in an 
amendment and, if applicable, in a supplement to this SAP.  
The list of important deviations and validity findings will only be final after assessment of 
conditional findings, which are validity findings that can only be identified after unblinding of 
study treatment. 
 


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5. 
Analysis Sets 
5.1 
Assignment of analysis sets 
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
blind review of study data and documented in the final list of important deviations, validity 
findings and assignment to analysis set(s) (see Section 4.6). 
The following statistical analysis sets will be defined: 
Full analysis set (FAS):  All randomized subjects, excluding randomized subjects who did 
not start TP1 due to the study being temporarily paused. Subjects will be analyzed as 
randomized.  
Per protocol set (PPS):  All subjects in the FAS without any validity findings impacting the 
primary efficacy variable in TP1.  
Safety analysis set (SAF):  All subjects who took at least 1 dose of study drug based on 
‘Study Drug Exposure’ eCRF page. Subjects will be analyzed as treated. Mistakes in the 
administration of study drug may affect the assignment to treatment. In general, subjects who 
receive a different study drug to the one they were randomized to will be assigned to the 
treatment most often received. 
The primary efficacy variable will be analyzed on the FAS and PPS, whereby the analysis on 
the FAS is considered to be the primary one. Safety analyses, medical history and 
concomitant medication will be performed on the SAF. Demographic data, baseline 
characteristics, exposure and compliance will be analyzed on the FAS, SAF and PPS. The 
FAS will be used for the display of all other variables. Analyses on the PPS will be 
additionally conducted as sensitivity analyses for selected secondary efficacy variables. 
All screened patients who are not included in the FAS, will be used solely in disposition 
tables, and will be listed only in Section 16 of the clinical study report, as described 
elsewhere.  
 
6. 
Statistical Methodology 
6.1 
Population characteristics 
In general, descriptive statistics will be presented for variables defined in this section. For 
continuous variables, number of observations, mean, standard deviation, minimum, median, 
and maximum will be presented. For categorical variables, number and percentage of subjects 
will be presented. Listings will be provided as appropriate.  
6.1.1 
Subject validity and disposition 
The following data related to subject validity and disposition will be summarized overall 
and/or by treatment group, if applicable and not specified otherwise: 
• Screening failures  
• Number of subjects enrolled – overall, by country and by study site  
• Number and percentage of subjects randomized,  


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o who received at least one dose of study drug (based on ‘Study Drug Exposure’ 
eCRF page),  
o for whom study drug was never administered (based on ‘Study Drug 
Exposure’ eCRF page),  
o who completed and did not complete the study, whereby completed refers to 
the completion of all phases of the study including the ‘last visit’ or ‘the last 
scheduled procedure shown in the Schedule of Activities’. 
• Number and percentage of subjects who completed and discontinued each epoch with 
the reasons for discontinuation 
• Number and percentage of subjects who discontinued study drug with the reasons for 
discontinuation  
• Subject validity and primary reasons for exclusion from analysis set  
• Number and percentage of subjects who performed adrenal monitoring, skin 
monitoring and endometrial monitoring within the safety closeout visit, and further 
details about the participation in the safety closeout visit. 
A listing of the subjects’ assignment to the FAS, SAF and PPS and the reasons for exclusion 
will also be provided by treatment group. 
 
6.1.2 
Demographics and baseline characteristics 
All demographic and baseline characteristics will be summarized by treatment group 
(including pooled treatment group A1+B2). The descriptive statistics will be presented for the 
FAS, SAF and PPS.  
Demographic and baseline assessments to be summarized will include: 
• Age (at inclusion), region/country, race, ethnicity 
• Weight (kg), height (cm), body mass index (BMI; kg/m2) 
• Categorized BMI (< 18.5, 18.5 to < 25, 25 to < 30, ≥ 30 kg/m2) 
• Smoking and alcohol consumption 
• Educational level (i.e., level of education, years of school and professional education) 
• Baseline MBL (by AH method/MP) and categorized MBL group (≤ 150 mL, >150 to 
300 mL, > 300 to 500 mL and > 500 mL)  
• Volume of 3 largest fibroids and location of largest fibroid (International Federation of 
Gynecology and Obstetrics [FIGO] classification) by ultrasound (mL)  
• Largest diameter of fibroid by ultrasound (mm)  
• Uterine volume by ultrasound (mL)  
• Endometrial thickness by ultrasound (mm)  
• Hemoglobin (g/dL) 
Demographic and baseline characteristics will be summarized also for the following 
subgroups: 


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• By region/country (Japan, US, other countries) 
• By ethnicity  
• By race 
 
6.1.3 
Medical history 
For medical history the Medical Dictionary for Regulatory Activities (MedDRA; current 
version at the time of analysis) will be used. Medical history findings (i.e., previous 
diagnoses, diseases or surgeries) not pertaining to the study indication, starting before signing 
of the informed consent and considered relevant to the study will be tabulated by primary 
system organ class (SOC) and preferred term (PT) by treatment group. Medical history will 
be presented for SAF. 
All new or worsened findings after signing the informed consent should be documented on 
the AE eCRF page. 
 
6.1.4 
Reproductive, menstrual, and fibroid history 
Reproductive and menstrual history will include information on age at menarche (in years), 
number of pregnancies, number of births, years since last birth or abortion and inability to 
conceive (at any time and during the last 1 year) and duration of unsuccessful attempts (in 
months). 
Fibroids history will include information on family history, time since initial diagnosis (in 
months), and reason for initial diagnosis, current and past symptoms, and previous medical 
treatments and procedures relevant for uterine fibroids, if applicable. 
In addition, any performed procedures for uterine fibroids or symptoms of uterine fibroids and 
the consideration of surgical procedures within the next 12 months in case of remaining 
symptoms (as they are at screening) will be summarized. 
These variables will be analyzed descriptively, separately for each treatment group based on 
the SAF. 
 
6.1.5 
Heavy menstrual bleeding questions 
This set of questions has been developed as a tool to identify women with HMB. It will be 
used at Visit 1 and the responses can be entered directly into electronic data capturing system 
RAVE, which will be considered as primary source data. The questionnaire includes 14 
questions in total. The response (yes/no) to each question will be presented descriptively in 
frequency tables separately for each treatment group based on the SAF. 
 
6.1.6 
Exposure and compliance to study drug 
Exposure, treatment duration and compliance to study drug will be analyzed descriptively 
based on the SAF, FAS and PPS. They will be presented by treatment period and overall, (i) 
by treatment group and (ii) by study drug. Overall treatment duration will be shown including 
and excluding treatment break. Both study drug exposure and compliance will be calculated 


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separately based on the eDiary data as well as on the eCRF (namely the ‘Study Drug 
Exposure’ and the ‘Drug Accountability’ pages).   
Subject’s exposure to the study drug will be calculated as total number of tablets taken during 
a time frame (i.e. either a specific treatment period or both treatment periods combined), using 
information from the ‘Drug Accountability’ eCRF page and the subject’s eDiary. Missing 
numbers of tablets taken based on eCRF page will not be replaced, while missing numbers of 
tablets taken based on eDiary will be replaced with 0. 
 
The treatment duration is defined as the number of days from the day of first study drug 
intake up to and including the day of last study drug intake in the treatment period of interest. 
Treatment duration will be calculated separately for the two treatment periods. In addition, it 
will be computed for both treatment periods combined excluding the time for treatment break 
and for the treatment phase (i.e. including the break). For the latter, treatment duration per 
specific study drug is calculated from start of TP1 until start of TP2 and from start of TP2 
until end of TP2 (i.e. the break is included in the duration of TP1). If a patient discontinued 
before TP2, treatment duration is calculated from start to end of TP1.  
The days of first and last study drug intake will be taken from the ‘Study Drug Exposure’ 
eCRF page. Missing dates in the eCRF will not be replaced. 
Treatment compliance of a subject is defined as the total number of tablets taken during a 
specific time frame (i.e. the exposure) divided by the treatment duration (in days) for that time 
frame, and will be given in percent. Compliance calculation is derived from exposure based 
on (i) the eCRF and (ii) eDiary and treatment duration (excluding breaks) based on the eCRF, 
as described above. 
Compliance will be derived as follows: 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
× 100% 
 
6.1.7 
Prior, concomitant and post-treatment medication 
For prior, concomitant and post-treatment medications, the following definitions in 
accordance with the Global Standards Catalogue V4.0 will be used in the analysis (see 
Figure 6–1): 
- 
Prior medication: Medication taken before start of the study drug intake, i.e. before 
start of TP1 (regardless of when it ended). 
- 
Concomitant medication: Medication taken during treatment phase, i.e. between first 
and last study drug intake (regardless of when it ended).  
- 
Post-treatment medication: Start of medication is after the treatment phase, i.e. after 
last study drug intake. 
In case it’s not clear if a medication is prior, concomitant or post-treatment (for example, due 
to partially missing dates), medication will be classified as “concomitant”. 
 


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Figure 6–1: Categories of medication (example)  
 
Categories are prior medication (A, B, C), concomitant medication (B, C, D, E) and post-treatment 
medication (F). Source: Global Standards Catalogue V4.0 
 
Medication, recorded as prior, concomitant or post-treatment medication in the eCRF, will be 
coded according to the World Health Organization Drug Dictionary WHODRUG GLOBAL 
B3 (initially September 1, 2017, within Bayer referred to as ‘2017SEP’), to the respective 
Drug Codes with their corresponding Anatomical Therapeutic Chemical (ATC) classification. 
The number of subjects taking prior, concomitant or post-treatment medication will be 
analyzed using frequency tables. Analysis of prior, concomitant and post-treatment 
medication will be done on the SAF. Prior, concomitant and post-treatment medication will 
be shown by treatment group. 
 
6.2 
Efficacy 
The following sections describe the efficacy analyses of primary, secondary, and other 
efficacy variables in detail. Further variables that were captured during the study will be either 
analyzed descriptively or displayed in subject listings. 
The primary efficacy variable and secondary efficacy variables will be calculated based on the 
AH method. Other efficacy variables related to MBL will be calculated based on both the AH 
method and MP. If an endometrial biopsy was conducted during a time period for which 
bleeding will be assessed, bleeding or ‘spotting’ on the day of biopsy and the 3 days thereafter 
will not be considered in the derivation of any variables that belong to primary, secondary or 
other efficacy variables. Thus, prior to the assessment of bleeding variables, such as 
amenorrhea, for example, the AH and UF-DBD entries during those days will be set to 0 mL 
and “No vaginal bleeding”, respectively. 


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For the confirmatory efficacy analysis, a hierarchical testing approach will be applied, 
involving the primary efficacy variable amenorrhea (yes/no) and the first three secondary 
efficacy variables HMB response, time to onset of amenorrhea, and time to onset of 
controlled bleeding. These tests always include a comparison of vilaprisan 2 mg versus 
placebo: 
After 12 weeks of treatment in TP1:  
Comparison of vilaprisan 2 mg in pooled treatment groups A1 and B2 (as the 
treatments are the same and pooling increases the power) vs. placebo in treatment 
group B1. 
In total, four tests will be carried out each to an alpha level of 0.05, see also Figure 6–2: First, 
the test for the primary efficacy variable amenorrhea (yes/no) will be carried, followed by the 
test for HMB response (yes/no), the test for time to onset of amenorrhea, and finally, the test 
for onset of controlled bleeding. As the hierarchical testing procedure follows a fixed 
sequence, it stops as soon as any of these tests cannot be rejected to an alpha level of 0.05, 
and all further tests after failing to reject one null hypothesis in the testing sequence will be 
considered exploratory. This fixed sequence procedure accounts for the multiplicity created 
by carrying out multiple tests.  
 
Figure 6–2: Hierarchical testing strategy for the confirmatory efficacy analysis 
 
Abbreviations: HMB: Heavy menstrual bleeding, CMH: Cochran-Mantel-Haenszel, H: Hypothesis 
to be tested related to the amenorrhea (H1), HMB response (H2), time to onset of amenorrhea (H3) or 
time to onset of controlled bleeding (H4), TP: Treatment period, A1: Vilaprisan 2mg; 2 treatment 
periods of 12 weeks, B1: Placebo; 1 treatment period of 12 weeks and Vilaprisan 2mg; 1 treatment 
period, B2: Vilaprisan 2mg; 1 treatment period of 12 weeks and placebo; 1 treatment period. 
 
The study will be considered successful if at least superiority of vilaprisan 2 mg vs. placebo in 
Treatment Period 1 (TP1) based on the primary efficacy variable can be demonstrated. In 
general, superiority of vilaprisan treatment is shown if the respective null hypothesis is 
rejected to a local alpha level of 0.05 and point estimates of treatment effect favor vilaprisan. 
The primary analysis will be conducted based on the FAS (see Section 5.1). 
 


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6.2.1 
Primary efficacy variable 
The primary efficacy variable is amenorrhea (yes/no), defined as MBL <2 mL during the last 
28 days of treatment. Evaluation of MBL will be based on AH method for a treatment period 
of interest.  
The primary efficacy variable will be derived after the imputation of missing values described 
in Section 4.3.  
If after the imputations described in Section 4.3 and considering potential biopsies, neither of 
the AH values for the last 28 days are missing, AH values and bleeding intensities of the last 
28 days of a treatment period are used to derive the primary efficacy variable.  
If, in contrast, there are AH values in the last 28 days of treatment which are still missing (i.e., 
where an imputation was not possible), it is further studied whether the corresponding 
bleeding intensities of the UF-DBD are missing on the same day(s) as well.  
(a) If the bleeding intensity is not missing and only the AH value is missing, the bleeding 
intensity must be at least ‘mild’, because for ‘no vaginal bleeding’ and ‘spotting’ the 
AH value would have been imputed with 0 mL. Accordingly, it must be assumed that 
bleeding has occurred on these day(s). Therefore, the subject is considered as not 
having amenorrhea. Step b) will then not be applied irrespective of whether there are 
also days for which both, the bleeding intensity and the AH value, are missing.  
(b) If both, the bleeding intensity and the AH value, are missing for any of the last 28 
days, the 28-day period will be extended: The left margin of the 28-day period will be 
displaced backwards in time and step-wise until the required number of 28 non-
missing AH values are included. The left margin may be displaced backwards at 
maximum up to the end of the first bleeding episode when treatment was started in 
respective treatment period.  
Considering this time window, a subject will be considered as not having amenorrhea 
if  
i) the sum of the non-missing (i.e. original or imputed) AH values is ≥ 2 mL, or  
ii) there is at least one day with missing AH value and bleeding intensity of ‘mild’ 
up to ‘very severe’ after having applied the imputation rules, or 
iii) the subject did not complete at least 8 weeks of treatment.  
If neither of i), ii) or iii) applies, the subject will be considered as having amenorrhea.  
 
 
Confirmatory analysis of the primary efficacy variable 
6.2.1.1
The primary efficacy variable will be analyzed descriptively in frequency tables by treatment 
period and region within each treatment group. Additionally, vilaprisan treatment after 12 
weeks, i.e. in TP1, of treatment groups A1 and B2 will be pooled.   
The confirmatory analysis will be performed only based on TP1. In the confirmatory analysis, 
the proportion of subjects with amenorrhea will serve as comparison criteria in the 
comparisons defined in Section 6.2. For simplicity, the confirmatory analysis will be 
formulated generally. The null hypothesis, 𝐻𝐻0, states that the common difference of 
proportions between the 2 mg vilaprisan group and the placebo group among the regions (US, 
Japan and other) 𝛿𝛿 is zero. Considering a two-sided test problem with hypotheses 


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𝐻𝐻0: 𝛿𝛿= 0  
vs. 
 𝐻𝐻1: 𝛿𝛿≠0, 
the alternative hypothesis, 𝐻𝐻1, states that the common difference of the proportion of subjects 
with amenorrhea between the 2 mg vilaprisan group and the placebo group among the regions 
is unequal to zero. 
The test problem will be investigated by means of a two-sided, continuity-corrected Cochran-
Mantel-Haenszel (CMH) test stratified by country/region at a local 0.05 significance level. 
The test statistic of the CMH test is defined as 
𝐶𝐶𝐶𝐶𝐶𝐶=
ൣห∑൫𝑛𝑛11𝑘𝑘−E𝐻𝐻0(𝑛𝑛11𝑘𝑘)൯ 
𝑘𝑘
ห−0.5൧
2
∑Var𝐻𝐻0(𝑛𝑛11𝑘𝑘)
𝑘𝑘
, 
with 𝑛𝑛𝑖𝑖𝑖𝑖𝑖𝑖 representing the number of subjects with (𝑖𝑖= 1) or without amenorrhea (𝑖𝑖= 0) and 
belonging to the vilaprisan group (𝑗𝑗= 1) or to the placebo group (𝑗𝑗= 0) and country/region 𝑘𝑘 
(1 =ෝ US, 2 =ෝ Japan, 3 =ෝ other countries). It compares the observed number of subjects with 
amenorrhea in the vilaprisan 2 mg group with the expected number under the null hypothesis 
[3]. Under the assumption of fixed 𝑛𝑛1+𝑘𝑘= ∑
𝑛𝑛1𝑗𝑗𝑗𝑗
1
𝑗𝑗=0
, the expected number and the variance 
under the null hypothesis are [4] 
E𝐻𝐻0(𝑛𝑛11𝑘𝑘) = 𝑛𝑛1+𝑘𝑘𝑛𝑛+1𝑘𝑘𝑛𝑛++𝑘𝑘
⁄
 
and  
Var𝐻𝐻0(𝑛𝑛11𝑘𝑘) = 𝑛𝑛1+𝑘𝑘𝑛𝑛0+𝑘𝑘𝑛𝑛+1𝑘𝑘𝑛𝑛+0𝑘𝑘
𝑛𝑛++𝑘𝑘2(𝑛𝑛++𝑘𝑘−1)  
The plus sign (+) denotes a summation over the respective index. 
Under the said assumption and the null hypothesis, the CMH test-statistic approximatively 
follows the 𝜒𝜒2-distribution with one degree of freedom [3]. Hence, the null hypothesis of 
conditional independence between the treatment and the presence of amenorrhea given the 
country/region will be rejected, if the observed test-statistic exceeds the 95% quantile of the 
𝜒𝜒2-distribution with one degree of freedom, which is 3.841. 
Along with the results of the CMH test, the Mantel-Haenszel estimate for the common risk 
difference of the proportion of subjects with amenorrhea between the 2 mg vilaprisan group 
and the placebo group among the regions 𝛿𝛿 will be reported together with its approximate 
95% confidence interval (two-sided).  
The Mantel-Haenszel estimator for the common risk difference 
𝛿𝛿̂ =
∑𝛿𝛿̂𝑘𝑘𝑤𝑤𝑘𝑘
𝑘𝑘
∑𝑤𝑤𝑘𝑘
𝑘𝑘
, 
is composed of the estimated risk difference of the proportion of subjects with amenorrhea in 
country/region k, 
𝛿𝛿̂𝑘𝑘= 𝑛𝑛11𝑘𝑘
𝑛𝑛+1𝑘𝑘
−𝑛𝑛10𝑘𝑘
𝑛𝑛+0𝑘𝑘
, 
and country/region-specific weights 
𝑤𝑤𝑘𝑘= 
𝑛𝑛+1𝑘𝑘 𝑛𝑛+0𝑘𝑘
𝑛𝑛++𝑘𝑘
 [5]. 


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An approximate 100(1 −𝛼𝛼)% confidence interval (two-sided) for the common risk 
difference 𝛿𝛿̂ is given by 
ቈ𝛿𝛿̂ ± z𝛼𝛼2
⁄ ට𝑉𝑉𝑉𝑉𝑉𝑉
෢൫𝛿𝛿̂൯቉, 
where z𝛼𝛼2
⁄  denotes the (𝛼𝛼2
⁄ )-quantile of the standard normal distribution and the variance 
estimator of the Mantel-Haenszel estimator 𝛿𝛿̂ will be computed as  
𝑉𝑉𝑉𝑉𝑟𝑟
෢൫𝛿𝛿෡൯= 𝛿𝛿෡∑𝑢𝑢𝑘𝑘
𝑘𝑘
+ ∑𝑣𝑣𝑘𝑘
𝑘𝑘
(∑𝑤𝑤𝑘𝑘
𝑘𝑘
)2
, 
where 
𝑢𝑢𝑘𝑘= ቈ𝑛𝑛+1𝑘𝑘
2
𝑛𝑛10𝑘𝑘− 𝑛𝑛+0𝑘𝑘
2
𝑛𝑛11𝑘𝑘+ 𝑛𝑛+1𝑘𝑘𝑛𝑛+0𝑘𝑘(𝑛𝑛+0𝑘𝑘−𝑛𝑛+1𝑘𝑘)
2
቉𝑛𝑛++𝑘𝑘
2
ൗ
 
and 
𝑣𝑣𝑘𝑘= 
𝑛𝑛11𝑘𝑘(𝑛𝑛+0𝑘𝑘−𝑛𝑛10𝑘𝑘) + 𝑛𝑛10𝑘𝑘(𝑛𝑛+1𝑘𝑘−𝑛𝑛11𝑘𝑘)
2𝑛𝑛++𝑘𝑘
 [6]. 
 
 
 
Sensitivity analyses of the primary efficacy variable 
6.2.1.2
6.2.1.2.1 Analysis in PPS population 
As a first sensitivity analysis, the impact of the choice of analysis set will be investigated. The 
confirmatory analysis of the primary efficacy variable will thus be repeated on the PPS 
population excluding subjects with validity findings impacting the assessment (see 
Section 5.1) of amenorrhea during the last 28 days of TP1. As opposed to the analysis on the 
FAS, this is intended to measure the actual effect in protocol adherers rather than 
investigating the effect of the treatment strategy in every randomized subject.   
 
6.2.1.2.2 Analysis based on alternative missing data imputation strategy  
The impact of missing data will be investigated in the FAS (according to the intention to treat 
principle) with multiple imputation, using a pattern-mixture framework as described by the 
National Research Council (NRC 2012) [7]. In the primary analysis, it is assumed that values 
in the UF-DBD or for the AH method are missing at random (MAR), i.e., they only depend 
on observed outcomes and can thus be imputed based on the observed data. However, it is 
possible that missing values are systematically different from observed values because 
patients are dissatisfied with their treatment and are consequently more likely to withdraw 
from the study, for example. If the differences between missing and observed values do not 
balance out between the treatment groups, then this creates a bias in the treatment effect. 
Therefore, this sensitivity analysis serves to examine the missing data mechanism and explore 
different scenarios under a MNAR (Missing Not at Random) assumption where an outcome 
depends on the fact whether it is observed or not and missing outcomes can thus differ 
systematically from observed outcomes by treatment group.  


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For the purpose of this sensitivity analysis for missing data, the standard procedure of 
imputing intermittent single or two consecutive days with missing UF-DBD bleeding 
intensities and the replacement of missing daily AH values with 0 mL for bleeding intensities 
of not more than ‘spotting’ are kept as sensible approaches because nothing out of line is 
expected to happen in the time frame of one or two days. In contrast to the primary analysis, 
however, days with biopsies and the three days thereafter will not be considered with an AH 
value of 0 mL (assuming no bleeding), but will be considered missing since the AH values on 
those days if the patient had not had the biopsy are unknown. This rule and further rules used 
to impute missing data in the primary analysis will be challenged with this analysis using 
multiple imputation in a pattern-mixture approach.  
Subjects are sorted into three categories based on the available UF-DBD and AH information 
from Day 57 to 84 of the TP1 (or the last 28 days of TP1, if study drug was taken for more 
than 84 days). Those three categories are comprised of clear responders and clear non-
responders (after the initial minimal imputation rules described above) as well as subjects 
with unclear response status. A clear responder for amenorrhea is defined as a subject  
• who has only UF-DBD bleeding intensities of no more than ‘spotting’ AND 
• for whom the sum of daily AH values is less than 2 mL AND 
• for whom there are no missing values for either the AH method (daily values) or the 
UF-DBD bleeding intensities. 
As opposed to this definition, a clear non-responder for amenorrhea is defined as a subject  
• who has at least one bleeding intensity of ‘mild’ or higher OR 
• for whom the sum of daily AH values is equal to or higher than 2 mL. 
All response criteria are set in relation to the planned time frame for the assessment of the 
primary efficacy variable, i.e., Day 57 to Day 84 of the TP1. An exception is made when a 
subject’s TP1 is longer than 84 days. In this case the last 28 days of TP1 are used for the 
assessment.  
A subject is considered as unclear responder for amenorrhea (and thus having a missing 
outcome) if in the relevant time frame, all the subject’s bleeding intensities do not exceed 
‘spotting’ and the sum of daily bleeding intensities is below 2 mL, but there are still missing 
values among both the UF-DBD bleeding intensities and the daily AH values between Day 57 
and 84 of the TP1. Therefore, it is still possible that replacement of the missing bleeding 
information turns an apparent responder into a non-responder for amenorrhea, signifying that 
no clear assessment about the response status can be made. 
A descriptive analysis of the number of subjects in each response category will be supplied by 
treatment group. 
Missing data imputation will only be applied to subjects with unclear response status, whereas 
not the AH values will be imputed but the response status. Response status of subjects with 
unclear outcome are generated in a three-step process [8] by  
1) Estimation of individual log-odds of amenorrhea for all patients from a logistic 
regression model, which is an imputation model fitted based on data of clear 
responders and non-responders, 
2) Simulation of response status using the predicted log-odds to create multiple datasets 
with imputed data; conduct of the Cochran-Mantel-Haenszel test on each imputed 
dataset; combination of the analysis results to generate statistical inference, 


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3) Assessment of the robustness of step 2 after adding/subtracting a penalty (shift 
parameter) from the log-odds in the placebo group and vilaprisan group, respectively, 
and determination of the “tipping point”. 
Those three steps are outlined in more detail in the following. 
Step 1: 
To impute the missing response status, a logistic regression model will be fitted to the binary 
variable amenorrhea yes/no (coded as 1 and 0) for subjects who are either clear responders or 
clear non-responders. Treatment group (𝑋𝑋𝑇𝑇), stratification factor region (𝑋𝑋𝑅𝑅), baseline 
covariates age (𝑋𝑋𝐴𝐴𝐴𝐴𝐴𝐴) and baseline MBL (𝑋𝑋𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) are used as covariates. This leads to the 
following model equations for the log-odds 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝1) = log (𝑝𝑝1/(1 −𝑝𝑝1)) of the response 
(amenorrhea=yes) probability 𝑝𝑝1: 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝1) = 𝛽𝛽0 + 𝛽𝛽1𝑋𝑋𝑇𝑇+ 𝛽𝛽2𝑋𝑋𝑅𝑅+ 𝛽𝛽3𝑋𝑋𝐴𝐴𝐴𝐴𝐴𝐴+ 𝛽𝛽4𝑋𝑋𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵. 
If the model does not converge, the stratification factor region will not be used as covariate in 
the model. 
Step 2: 
Following the multiple imputation approach with the monotone logistic regression method 
[9], new parameters 𝛽𝛽∗= (𝛽𝛽∗0, … , 𝛽𝛽∗4)′ are drawn from the posterior predictive distribution of 
the regression parameters 𝛽𝛽= (𝛽𝛽0, … , 𝛽𝛽4)′. For a subject with unclear response status and 
covariate vector 𝑥𝑥= (1, 𝑥𝑥𝑇𝑇, 𝑥𝑥𝑅𝑅, 𝑥𝑥𝐴𝐴𝐴𝐴𝐴𝐴, 𝑥𝑥𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵)′ the predicted response probability of 
amenorrhea is given by 
𝑝𝑝1 =
exp (𝑥𝑥′𝛽𝛽∗+𝛿𝛿)
1+exp (𝑥𝑥′𝛽𝛽∗+𝛿𝛿), 
where 𝛿𝛿 denotes the penalty or shift parameter which is 0 under the MAR assumption. A 
random variable 𝑢𝑢 is drawn from a standard uniform distribution and if the unequality 𝑢𝑢< 𝑝𝑝1 
holds for a subject then the subject’s response status for amenorrhea is imputed with yes (=1), 
else it is imputed with no (=0). After imputing all subjects’ response statuses in this manner, 
the primary analysis is repeated, i.e., the Cochran-Mantel-Haenszel test is conducted based on 
the complete imputed data set. This imputation and analysis will be repeated 1,000 times. 
Inferences for combined parameters will be done using Rubin’s multiple imputation rules [10] 
which reflect imputation uncertainty. 
Step 3: 
To assess the robustness of the analyses for deviations from the MAR assumption, step 2 will 
be repeated with different choices of the shift parameter for subjects from the vilaprisan group 
and placebo group, respectively. To explore the whole range of possibilities unfavorable to 
vilaprisan, choices of non-positive shift parameters 𝛿𝛿𝑣𝑣= 0, −1, −2, … , 𝜋𝜋𝑚𝑚𝑚𝑚𝑚𝑚, 𝜋𝜋𝑚𝑚𝑚𝑚𝑚𝑚< 0, for 
the log-odds of subjects with unclear response status in the vilaprisan group will be combined 
with choices of non-negative shift parameters 𝛿𝛿𝑝𝑝= 0, 1, 2, …, 𝜋𝜋𝑚𝑚𝑚𝑚𝑚𝑚, 𝜋𝜋𝑚𝑚𝑎𝑎𝑎𝑎> 0, for the log-
odds of subjects with unclear response status in the placebo group. The combination 𝛿𝛿𝑣𝑣= 0 
and 𝛿𝛿𝑝𝑝= 0 signifies a MAR assumption and represent the “best case” among the presented 
scenarios. In this scenario, patients with unclear response status are assumed to have the same 
chance of amenorrhea as similar patients for whom response status is known. Any 
combinations different from 𝛿𝛿𝑣𝑣= 0 and 𝛿𝛿𝑝𝑝= 0 refer to the situation where unobserved 
bleeding is missing not at random (MNAR), with larger absolute values for the penalities 


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indicating larger deviations from the MAR assumption. Values of 𝛿𝛿𝑣𝑣<0 are equivalent to a 
multiplication of the odds (chance) of having amenorrhea with the factor exp(𝛿𝛿𝑣𝑣) and imply 
vilaprisan patients with unclear response status have a systematically lower chance of 
amenorrhea than similar patients with clear response status. Choices of 𝛿𝛿𝑝𝑝>0 or, equivalently, 
multiplication of the odds with exp൫𝛿𝛿𝑝𝑝൯ imply that placebo patients with unclear response 
status have a systematically higher chance of amenorrhea than those with clear response 
status. Therefore, a combination of 𝛿𝛿𝑣𝑣= 𝜋𝜋𝑚𝑚𝑚𝑚𝑚𝑚< 0 and 𝛿𝛿𝑝𝑝= 𝜋𝜋𝑚𝑚𝑚𝑚𝑚𝑚> 0 represents the “worst 
case” among these scenarios in which all subjects with unclear response status in the 
vilaprisan group are set to non-responders whereas all subjects with unclear response status in 
the placebo group are set to responders for amenorrhea. 
 
6.2.2 
Secondary efficacy variables 
The secondary efficacy variables are defined in the following. The confirmatory analysis of 
selected secondary efficacy variables will be performed only for data from TP1. In addition, 
secondary efficacy variables will be analyzed descriptively for both treatment periods.  
 
• Heavy menstrual bleeding (HMB) response: HMB response is defined as MBL 
<80.00 mL during last 28 days of treatment and >50% reduction from baseline 
(assessed by AH method). Missing AH data will be imputed as explained in Section 
4.3.  
If an endometrial biopsy was conducted, bleeding on the day of intervention and the 
3 days thereafter will not be considered in this evaluation, i.e., bleeding/‘spotting’ on 
the day of biopsy and 3 days thereafter will not be considered as day(s) with 
bleeding/‘spotting’ and AH values will be set to 0 mL.  
After imputing missing bleeding intensities and AH values (see Section 4.3) and 
considering potential biopsies, the 28-day period will be extended in case there are 
still any AH values missing in the last 28 days (similar to the description in Section 
6.2.1 b); a) will not be applied). Based on the 28-day period a subject will be 
considered as not being an HMB responder if  
i) the sum of the non-missing (i.e., original or imputed) AH values is ≥80.00 mL 
or the reduction of blood loss is ≤50% as compared to baseline or  
ii) the subject did not complete at least 8 weeks of treatment.  
If neither of i) or iii) applies, the subject will be considered as an HMB responder. 
 
• Time to onset of amenorrhea: Onset of amenorrhea is defined by the first day for 
which the MBL for all subsequent 28-day periods up to the end of a treatment period 
is <2 mL (amenorrhea defined similar to primary endpoint). The first 28 days with 
non-missing AH values until the last 28 days with non-missing AH values under 
treatment will be considered for deriving the time to onset of amenorrhea. An 
analogous approach as described for amenorrhea in the last 28 days of treatment 
(Section 6.2.1) will be applied to assess the amenorrhea status for each of the 
subsequent, overlapping 28-day periods within a treatment period (except for criterion 
iii), which does not apply). The censoring mechanism is assumed to be non-


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informative and the subjects will be handled as right-censored, if applicable. If a 
subject completed the 84 days of a treatment period and did not experience an onset of 
amenorrhea, the subject will be censored on Day 57 of the treatment period.  
For prematurely discontinued subjects, censoring also depends on whether an onset of 
amenorrhea can be ruled out or not during the time the subject was in the respective 
treatment period. An onset of amenorrhea can be ruled out if in the last 28-day period 
before the subject discontinued the respective treatment period, the sum of AH values 
exceeds 2 mL. If this is not the case, then an onset of amenorrhea cannot be ruled out 
for the respective treatment period. Thus, there are in principle the two possibilities: 
• In case the subject discontinued from the respective treatment period 
prematurely and an onset can be ruled out, subjects will be treated as right-
censored at the first day of the last 28-day period after which AH bleeding 
values for all further days are missing (see Figure 6–3 (a)).  
If the subject prematurely discontinued from the respective treatment period but an 
onset cannot be ruled out, the subject will be censored on the day before the first day 
of the first 28-day period which indicates that an onset may have taken place (see 
Figure 6–3 (b)). 
 
• Time to onset of controlled bleeding: Onset of controlled bleeding is defined by the 
first day for which the MBL for all subsequent 28-day periods up to the end of a 
treatment period is <80.00 mL. The first 28 days with non-missing AH values until the 
last 28 days with non-missing AH values under treatment in the respective treatment 
period will be considered for deriving the time to onset of controlled bleeding. An 
analogous approach as described for HMB response (Section 6.2.2) will be applied to 
each of the subsequent, overlapping 28-day periods within a treatment period (except 
for criterion ii), which does not apply). Time to onset of controlled bleeding is then 
derived analogous to time to onset of amenorrhea.  
 
• Absence of bleeding (spotting allowed) during last 28 days of treatment (assessed 
by the UF-DBD): Absence of bleeding is defined as no scheduled or unscheduled 
bleeding during the last 28 days of a treatment period based on the UF-DBD. Missing 
data will be imputed as described in Section 4.3. The last days under treatment with 28 
days with non-missing bleeding eDiary data will be used to calculate whether absence 
of bleeding occurred. Thus, if the last 28 days of treatment include days with missing 
bleeding eDiary data, the left margin of this interval will be displaced backwards in 
time and step-wise until the required number of 28 non-missing values are included. 
The left margin may be displaced backwards at maximum up to the end of the first 
bleeding episode when treatment was started in respective treatment period. 
If an endometrial biopsy was conducted, bleeding on the day of intervention and the 
3 days thereafter will not be considered in this evaluation, i.e. bleeding on the day of 
biopsy and 3 days thereafter will not be considered as day(s) with bleeding and UF-
DBD values will be set to ‘no vaginal bleeding’.  
Subjects who discontinue treatment prior to completion of 8 weeks of treatment will 
be considered as not experiencing absence of bleeding. 


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Figure 6–3: Illustration of censoring rules for subjects prematurely discontinuing a 
treatment period. 
 
An illustration of censoring for a subject who both discontinued on Day 31 of a treatment period. (a) 
The onset of amenorrhea during the subject’s treatment period can be ruled out (MBL ≥ 2mL in last 
28-day period), and the subject is censored at the first day of her last 28-day period. (b) An onset of 
amenorrhea on Day 3 cannot be ruled out (MBL < 2mL in her last 28-day period(s)), and the subject 
is censored on Day 2. 
 
 
Analysis of the secondary efficacy variables 
6.2.2.1
HMB response and absence of bleeding (spotting allowed) will be analyzed descriptively in 
frequency tables by treatment period and region within each treatment group. The time to 
event variables will be analyzed for each treatment group using Kaplan-Meier estimates 
(including number of events, number of censored subjects, median, 25th and 75th 
percentiles). Kaplan-Meier plots will also be presented. 
Additionally, treatment groups A1 and B2 with vilaprisan treatment in TP1 will be pooled and 
results will be presented for this pooled population. 
The first three secondary endpoints evaluated for TP1 are part of the testing hierarchy within 
the confirmatory analysis. The confirmatory analysis of these variables is described in the 
following.  
 
HMB response  
The first secondary efficacy variable HMB response (yes/no) will be analyzed analogously to 
the primary efficacy variable amenorrhea.  
 
Time to onset of amenorrhea  


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The time to onset of amenorrhea can be described in terms of a hazard rate. The null 
hypothesis of no treatment effect with respect to the onset of amenorrhea (see Figure 6–2) can 
thus be stated as an equality of hazard rates 𝜆𝜆𝑣𝑣,𝑘𝑘(𝑡𝑡) and 𝜆𝜆𝑝𝑝,𝑘𝑘(𝑡𝑡) in the 𝑘𝑘-th stratum/region for 
the vilaprisan group (𝑣𝑣) and the placebo group (𝑝𝑝): 
𝐻𝐻0: 𝜆𝜆𝑣𝑣,𝑘𝑘(𝑡𝑡) = 𝜆𝜆𝑝𝑝,𝑘𝑘(𝑡𝑡) for 𝑘𝑘= 1, 2, 3, 𝑡𝑡≤𝜏𝜏, 
where 𝑘𝑘 corresponds to the strata/regions (1 =ෝ US, 2 =ෝ Japan, and 3 =ෝ other) and 𝜏𝜏 is the 
largest observed event time in the pooled treatment groups used for the comparison. 
In order to test the null hypothesis of no difference in time to onset of amenorrhea between 
vilaprisan 2mg and placebo versus the alternative hypothesis of a difference for at least one 
stratum/region, a logrank test stratified by region/country is conducted at a local 0.05 
significance level.  
The test statistic of the logrank test compares the observed number of events and the numbers 
of events expected under the null hypothesis in each treatment group per stratum. It is defined 
as 
𝑍𝑍= ∑
𝑍𝑍𝑣𝑣,𝑘𝑘(𝜏𝜏)
3
𝑘𝑘=1
ට∑
𝜎𝜎ො𝑣𝑣,𝑘𝑘
2
3
𝑘𝑘=1
ൗ
, 
where in each stratum 𝑘𝑘, the values for 𝑍𝑍𝑣𝑣,𝑘𝑘and 𝜎𝜎ො𝑣𝑣,𝑘𝑘 are derived in the following way (the 
stratum index 𝑘𝑘 is left out for all variables out of convenience):  
𝑍𝑍𝑣𝑣(𝜏𝜏) = ∑
ቀ𝑑𝑑𝑣𝑣,𝑖𝑖−𝑌𝑌𝑣𝑣,𝑖𝑖 
𝑑𝑑𝑖𝑖
𝑌𝑌𝑖𝑖ቁ
𝐷𝐷
𝑖𝑖=1
 , 
𝜎𝜎ො𝑣𝑣
2(𝜏𝜏) = ∑
𝑌𝑌𝑣𝑣,𝑖𝑖
𝑌𝑌𝑖𝑖
𝐷𝐷
𝑖𝑖=1
ቀ1 −
𝑌𝑌𝑣𝑣,𝑖𝑖
𝑌𝑌𝑖𝑖ቁቀ
𝑌𝑌𝑖𝑖−𝑑𝑑𝑖𝑖
𝑌𝑌𝑖𝑖−1ቁ𝑑𝑑𝑖𝑖 . 
In these formulae, if 𝑡𝑡1 < ⋯< 𝑡𝑡𝐷𝐷= 𝜏𝜏 are the distinct event times, i.e. times of onset of 
amenorrhea,  
• the values of 𝑑𝑑𝑣𝑣,𝑖𝑖 represent the number of events observed in the vilaprisan group at 
time point 𝑡𝑡𝑖𝑖  
• 𝑌𝑌𝑣𝑣,𝑖𝑖 denotes the number of subjects at risk just prior to 𝑡𝑡𝑖𝑖 in the vilaprisan group,  
• 𝑑𝑑𝑖𝑖 denotes the number of events observed in the vilaprisan group and placebo group 
combined at time point 𝑡𝑡𝑖𝑖 and  
• 𝑌𝑌𝑖𝑖 denotes the number of subjects at risk just prior to 𝑡𝑡𝑖𝑖 in the vilaprisan group and 
placebo group combined [11]. 
The logrank test statistic 𝑍𝑍 asymptotically follows a standard normal distribution under the 
null hypothesis. 
 
Time to onset of controlled bleeding 
Time to onset of controlled bleeding will be analyzed analogously to the secondary efficacy 
variable time to onset of amenorrhea. 
 


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Absence of bleeding 
Absence of bleeding (yes/no) will be analyzed descriptively with frequency tables by 
treatment period within each treatment group. 
 
 
Sensitivity analyses of the secondary efficacy variables 
6.2.2.2
Sensitivity analyses for the variables HMB response, time to onset of amenorrhea and time to 
onset of controlled bleeding will be conducted on the PPS analogously to the primary efficacy 
variable (see Section 6.2.1.2).  
 
6.2.3 
Further efficacy variables and analyses 
All further variables will be presented by means of descriptive statistics based on the FAS 
population. Time to event variables will be analyzed using the Kaplan-Meier estimates 
(including number of events, number of censored subjects, median, 25th and 75th percentiles) 
and Kaplan-Meier plots will also be presented. For continuous variables, the number of 
observations, mean, median, standard deviation, minimum, and maximum as well as change 
from baseline will be computed. For categorical (dichotomous) variables the data will be 
presented using frequency tables. The data will be presented by treatment period and 
treatment group. Additionally, results for all patients receiving vilaprisan treatment for 12 
weeks will be presented, i.e. results for TP1 of treatment groups A1 and B2 will be pooled.  
The further efficacy variables and their analysis are outlined in the following subsections. 
 
 
Binary bleeding variables 
6.2.3.1
• Treatment success rate 
The treatment success rate is defined as percentage of subjects who fulfill the criteria 
of HMB response (MBL <80.00 mL and >50% reduction in MBL as compared to 
baseline) and who have not been withdrawn from the study due to AEs, due to non-
fulfillment of selection criteria (related to fibroid size or HMB at baseline), due to 
fibroid surgery having been performed during the study. Treatment success rate will 
be derived separately for the AH method and for MP. 
Only fibroid surgeries that occur during the length of the originally planned study 
design (including FUP) prior to the temporary pause (Integrated Clinical Study 
Protocol, version 3.0, and protocol versions before) will be considered for deriving the 
treatment success rate. The FUP visit of the originally planned study design is on Day 
7-15 of the 2nd menstrual cycle after the subject’s end of treatment. That means that 
for subjects who have a prolonged FUP due to the temporary pause, the FUP 
according to the original study design will be derived. The derivation will be based on 
the end date of the subject’s last treatment period and a follow-up time fixed to 12 
weeks. Assuming a time to first menses after end of treatment of about 4 weeks and a 
cycle length of 4 weeks, 12 weeks of follow-up will cover at least the time period until 
the FUP visit would have been conducted according to the original study design. 
Treatment success will be summarized with frequency tables by treatment period 
within treatment group. Number of observations and percentages will be presented. 


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• Amenorrhea  
Amenorrhea, as further efficacy variable, is defined as MBL < 2 mL per 28 days of 
treatment for consecutive, non-overlapping 28-day periods not considered for the 
primary efficacy variable. An analogous approach as described for amenorrhea in the 
last 28 days of treatment (Section 6.2.1) will be applied to assess the amenorrhea 
status for each of the consecutive, non-overlapping 28-day periods within a treatment 
period (except for the 28-day period extension in case of missing values and criterion 
iii), which both do not apply).  
In case of no premature discontinuation, amenorrhea will be evaluated for the first and 
second 28-day periods of the subject’s TP1 and TP2 when the AH method is used. 
When the MP is used, amenorrhea will be evaluated in all non-overlapping 28-day 
periods of TP1 and TP2. Only subjects with completed 28-day periods will be 
considered for the analysis of amenorrhea in those 28-day periods.  
In addition, amenorrhea will be analyzed for an incomplete period which does not 
comprise 28 days. This analysis is based on all subjects for whom the length of the 
treatment period is not a multiple of 28 days. The reason for this might be premature 
discontinuation from the study or prolonged treatment.  
Amenorrhea will be summarized by a frequency table by (pooled) treatment group and 
the 28-day periods grouped by treatment period. 
• HMB response 
HMB response, as further efficacy variable, is defined as MBL <80.00 mL per 28 days 
of treatment and >50% reduction from baseline where MBL is assessed for 
consecutive, non-overlapping 28-day periods not considered for the secondary 
efficacy variable. An analogous approach as described for HMB response in the last 
28 days of treatment (Section 6.2.2) will be applied to assess HMB response for each 
of the consecutive, non-overlapping 28-day periods within a treatment period (except 
for the 28-day period extension in case of missing values and criterion ii), which both 
do not apply).  
In case of no premature discontinuation, HMB response will be evaluated for the first 
and second 28-day periods of the subject’s TP1 and TP2 when the AH method is used. 
When the MP is used, HMB response will be evaluated in all non-overlapping 28-day 
periods of TP1 and TP2. Only subjects with completed 28-day periods will be 
considered for the analysis of HMB response in those 28-day periods. In addition, 
HMB response will be analyzed for an incomplete period which does not comprise 28 
days. This analysis is based on all subjects for whom the length of the treatment period 
is not a multiple of 28 days. The reason for this might be premature discontinuation 
from the study or prolonged treatment.  
HMB response will be summarized by a frequency table by (pooled) treatment group 
and the 28-day periods grouped by treatment period. 
 


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Time to onset variables 
6.2.3.2
The time to onset variables described in the following will be analyzed analogous to the 
descriptive analysis described in Section 6.2.2.1, namely by Kaplan-Meier estimates and 
Kaplan-Meier plots for all regions combined. 
• Time to onset of amenorrhea and time to onset of controlled bleeding (see 
Section 6.2.2)  
These variables will be assessed by the MP separately for TP1 and TP2.  
• Time to start of bleeding after last study drug intake 
The start of bleeding after last study drug intake is defined by the first day for which 
bleeding intensity is “mild” or higher according to the UF-DBD. Only data from the 
UF-DBD will be considered to determine “start of bleeding after last study drug 
intake” because UF-DBD data are typically available even if there are missing values 
for one or both of the other two methods (MP, AH method). 
The last study drug intake refers to the end of TP1 and the end of TP2, as defined in 
Section 4.5 (“Treatment period”).  
If an endometrial biopsy was conducted during the evaluation time period, any 
bleeding reported on the day of biopsy and the 3 days thereafter will not be considered 
in this evaluation, that is, if a bleeding intensity is reported on these days, the bleeding 
intensity will be overwritten to “no vaginal bleeding”.  
If a subject did not experience a start of bleeding, she will be censored at latest 
available date from the bleeding eDiary data from the UF-DBD. If bleeding has to be 
induced, subjects will be censored on the date of bleeding induction. For the analyses 
after TP1, the subject will be censored at latest at TP2 start date if she starts TP2. 
 
 
Volume of menstrual blood loss (MBL) related variables 
6.2.3.3
The following variables related to volume of MBL will be evaluated both on the AH method 
and the MP:  
• Volume of MBL per 28 days: Volume of MBL will be derived for each non-
overlapping 28 days within a treatment period based on subjects who entered the 
respective 28-day period. 
• Volume of MBL per bleeding episode for the first, second, and if applicable third 
bleeding episode after the end of treatment.  
• Volume of MBL per bleeding episode within the treatment break. All days of the 
bleeding episodes will be used even if some days of the episode lie outside the 
treatment break. The first, second and third bleeding episode will be considered.  
• Percentage of subjects with ≥ 50% reduction in MBL per each non-overlapping 28-
day periods compared to baseline (based on subjects who entered the respective 28-
day period). 
Bleeding on the day of biopsy and the 3 days thereafter will not contribute to the MBL in this 
evaluation. Analysis of volume of MBL will be done by treatment group separately for TP1, 
break period, TP2 and FUP. An incomplete period which does not comprise 28 days will be 
analyzed for any of TP1, break period, TP2 and FUP. The analysis of this incomplete period 


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is based on all subjects for whom the length of the considered time period (TP1, break period, 
TP2 or FUP) is not a multiple of 28 days. A subject’s data from the last x < 28 days of the 
considered time period will be included. 
 
 
Ultrasound examination related variables 
6.2.3.4
The following variables will be presented by (pooled) treatment group and by Intervals B as 
well as by post-baseline visit (i.e. Visit 4, Visit 5, Visit 6, EoT visit, FUP visit, safety closeout 
visit): 
• Percent change in the sum of the volume of the 3 largest fibroids compared to baseline 
(measured by ultrasound). If less than 3 fibroids are present, the volume of the actual 
number of fibroids will be summed. 
• Percentage change in volume of the largest fibroid from baseline (measured by 
ultrasound) 
• Percent change in volume of uterus compared to baseline (measured by ultrasound) 
• Percentage of subjects with a reduction of ≥ 25% of the sum of the volume of the 3 
largest fibroids compared to baseline (measured by ultrasound). If less than 3 fibroids 
are present, the volume of the actual number of fibroids will be summed. 
• Percentage of subjects with a volume reduction of ≥ 25% of the largest fibroid 
compared to baseline (measured by ultrasound) 
• Percentage of subjects with a reduction of ≥ 25% of uterine volume compared to 
baseline (measured by ultrasound)  
If multiple volume assessments are available for a time period, the smallest volume 
measurement will be used for the Baseline time period, and the largest volume measurement 
will be used for any other time periods of Intervals B. 
 
 
Uterine fibroids surgeries 
6.2.3.5
The number and proportions of subjects undergoing surgical treatment for uterine fibroids 
will be displayed in a frequency table by treatment group and by the following time periods: 
treatment period, break period, FUP (including prolonged FUP). In contrast to other efficacy 
variables, any fibroid surgeries performed during FUP of patients who did not start TP2 will 
be evaluated for FUP rather than for break period. 
 
 
Patient-reported outcome and Clinician-reported outcome  
6.2.3.6
Change in UF-DSD individual items compared to baseline 
The UF-DSD is a newly developed multi-item PRO instrument designed to assess cardinal 
symptoms of uterine fibroids using a 24-hour recall period. 
The UF-DSD includes 2 items (items 1 and 2) to assess swelling and bloating symptoms in 
the abdomen and pelvic area using a 5-graded Likert-type severity rating (‘no symptom’ to 
‘very severe symptom’), and 2 items (items 3 and 4) using a 0 to 10 numerical rating scale to 
assess pain at its worst in the abdominal/pelvic and lower back areas respectively, with 0 
indicating ‘no pain’ and 10 ‘pain as bad as you can imagine’. Additionally, item 5 assess the 


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intake of pain medication using a 4-point verbal rating scale (“no”; “yes, over the counter 
(non-prescription) pain medication”; “yes, prescription pain medication”; or “yes, both (over 
the counter and prescription pain medication”). Further information can be found in 
Appendix 3). 
The following variables in each domain will be summarized by treatment group. Mean values 
will be evaluated per 28-day period within each of the following time periods: screening, 
baseline (only the last 28 days before first study drug intake), 1st 28-day period, 2nd 28-day 
period, 3rd 28-day period for any of TP1, break, TP2, FUP1, FUP2, etc.. Absolute changes 
from baseline will be provided as well. Graphical displays will also be provided. 
Bulk symptoms (items 1 and 2): 
• Mean of subjects’ relative frequencies (relative frequency is calculated for each 
subject as ratio of given severity to all severities) of the symptom scores  
• Mean of subjects’ symptom scores of the 7 days with worst assessment (i.e., highest 
score) 
Pain (items 3 and 4): 
• Mean numerical rating pain score  
• Mean numerical rating pain score of the 7 days with worst pain (i.e., highest score)  
Pain medication (item 5): 
• Proportion of days with pain medication intake  
 
Change in UFS-QoL scores compared to baseline 
The UFS-QoL is a widely used disease-specific instrument that assesses symptom severity 
and health-related quality of life (HRQoL) in subjects with uterine fibroids [12]. 
It consists of 37 items including an 8-item symptom severity scale and 29 health-related 
quality of life questions comprising 6 subscales: concern, activities, energy/mood, control, 
self-consciousness, and sexual function which are responded to using a recall period of 3 
months. All items are scored on a 5-point Likert scale, ranging from “not at all” to “a very 
great deal” for symptom severity items and “none of the time” to “all of the time” for the 
HRQoL items.  
Symptom Severity, Activities, Revised Activities, HRQoL subscale scores and revised 
HRQoL scores are summed respectively and transformed into a 0-100-point scale each. The 
Symptom Severity scale and the HRQoL subscale scores are inversely related with higher 
Symptom Severity scores indicating greater symptoms while higher HRQoL subscale scores 
indicate better HRQoL.  
Details can be found in Appendix 4. 
For each subscale (including the symptom severity scale), raw scores and transformed scores 
will be summarized using descriptive statistics within treatment group by visit (Visit 3, Visit 
5, EoT visit and FUP visit), as well as the absolute change from baseline. The time course for 
each subscale (raw scores and transformed scores) by visit and by treatment group will be 
shown using line plots depicting the mean ± standard deviation. 
 


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Change in CGI-I scores compared to baseline  
The Clinical Global Impression (CGI-I) is a widely used single item questionnaire which asks 
the investigator to describe the subject’s overall severity of uterine fibroids symptoms. The 
verbal response options for CGI-I are: 
• None 
• Very mild 
• Mild 
• Moderate 
• Severe 
• Very severe 
Each item will be summarized by a frequency table with the number of observations and 
percentage for each treatment group. CGI-I is recorded at Visit 3 (baseline), EoT visit and 
FUP visit. CGI-I assessments will be shown by visit. Graphical displays of scores at the three 
visits will also be provided. 
The change from baseline to EoT visit and FUP visit, respectively, will be analyzed using 
shift tables.  
 
 
Variables related to laboratory parameters 
6.2.3.7
Intervals C will be used for the following assessments: 
• Change from baseline in hemoglobin, hematocrit, and ferritin: 
Absolute change from baseline will be summarized using descriptive statistics and 
displayed by time period within treatment group. 
• Percentage of subjects with normal hemoglobin >12 g/dL and normal hematocrit 
>36% : 
Frequency tables with number of observations and percentage will be displayed by 
time period within treatment group. 
If multiple measurements for a patient are available for any of the parameters during a time 
period, the smallest value is used in the analysis, as specified in Appendix 5. 
 
6.2.4 
Subgroup analyses 
Descriptive statistics for the primary and the first three secondary efficacy variables will be 
reported separately for each region/country (the US, Japan, other countries), race and ethnicity 
for the FAS population. 
 
6.3 
Pharmacokinetics/pharmacodynamics 
The planned analysis of pharmacokinetic and pharmacodynamics data will be described in a 
separate M&S Analysis Plan and results will be reported in a separate M&S Report. 
 


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6.4 
Safety 
The safety variables will include the following secondary and other safety variables:  
The secondary safety variables are: 
• Endometrial histology (e. g., benign endometrium, presence or absence of hyperplasia 
or malignancy) 
• Endometrial thickness  
The other safety variables are:  
• Endometrial histology (diagnosis of Progesterone receptor modulator-associated 
changes (PAEC), individual features of PAEC)  
• Ovarian cysts (number, size)  
• Laboratory parameters 
• AEs  
• Cervical smear 
• Vital signs  
• Percentage of subjects with hemoglobin ≤10.9 g/ dL 
• Findings resulting from liver monitoring 
• Findings resulting from adrenal monitoring 
• Findings resulting from skin monitoring 
• UF-DBD bleeding pattern per 28 days and 84 days 
 
All safety analyses are descriptive, and variables will be summarized by descriptive statistics 
as appropriate. All safety analyses are done for the actual treatment (as-treated) and 
performed on the SAF.  
In contrast to the derivation of efficacy variables, even if an endometrial biopsy was 
conducted, bleeding and ‘spotting’ reported on such days will also be used when deriving 
safety variables. 
No results for the pooled treatment group A1+B2 will be presented, if not specified otherwise. 
Pregnancy test results based on ultrasound and urine pregnancy test will be reported by 
treatment group and visit. Ultrasound is performed as confirmation after positive urine 
pregnancy test. 
 
6.4.1 
Secondary safety variables 
 
Endometrial histology 
6.4.1.1
For endometrial histology evaluations (e.g., benign endometrium, presence or absence of 
hyperplasia or malignancy) the following time intervals / time points will be considered: 
• Any time point 


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• Intervals A (acc to Figure 4–1) 
• Intervals B (acc to Figure 4–1) 
• “Exit examination” intervals 
• Bleeding episode after last treatment period time windows in subjects with at least 56 
days of treatment within the treatment period (by TP1, TP2 and overall): 
o From start of the patients’ last treatment period until Day 55 of the same 
treatment period 
o From Day 56 of the same treatment period until the last day of the 1st bleeding 
episode after the treatment period 
o After 1st bleeding episode of the same treatment period, i.e., from 1st day after 
the end of the 1st bleeding episode to the last day of the 2nd bleeding episode 
o After 2nd bleeding episode of the same treatment period, i.e., from 1st day after 
the end of the 2nd bleeding episode to the last day of the 3rd bleeding episode 
o After 3rd bleeding episode of the same treatment period, i.e., from 1st day after 
the end of the 3rd bleeding episode to the last day of the 4th bleeding episode 
Analyses will present the number and percentage of either subjects or biopsies. A subgroup 
analysis by exposure group (i.e., treatment duration ≤ 90 days, 91 to 180 days, etc.) will be 
presented for endometrial biopsy main results. 
Presentations will be done for  
• the Safety read (Reader #1 or #5)  
• the Majority read (Reader #2 - #4) 
• All reads (Reader #1 - #5) 
Safety read: For the safety read only one result will be available per biopsy (based on either 
Reader #1 or #5), whereas for the “majority read” and “all reads” more than one reader result 
needs to be considered.  
Majority read: Majority read results will only be provided in case biopsy data from Readers 
#2, #3 and #4 are available. Majority read will be determined for main results and 
subcategories (see Table 6–1). First, adequacy (for part II and III) or sufficiency (for part IV) 
of tissue will be investigated by all readers. If at least 2 of the 3 readers consider the tissue 
adequate/sufficient, the majority for the main results will be assessed. If there is a majority 
with respect to the main result, majority of the respective subcategories will be determined. If 
no majority result is available (3 different results in 3 readers, 2 different results in 2 readers), 
either “no consensus” or the worst case will be presented. Table 6–1 presents an overview of 
the biopsy results including the approach which is used in case no majority is available. 
For subcategories where multiple selections are possible, an individual feature will be 
considered a majority read result if at least 2 readers have ticked this feature. That means that 
more than just one subcategory can be a majority read result for a biopsy. 
All read: All read results will be based on all biopsies with results from at least one reader.  
A biopsy is considered non-benign in case “Benign endometrium” = “No” or “Endometrial 
Hyperplasia (WHO 2014)” or “Endometrial Hyperplasia (WHO 1994)” or “Malignant 
Neoplasm” = “Yes”. 


 
St atistic al A n al ysis Pl a n  
 
 
B A Y 1 0 0 2 6 7 0 / 1 5 7 9 0  
Pa ge : 3 9  of  5 8  
 
 
M ulti ple bi o psies per ti me i nterv al/ti me p oi nt : F or t he e xit e x a mi nati o n t he last a vaila ble 
meas ure me nt will be use d if t here are se v eral meas ure me nts. F or a n y ot her ti me i nter vals / 
ti me p oi nts, t he a nal yses i n w hic h n u m bers of s u bj ects are re p orte d will be base d o n a ‘ w orst 
case a p pr oac h’. I n t his a p pr oac h, t he w orst meas ure me nt wit hi n eac h of t h e a b o ve- me nti o ne d 
ti me i nter vals / ti me p oi nts will be use d. T hese worst o utc o mes acr oss ti me i nter vals / ti me 
p oi nts are deter mi ne d f or eac h e n d p oi nt i n Ta ble  6 – 1. 
T a bl e 6 – 1 : O v er vi e w of bi o p s y e n d p oi nt s i n cl u di n g m aj orit y r e s ult h a n dli n g a n d w or st 
c a s e  
P art  
 
E n d p oi nt  
N o m aj orit y 
a v ail a bl e  
W or st c a s e 
a c r o s s ti m e 
i nt er v al s f or 
s u bj e ct -
b a s e d 
a n al y s e s  
M ai n r e s ult s  
 
I 
M ai n 
di a g n o si s  
A d e q u at e e n d o m etri al ti s s u e  
- ( n ot p o s si bl e) 
“ Y e s” 
II 
 
B e ni g n e n d o m etri u m  
E n d o m etri al H y p er pl a si a ( W H O 2 0 1 4)  
M ali g n a nt N e o pl a s m  
W or st c a s e:  
Li st i s or d er e d b y 
s e v erit y, fr o m l o w 
t o hi g h 
Li st i s or d er e d 
b y s e v erit y, 
fr o m l o w t o 
hi g h  
III 
E n d o m etri al P ol y p  
W or st c a s e: y e s  
“ Y e s” 
I V 
P A E C  Ti s s u e s uffi ci e nt f or P A E C r e a d  
- ( n ot p o s si bl e) 
“ Y e s” 
P A E C pr e s e nt  
W or st c a s e: y e s  
“ Y e s” 
S u b c at e g ori e s  
 
II 
M ai n di a g n o si s  
B e ni g n e n d o m etri u m ( s el e ct o n e)  
 Atr o p hi c  I n a cti v e  Pr olif er ati v e  Di s or d er e d 
Pr olif er ati v e  S e cr et or y i n cl u di n g pr o g e sti n a n d O C P 
eff e ct  M e n str u al  E n d o m etriti s  Ot h er, s p e cif y  
“ n o c o n s e n s u s” 
- ( will n ot b e 
pr e s e nt e d)  
E n d o m etri al H y p er pl a si a ( W H O 2 0 1 4) 
( s el e ct o n e) 
 H y p er pl a si a wit h o ut at y pi a  At y pi c al h y p er pl a si a / 
E n d o m etri oi d I ntr a e pit h eli al N e o pl a si a ( EI N)  
W or st c a s e: 
At y pi c al 
h y p er pl a si a / 
E n d o m etri oi d 
I ntr a e pit h eli al 
N e o pl a si a ( EI N)  
At y pi c al 
h y p er pl a si a / 
E n d o m etri oi d 
I ntr a e pit h eli al 
N e o pl a si a 
( EI N) 
III 
E n d o m etri al P ol y p ( s el e ct o n e)  
 Atr o p hi c  F u n cti o n al  H y p er pl a sti c  
“ n o c o n s e n s u s” 
- ( will n ot b e 
pr e s e nt e d)  
I V 
P A E C  P A E C (ti c k all t h at a p pl y)  
 Pr e -D e ci d u a A b s e nt  E xt e n si v e c y st s Pr e s e nt  
S e cr et or y C h a n g e s, E xt e n si v e  Mit o s e s (r e q uir e d, 
m a y b e r ar e)  A p o pt o si s  A b n or m al V e s s el s  
“ n o c o n s e n s u s” 
- ( will n ot b e 
pr e s e nt e d)  
 
 
E n d o metri al t hic k ness 
6. 4. 1. 2
F or t he a nal ysis of e n d o metrial t hic k ness, t he f oll o wi n g ti me i nter vals will be c o nsi dere d: 
•  I nter vals A (acc t o Fi g ur e 4 – 1 ) 
•  I nter vals C (acc t o Fi g ure 4 – 1 ) 
•  “E xit e x a mi nati o n ” i nter vals  
N u m ber of s u bjects wit h ultras o u n d perf or me d f or t he ti me i nter vals will be prese nte d  as well.  
Descri pti ve statistics f or c ha n ge fr o m baseli ne i n e n d o metrial t hic k ness will be pr o vi de d. I n 
a d diti o n, t he pr o p orti o n of s u bjects wit h e n d o metri al t hic k ness > 1 8 m m will be i n vesti gat e d. 
A s u b gr o u p a nal ysis b y e x p os ure gr o u p (i.e., treat me nt d urati o n ≤ 9 0 da ys, 9 1 t o 1 8 0 da ys, 


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etc.) will present the proportion of subjects with endometrial thickness >18 mm and cyst like 
structure either ovary > 3cm. 
The correlation between endometrial thickness and biopsy results will be studied based on 
biopsies with endometrial thickness value measured on the day of an endometrial biopsy. The 
following proportions will be compared between patients with endometrial thickness >18 mm 
and patients with endometrial thickness ≤18 mm (measured by ultrasound): 
• Proportion of biopsies with non-benign and benign results in all readers, 
• Proportion of biopsies with PAEC present and PAEC not present, 
• Proportion of biopsies with extensive cysts present and not present. 
Intervals A will be used for this analysis. 
 
6.4.2 
Other safety variables 
 
Endometrial histology (PAEC) 
6.4.2.1
The analysis of progesterone receptor modulator-associated endometrial changes (PAEC) will 
be presented together with further results of endometrial histology. A detailed description of 
the analyses can be found in Section 6.4.1.1. 
 
 
Ovarian cysts 
6.4.2.2
Ovarian cysts will be examined by ultrasound. All scheduled and unscheduled assessments 
will be considered for the analysis. Three analyses will be performed for ovarian cysts: 
• Number of subjects showing cyst like structures with largest diameter >3 cm in the 
ovary 
• Analysis of ovarian cyst episodes (see below for definition) 
• Analysis of AEs associated with ovarian cysts 
The analysis of Number of subjects with ovarian cyst like structures > 3 cm in largest 
diameter in ovary will be shown by treatment group and by time intervals. Intervals A and 
Intervals B will be considered. One table will be produced for Intervals A and one table for 
Intervals B. 
For each time interval it will be determined whether an individual subject shows cysts like 
structures with a largest diameter > 3 cm at least once during that time interval. In addition to 
the corresponding time intervals, both tables will contain the assessment for the ‘Exit 
examination’. 
Frequencies for the type of cyst like structures identified will be included in the table. Type of 
cyst like structures will be shown as recorded in the eCRF: ‘Follicle-like structure’, ‘Corpus 
luteum cyst’, ‘Endometrioma’ and ‘Other’. 
The overall assessment for both ovaries will be displayed, and information about ovary 
laterality will not be included in the table.  
If cyst like structures with diameter > 3 cm are visualized in the ovaries, unscheduled 
ultrasound examinations should be performed at least every 4 weeks to document the 
regression or outcome. An ovarian cyst episode is defined as the time period from occurrence 


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of a cyst like structure with diameter > 3 cm until its resolution. Ovarian cyst episodes will 
only take account of the occurrence of follicle-like structures and corpus luteum cysts. Two 
different definitions of “resolution” are used in the analysis: 
• The subject does not show in the same ovary (left or right) a cyst like structure of the 
same type, 
• The subject does not show in the same ovary (left or right) a cyst like structure of the 
same type with diameter > 3 cm. 
For both definitions, the date of the first observation of the cyst like structure is the start of 
the episode. The date when the cyst like structure appears for the first time as resolved 
(absence of cyst like structure or cyst like structure with diameter > 3 cm) is considered the 
end of the episode. The length of time between start and end of the episode is the duration of 
the episode. 
If the cyst resolution does not occur, then the length of time between the start of the episode 
and the last observation will be considered the cyst episode duration. 
If only the start of the episode is recorded but no follow-up has been performed, then the 
duration of the episode is unknown. 
The analysis will include cysts episodes occurring in both ovaries with no distinction of ovary 
laterality (left or right). Although the information of ovary laterality will not be displayed in 
the table, it will be critical to monitor the progression of individual cyst like structures. 
The Intervals A and B (acc to Figure 4–1) will be considered. Therefore, two sets of tables 
will be produced. Ovarian cyst episodes will be assigned to the time interval when the start of 
the episode occurs. 
Two analyses will be produced for ovarian cyst episodes: 
• Number of subjects with at least one ovarian cyst episode by time intervals.  
• Number of ovarian cyst episodes by time intervals including: i) descriptive statistics of 
ovarian cyst episode duration, ii) by categorization of the duration by 4-week 
intervals, and iii) descriptive statistics of largest diameter of the cyst like structure per 
episode and per time interval. 
Two tables will be produced for these two analyses, one for each definition of cyst episode 
resolution. 
The analysis of AEs originating from ovarian cysts will include AEs identified by the Bayer 
MedDRA query (BMQ) for ‘Benign ovarian cyst and associated complications’ [V21], which 
include the preferred terms (PTs): Haemorrhagic ovarian cyst, Ovarian cyst, Ovarian cyst 
ruptured and Ovarian cyst torsion. 
The table will show number of subjects with AEs, non-serious AEs and serious AEs (SAEs). 
For each one of these AE categories the table will include severity, whether the AE led to 
drug withdrawal (if applicable) and AE duration. In addition, SAEs will include the reason for 
being classified as serious as recorded in the eCRF. 
The analysis will be done for pre-treatment AEs, TEAEs and post-treatment AEs. Pre-
treatment and post-treatment AEs will be shown by treatment group (including pooled group 
A1+B2) only. TEAEs will be shown by treatment group for TP1, TP2 and overall, and 
additionally they will be shown by study drug. AEs with onset during a treatment period or up 
to 8 days after last study drug intake in any treatment period will be considered ‘on-


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treatment’. AEs with onset after date of last study drug intake in any treatment period + 8 
days and before the start of the next treatment period will be considered ‘off-treatment’. The 
summary table for TEAEs will be presented by overall AEs, on-treatment AEs and off-
treatment AEs. 
 
 
Laboratory parameters 
6.4.2.3
Laboratory parameters which will be descriptively analyzed are included in Appendix 5. The 
tabulation of laboratory data will follow in principle the Bayer Global Standard Tables 
catalogue (currently version 4.0 default), with the necessary modifications like for time 
interval presentation instead of visit presentation. Treatment-emergent high and low 
laboratory abnormalities will be summarized by treatment periods (TP1, TP2) and overall. 
For immunology and coagulation parameters Intervals ‘BL/Post baseline’ will be used, while 
for all other parameters Intervals C will be used (see Figure 4–1). If several laboratory 
measurements are available for a patient, depending on the laboratory parameter only either 
the smallest (if small values are considered worse for the parameter) or largest (if large values 
are considered worse) measurement within Intervals C will be used (see Appendix 5 for 
details). If both largest and smallest values are specified for a particular parameter, two 
separate analyses will be done for this parameter, one analysis using the patient’s largest 
measurement across the considered time period and another analysis using the smallest 
measurement. Both scheduled and unscheduled measurements will be considered.  
Central as well as local lab measurements are available. Descriptive statistics will be provided 
for central lab measurements. Local lab measurements will be listed.  
Values below the lower limit of quantification (LLOQ) will be set to LLOQ/2. Values above 
the upper limit of quantification (ULOQ) will be set to ULOQ. 
 
Estradiol 
Absolute values will be analyzed using descriptive statistics by treatment group using Interval 
C and Interval D (see Figure 4–1). The smallest value (i.e. “worst case”) per patient per time 
interval will be used in the analyses. 
The distribution of estradiol values by treatment group using Intervals C and D will be 
graphically depicted with boxplots. The time course will be shown using line plots depicting 
the mean and 95% confidence interval (two-sided) and using Intervals C and D as described 
above. Time intervals including data from less than 10 patients in the respective group will be 
excluded from the plots. 
For estradiol frequency tables with number and percentage of subjects with estradiol (pg/mL) 
<13, <30 will be displayed by treatment group and Intervals A and B. The subjects with at 
least one lower value based on each cut-off in any visit during that time interval will be 
counted.  
 
 
Adverse events 
6.4.2.4
All AEs will be coded by MedDRA terms (the current version at the time of analysis) and 
classified into pre-treatment AEs, treatment-emergent (TEAE) and post-treatment AEs. 


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AEs will be flagged as TEAE except for AEs for which there is clear evidence that the AE 
starts before date of first study drug intake (pre-treatment AEs) or after the date of last study 
drug intake + 60 days (post-treatment AEs).  
AEs with clear evidence of start before the date of first study drug intake are flagged as pre-
treatment AE unless the AE worsens at or after the date of first study drug intake and before 
or at the date of last study drug intake + 60 days. AEs starting before but worsening at or after 
the date of first study drug intake and before or at the date of last study drug intake + 60 days 
will be considered as two AEs, a pre-treatment AE and a TEAE. The pre-treatment AE will 
end at the date of worsening and the new TEAE will start at the date of worsening.  
Same applies in case an AE starts at or after the date of first study drug intake, but before the 
date of last study drug intake + 60 days and worsens afterwards, then e.g. leading to a TEAE 
and a post-treatment AE. 
Worsening of an AE is defined as follows: 
• 
AE intensity/grade is worsened (e.g., moderate to severe) 
• 
AE changed to a serious event 
• 
AE ends with death 
• 
AE is drug-related 
TEAEs will further be categorized into on-treatment and off-treatment events.  
TEAEs will be flagged as on-treatment except for TEAEs where there is clear evidence that 
the TEAE starts outside all on-treatment phases. Each on-treatment phase starts with the date 
of first study drug intake and ends with the date of last study drug intake during a treatment 
period plus 8 days. TEAEs with clear evidence of start outside all on-treatment phases will be 
flagged as off-treatment TEAEs unless the TEAE worsens during an on-treatment phase. 
TEAEs starting during off/on-treatment phase, but worsening during an on/off-treatment 
phase will be considered as two TEAEs, an off/on-treatment TEAE and an on/off-treatment 
TEAE. The off/on-treatment TEAE will end at the time of worsening and the on/off-treatment 
TEAE will start at the time of worsening. 
Descriptive analysis will be performed (i) by treatment group for both TP1 and TP2 combined, 
(ii) by treatment group (including pooled treatment group A1+B2) separately for each 
treatment period and (iii) by study drug for both TP1 and TP2 combined. The tabulation will 
follow in principle the Bayer Global Standard Tables catalogue (currently V 4.0), with the 
necessary modifications like for on- and off-treatment TEAEs.  
 
6.4.2.4.1 Assignment to study drug 
Depending on the TEAE onset, the AE will be assigned to a study drug. This is relevant for 
subjects with switch in study drug (i.e., treatment groups B1 and B2), as it may not be clear 
whether the TEAE is assigned to the study drug given in TP1 or to the study drug given in 
TP2.  
• AEs with an onset before the start of TP2 will be assigned to the study drug given in 
TP1.  
• AEs with an onset at or after the start of TP2 will be assigned to the study drug taken 
during TP2.  


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Consequently, AEs with an onset before start of TP2 which are ongoing during TP2 will not 
be assigned to the study drug given in TP2 unless the TEAE worsens after start of TP2. In 
case it is not clear to which study drug the AE will be assigned (for example, due to partially 
missing dates), those AEs will be assigned to vilaprisan (conservative approach). 
 
6.4.2.4.2 Classifications of adverse events 
Serious Adverse Events (SAEs) will be summarized in the same way as described for 
TEAEs. 
Non-serious AEs will be shown on a summary table by primary SOC/PT. 
Adverse events of special interest (AESI) will be identified in two different ways: 
1) The investigators will assess all AEs to determine if they are AEs of special interest 
(AESIs) and document this in the eCRF. The following AEs are included: 
a. HMB 
b. Liver disorders 
c. Endometrial disorders 
d. Skin disorders 
e. Adrenal disorders 
2) Adverse events will be categorized into AE groupings of special interest based on 
MedDRA groupings as defined within expert statement for compound vilaprisan 
(Selection of coding conditions applicable for AESIs as defined in the study protocols 
of vilaprisan phase II/III studies). 
 
 
Table 6–2: List of AESIs in current expert statement based on MedDRA Version 
22.1 (version 5.0, status 19FEB2020) 
No. 
AESI 
Grouping 
1 
HMB (especially after end of treatment): 
HMB will be documented in detail 
throughout the study  
MTG: [BMQ] Increased female genital bleeding[V8] 
2 
Liver enzymes  
SMQ: Drug related hepatic disorders - comprehensive 
search (SMQ)[V29] 
3 
Endometrial hyperplasia (all subcategories 
according to WHO 2014 (and WHO 1994) 
classification  
PT selection: 
PT:  Endometrial hyperplasia 
PT:  Biopsy endometrium abnormal 
PT:  Endometrial dysplasia 
PT:  Endometrial metaplasia 
PT:  Biopsy uterus abnormal 
4 
Endometrial thickening >18 mm  
PT selection: 
PT: Endometrial thickening  
PT: Endometrial disorder 


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Table 6–2: List of AESIs in current expert statement based on MedDRA Version 
22.1 (version 5.0, status 19FEB2020) 
No. 
AESI 
Grouping 
PT: Endometrial hypertrophy  
5  
Adrenal neoplasms, Adrenal diagnoses 
related to cortical hyperfunction and 
cortical hypofunction  
 
PBMQ: Adrenocortical gland pathology including 
tumors and related hormonal changes and conditions 
Vilaprisan (narrow scope) 
PT Addison's disease 
PT Adrenal adenoma 
PT Adrenal androgen deficiency 
PT Adrenal atrophy 
PT Adrenal calcification 
PT Adrenal cortex dysplasia 
PT Adrenal cortex necrosis 
PT Adrenal cyst 
PT Adrenal disorder 
PT Adrenal gland abscess 
PT Adrenal gland cancer 
PT Adrenal gland cancer metastatic 
PT Adrenal gland injury 
PT Adrenal gland tuberculosis 
PT Adrenal glomerular zone abnormal 
PT Adrenal haematoma 
PT Adrenal haemorrhage 
PT Adrenal insufficiency 
PT Adrenal insufficiency neonatal 
PT Adrenal mass 
PT Adrenal neoplasm 
PT Adrenal suppression 
PT Adrenal thrombosis 
PT Adrenalitis 
PT Adrenocortical carcinoma 
PT Adrenocortical insufficiency acute 
PT Adrenocortical insufficiency neonatal 
PT Adrenogenital syndrome 
PT Adrenoleukodystrophy 
PT Adrenomegaly 
PT Benign neoplasm of adrenal gland 
PT Catecholamine crisis 
PT Congenital adrenal gland hypoplasia 
PT Congenital anomaly of adrenal gland 
PT Cortisol deficiency 
PT Cushingoid 
PT Cushing's syndrome 
PT Familial glucocorticoid deficiency 
PT Glucocorticoid deficiency 
PT Haemorrhagic adrenal infarction 
PT Hyperadrenalism 
PT Hyperadrenocorticism 
PT Hyperaldosteronism 
PT Hypercorticoidism 
PT Hypoaldosteronism 
PT Metastases to adrenals 
PT Mineralocorticoid deficiency 
PT Myelolipoma 


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Table 6–2: List of AESIs in current expert statement based on MedDRA Version 
22.1 (version 5.0, status 19FEB2020) 
No. 
AESI 
Grouping 
PT Primary adrenal insufficiency 
PT Primary hyperaldosteronism 
PT Pseudohypoaldosteronism 
PT Secondary adrenocortical insufficiency 
PT Secondary aldosteronism 
PT Steroid withdrawal syndrome 
PT Triple A syndrome 
6 
Cutaneous sarcomas  
PT selection: 
PT: Dermatofibrosarcoma protuberans 
PT: Atypical fibroxanthoma 
PT: Leiomyosarcoma 
PT: Liposarcoma 
PT: Skin angiosarcoma 
PT: Kaposi´s sarcoma 
PT: Malignant fibrous histiocytoma 
PT: Soft tissue sarcoma 
 
AESIs based on investigator assessment and AESIs based on MedDRA groupings will be 
presented separately. They will be presented by AESI group (if available), MedDRA primary 
SOC and PT and study drug. Summary tables for AESIs by maximum intensity and by worst 
outcome will be produced. Furthermore, listings will be provided. 
 
 
Cervical smear 
6.4.2.5
A frequency table for cervical smears findings at screening (Visit 1), FUP visit and safety 
closeout visit will be produced by treatment group. 
 
 
Vital signs 
6.4.2.6
Vital signs (heart rate, systolic blood pressure and diastolic blood pressure, and weight) will 
be summarized by treatment group and visit, including change from baseline where 
appropriate, using descriptive statistics. Boxplot for absolute values at each visit will be 
presented by treatment group. The time course by visit and by treatment group will be shown 
using line plots depicting the mean and 95% confidence interval (two-sided). 
At the safety closeout visit the blood pressure will be measured as triplicates. The mean value 
of those will be reported in tables. 
 
 
Anemia 
6.4.2.7
Frequency presentations will be provided for moderate to severe anemia with hemoglobin 
≤10.9 g/dL. Frequency tables with number of subjects and percentage will be displayed within 
treatment group and by Intervals C. If a subject has more than one hemoglobin measurement 
within a time interval of Intervals C, the smallest value (i.e. worst) will be used.  


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A listing will be provided for subjects with abnormal values. 
 
 
Findings resulting from liver monitoring 
6.4.2.8
Hepatic safety will be evaluated based on Intervals A and BL/Post baseline. The following 
parameters will be investigated in addition to the standard lab presentations:  
• Aspartate aminotransferase (AST) (in U/L),  
• Alanine aminotransferase (ALT) (in U/L),  
• Alkaline phosphatase (AP) (in U/L),  
• Bilirubin in serum (in mg/dL).  
If a subject has more than one measurement of a parameter within the above specified time 
interval, the largest value (i.e. worst) will be used for the statistical analysis. 
Frequency tables presenting number and percentage of subjects will be presented for the 
following categorizations: 
• For ALT and AST, separately: 
o Normal (≤1×ULN); >1×ULN to <3×ULN; ≥3×ULN to <5×ULN; ≥5×ULN to 
< 8×ULN; ≥8×ULN to <10×ULN; ≥10×ULN to <20×ULN; ≥20×ULN 
o ≥ 3×ULN, ≥ 5×ULN, ≥ 8×ULN, ≥ 10×ULN, ≥ 20×ULN 
• For ALT and AST combined (if at least one of ALT and AST falls into the category): 
≥ 3×ULN, ≥ 5×ULN, ≥ 8×ULN, ≥ 10×ULN, ≥ 20×ULN 
• For bilirubin:  
o >1×ULN, >2×ULN  
o ≤1×ULN; >1×ULN to ≤2×ULN; >2×ULN 
• For AP: 
o >1.5×ULN 
o ≤1×ULN; >1×ULN to ≤1.5×ULN, >1.5×ULN 
• For combinations of ALT/AST and bilirubin: 
o >3×ULN for ALT or AST accompanied by >1.5×ULN in bilirubin (measured 
at any time point) 
o >3×ULN for ALT or AST accompanied by >2×ULN in bilirubin (measured at 
any time point) 
o ≥3×ULN of ALT or AST accompanied by ≥2×ULN of bilirubin (measured 
within 30 days afterwards) (Hy’s Law criteria). The event will be assigned to 
the time interval of the ALT/AST elevation. 
Kaplan Meier estimates for the time to ALT > 3×ULN will be derived for each considered 
time interval. If no such an increase is observed within the considered time interval, the 
observation is censored at the end date of the time interval. Tables with the number of 


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subjects under risk, cumulative number of subjects with ALT > 3×ULN, and estimated 
probability for an event including 95% confidence intervals (two-sided) will be presented per 
28 days. Furthermore, Kaplan Meier plots will be provided. 
eDISH plots (x-axis: maximum of ALT or AST, resp., within time interval; y-axis: maximum 
of total bilirubin within 30 days thereafter) and a scatter plot (x-axis: maximum ALT within 
time interval; y-axis: maximum AST within time interval) will be provided for each 
considered time interval. 
If a patient has ALT ≥ 3×ULN at any time point, a plot for her individual time course in the 
following laboratory parameters will be presented: ALT, AST, bilirubin, and AP relative to 
ULN over time. It will be indicated within the plot on which days the study drug was taken 
(i.e. start and stop of treatment periods). Furthermore, listings will be provided with results 
relative to ULN for liver-related parameters, i.e. ALT, AST, bilirubin, AP. 
 
 
Liver symptom inquiry 
6.4.2.9
Before the implementation of Integrated Clinical Study Protocol, version 5.0, investigators 
were asked to regularly inquire about symptoms that according to their medical judgement 
may indicate liver disturbance and document the result of this inquiry in the respective eCRF 
page. This data will be listed only. 
 
 
Findings resulting from adrenal monitoring 
6.4.2.10
Subjects were asked to undergo scheduled adrenal monitoring at the safety closeout visit. The 
adrenal monitoring comprises the following assessments:  
• Adrenal gland imaging 
• Laboratory testing 
• Signs and symptoms suggestive of hypercortisolism, hyperaldosteronism 
All tables generated within this adrenal monitoring section will contain the absolute number 
of subjects and percentage among subjects who performed the safety closeout visit. 
An overview table will be provided. This table includes the number and percentage of subjects 
taking part at the specific adrenal monitoring assessments. The following numbers and 
percentages of subjects will be provided in addition: 
• Subjects with abnormal result in at least one of the assessments.  
• Subjects with abnormal result for each specific assessment separately. 
• Subjects for whom an external expert recommendation was obtained. Among those, 
also the number and percentage of subjects with any findings suspicious of an adrenal 
disorder and recommendation for further handling will be provided. 
• Subjects who have seen a local specialist (including information on type of specialist). 
Details of the final diagnosis by the expert panel will be provided in another table. This table 
contains the number and percentage of subjects assessed by an expert, subjects needed expert 
panel meeting, subjects where expert panel met, and subjects with at least one diagnosis by 
the expert panel. Among those, the following numbers and percentages of subjects will be 
provided: 


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• Subjects with agreement of the diagnosis among all three experts. 
• Subjects with a specific diagnosis (multiple diagnoses are possible).  
A listing of subjects with other diagnosis (i.e. diagnosis entered by the expert panel in a text 
field) will be provided. A listing of subjects with adrenal tumor will presented as well. It 
includes diagnosis, time from last study drug until date of panel assessment and possible 
causal relationship to study drug. Cases where the three experts did not agree on a diagnosis, 
are presented in a separate listing including also the diagnosis of the local specialist. 
A third table will summarize the diagnosis by a local specialist. This table contains the 
number and percentage of subjects with at least one diagnosis by the local specialist. Among 
those, the numbers and percentages of subjects with a specific diagnosis (multiple diagnoses 
are possible) will be reported. 
A listing of subjects with other diagnosis (i.e. diagnosis entered by a local expert in a text 
field) will be provided as well as a listing of reasons if a local specialist consultation did not 
take place despite referral. 
A listing of local laboratory measurements with reference ranges will be provided (no 
descriptive analyses will be performed on those).  
A table with results of the adrenal glands imaging will be provided. This table contains the 
number and percentage of subjects who did and who did not perform adrenal imaging (and 
reasons if not performed), and who have at least one evaluable image. Among subjects having 
performed adrenal glands imaging the type of procedure (e.g. computed tomography [CT] 
scan with contrast) will be reported. The following numbers and percentages of subjects will 
be derived among subjects with at least one evaluable image: 
• Subjects with one or two evaluable lateralities.  
• Subjects with adrenal mass (if yes, in one or in both adrenal glands). 
• Subjects with specified diagnostic benign imaging features. 
• Subjects with specified indeterminate imaging features. 
Reader results where an adjudicator was needed due to discrepant diagnoses between the two 
readers will be provided in a listing.  
 
 
Findings resulting from skin monitoring 
6.4.2.11
Findings resulting from skin monitoring will be analyzed descriptively by treatment group. 
All subjects who consent for safety follow-up and attend the safety closeout visit will undergo 
a thorough skin examination by a dermatology expert. The information will be recorded on 
the eCRF assigned to the safety closeout visit. The analysis will show the number of subjects 
who consented to participate in the Safety Follow-up, how many were assessed by a 
dermatologist or other clinician, which diagnostic tests were used and the results of the 
assessment as follows: number of normal and abnormal findings; and following an abnormal 
finding which type of abnormality as recorded in the eCRF: ‘Precancerous skin lesion’, 
‘Cutaneous sarcoma’, ‘Other malignant skin tumor’ and ‘Other skin abnormality’. 
Relevant cases will be reported as AEs, potentially as an AESI (pre-cancerous and malignant 
skin lesions). Malignant skin tumors will be classified as SAEs. Narratives will be written for 
skin-related AESI and SAEs.   


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Bleeding patterns per 28 days and per 84 days based on UF-DBD 
6.4.2.12
The bleeding data recorded on the UF-DBD will be summarized using descriptive statistics in 
the SAF by treatment groups (including pooled treatment group A1+B2) using Intervals C 
and D. A reference period of 28 days will be used for most analyses, which corresponds to the 
Intervals D. When a reference period of 84 days is used, the Intervals D will be modified 
accordingly. 
The bleeding intensity will be summarized by bleeding category using frequency tables by 
reference period of 28 days and 84 days.  
The maximum bleeding intensity will be summarized using frequency tables by 28 days 
reference period.  
The number of bleeding days will be analyzed by 28 days reference period and with the 
following bleeding categories:  
• non-bleeding,  
• spotting-only,  
• bleeding (bleeding intensity of ‘mild’ or higher), 
• bleeding including spotting (bleeding intensity of ‘spotting’ or higher), 
• mild, 
• moderate, 
• severe, 
• very severe. 
An incomplete period which does not comprise 28 (or 84, respectively) days will be analyzed 
for any of the considered time periods of Intervals C. The analysis of this incomplete period is 
based on all subjects for whom the length of the considered time period is not a multiple of 28 
(or 84, respectively) days. A subject’s data from the last x < 28 (x < 84) days of the 
considered time period will be included. 
 
7. 
Document history and changes in the planned statistical analysis 
The following variables will be analyzed descriptively, even those were not listed as other 
efficacy/safety variables in the protocol: 
• Percentage change in volume of the largest fibroid from baseline (measured by 
ultrasound) 
• Percentage of subjects with a volume reduction of ≥ 25% of the largest fibroid 
compared to baseline (measured by ultrasound)  
• Uterine fibroid surgery performed during the study 
• Bleeding patterns per 28 days and per 84 days based on UF-DBD 
 
 
 


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8. 
References 
[1] Best practice document RD-SOP-1107: Recording and Evaluation of Bleeding Data. 
Version 10.0 
[2] Zivković N, Zivković K, Despot A, Paić J, Zelić A. Measuring the volume of uterine 
fibroids using 2-and 3-dimensional ultrasound and comparison with histopathology. 
Acta Clin Croat. 2012 Dec 1;51(4):579-89. 
[3] Upton GJ. Conditional independence, the Mantel-Haenszel test, and the Yates 
correction. The American Statistician. 2000 May 1;54(2):112-5. 
[4] Agresti A. Categorical data analysis. 2nd edition. Hoboken, New Jersey: John Wiley 
& Sons; 2003. 
[5] Greenland S, Robins JM. Estimation of a common effect parameter from sparse 
follow-up data. Biometrics. 1985 Mar 1:55-68. 
[6] Sato T. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics. 
1989;45(4):1323-4. 
[7] National Research Council. The prevention and treatment of missing data in clinical 
trials. Washington, DC: National Academy Press; 2010. 
[8] Carpenter J, Kenward M. Multiple imputation and its application. 1st edition, 
Chichester, UK, John Wiley & Sons; 2012. 
[9] SAS/STAT 13.1 User’s Guide. Cary, NC: SAS Institute Inc.; 2013. 5033p. 
[10] Rubin DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 1987. 
[11] Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated 
data. New York, Springer; 2003. 
[12] Spies JB, Coyne K, Guaou NG, Boyle D, Skyrnarz-Murphy K, Gonzalves SM. The 
UFS-QOL, a new disease-specific symptom and health-related quality of life 
questionnaire for leiomyomata. Obstetrics & Gynecology. 2002 Feb 1;99(2):290-300. 
 
 


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9. 
Appendices 
Appendix 1: Menstrual pictogram (MP) mapping to menstrual blood loss volume 
(in mL) 
During the study, subjects will be required to use selected types of sanitary products (pads 
and/or tampons), and to assess the intensity of their menstrual blood loss per sanitary product 
using a visual scoring system. The analysis value can be obtained from Table 9–1. 
 
Table 9–1: Mapping of the menstrual pictogram (MP) to menstrual 
blood loss 
Sanitary product 
Menstrual spot shape 
Menstrual blood loss (mL) 
always Ultra normal 
Towel pictogram a 
0.79 
 
Towel pictogram b 
1.51 
 
Towel pictogram c 
3.08 
 
Towel pictogram d 
4.64 
 
Towel pictogram e 
6.75 
 
Towel pictogram f 
11.91 
always Ultra night 
Towel pictogram a 
0.74 
 
Towel pictogram b 
2.20 
 
Towel pictogram c 
4.21 
 
Towel pictogram d 
6.84 
 
Towel pictogram e 
9.42 
 
Towel pictogram f 
15.2 
always Ultra long 
Towel pictogram a 
1.36 
 
Towel pictogram b 
1.89 
 
Towel pictogram c 
3.68 
 
Towel pictogram d 
6.12 
 
Towel pictogram e 
8.69 
 
Towel pictogram f 
13.41 
o.b. Pro Comfort light 
Tampon pictogram a 
0.16 
 
Tampon pictogram b 
0.55 
 
Tampon pictogram c 
1.19 
 
Tampon pictogram d 
2.98 
o.b. Pro Comfort regular 
Tampon pictogram a 
0.35 
 
Tampon pictogram b 
1.31 
 
Tampon pictogram c 
2.09 
 
Tampon pictogram d 
5.66 
o.b. Pro Comfort super 
Tampon pictogram a 
1.29 
 
Tampon pictogram b 
1.87 
 
Tampon pictogram c 
3.49 
 
Tampon pictogram d 
9.37 
o.b. Pro Comfort super plus 
Tampon pictogram a 
1.34 
 
Tampon pictogram b 
3.36 
 
Tampon pictogram c 
5.81 
 
Tampon pictogram d 
12.23 
Tampax light 
Tampon pictogram a 
1.24 
 
Tampon pictogram b 
1.52 
 
Tampon pictogram c 
1.73 
 
Tampon pictogram d 
3.10 
Tampax regular 
Tampon pictogram a 
0.63 
 
Tampon pictogram b 
1.58 
 
Tampon pictogram c 
2.20 
 
Tampon pictogram d 
5.62 


 
St atistic al A n al ysis Pl a n  
 
 
B A Y 1 0 0 2 6 7 0 / 1 5 7 9 0  
Pa ge : 5 4  of  5 8  
 
 
T a bl e 9 – 1 : M a p pi n g of t h e m e n str u al pi ct o gr a m ( M P) t o m e n str u al 
bl o o d l o s s  
S a nit ar y pr o d u ct  
M e n str u al s p ot s h a p e  
M e n str u al bl o o d l o s s ( m L ) 
T a m p a x s u p er  
T a m p o n pi ct o gr a m a  
1. 2 9  
 
T a m p o n pi ct o gr a m b  
2. 3 8  
 
T a m p o n pi ct o gr a m c  
4. 0 1  
 
T a m p o n pi ct o gr a m d  
7. 7 6  
T a m p a x s u p er pl u s  
T a m p o n pi ct o gr a m a  
1. 2 0  
 
T a m p o n pi ct o gr a m b  
2. 5 6  
 
T a m p o n pi ct o gr a m c  
4. 9 8  
 
T a m p o n pi ct o gr a m d  
9. 4 9  
Ot h er T a m p o n  
T a m p o n pi ct o gr a m a  
3. 5 5  
 
T a m p o n pi ct o gr a m b  
4. 3 3  
 
T a m p o n pi ct o gr a m c  
6. 2 5  
 
T a m p o n pi ct o gr a m d  
8. 3 0  
 
 
A p pe n di x 2: Ute ri ne Fi br oi d D ail y Blee di n g Di ar y ( U F- D B D)  
S u bjects will be as ke d t o rate a n y v a gi nal blee di n g i n t he past 2 4 h o urs o n a dail y basis i n t he 
e Diar y. T h e res p ecti ve q uesti o n was: “ Rate t he se verit y of a n y va gi n al blee di n g i n  t he past 2 4 
h o urs” . T he f oll o wi n g a ns wers c o ul d be s electe d i n t he e Diar y b y t he s u bj ects: 
 N o va gi n al blee di n g 
 S potti n g 
 Mil d 
 M oderate 
 S e vere 
 V ery se vere 
 
A p pe n di x 3: Ute ri ne Fi br oi d D ail y S y m pt o ms Di ar y ( U F- D S D) 
 
T a bl e 9 – 2 : Ut eri n e Fi br oi d D ail y S y m pt o m s Di ar y q u e sti o n n air e 
It e m 
R e s p o n s e s c ori n g  
1 . R at e t h e s e v erit y of a n y s w elli n g i n y o ur a b d o m e n or p el vi c ar e a i n t h e 
p a st 2 4 h o ur s  
5 p oi n t Li k ert s c al e 
2 . R at e t h e s e v erit y of a n y bl o ati n g i n y o ur a b d o m e n or p el vi c ar e a i n t h e 
p a st 2 4 h o ur s  
5 p oi n t Li k ert s c al e 
3 . H o w s e v er e w a s t h e p ai n i n y o ur a b d o m e n or p el vi c ar e a, at it s W O R S T , 
i n t h e p ast 2 4 h o ur s ?  
1 0 p oi n t s c al e 
4 . H o w s e v er e w a s t h e p ai n i n y o ur l o w er b a c k, at it s W O R S T , i n t h e p a st 
2 4 h o ur s ?  
1 0 p oi n t s c al e 
5 . H a v e y o u t a k e n a n y p ai n m e di c ati o n i n t h e p a st 2 4 h o ur s ?  
N o  
Y e s, o v er t h e c o u nt er  
Y e s, pr e s cri pti o n  
Y e s, b ot h  
 


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Categories Item 1: 
• No swelling 
• Mild 
• Moderate 
• Severe 
• Very severe 
Categories Item 2: 
• No bloating 
• Mild 
• Moderate 
• Severe 
• Very severe 
 
Appendix 4: Uterine Fibroid Symptom and Quality of Life questionnaire (UFS-
QoL) 
To calculate a symptom score for the symptom severity, a summed score based on items 1-8 is 
created. This will provide symptom scores with higher score values indicative of greater 
symptom severity or bother, and lower scores are indicative of lesser symptom severity. 
Based on the lowest possible score that can be obtained and the range of raw scores, an 
observed sum score for the symptom severity can be projected into a percentage according to 
the transformation:   
Transformed symptom severity score = ቂ
(𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 −𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 )
𝑃𝑃𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
× 100%ቃ, 
with transformed scores taking values in the range 0% to 100%.  
The lowest possible raw score for symptom severity as well as the score range is provided in 
Table 9–3. 
 
Table 9–3: Description of the UFS-QoL scoring system for assessing symptom 
severity. 
Scale 
Sum item values 
Lowest and highest 
possible raw scores 
Possible raw score 
range 
Symptom severity 
Sum scores of items 1-
8 
8, 40 
32 
 
 
Similar to the symptom severity, raw and transformed scores for the Health-Related Quality 
of Life (HRQoL) subscales can be derived. The HRQoL subscales comprise the 6 domains: 
concern, activities, energy/mood, control, self-conscious, and sexual function. The sum score 
for the HRQoL subscales can be derived based on the items 9-37 (see Table 9–4). Based on 


Statistical Analysis Plan 
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the highest possible score and the raw score range, these raw sum scores can be transformed 
to a percentage according to the transformation: 
Transformed HRQoL score = ቂ
(𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑒𝑒𝑒𝑒𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 −𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 )
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑟𝑟𝑟𝑟𝑟𝑟 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
× 100%ቃ. 
The respective highest possible raw scores and the range for each subscale is provided in 
Table 9–4. 
Note that the scale is inverted when transforming raw HRQoL scores, such that lower raw 
HRQoL scores indicate a better HRQoL, while lower transformed HRQoL scores indicate a 
worse HRQoL. 
 
Table 9–4: Description of the UFS-QoL scoring system. 
Scale 
Sum item values 
Lowest and highest 
possible raw scores 
Possible 
raw 
score 
range 
Concern 
I9+I15+I22+I28+I32 
5, 25 
20 
Activities 
I10+I11+I13+I19+I20+I27+I29 
7, 35 
28 
Energy/mood 
I12+I17+I23+I24+I25+I31+I35 
7, 35 
28 
Control 
I14+I16+I26+I30+I34 
5, 25 
20 
Self-conscious 
I18+I21+I33 
3, 15 
12 
Sexual function 
I36+I37 
2, 10 
8 
HRQoL total 
score 
Sum of 6 subscale scores 
29,145 
116 
Revised 
activities 
I11+I13+I19+I20+I27 
5, 25 
20 
Revised HRQoL 
total score 
Sum of 6 subscale scores 
(replacing activities with 
revised activities) 
27, 135 
108 
Item scores for items 9 to 37 are abbreviated with I9 to I37. 
 
To calculate the (raw) HRQoL total score, the values of the individual subscales are summed 
(note that this is not the sum of the individual items). Transformed HRQoL total scores based 
on the formula above can be obtained as well. 
For the subscale analyses, if < 50% of items of a subscale is missing, the subscale should be 
retained with the mean subscale score generated based on the non-missing items ("half item 
rule"). If ≥ 50% of the items are missing, no subscale score should be calculated, and the 
subscale score should be considered missing. If one or more subscale scores are missing, the 
HRQoL total score is not calculated. 
 
 


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Appendix 5: List of laboratory parameters 
Table 9–5: List of laboratory parameters 
Laboratory category 
Laboratory test 
In case of multiple measurements 
for a patient, which measurement 
to use 
Smallest 
Largest 
VITAMINS 
25-Hydroxyvitamin D 
X 
  
COAGULATION 
Activated Partial Thromboplastin Time 
  
X 
HORMONES 
Adrenocorticotropic Hormone 
X 
X 
GENERAL CHEMISTRY 
Alanine Aminotransferase 
  
X 
GENERAL CHEMISTRY 
Albumin 
X 
  
GENERAL CHEMISTRY 
Alkaline Phosphatase 
  
X 
IMMUNOLOGY 
Alpha-1 Antitrypsin 
  
X 
IMMUNOLOGY 
Anti Mitochondiral Antibody 
  
X 
IMMUNOLOGY 
Antinuclear Antibodies 
  
X 
GENERAL CHEMISTRY 
Aspartate Aminotransferase 
  
X 
HEMATOLOGY 
Basophils 
X 
X 
HEMATOLOGY 
Basophils/Leukocytes 
  
X 
GENERAL CHEMISTRY 
Bilirubin 
  
X 
URINALYSIS 
Bilirubin 
  
X 
URINALYSIS 
Blood 
  
X 
GENERAL CHEMISTRY 
Bone Specific Alkaline Phosphatase 
  
X 
MICROBIOLOGY 
Brucellae 
  
X 
GENERAL CHEMISTRY 
Calcium 
X 
X 
PROTEINS 
Ceruloplasmin 
  
X 
GENERAL CHEMISTRY 
Chloride 
  
X 
GENERAL CHEMISTRY 
Cholesterol 
  
X 
  
Choriogonadotropin Beta 
  
X 
HORMONES 
Choriogonadotropin Beta 
  
X 
URINALYSIS 
Choriogonadotropin Beta 
  
X 
HORMONES 
Cortisol 
X 
X 
GENERAL CHEMISTRY 
Creatine Kinase 
  
X 
GENERAL CHEMISTRY 
Creatinine 
  
X 
IMMUNOLOGY 
Cytomegalovirus DNA 
  
X 
GENERAL CHEMISTRY 
Direct Bilirubin 
  
X 
HEMATOLOGY 
Eosinophils 
  
X 
HEMATOLOGY 
Eosinophils/Leukocytes 
  
X 
IMMUNOLOGY 
Epstein-Barr Capsid IgG Antibody 
  
X 
IMMUNOLOGY 
Epstein-Barr Capsid IgM Antibody 
  
X 
IMMUNOLOGY 
Epstein-Barr Nuclear Antigen 1 IgG Ab 
  
X 
HEMATOLOGY 
Ery. Mean Corpuscular Hemoglobin 
  
X 
HEMATOLOGY 
Ery. Mean Corpuscular Volume 
X 
  
HEMATOLOGY 
Erythrocytes 
X 
  
HORMONES 
Estradiol 
X 
  
GENERAL CHEMISTRY 
Ferritin 
X 
  
HORMONES 
Follicle Stimulating Hormone 
  
X 
GENERAL CHEMISTRY 
Gamma Glutamyl Transferase 
  
X 
URINALYSIS 
Glucose 
  
X 
IMMUNOLOGY 
HCV PCR Viral Load 
  
X 
GENERAL CHEMISTRY 
HDL Cholesterol 
X 
X 
HEMATOLOGY 
Hematocrit 
X  
HEMATOLOGY 
Hemoglobin 
X 
  
GENERAL CHEMISTRY 
Hemoglobin A1C 
  
X 
IMMUNOLOGY 
Hepatitis A Virus Antibody 
  
X 
IMMUNOLOGY 
Hepatitis A Virus Antibody IgM 
  
X 
IMMUNOLOGY 
Hepatitis B Virus Core Antibody 
  
X 
IMMUNOLOGY 
Hepatitis B Virus DNA 
  
X 
IMMUNOLOGY 
Hepatitis B Virus Surface Antibody 
  
X 
IMMUNOLOGY 
Hepatitis B Virus Surface Antigen 
  
X 
IMMUNOLOGY 
Hepatitis C Virus Antibody Surface 
  
X 
IMMUNOLOGY 
Hepatitis D Virus Antibody 
  
X 
IMMUNOLOGY 
Hepatitis D Virus IgG Antibody 
  
X 
IMMUNOLOGY 
Hepatitis D Virus IgM Antibody 
  
X 
IMMUNOLOGY 
Hepatitis D Virus RNA 
  
X 
IMMUNOLOGY 
Hepatitis E Virus Antibody 
  
X 
IMMUNOLOGY 
Hepatitis E Virus IgG Antibody 
  
X 


Statistical Analysis Plan 
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Table 9–5: List of laboratory parameters 
Laboratory category 
Laboratory test 
In case of multiple measurements 
for a patient, which measurement 
to use 
Smallest 
Largest 
IMMUNOLOGY 
Hepatitis E Virus IgM Antibody 
  
X 
IMMUNOLOGY 
Hepatitis E Virus RNA 
  
X 
IMMUNOLOGY 
Herpes Simplex Virus 1 IgG Antibody 
  
X 
IMMUNOLOGY 
Herpes Simplex Virus 1 IgM Antibody 
  
X 
IMMUNOLOGY 
Immunoglobulin A 
  
X 
IMMUNOLOGY 
Immunoglobulin G 
  
X 
IMMUNOLOGY 
Immunoglobulin M 
  
X 
GENERAL CHEMISTRY 
Iron 
X 
  
URINALYSIS 
Ketones 
  
X 
GENERAL CHEMISTRY 
Lactate Dehydrogenase 
  
X 
GENERAL CHEMISTRY 
LDL Cholesterol 
  
X 
MICROBIOLOGY 
Leptospirae 
  
X 
HEMATOLOGY 
Leukocytes 
X 
  
URINALYSIS 
Leukocytes 
  
X 
HORMONES 
Luteinizing Hormone 
  
X 
HEMATOLOGY 
Lymphocytes 
X 
  
HEMATOLOGY 
Lymphocytes/Leukocytes 
  
X 
HEMATOLOGY 
Monocytes 
X 
  
HEMATOLOGY 
Monocytes/Leukocytes 
  
X 
IMMUNOLOGY 
MPO ANCA 
  
X 
HEMATOLOGY 
Neutrophils 
X 
  
HEMATOLOGY 
Neutrophils/Leukocytes 
  
X 
URINALYSIS 
Nitrite 
  
X 
GENERAL CHEMISTRY 
Osteocalcin 
  
X 
HEMATOLOGY 
Platelets 
X 
  
GENERAL CHEMISTRY 
Potassium 
X 
x 
IMMUNOLOGY 
PR3 ANCA 
  
X 
HORMONES 
Progesterone 
X 
  
HORMONES 
Prolactin 
  
X 
GENERAL CHEMISTRY 
Protein 
  
X 
URINALYSIS 
Protein 
  
X 
COAGULATION 
Prothrombin Intl. Normalized Ratio 
X 
  
COAGULATION 
Prothrombin Time 
  
X 
GENERAL CHEMISTRY 
Pseudocholinesterase 
  
X 
IMMUNOLOGY 
Smooth Muscle Antibody 
  
X 
GENERAL CHEMISTRY 
Sodium 
X 
  
HORMONES 
Testosterone 
  
X 
HORMONES 
Thyrotropin 
X 
X 
GENERAL CHEMISTRY 
Time to event 
  
X 
GENERAL CHEMISTRY 
Total Iron Binding Capacity 
  
X 
IMMUNOLOGY 
Toxoplasma gondii antibody 
  
X 
GENERAL CHEMISTRY 
Triglycerides 
  
X 
GENERAL CHEMISTRY 
Type I Collagen C-Telopeptides 
  
X 
URINALYSIS 
Urobilinogen 
  
X 
  
all parameters not otherwise specified 
  
X