Conditions: Endometriosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 215
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess safety and efficacy of BAY 1817080 compared to elagolix and placebo in women with symptomatic endometriosis. Study details include:

* Study duration: 155 up to 285 days
* Treatment duration: 84 days
* Visit frequency: 3 laboratory every 2 weeks for participants on BAY 1817080 or placebo

Detailed description:

Arms:
arm 1: Participants will receive 150 mg of BAY1817080 twice daily over a 12-week intervention period arm 2: Participants will receive 75 mg of BAY1817080 twice daily over a 12-week intervention period arm 3: Participants will receive 25 mg of BAY1817080 twice daily over a 12-week intervention period arm 4: Participants will receive 150 mg of Elagolix once daily over a 12-week intervention period arm 5: Participants will receive placebo matching BAY1817080 twice daily over a 12-week intervention period

Interventions: intervention 1: BAY1817080 intervention 2: Elagolix intervention 3: Placebo
Intervention descriptions: intervention 1: Tablet, oral administration intervention 2: Tablet, oral administration intervention 3: Tablet, oral administration

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study protocol 
Official Title: 
A randomized, double-blind, open for active comparator, parallel-
group, multicenter Phase 2b study to assess the efficacy and safety 
of three different doses of P2X3 antagonist (BAY 1817080) versus 
placebo and elagolix 150 mg in women with symptomatic 
endometriosis 
NCT Number: 
NCT04614246  
Document Date: 
27-JAN-2022 
 


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Title Page
Protocol Title: A randomized, double-blind, open for active comparator, parallel-group, 
multicenter Phase 2b study to assess the efficacy and safety of three different doses of P2X3 
antagonist (BAY 1817080) versus placebo and elagolix 150 mg in women with symptomatic 
endometriosis
Protocol Number:
20584
Protocol Version:
3.0
Amendment Number:
2
Compound Number:
BAY 1817080
Brief Title: Assess efficacy and safety of three different doses of P2X3 antagonist in women 
with symptomatic endometriosis
Study Phase:
2b
Acronym: SCHUMANN
Sponsor Name: Non-US territory: Bayer AG, US territory: Bayer HealthCare 
Pharmaceuticals Inc.
Legal Registered Address:
Non-US: Bayer AG, 51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
Regulatory Agency Identifier Number(s):
IND: 143488
EudraCT: 2020-003131-16
Amendment Date:
27JAN 2022
Medical Monitor name and contact information will be provided separately.
Name:
 
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance 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


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Document History Table
DOCUMENT HISTORY
Document
Version
Date
Amendment 2
3.0
27 JAN 2022
Amendment 1
2.0
22 JUN 2021
Local Amendment CHN-1
Not applicable
11 JAN 2021
Original Protocol
1.0
25 SEP 2020
Protocol Amendment Summary of Changes Table
Amendment 2 (27 JAN 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Bayer has decided for a clinical hold with an immediate stop of treatment of this Phase 2b
study with BAY 1817080. 
Considering one confirmed and one potential case of drug-induced liver injury (DILI) in  
patients exposed to BAY 1817080 for 812 weeks of treatment during the phase 2 program in 
all indications, the benefit-risk ratio for the ongoing study 20584 is no longer considered to be 
positive.
No new patients should be enrolled into the study and no study participants should be 
randomized.
Study participants who are currently treated should immediately stop treatment and
participants who have been randomized should not start treatment with the study drug, 
respectively. Study participants randomized to the open label elagolix arm can continue taking 
tablets from the current blister but must not start with a new one. 
All participants should come to the end of treatment and follow up visits as soon as possible.
Following are the description of change and a brief rationale.
Section # and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Activities (SoA)
Section 1.2 Schema
Section 4.1 Overall Design
Visits 5a and 6a were added 
for additional safety 
laboratory tests. All 
participants, except those 
randomized to elagolix, will 
have a 90-day follow up
Comprehensive safety follow up of 
study participants exposed to 
BAY1817080
Section 2.3.1 Risk 
Assessment
Text on potential changes in 
liver function laboratory 
parameters updated
Updated benefit/risk assessment
Section 2.3.3 Overall 
Benefit-Risk Conclusion
Text updated to reflect the 
updated benefit/risk 
assessment
Updated benefit/risk assessment
Section 8.3.7 Adverse 
Events of Special Interest
Section 10.6.2 Close 
observation of participants 
with ALT or AST > 3 x ULN
Abnormal laboratory results 
meeting the criteria of 
transaminases (ALT and/or 
AST) >8x ULN or >3x ULN 
with total bilirubin >2x ULN 
will be reported as adverse 
Comprehensive safety follow up of 
exposed study participants 


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events of special interest.
Section 10.2 Appendix 2 
Clinical Laboratory tests
Measurement of total bile 
acids was added to the 
biochemistry laboratory 
parameters.
Comprehensive safety follow up of 
exposed study participants
Section 10.6.2 Close 
observation of participants 
with ALT or AST > 3 x ULN
Liver imaging was added to 
the close observation 
assessments, and HCV-RNA 
was added to the parameters 
for samples to be analyzed 
for initial close liver 
observation.
Comprehensive safety follow up of 
exposed study participants 


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Table of Contents
Title Page................................................................................................................................... 1
Document History Table.......................................................................................................... 2
Protocol Amendment Summary of Changes Table............................................................... 2
Table of Contents ..................................................................................................................... 4
Table of Tables ......................................................................................................................... 7
Table of Figures........................................................................................................................ 7
1.
Protocol Summary ............................................................................................................ 8
1.1
Synopsis........................................................................................................................... 8
1.2
Schema........................................................................................................................... 10
1.3
Schedule of Activities (SoA) ......................................................................................... 11
2.
Introduction..................................................................................................................... 18
2.1
Study Rationale.............................................................................................................. 18
2.2
Background.................................................................................................................... 18
2.2.1
Endometriosis............................................................................................................. 18
2.2.2
BAY 1817080............................................................................................................. 19
2.3
Benefit/Risk Assessment ............................................................................................... 19
2.3.1
Risk Assessment......................................................................................................... 20
2.3.2
Benefit Assessment .................................................................................................... 26
2.3.3
Overall Benefit-Risk Conclusion ............................................................................... 26
3.
Objectives, Endpoints and Estimands........................................................................... 27
4.
Study Design .................................................................................................................... 29
4.1
Overall Design ............................................................................................................... 29
4.2
Scientific Rationale for Study Design ........................................................................... 31
4.3
Justification for Dose..................................................................................................... 33
4.4
End of Study Definition................................................................................................. 36
5.
Study Population............................................................................................................. 36
5.1
Inclusion Criteria ........................................................................................................... 36
5.2
Exclusion Criteria .......................................................................................................... 37
5.3
Lifestyle Considerations ................................................................................................ 40
5.4
Screen Failures............................................................................................................... 40
5.5
Criteria for Temporarily Delaying Enrollment.............................................................. 41
6.
Study Intervention(s) and Concomitant Therapy........................................................ 41
6.1
Study Intervention(s) Administered............................................................................... 41
6.2
Preparation/Handling/Storage/Accountability............................................................... 42
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 43
6.4
Study Intervention Compliance ..................................................................................... 44
6.5
Dose Modification ......................................................................................................... 45
6.6
Continued access to Study Intervention after the End of the Study .............................. 45
6.7
Treatment of Overdose .................................................................................................. 45
6.8
Concomitant Therapy .................................................................................................... 45
6.8.1
Standardized Rescue Pain Medication ....................................................................... 46
6.8.2
Prohibited Medications............................................................................................... 46
6.8.2.1
Pain Medication other than permitted standardized rescue medication.................. 46


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6.8.2.2
Hormonal Medications............................................................................................ 47
6.8.2.3
Medication Prohibited Due to Potential Drug-Drug Interaction............................. 48
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 49
7.1
Discontinuation of Study Intervention........................................................................... 49
7.1.1
Rechallenge ................................................................................................................ 49
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 49
7.3
Lost to Follow Up.......................................................................................................... 50
8.
Study Assessments and Procedures............................................................................... 51
8.1
Efficacy Assessments .................................................................................................... 51
8.1.1
Patient-Reported Outcomes (PROs)........................................................................... 51
8.1.1.1
Endometriosis Symptom Diary (ESD).................................................................... 52
8.1.1.2
Endometriosis Impact Scale (EIS) .......................................................................... 53
8.1.1.3
Visual Analogue Scale (VAS) for Pelvic Pain........................................................ 53
8.1.1.4
Patient Global Impression of Severity (PGI-S) and Change (PGI-C)..................... 54
8.1.1.5
PainDETECT .......................................................................................................... 54
8.1.1.6
EuroQoL 5-dimension 5-level (EQ-5D-5L)............................................................ 55
8.1.1.7
Modified Work Productivity and Activity Impairment questionnaire (mWPAI)... 55
8.1.1.8
Pain Catastrophizing Scale (PCS)........................................................................... 55
8.1.1.9
Additional daily symptom items ............................................................................. 56
8.2
Safety Assessments........................................................................................................ 56
8.2.1
Physical and Gynecological Examinations ................................................................ 56
8.2.2
Vital Signs .................................................................................................................. 56
8.2.3
Ultrasound .................................................................................................................. 56
8.2.4
Cervical cytology........................................................................................................ 57
8.2.5
Clinical Safety Laboratory Assessments .................................................................... 57
8.2.6
Pregnancy Testing ...................................................................................................... 58
8.2.7
Suicidal Ideation and Behavior Risk Monitoring....................................................... 58
8.3
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting.. 58
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 58
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 59
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 59
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 59
8.3.5
Pregnancy ................................................................................................................... 59
8.3.6
Taste Related AEs ...................................................................................................... 60
8.3.7
Adverse Events of Special Interest............................................................................. 60
8.4
Pharmacokinetics........................................................................................................... 60
8.5
Genetics ......................................................................................................................... 62
8.6
Biomarkers..................................................................................................................... 62
8.6.1
Biomarkers Monitoring Disease Activity................................................................... 62
8.6.2
Biomarkers Related to Ovarian Activity.................................................................... 63
8.6.2.1
Bleeding Pattern ...................................................................................................... 63
8.6.2.2
Diameter of Ovarian Follicles................................................................................. 63
8.6.2.3
Serum Progesterone................................................................................................. 64
8.6.3
Sleep Quality and Activity Measurement................................................................... 64
8.6.4
Other Biomarkers ....................................................................................................... 64
8.7
Immunogenicity Assessments........................................................................................ 64
8.8
Health Economics.......................................................................................................... 64


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9.
Statistical Considerations ............................................................................................... 65
9.1
Statistical Hypotheses.................................................................................................... 65
9.2
Sample Size Determination ........................................................................................... 65
9.3
Analysis Sets.................................................................................................................. 66
9.4
Statistical Analyses........................................................................................................ 67
9.4.1
General Considerations............................................................................................... 67
9.4.2
Primary Endpoint(s) ................................................................................................... 68
9.4.3
Secondary Endpoint(s) ............................................................................................... 69
9.4.4
Other Endpoints.......................................................................................................... 70
9.4.5
Safety Analysis........................................................................................................... 70
9.4.6
Other Analysis............................................................................................................ 70
9.5
Interim Analysis............................................................................................................. 70
10. Supporting Documentation and Operational Considerations .................................... 70
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 70
10.1.1
Regulatory and Ethical Considerations ...................................................................... 70
10.1.2
Financial Disclosure ................................................................................................... 71
10.1.3
Informed Consent Process.......................................................................................... 71
10.1.4
Data Protection ........................................................................................................... 72
10.1.5
Committees Structure ................................................................................................. 72
10.1.6
Dissemination of Clinical Study Data ........................................................................ 72
10.1.7
Data Quality Assurance.............................................................................................. 73
10.1.8
Source Documents...................................................................................................... 73
10.1.9
Study and Site Start and Closure................................................................................ 74
10.1.10 Publication Policy....................................................................................................... 74
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 75
10.3
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 78
10.3.1
Definition of AE......................................................................................................... 78
10.3.2
Definition of SAE....................................................................................................... 79
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 80
10.3.4
Reporting of SAEs...................................................................................................... 83
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 84
10.5
Appendix 5: Genetics..................................................................................................... 85
10.6
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments................. 85
10.6.1
Liver safety -related monitoring and discontinuation criteria .................................... 86
10.6.2
Close observation of participants with ALT or AST ＞3 x ULN ............................ 86
10.7
Appendix 7: Examples of Most Common Medication Regarded as Strong CYP3A4 
Inhibitors or Inducers..................................................................................................... 89
10.8
Appendix 8: Actigraphy Substudy................................................................................. 90
10.9
Appendix 9: Country-specific Requirements ................................................................ 91
10.9.1
Japan........................................................................................................................... 91
10.9.2
China........................................................................................................................... 92
10.10 Appendix 10: Abbreviations.......................................................................................... 93
10.11 Appendix 11: Protocol Amendment History ................................................................. 96
10.11.1 Amendment 1 ............................................................................................................. 96
11. References ........................................................................................................................ 97


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Table of Tables
Table 6–1: Study interventions administered........................................................................... 41
Table 6–2: Discontinuation of Hormonal Medications............................................................ 47
Table 9–1: Definition of the analysis sets. ............................................................................... 67
Table 9–2: Parameters of the dose-response-curves in the candidate set. ............................... 68
Table 10–1: Protocol-Required Safety Laboratory tests.......................................................... 76
Table 10–2: Liver Safety-Related Monitoring and Discontinuation Criteria .......................... 86
Table 10–3: Samples during close observation for liver safety ............................................... 87
Table 10–4: Cytochrome P450 (CYP) 3A4: List of most common prohibited concomitant 
medication ............................................................................................................. 89
Table 10–5: Cytochrome P450 (CYP) 3A4: List of most common allowed concomitant 
medication ............................................................................................................. 90
Table of Figures
Figure 4–1: Model-Based Predicted Average Concentrations After Administration of 25 mg, 
75 mg and 150 mg BID of BAY 1817080 Formulation B.................................... 35
Figure 9–1: Candidate set of dose-response-curves................................................................. 69


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1.
Protocol Summary
1.1
Synopsis
Protocol Title:
A randomized, double-blind, open for active comparator, parallel-
group, multicenter Phase 2b study to assess the efficacy and safety of three different doses of 
P2X3 antagonist (BAY 1817080) versus placebo and elagolix 150 mg in women with 
symptomatic endometriosis
Brief Title:
Assess efficacy and safety of three different doses of P2X3 antagonist 
in women with symptomatic endometriosis
Rationale:
This study is designed to investigate effects of three different doses of 
BAY 1817080, i.e., 150 mg, 75 mg and 25 mg, twice daily on endometriosis-associated pelvic 
pain over a 12-week intervention period in comparison to placebo and elagolix 150 mg once 
daily.
Objectives and Endpoints and/or estimands:
Objectives
Endpoints
Primary

To assess the dose-response 
relationship and demonstrate efficacy of 
BAY 1817080 compared to placebo in 
women with symptomatic endometriosis 

Absolute change in mean worst EAPP 
from baseline to end of intervention 
(measured daily on the NRS by item 1 of 
the ESD)
Secondary

To identify at least 1 superior effective 
dose of BAY 1817080 compared to 
placebo

Absolute change in mean worst EAPP 
from baseline to end of intervention 
(measured daily on the NRS by item 1 of 
the ESD)

To evaluate the safety and tolerability of 
3 doses of BAY 1817080 compared to 
placebo and elagolix 150mg in women 
with symptomatic endometriosis

Number of participants with treatment 
emergent adverse events
Overall Design:
This is a parallel-group intervention study in endometriosis patients with 5 treatment groups, 
including a double-blinded placebo treatment group and an open-label active comparator 
treatment group.
Participants who fulfill all eligibility criteria will be randomized to receive:

BAY 1817080 (150 mg, 75 mg, or 25 mg BID) OR 

elagolix (150 mg QD), OR 

placebo
Brief Summary:
The purpose of this study is to assess safety and efficacy of BAY 1817080 compared to 
elagolix and placebo in women with symptomatic endometriosis. Study details include:

Study duration: 155 up to 285 days

Treatment duration: 84 days


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
Visit frequency: approximately once a month
Study interventions will not be available through an expanded access program.
Number of Participants:
Approximately 840 participants will be screened to start study intervention in about 420 
randomized participants for at least 50 participants evaluable for the primary analysis (i. e. 
included in the pPPS) per intervention group. 
Intervention Groups and Duration:
Study Periods
Duration
1.
Screening
2.
pre-intervention
3.
Intervention 
4.
Follow-up 
1.
28 to 70 days (4 to 10 weeks)
2.
approximately 8-35 days
3.
84 days (12 weeks)
4.
38 or 90 days (5-13 weeks)
Total number of participants
Total study duration
420 treated
155 to 285 days
Intervention groups: 

Group 1: 150 mg of BAY 1817080 BID

Group 2: 75 mg of BAY 1817080 BID

Group 3: 25 mg of BAY 1817080 BID

Group 4: placebo

Group 5: elagolix 150 mg QD 
Data Monitoring Committee:
no


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1.2
Schema
*Follow-up 2 will be performed in all randomized participants, except for those randomized to the open label elagolix arm. 
Follow-up 2 will extend to 90±3 days after the last administration of study intervention
In addition to visits displayed in the schema, 5 additional visits (2a, 3a, 4a, 5a and 6a) are included for taking blood samples 
for liver monitoring, see SoA for details.


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1.3
Schedule of Activities (SoA)
Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
Informed consents
Informed consent
X
Informed consent for 
genetic sampling 
(optional)
X
Can be done at either Visit 1a or 2
Informed consent for 
actigraphy (optional)
X
Baseline characteristics and medical history
Demography
X
Eye and hair color
X
Natural hair color at age 18
Collection of eye and hair color as 
recommended by the World 
Endometriosis Research 
Foundation Endometriosis 
Phenome and biobanking 
harmonization project (1)
                                                
1 At day 28 of the menstrual cycle starting at or after Visit 1a at least 24 available entries in the ESD item 1 (‘worst pain’ on the daily numerical rating scale; 24-hour recall) sum 
up to 98 or more.
2 Ultrasound and cervical smear sampling can be done on a different day from other screening procedures.


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Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
History of 
endometriosis surgery
X
Previous medical 
treatments relevant for 
endometriosis
X
Reproduction and 
menstrual history
X
Medical history and 
concurrent medical 
conditions
X
Medical occurrences that began 
before the signing the informed 
consent form 
Endometriosis or chronic pelvic 
pain diagnosed in female blood 
relatives
Diagnosis of endometriosis and confirmation of moderate to severe pelvic pain
Confirmation of 
previous endometriosis 
diagnosis
X
Ultrasound confirmation, if needed 
(for Japanese participants only)
(Section 5.1: Inclusion criterion #1 
in the category „Type of 
participant and disease 
characteristics“)
ESD eligibility check
X
Check eligibility as per Inclusion 
criteria #3 from eDiary for 
a) compliance with daily entries 
and 
b) average of pain scores


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Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
Eligibility assessment and randomization
Inclusion and exclusion 
criteria
X
X
a) A negative urine home 
pregnancy test result at V1b is 
a prerequisite for 
randomization
b) Recheck of all inclusion and 
exclusion criteria that do not 
require physical presence by 
phone at Visit 1b
Randomization
X
Randomization visit is a phone 
call during which site personnel 
inter alia informs the subject 
whether she is eligible 
IWRS
Study intervention (study drug, pharmacokinetics and biomarkers)
Study intervention 
dispensed
X
X
X
Dispensed after a negative urine 
pregnancy test result 
Start of study 
intervention
X
a) Within 8 to 15 days from the 
onset of menstruation that 
triggered Visit 2
b) The first dose to be taken at 
the study site
Study intervention 
return and 
accountability
X
X
X
Blood sample for pre-
dose PK
X
X
X
See Section 8.4 for further 
information


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Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
Blood samples post-
dose PK
X
X
X
Blood sample for BM
X
X
X
X
X
X
X
Not relevant for China. 
See Section 10.2 Parameters
Blood sample for 
genetics
X
Not relevant for China. Only 
participants who consented. Can 
be taken also on Visit 3. 
Safety-related assessments
Physical examination 
X
X
X
Height
X
Weight
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Gynecological 
examination
X
X
X
X
X
Transvaginal 
ultrasound
X
X
X
X
X
Cervical cytology
X
Not needed if normal result 
available from test conducted 
within 1 year before the Visit 1a
Confirmation of 
preferred method of 
contraception
X
X
X
X
X
X
X
Options: spermicide-coated 
condoms, copper IUD, female 
sterilization, vasectomized 
partner(s) or abstinence
Samples for safety 
laboratory assessments
X
X
X
X
X
X
X
See Section 10.2


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Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
Liver safety laboratory 
assessments
X
X
X
X
X
These visits are not to be 
performed in participants 
randomized to active control 
elagolix
Urine pregnancy test
X
X
X
X
X
X
X
X
Pregnancy test at V1b is to be 
conducted at home by the 
participant
SARS-CoV-2 virus 
antibody tests
X
X
X
To be performed at Visit 6 only if 
this is the only scheduled Follow-
up visit for a participant. For 
further information see Section 
10.2
Adverse events
X
X
X
X
X
X
X
X
Visit 5: Participants who reported 
taste-related AE(s) occurring 
during the intervention period will 
be asked additional questions 
regarding AE character 
Prior and concomitant 
medication 
X
X
X
X
X
X
X
X
Training for pain 
reporting
X
X
X
X
X
X
To be performed at Visit 6 only if 
this is not the last Follow-up visit 
for a participant.


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Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
Efficacy / patient reported outcomes assessments
ESD, check 
completeness of eDiary 
via web report 

Daily data entry with eDiary 
device. 
The site personnel will be blinded 
to Item 1 entries prior to assessing 
the ESD eligibility criteria.
Dyschezia, dysuria, 
and hot flushes

Daily data entry with eDiary 
device. 
EIS

Weekly data entry with eDiary 
device
EQ-5D-5L
X
X
X
X
X
X
X
Weekly on eDiary during the pre-
intervention period and monthly 
on eDiary during the intervention 
and follow-up.
VAS 
X
X
X
X
X
X
X
Data entry with eDiary device 
during visit.
PGI-S
X
X
X
X
X
X
X
Data entry with eDiary device 
during visit.
PGI-C
X
X
X
X
X
Data entry with eDiary device 
during visit.
mWPAI
X
X
Data entry with eDiary device 
during visit.
PSQ3
X
X
Data entry with eDiary device 
during visit.
PainDETECT 
X
X
X
X
X
Data entry during site visits with 
paper questionnaire
PCS 
X
Data entry during site visits with 
paper questionnaire


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Procedure
Screening 
Period 
Pre-
Intervention 
Period1
Intervention 
Period (Days)
Follow-up Period
Notes
28 to 70 
days
8 to 35 days
1
14
±3
28 
±3
42
±3
56 
±3
70
±3
84 
+3
14 ±3 
days 
after 
the last 
dose
38 ±3
days 
after 
the last 
dose
68 ±3 
days 
after 
the last 
dose
90 ±3 
days 
after 
the last 
dose
Visit number
1a2
(1b)
2
2a
3
3a
4
4a
5
5a
6
6a
7
Visit 5 is to be performed as the 
end of intervention visit in case of 
a premature discontinuation
Distribution and return of other study supplies
eDiary device
D
R
R
Guidance for use given. 
Actigraphy device
D
R
D
R
Only participants who consented. 
Guidance for use given.
Use of actigraphy 
device
Only participants who consented.
Standardized rescue 
medication
D
D
D
D
D
D
See Section 6.8.1
Spermicide-coated 
condoms
D
D
D
D
D
D
Guidance for use given. Re-
supply as needed.
Abbreviations: AE = adverse event; BM = biomarker; D = distribution; EIS = Endometriosis Impact Scale; eDiary = electronic diary; ESD = Endometriosis Symptom Diary; EQ-
5D-5L = EuroQoL 5-dimension 5-level; IUD = intrauterine device; IWRS = interactive web response system; MRI = magnetic resonance imaging; mWPAI = modified Work 
Productivity and Activity Impairment questionnaire; NA = not applicable; PCS = pain catastrophizing score; PGI-C = Patient’s Global Impression of Change; PGI-S = Patient’s 
Global Impression of Severity; PK = pharmacokinetic(s); R = return; VAS = visual analogue scale 


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2.
Introduction
2.1
Study Rationale
Suspected endometriosis is treated initially with combined oral contraceptives (COCs; off-
label use) or progestins mostly in combination with non-steroidal anti-inflammatory drugs. 
After failure of this initial drug treatment, the current gold standard treatment is the surgical 
ablation of the endometriotic lesions. Surgery is associated with a high recurrence rate.
Currently, there is no long-term medication available for patients in which COCs and 
progestins failed. The treatment with gonadotropin-releasing hormone (GnRH) agonist as 
second-line therapy is only approved for short term treatment (6 months), since GnRH 
agonists completely suppress hormonal production and are therefore associated with 
menopausal side-effects like bone mass loss and hot flushes. GnRH antagonists are approved
in the US at the time this protocol was written. Side effects associated with the high dose, i.e., 
200 mg twice daily, are comparable to those of GnRH agonists and therefore the duration of 
intake is also limited to 6 months. Less bone loss and hot flushes have been reported with the 
intake of the low dose, i.e., 150 mg/day and the treatment is limited to 2 years. Considering all 
available treatment modalities, recent data confirm a significant degree of unmet medical 
need, since up to 70% of treated patients have persistent symptoms like chronic pelvic pain 
that are not sufficiently managed (Bayer market research, 2009; 21,700 women in 8 
countries).
This study is designed to investigate effects of three different doses of BAY 1817080, i.e., 
150 mg, 75 mg and 25 mg, twice daily on endometriosis-associated pelvic pain over a 
12-week intervention period in comparison to placebo and elagolix 150 mg once daily. The 
study encompasses the following design elements: double-blinding, randomization, active and 
placebo-controlled parallel group design. The study will be conducted in multiple clinical 
centers across Europe, North America, China, and Japan where women with symptomatic 
endometriosis receive medical care. The sponsor reserves the right to limit a country’s 
participation in the actigraphy substudy to only certain countries. Such limitation will be 
communicated to the relevant authority at the time of submission of the study.
2.2
Background
2.2.1
Endometriosis
Endometriosis is a hormone-dependent gynecological disease characterized by painful 
symptoms like dysmenorrhea, chronic and non-cyclic pelvic pain and dyspareunia. Neither 
the etiology of endometriosis nor the precise mechanisms of the associated pelvic pain and 
infertility are completely understood. Also, there is no direct correlation between stage of 
disease, type of endometriotic lesions, and frequency and the severity of symptoms.
Pathologically the disease is defined by the presence of endometrial tissue outside the uterine 
cavity (endometriotic lesions). These endometriotic lesions undergo cyclical changes 
including bleeding and tissue remodeling and degradation. Hormonal treatments are believed 
to reduce proliferation of endometrial lesions by reducing estrogen activity. However, 
endometrial lesions also exhibit signs of inflammation. Increased concentrations of 
prostaglandins have been reported in peritoneal fluid of endometriosis patients and may be 
involved in the progression of the disease. Moreover, various processes that can lead to 


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release of ATP play an important role in the disease pathophysiology of endometriosis. 
Besides inflammation itself, mechanical stretch due to displaced tissue growth or e.g. 
peritoneal adhesions as well as movement and distension contribute to processes that lead to 
the release of ATP, which is suggested to play a dominant role in nociception and neurogenic 
inflammation (2, 3); for review see (4, 5).
2.2.2
BAY 1817080
The P2X3 receptor belongs to the P2 receptor family that is activated by purine and 
pyrimidine nucleotides and can be subdivided into ionotropic P2X receptors and metabotropic 
P2Y receptors based on their molecular properties. Among the P2X family members, in 
particular P2X3 (natural ligand ATP) has been recognized as an important mediator of 
nociception and other disorders with an over-activation of sensory nerve fibers including 
genitourinary, gastrointestinal and respiratory conditions (6-9). 
While the expression of P2X3 in sensory neurons of dorsal root ganglions has been 
extensively described, the presence in nerve fibers of endometriotic lesions has only been 
recently described (10) and was confirmed by the sponsor (See IB for further information). 
These characteristics together with the role of P2X3 in neurogenic inflammation present a 
novel disease mechanism in endometriosis that could combine a high efficacy on pain 
together with an innovative mechanism of action for disease modification.
BAY 1817080 has been identified as a human P2X3 receptor antagonist discriminating 
between the P2X3 homomer and the P2X2/3 heteromer. Secondary in vitro assays revealed a 
high functional potency on rat P2X3 and P2X2/3 receptors.  
BAY 1817080 showed robust effects on complete Freund’s adjuvant-induced pain after oral 
administration in in vivo studies in rats and mice and almost completely reversed neurogenic 
inflammation back to vehicle levels in rats, demonstrating experimentally that blocking P2X3 
addresses this mechanism.
BAY 1817080 significantly reduced dyspareunia in a rat endometriosis model. The study 
revealed a sustained effect which was still observed one week after treatment cessation.
Taken together, BAY 1817080 demonstrated robust efficacy in different in vivo and in vitro
models including effects on neurogenic inflammation with high relevance for endometriosis.
2.3
Benefit/Risk Assessment
Relevant emerging safety data, e.g., SAEs, SUSARs, and serious safety-related protocol 
deviations, will be communicated as soon as possible between the sponsor, all study sites and 
investigators and trial subjects according to the requirements of the European Medicines 
Agency guideline on strategies to identify risks for First in Human and Early Clinical trials. 
For a detailed description of the communication process see to Section 10.3.4.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of BAY 1817080 may be found in the IB, and for the comparator 
elagolix in the package insert.
BAY 1817080 is believed to carry the potential to relieve pain and improve quality of life of 
patients with endometriosis. Target engagement of BAY 1817080 has been demonstrated in a 


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Phase 2a study in patients with recurrent and/or unexplained chronic cough, i.e., efficacy was 
demonstrated in this patient population (study 18184, see the latest available version of the 
IB).
Taste-related AEs which were reported as mild and reversible upon cessation of treatment 
were assessed as an identified risk which will be monitored.
The benefit/risk ratio for BAY 1817080 is considered favorable for the planned study.
2.3.1
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention BAY 1817080
Taste-related AEs
To date, the influence of BAY 1817080 
on taste perception has been 
investigated in a limited number of study 
participants only and was reported as 
non-serious and mild. Changes were 
fully reversible after the end of treatment 
with BAY 1817080. No participants 
discontinued the treatment because of 
taste disturbances.
Study 18184 (11) was a two-part study, 
investigating safety and PK of BAY 
1817080 in healthy volunteers (Part 1) 
and safety, efficacy and PK in patients 
with refractory chronic cough (Part 2). In 
Part 1, the frequency of the taste-related 
AEs was evenly distributed between 
participants receiving active treatment 
with BAY 1817080 (3 participants; 8.6%) 
and participants receiving placebo 
(1 participant; 8.3%). In Part 2 of study 
18184, overall 10 out of 40 participants 
treated reported a taste-related AE. 
Some of the AEs lasted for two or more 
consecutive treatment intervals with 
different doses. There was a dose-
dependent frequency increase of taste-
related AEs from 5.1% of participants 
reporting the AE at the lowest dose to 
20.5% at the highest dose 
(corresponding to the 150 mg BID given 
in this trial). Taste-related AEs were 
reported by 2.5% of participants  
receiving placebo. At this stage of 
clinical development taste disturbance is 
regarded an identified risk.
In this study, the frequency of taste-
related AEs will be evaluated, including 
the assessment of how bothersome the 
AEs are perceived to be.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Antithrombin III activity 
increase
In study 18184 (11) (Part 1), ATIII 
activity increases were observed in 
healthy participants treated with 200 mg 
and 750 mg BID of BAY 1817080 . 
Effect was first observed 3 days after 
the first dose. Increase was up to ~20% 
above baseline in the 200 mg BID 
group, and up to ~30% above baseline 
in the 750 mg BID. In study 18184 (Part 
2), in patients with refractory chronic 
cough, there were similar time and 
dose-dependent increases of ATIII 
activity observed as in the healthy 
volunteers in Part 1 of the study. 
No changes in coagulation parameters 
were observed and no signs of bleeding/ 
bruising related to BAY 1817080 were 
observed in study 18184 or other 
studies, to date, with BAY 1817080. 
Furthermore, there is no established 
clinical relevance linked to increased 
ATIII activity in medical literature. 
Therefore, it is concluded that at this 
stage of development, the increase in 
ATIII activity can be considered as not 
clinically relevant.
Increased antithrombin III activity at this 
stage of development is regarded a 
potential risk.
ATIII activity will be measured in this 
study. Coagulation parameters 
prothrombin time (Quick), aPTT, 
fibrinogen, and INR will be monitored 
regularly during the study as part of 
safety laboratory assessments. Study 
participants will also be monitored for 
signs of bleeding and bruising during 
the planned physical examinations.
Potential decrease in 
heart rate and diastolic 
blood pressure
In study 18184, a decrease in DBP (4-7 
mmHg) and HR (5-11 bpm) was 
observed in the highest dose group 
(Part 1; mainly in 2-3 participants with 
high baseline values). The decrease in 
DBP and HR was not observed in 
patients with refractory chronic cough 
(Part 2). In the absence of AEs related 
to the changes in DBP and HR, such as 
dizziness or syncope, this observation 
was considered as not clinically 
significant. Decrease in HR and DBP at 
this stage of development is regarded 
as a potential risk.
HR and blood pressure will be 
monitored in this study.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Potential changes in liver 
function laboratory 
parameters
Inhibition of bile salt transport in the liver 
is linked to an increased risk of DILI. 
Eliapixant was not an inhibitor of bile 
salt transporter BSEP in an in vitro 
assay in human hepatocytes up to 
concentrations of 300 µM, although 
inhibition of BSEP in a vesicle assay 
only expressing human BSEP was 
detected.
In dogs, findings on the liver included 
elevated enzymes at the high dose 
(mainly GLDH and ALT, without relevant 
effects on total-bilirubin) in individual 
animals in the subchronic and chronic 
studies (up to 39 weeks) without an 
apparent histopathological correlate.  
No relevant increase in bile acid 
concentration was observed in the 
multiple dose escalation phase 2a study 
18184 in humans. No relevant change in 
liver related parameters was seen in 
Study 18183 and Study 18184 after 
administration of eliapixant, both in 
healthy volunteers and participants with 
chronic cough (12).
As of 16 DEC 2021, four cases of 
increased transaminases are reported in 
the ongoing phase II program (two in 
study 20393, refractory and/or 
unexplained chronic cough, one in study 
19733, overactive bladder, and one in 
study 20584, endometriosis) 
investigated by close liver observation 
as described in the FDA DILI guidance 
(13) and in this study protocol.
There has been one serious case of 
moderate hepatocellular liver injury, 
seen 4 weeks after start of treatment in 
study 20393, with the study drug as 
most likely cause. This patient was 
administered 150 mg of eliapixant (BID). 
The 
 female study participant 
reported nausea and vomiting starting 
approx.14 days after start of treatment 
with the study drug. She presented with 
ALT of 9.3-fold ULN AST of 4.6-fold 
ULN at the regular visit after four weeks 
of treatment with the study drug, after 
normal values being recorded at
screening. Treatment with study drug 
was discontinued immediately.   ALT
peaked at 19.9-fold ULN three days 
after discontinuation of study drug, AST 
reached the 14.9 fold ULN at the same 
time, serum bilirubin levels peaked at 
1.6 fold ULN. The detailed workup on 
alternative causes of this patient’s liver 
injury did not reveal a conclusive 
Liver-specific exclusion criteria and 
discontinuation rules have been 
defined. Liver function laboratory 
parameters will be assessed at 2-
weekly intervals.
Investigators and participants should 
pay special attention to non-specific
symptoms which may be associated 
with liver dysfunction, including 
anorexia, nausea, fatigue, right upper 
abdominal discomfort, vomiting, 
malaise, jaundice, fever, and rash. 
Information on these symptoms should 
be asked for in case of abnormal liver 
laboratory values (see Section 10.6.2) 
or any other suspicion of liver 
dysfunction. The study participants 
should be reminded to contact the study 
site immediately, if they are concerned 
about such symptoms and unscheduled 
liver laboratory assessments should be 
considered.
In addition, study participants will be 
instructed to limit alcohol consumption 
while participating in the study
PPD


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
alternative cause. The patient recovered 
from increase in transaminases as well 
as from nausea and vomiting, total 
bilirubin also returned to normal. There 
were two cases of mild ALT increase 
above the threshold of 3-fold ULN, one 
in the refractory and/or unexplained 
chronic cough study 20393, the other 
one in the overactive bladder study 
19733. Eight weeks after start of 
treatment, the ALT values in these 
female participants peaked at 3.9-fold 
ULN and 3.1-fold ULN, respectively. The 
patient from study 20393 received 75 
mg of eliapixant BID, the treatment 
information for the patient in the 
overactive bladder study 19733 is still 
blinded. Both participants were 
asymptomatic with regard to signs or
symptoms suggestive of liver disease. 
For both cases, transaminases started 
to decrease under ongoing treatment 
with the study drug. The patient in study 
20393 decided to stop treatment before 
the 12-week-visit and reached normal 
values during the 4-weeks follow-up 
period, approx. two months after the 
maximum ALT increase. The other 
patient recovered under treatment, 
transaminase values returned to normal 
approx. four weeks after the maximum
elevation. These two cases did not meet 
the biochemical criteria for liver injury 
according to the criteria defined by DILI 
Expert Working Group (13, 14).
The 4th case, a moderate liver injury of 
hepatocellular pattern, occurred in study 
20584. The patient complained about 
malaise about 3 weeks after start of 
treatment with the study drug. An 
increase in ALT of 7.5-fold ULN and of 
3.9-fold ULN in AST was diagnosed at
week 4 after start of treatment with 
eliapixant. Close liver observation 
revealed that this patient was positive
for Anti Hepatitis A Virus IgM at baseline
and at least until 6 weeks after start of 
treatment. However, no HAV RNA was
detected in serum at any point in time, 
and until 11 weeks after the first finding 
of anti-HAV IgM antibodies, also no anti-
HAV IgG antibodies were detected, 
what would be expected during the 
typical course of a HAV infection. The 
totality of data gathered to clarify the 
causality of this case do not support a 
recent acute infection by hepatitis A 
virus. In conclusion, the case was 
assessed as an acute hepatocellular 
liver injury of moderate severity 
considering the associated symptoms. 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
The suggestive chronology and the 
absence of clearly potential other 
causes make eliapixant the most 
probable cause. The study drug was 
stopped immediately, the transaminases
returned to normal values.
Changes in liver function values at this 
stage of development are regarded as a 
potential risk.
Reproductive toxicity
Studies on reproductive and 
developmental toxicity of BAY 1817080 
were conducted in rats and rabbits. No 
effects of BAY 1817080 on male/female 
reproduction, fertility or developmental 
toxicity have been detected with 
multiples of exposures relative to the 
anticipated human therapeutic 
exposures of about 6-fold (rats) and 0.8-
fold (rabbits).
In the absence of findings with 
BAY 1817080, the CTFG guideline (15)
recommends use of at least ‘acceptable 
effective’ methods of contraception in 
clinical trials with women of childbearing 
potential. 
For this study, barrier contraception in 
the form of spermicide-coated condoms 
(supplied by the sponsor) is considered 
to be practically the only commonly 
used and hence feasible method of 
contraception (for reasons outlined 
below). Hormonal contraception (‘highly 
effective’ methods of contraception per 
CTFG guideline (15)) would interfere 
with efficacy study endpoints.
The following methods of contraception 
are allowed in addition to barrier 
contraception (spermicide-coated 
condoms): copper IUD (placed at least 
6 months before visit 1a); total sexual 
abstinence; tubal-ligation; vasectomized 
partner.
To minimize the risk of pregnant women 
entering the intervention phase, 
intervention will only be started 
following menstruation and a negative 
urine pregnancy test, to be further 
confirmed by a serum pregnancy test. 
Urine pregnancy tests will be conducted 
at every visit after start of intervention 
(home urine pregnancy testing kits are 
centrally distributed. A pregnancy test is 
to be taken every 4 weeks).
Active Comparator Elagolix (16)
Elagolix is contraindicated in women who are pregnant, with known osteoporosis, with severe hepatic 
impairment, and with concomitant use of strong OATP 1B1 inhibitors (e.g., cyclosporine and gemfibrozil). The 
following warnings and precautions apply:
Bone loss
Bone mineral density loss is greater with 
increasing duration of use and may not 
be completely reversible after stopping 
treatment.
Specific exclusion criteria have been 
defined, i.e., women with known 
osteoporosis and a history of low-
trauma fracture are excluded. 
Change in menstrual 
bleeding pattern and 
reduced ability to 
recognize pregnancy
Reduction in the amount, intensity or 
duration of menstrual bleeding
Pregnancy testing performed in a 
regular manner
Suicidal ideation, suicidal 
behavior, and 
exacerbation of mood 
Higher incidence of depression and 
mood changes compared to placebo in 
clinical trials
Patients with new or worsening 
depression, anxiety or other mood 
changes should be referred to a mental 


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Potential Risk of 
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Summary of Data/Rationale for 
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Mitigation Strategy
disorders
health professional, as appropriate. 
Advise patients to seek immediate 
medical attention for suicidal ideation 
and behavior.
Hepatic transaminase 
elevations
In clinical trials, dose-dependent 
elevations of serum ALT at least 3 times 
the upper limit of the reference range 
occurred
Liver-specific exclusion criteria and 
discontinuation rules have been 
defined. Liver function laboratory 
parameters will be assessed at 4-week 
intervals.
Please refer to elagolix prescriber 
information for more information
Study Procedures
Participation in this study 
presents a minimal risk as 
the documented AEs
observed in prior studies 
were mild and completely 
resolved.
Frequent blood sampling (by single vein 
puncture and/or indwelling cannula) may 
be accompanied by mild pain, 
hematoma, feeling faint or dizzy, and in 
rare cases inflammation of the vessel 
wall or injury of a nerve.
Collection of a cervical smear may be 
associated with discomfort and spotting.
Participants may experience discomfort 
and pain while a transvaginal ultrasound
is performed. A transrectal ultrasound is 
in addition associated with the risk of 
bowel perforation and bleeding.
All study assessments will be carried 
out by trained clinical staff.


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2.3.2
Benefit Assessment
Administration of BAY 1817080 may be associated with the following benefits

may lead to relief of pain symptoms with long-term benefit, which is expected to be 
associated with increased quality-of-life and social functioning

may have disease modifying activity by attenuating neurogenic inflammation

may prolong the intervals between laparoscopic interventions due to the improvement 
of symptoms, thereby reducing the overall amount of surgical interventions needed

is expected to have no impact on the menstrual cycle
Hence there is a potential benefit in developing BAY 1817080 for patients with 
endometriosis. However, to date only preclinical evidence supports this notion (animal data 
demonstrated that BAY 1817080 blocks neurogenic inflammation and attenuates 
inflammatory pain). Accordingly, study 20584 is the first to assess clinical efficacy of BAY 
1817080 in patients with endometriosis.
2.3.3
Overall Benefit-Risk Conclusion
Considering one confirmed and one potential case of DILI in patients exposed to 
BAY 1817080 for 8-12 weeks of treatment during the phase 2 program in all indications, the 
benefit-risk ratio of BAY 1817080 is no longer considered to be positive.


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3.
Objectives, Endpoints and Estimands
Objectives
Endpoints
Primary

To assess the dose-response 
relationship and demonstrate efficacy of 
BAY 1817080 compared to placebo in 
women with symptomatic endometriosis 

Absolute change in mean worst EAPP 
from baseline3 to end of intervention4
(measured daily on the NRS by item 1 of 
the ESD) 
Secondary

To identify at least 1 superior effective 
dose of BAY 1817080 compared to 
placebo

Absolute change in mean worst EAPP 
from baseline3 to end of intervention4
(measured daily on the NRS by item 1 of 
the ESD)

To evaluate the safety and tolerability of 
3 doses of BAY 1817080 compared to 
placebo and elagolix 150mg in women 
with symptomatic endometriosis

Number of participants with treatment 
emergent adverse events
Other pre-specified

Assessment of efficacy of 
BAY 1817080 compared to placebo 
and elagolix 150mg in the treatment of 
EAPP at weeks 4 / 8 and end of 
intervention period

Absolute change in mean worst EAPP 
from baseline3 to the first 4 weeks/ 8 
weeks of intervention5/end of 
intervention4 (measured daily on the 
NRS by item 1 of the ESD)

Assessment of efficacy of 
BAY 1817080 compared to placebo 
and elagolix 150mg in the treatment of 
EAPP during days with vaginal bleeding 
(dysmenorrhea/menstrual pelvic pain) 
at weeks 4/ 8 and end of intervention 
period

Absolute change in mean worst EAPP
on bleeding days from baseline3 to the 
first 4 weeks/ 8 weeks of 
intervention5/end of intervention4
(measured on the NRS by item 1 and 
item 4 of the ESD)

Assessment of efficacy of BAY 
1817080 compared to placebo and 
elagolix 150mg in the treatment of 
EAPP during days without vaginal 
bleeding (‘non-menstrual pelvic pain’) at 
weeks 4 / 8 / and of intervention 
period

Absolute change in mean worst EAPP
on non-bleeding days from baseline3 to 
the first 4 weeks/ 8 weeks of 
intervention5/end of intervention4
(measured on the NRS by item 1 and 
item 4 of the ESD)

To further describe the patient 
population, efficacy profile of BAY 
1817080 and change during the study 
period using the data collected by 
patient reported outcomes (see Section 
8.1.1)

Item level, total and/or domain scores at 
screening, baseline, weeks 4/8/end of 
intervention and absolute change from  
baseline, as applicable
                                                
3 Baseline: Last 28 days before start of the intervention visit
4 End of Intervention: Last 28 days of the treatment period, Day 57 - 84 (+3)
5 28 days of the intervention period: Day 1-28 / 29-56, respectively


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Objectives
Endpoints

To assess sustainability of treatment 
effect and recurrence of symptoms

Absolute change in mean worst EAPP
(overall, during and outside days with 
vaginal bleeding) from end of 
intervention4 to non-overlapping, 
consecutive 28-day intervals during 
follow-up (measured daily on the NRS by 
item 1 of the ESD)

Details of the endpoints on other 
symptoms will be described in the SAP

Other endpoints not mentioned as 
primary, secondary, biomarker or 
pharmacokinetic endpoint

Details will be described in the SAP
Other pre-specified: biomarkers

To further investigate the study 
intervention and similar compounds 
(e.g., mode-of-action-related effects, 
safety) and to further investigate 
pathomechanisms deemed relevant to 
endometriosis and associated health 
problems

Various biomarkers (e.g., diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers)

To evaluate potential associations 
between disease-associated genotypic 
information and clinical efficacy and /or 
pharmacodynamic effects

Exploration of potential differential safety 
or efficacy in the presence or absence of 
genetic polymorphisms

Support of the development of a blood-
based diagnostic test for endometriosis

Measurement of panel of blood-based 
candidate biomarkers hypothesized to be 
diagnostic for endometriosis

To examine sleep quality and activity as 
a response marker for intervention

Actigraphy (e.g. total minutes asleep, 
sleep effectiveness, sleep latency, 
awakenings) by a wrist monitoring device 
worn for up to 30 days before and during 
intervention
Other pre-specified: pharmacokinetics

To investigate pharmacokinetics of BAY 
1817080 in patients with endometriosis

Systemic exposure of BAY 1817080 via 
sparse PK sampling in patients with 
endometriosis
Primary efficacy variable
The primary efficacy variable will be the absolute change in mean worst EAPP from baseline 
(last 28 days before the first intake of study drug) to end of intervention (last 28 days ending 
with the last intake of study drug planned on Day 84 (+3)).The worst EAPP will be measured 
daily on the NRS by item 1 of the ESD. The time frame of 28 days captures a menstrual cycle 
on average.
Intercurrent events
Details on the incorporation of intercurrent events (ICEs) considered as treatment 
failure/success and as such addressed by the composite strategy will be provided in the SAP. 
These ICEs are premature discontinuation of study treatment due to a non-COVID-19-related 
AE and a premature discontinuation of study treatment due to lack of efficacy.
Increased and decreased intake of standardized rescue medication taken for EAPP will be 
addressed by the treatment policy strategy. One argument to consider standardized rescue 
medication as part of the treatment is its availability over the counter. On the other hand, a 


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higher/lower need for rescue medication is a sign of treatment failure/success that is not or 
only partly reflected in the worst EAPP. Since a novel approach is considered to apply the 
composite strategy, this strategy will be used in supplementary analyses. Earlier trials (outside 
from the US) suggest that a primary analysis using the treatment policy strategy will likely 
not be overly conservative. The observed intake of standardized rescue medication taken for 
EAPP was generally low.
Any change in intake of standardized rescue medication taken for other reasons than EAPP is 
considered as part of a general treatment. Consequently, the treatment policy strategy will be 
used. Thus, standardized rescue medication is part of the treatment attribute described below.
Premature discontinuations due to the COVID-19 pandemic, i.e. participant’s pandemic-
related inability or unwillingness to continue due to an actual COVID-19 infection, including 
related AEs, or other/administrative reasons or pandemic-related administrative reasons on 
site level, will be addressed by the hypothetical strategy. The affected participants are 
assumed to have similar outcomes to completers. Details will be provided in the SAP.
In the spirit of the hypothetical strategy, EAPP values that are missing while a confirmed 
COVID-19 infection is classified as severe AE will be considered Missing at Random and 
modelled based on participant’s EAPP observed on days with no severe COVID-19 infection.
The impact of other potential ICEs (e. g. death of any cause, including COVID-19 infection, 
pregnancy, or surgery) is expected to be negligible, even in total. If a blind review will show 
an unexpected high number, the definition of the primary estimand may be complemented in 
the SAP.
Remaining attributes of the primary estimand
The treatments will be BAY 1817080 25 mg or 75 mg or 150 mg or placebo each, plus 
standardized rescue medication taken for any reason.
The target population is defined by the inclusion/exclusion criteria described in section 5
restricted to non-Chinese participants with surgically -confirmed endometriosis.
The population-level treatment group summary is the estimated model-based group mean of
the primary variable‘s values adjusted for region (Japan vs. ROW excluding China) and 
baseline EAPP. Treatment effect will be evaluated as difference between group means.
4.
Study Design
4.1
Overall Design

Study design summary: Multicenter, randomized, placebo- and active comparator 
controlled, double blind to placebo and open-label comparator; parallel group

Intervention group: Parallel

Study duration: Maximum of 233 days (Follow-up 1: subjects with 38±3 days 
follow-up) or 285 days (Follow-up 2: subjects with 90±3 days follow-up)

Intervention duration: 84 days (+3 days)


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
Study Periods:
o
Screening
o
Pre-intervention
o
Intervention
o
Follow-up 

Diagnosis group: Endometriosis
Approximately 840 participants will be screened to start study intervention in about 420 
randomized participants for at least 50 participants evaluable for the primary analysis (i.e. 
included in the pPPS) per intervention group. The primary analysis will not include the 
participants enrolled based on visually-confirmed diagnosis, i.e. about half of the women 
randomized in Japan, nor the participants randomized in China, who are mainly included to 
generate further data using the ESD in this population. Refer to Section 9.3 for further 
information of inclusion of participants into analysis sets.
Screening period
The duration of the screening period should be kept to a minimum. Investigators are advised 
to schedule screening visit during the 2nd half of the menstrual cycle, ideally closely before 
the next menstrual bleeding, to minimize the time in the screening period. In rare cases of 
technical issues it may not be feasible to complete the screening within 70 days. In these cases 
the screening period may be extended over 70 days with prior approval from Sponsor, on case 
by case basis.
Daily ESD completion will begin from Visit 1a. The 28-day assessment period for ESD 
eligibility criteria (see Section 5.1) starts from Day 1 of the first menstrual bleeding on or 
after Visit 1a (Day 1 of the menstrual cycle is defined as the first of the 2 consecutive days 
with more than spotting). 
Randomization
Participants who fulfill all eligibility criteria will be randomized at Visit 1b in a ratio of 
1:1:1:1:1 into one of the 5 treatment groups:

Treatment group 1: 150 mg of BAY 1817080 BID

Treatment group 2: 75 mg of BAY 1817080 BID

Treatment group 3: 25 mg of BAY 1817080 BID

Treatment group 4: placebo

Treatment group 5: elagolix 150mg QD 
Participants from Japan and China will be randomized to treatment groups 1 through 4. 
The chosen stratification factors are region (China, Japan and rest of the world) and type of 
diagnosis (surgically vs clinically [for Japanese participants only]).
Pre-Intervention period
The duration of the pre- intervention period should be kept to a minimum. In rare cases it may 
not be feasible to complete the pre-intervention period within 35 days. In these cases the pre-
intervention period may be extended over 35 days with prior approval from Sponsor, on case 
by case basis.


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Double-blind Intervention Period 
The randomization and the start of intervention will take place on two different visits in order 
to supply the study drug per shipment on demand. To have a synchronized start of 
intervention with menstrual cycle, Visit 2 should be scheduled between Day 8 and Day 15 of 
the menstrual cycle. 
Intervention period for primary analyses is 84+3 days.
Follow-up Period
The follow-up period will last for at least 90 days (13 weeks) for all study participants 
randomized to blinded treatment. Participants randomized to the open label elagolix arm will 
have a follow-up period of at least 38 days (5 weeks) after the last dose of study intervention. 
Interim Analysis
Interim analyses may be performed after approximately 50% of the study participants have 
completed the 12-week intervention period in order to plan subsequent studies.
4.2
Scientific Rationale for Study Design
Study population
The study objective is to investigate whether treatment with BAY 1817080 is associated with 
relief from EAPP. Eligible participants must have been diagnosed with endometriosis and 
experience moderate to severe EAPP. Participants with mild EAPP are not included as they 
are considered to have lower medical need. In addition, potential floor effects may preclude 
identification of therapeutic effects of BAY 1817080 in participants with low pain scores.
Adolescents/ minors are excluded due to the limited clinical experience with BAY 1817080. 
No upper age limit is defined since the requirement for menstrual bleedings during the 
screening period limits the population to premenopausal women. Peri-/menopause is typically 
entered at age between 40 and 55 years. Hence elderly participants will not be included. 
Participants need to be legally able to consent themselves.
Choice of the primary variable
Participants with endometriosis report pelvic pain as a key symptom. It is commonly the 
reason for presentation to the physician. Accordingly, a primary endpoint assessing pelvic 
pain is suitable. 
Daily worst pain measurements using NRS are used to assess EAPP. Worst pain recording 
with a 24-hour recall period (ESD) has been successfully used in previous therapeutic studies 
(17, 18). The pain threshold for inclusion in this study is identical to the one used in two 
previous endometriosis studies (sum NRS score of ≥98 over 28 days (17, 18). 
In addition to the daily ESD measurements complemented by application of visual analogue 
scale, VAS (4-week recall period) will be completed, for comparison with historic data. 


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Study periods
Screening period is needed for the assessment of pain level in the absence of hormonal 
treatments (daily pain recordings, ESD). The maximum duration of the screening period is 
driven by the following consideration: 

time required for stopping use of oral contraceptives after Visit 1a

repetition of ESD eligibility assessment based on menstrual bleeding, if required 
Intervention period of 84 days was chosen to cover at least two menstrual cycles. The 
maximum intervention duration covered by animal toxicology is 90 days.
A follow-up period of at least 35 days was chosen to cover at least one menstrual cycle for 
most of the participants while also offering the possibility to assess sustainability of the 
assumed therapeutic effect of BAY 1817080. In about 50% of randomized participants the 
follow-up period is extended to 90 days to generate further data on sustainability of the 
assumed treatment effect.
Dose
See Section 4.3 for justification of the selected dose. 
Placebo control and standardized rescue medication
Placebo effects have been observed in previous endometriosis studies using patient-reported 
outcomes as endpoints. The size of the placebo effect varies across studies. While causes of 
the observed variability are not fully understood, the size of placebo effect is associated with 
expectations of participants, type of rescue medication provided and study design (e.g. larger 
effects in studies with active control than in placebo-controlled studies or inclusion/exclusion 
criteria that introduce regression towards the mean). Accordingly, a placebo-controlled design 
is considered scientifically necessary to differentiate drug effects from the natural course of 
the disease and placebo effects. 
In two studies (17, 18) with similar provision of rescue medication (ibuprofen), the rate of 
early discontinuations was in the range typically encountered in clinical trials (approximately 
20-30%). Based on the randomization ratio (see Section 4.1), it is planned that approximately 
4 of 5 participants (80%) will receive active intervention. In summary, use of a placebo 
control is considered justified and feasible.
Active comparator 
The active comparator elagolix 150mg will be provided open label as blinding was not 
possible due to technical reasons.
Blinding 
Blinding of study participants for BAY 1817080 is considered appropriate because endpoints 
based on reporting by participants and/or physicians might be influenced by the knowledge 
about the intervention received. 
Contraception
The rationale for the methods of contraception permitted during study participation is outlined 
in the benefit-risk assessment (see Section 2.3).


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4.3
Justification for Dose
This dose finding study aims to generate first evidence of efficacy of the P2X3 antagonist 
BAY 1817080. Specifically, this study is designed to investigate effects of three different 
doses of BAY 1817080, i.e., 150 mg, 75 mg and 25 mg, twice daily on endometriosis-
associated pelvic pain over a 12-week intervention period in comparison to placebo and 
elagolix 150 mg once daily. 
In this study, the doses were selected based on the following:

The selected dose should result in sufficiently high exposures that blocks the target to 
an extent, which allows to conclusively confirm or refute the hypothesis that targeting 
P2X3 translates into pain relief for patients with endometriosis and to determine the 
optimal dose to be tested in the subsequent confirmatory Phase 3 trials in this 
population.

The safety/ tolerability profile based on clinical evidence gathered to date should 
ensure participants’ safety during trial participation and reduce the risk of early 
discontinuations due to adverse events or perceived lack of efficacy.
For BAY 1817080, the above-mentioned criteria are fulfilled for the selected doses of 75 and 
150 mg BID6:

Based on current dose predictions from preclinical studies and data from the proof of 
concept study in patients with refractory and/or unexplained chronic cough (study 
18184), the lowest fully effective dose was observed at a dose of 200 mg BID with 
formulation A7. Exposures after dosing of 200 mg BID with formulation A correspond 
to exposures expected with ~75 mg BID with formulation B. In this study, formulation 
B is used.

The doses of 25 mg, 75 mg and 150 mg BID were chosen in order to allow 
investigating the full dose response on endometriosis-associated pelvic pain, i.e., 
testing one lower, partially effective dose of 25 mg and one higher, also fully effective 
dose of 150 mg BID (formulation B). The doses of 25 mg, 75 mg and 150 mg BID of 
formulation B are expected to be similar in terms of systemic exposure to the doses of 
50 mg, 200 mg and 750 mg of formulation A previously tested in Phase 2a (see Figure 
4–1).

Expected exposures after administration of 25 mg, 75 mg and 150 mg BID of BAY 
1817080 are believed to be sufficient to conclusively investigate the dose response in 
patients with symptomatic endometriosis.
                                                
6 Formulation B (formulation A is an immediate release tablet, which was used in Phase 1 studies, while 
formulation B is a solid dispersion tablet [see the latest available version of the IB for further details])
7 Clinical proof of target engagement is derived from the proof of concept study with BAY 1817080 in patients 
with refractory and/or unexplained chronic cough (study 18184; see the latest available version of the IB). For 
patients who had received the maximum technically feasible dose of 750 mg BID or the next lower dose of 200 
mg BID, awake cough counts were reduced on top of placebo by 24.4% and 26.1% , respectively.


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
In study 18184, the highest exposure (after multiple doses of 750 mg of formulation 
A) was found to be well tolerated and safe (see the latest available version of the IB 
for further details). 750 mg BID of formulation A translates into approximately 
150 mg BID of formulation B in terms of systemic exposure. Accordingly, exposures 
following administration of 25 mg, 75 mg and 150 mg BID of formulation B are 
expected to be similar to the concentrations covered in the multiple dose study 18184 
(see the latest available version of the IB and Figure 4–1 below; applies to both fasted 
and fed state).

In study 19519, a 400 mg single dose of formulation B was found to be safe. Study 
19519 assessed bioavailability after administration of single doses of formulations A 
and B of BAY 1817080 in healthy young males (see the latest available version of the 
IB).
Therefore, there are no anticipated safety concerns with the selected doses of 25 mg, 75 mg
and 150 mg BID of BAY 1817080 in study 20584. Tolerability is expected to facilitate 
completion of the study by the required number of participants and accordingly interpretation 
of study results (i.e. rate of early discontinuations within expectations).  


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Figure 4–1: Model-Based Predicted Average Concentrations After Administration of 
25 mg, 75 mg and 150 mg BID of BAY 1817080 Formulation B
A)
Model-based predicted average concentrations (including 95% confidence interval) after multiple dose 
administration (BID) of 25 mg, 75 mg and 150 mg of BAY 1817080 formulation B given fasted, in comparison to 
the geometric mean concentrations (steady-state, BID) observed in study 18184 Part 2 with 50 mg, 200 mg and 
750 mg of formulation A (black circles & black lines). 75 mg: based on 25 mg fasted model.
B)
Model-based predicted average concentrations (including 95% confidence interval) after multiple dose 
administration (BID) of 25 mg, 75 mg and 150 mg of BAY 1817080 formulation B given fed (high fat, high calorie 
meal), in comparison to the geometric mean concentrations (steady-state, BID) observed in study 18184 Part 2
with 50 mg, 200 mg and 750 mg of formulation A (black circles & black lines). 75 mg: based on 100 mg fed 
model.
Abbreviations: BID = bis in die (twice daily); HFHC = high fat, high calorie; RO = receptor occupancy


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4.4
End of Study Definition
A participant is considered to have completed the study if she has completed all phases of the 
study including the last visit (Visit 6 or Visit 7, respectively).
The primary completion is defined as the date of the end of intervention visit (Visit 5) of the 
last participant in the study globally.
The end of the study is defined as the date of the last visit of the last participant in the study 
globally.
5.
Study Population
Women with symptomatic endometriosis meeting all inclusion criteria and presenting none of 
the exclusion criteria will be eligible for randomization.
Prospective approval of protocol deviation to inclusion and exclusion criteria, also known as 
protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible only if all of the following criteria apply:
Age
1. Participant must be ≥ 18 years of age at the time of signing the informed consent
Type of Participant and Disease Characteristics
2. Visually-confirmed endometriosis: detection of endometriotic lesions during 
laparoscopy or laparotomy (with or without pathological diagnosis) within 10 years 
but no less than 8 weeks from Visit 1a (surgically diagnosed endometriosis).
For Japan only and limited to no more than half of all randomized Japanese 
participants: the diagnosis can be based on previous imaging (i.e. endometriosis 
lesion detected by ultrasound or MRI). If the participant was diagnosed by ultrasound, 
the lesion must be visualized again by ultrasound at the screening visit. If the 
participant was diagnosed by MRI, the diagnosis must have been made within 12 
months before Visit 1a (clinically diagnosed endometriosis).
3. Both sub-criteria regarding pain symptoms must be fulfilled:

At Visit 1a, participant presents self-reported moderate to severe pain 
which – based on the judgement of the investigator – carries a reasonable 
likelihood to translate into a severity of pain symptoms sufficient to fulfil 
the eligibility criterion and be caused by endometriosis, and

During the screening period at least 24 daily ESD entries during the 28
consecutive days starting on the first day with menstrual bleeding at or 
after Visit 1a and entries in the ESD item 1a (‘worst pain’ on the daily 
numerical rating scale) sum up to 98 or more.


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4. Willingness to use standardized rescue pain medications for EAPP (i.e. ibuprofen, 
acetaminophen and tramadol) and not use any prophylactic pain medication, 
according to investigator’s instruction
5. Ability to swallow the study intervention, i.e., the different kinds of tablets, as 
complete units
6. Good general health (except for findings related to endometriosis) as proven by 
medical history, physical and gynecological examinations and laboratory test results
7. Normal or clinically insignificant cervical cytology not requiring further follow-up:

A cervical cytology sample has to be obtained during screening, or 

A documented normal result has to be available from cervical cytology 
conducted within 12 months prior to Visit 1a.

Human papilloma virus (HPV) testing in participants with atypical 
squamous cells of unknown significance (ASCUS) will be used as an 
adjunctive test automatically. Participants with ASCUS can be included if 
they are negative for high-risk HPV strains.
Sex
8. Female
Contraceptive use by participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Participants must be willing to use a non-hormonal barrier method for contraception 
(spermicide-coated condoms for their partners) from screening visit until the end of 
the study. This is not required if adequate contraception is achieved by vasectomy of 
the male partner(s), female sterilization, use of copper IUD for at least 6 months or
total abstinence from heterosexual intercourse (for details refer to section 10.4).
Informed Consent
9. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol
5.2
Exclusion Criteria 
Participants are to be excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Current pregnancy or less than 3 months since delivery, abortion or stop of 
lactation before Visit 1a
2.
Hypersensitivity to any ingredient of the study intervention and/or the 
standardized rescue medications (see the latest available version of the IB for 
BAY1817080 and placebo, and the prescriber information for elagolix and the 
standardized rescue medications)
3.
Known osteoporosis


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4.
History of a low trauma fracture
5.
Contraindications for elagolix or the standardized rescue medications
6.
Current malignancy or history of cancer (exception: basal cell or squamous cell 
carcinoma of the skin) within the last 5 years prior to Visit 1a
7.
Any other disease or condition that, according to the investigator, can compromise 
the function of the body systems and could result in altered absorption, excessive 
accumulation, impaired metabolism, or altered excretion of the study intervention 
(e.g., extremely low body weight, chronic bowel diseases, Crohn’s disease and 
ulcerative colitis)
8.
Menopause or signs of menopausal transition, such as absence of regular 
menstrual cycles based on investigator’s judgment (absence of information 
regarding menstrual bleeding pattern e.g. due to long term use of hormonal 
contraception is not an exclusion criterion)
9.
Any disease or condition that may worsen during the study period according to 
the assessment and opinion of the investigator
10.
Abnormal uterine bleeding in terms of regularity or heaviness (with the exception 
of heavy menstrual bleeding that does not require treatment)
11.
Any findings that require further diagnostic procedures to avoid harm to the 
participant (e.g. ovarian tumors of uncertain origin or pelvic masses of unclear 
etiology)
12.
Any serious or unstable diseases or medical conditions, including psychiatric 
disorders, that might interfere with the conduct of the study or the interpretation of 
the result, including for example:

history of hysterectomy and/or bilateral oophorectomy

any conditions considered to contribute significantly to pelvic pain by the 
investigator, e.g. fibromyalgia, uterine fibroids, irritable bowel syndrome 
or other bowel disorders

any other underlying diseases requiring regular use of pain medication 
(e.g. migraine)

history of or current anxiety or depression unless stable with or without 
medical treatment ≥ 6 months before Visit 1a
13.
Major surgery scheduled during the study period
14.
Non-responsiveness of EAPP to earlier treatment with GnRH-agonists or GnRH-
antagonists, based on the judgement of the investigator
15.
SARS-CoV-2- positive virus RNA test within 4 weeks prior to Visit 1a reported 
by participant, regardless of whether the participant had symptoms.
16.
History of COVID-19 infection with persistent/ongoing symptoms
17.
Contact with SARS-CoV-2- positive or COVID-19 patient within the last 4 weeks 
prior to Visit 1a
Prior/Concomitant Therapy
18.
Intake of medication prohibited due to potential drug-drug interaction (see Section 
6.8.2.3, local administration is permitted).


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19.
Use of other treatments that might interfere with the conduct of the study or the 
interpretation of the results, including:

hormonal medications (see Section 6.8.2.2) 

other treatments intended for endometriosis/pelvic pain during 
participation in the study, including the use of herbal products or 
traditional Chinese medicine for symptom relief, with the exception of the 
standardized rescue pain medications.
Prior/Concurrent Clinical Study Experience
20.
Simultaneous participation in another clinical trial with investigational medicinal 
product(s). Participation in another trial 3 months prior to Visit 1a that might have 
an impact on the study objectives, at the discretion of the investigator.
21.
Previous assignment to study intervention (randomization) in this study (allowing 
previously randomized participants to be re-included into the study may lead to 
bias)
Diagnostic assessments
22.
Laboratory values outside the inclusion range (specified in the laboratory manual) 
and considered clinically relevant8.
23.
Liver safety-related exclusion criteria: 

ALT above 2 x ULN, OR

AST above 2 x ULN, OR 

Total bilirubin greater than ULN, OR

AP above 2 x ULN, OR

INR greater than ULN, OR 

Positive hepatitis B virus surface antigen, OR 

Positive hepatitis C virus antibodies and detection of mRNA (HCV-
mRNA only tested if hepatitis C virus antibodies were detected) 
24.
Severe hypertension, defined as a sitting systolic blood pressure ≥ 160 mmHg 
and/or diastolic blood pressure ≥ 100 mmHg
25.
eGFR < 30 mL/min/1.73 m2, calculated by MDRD formula. A different eGFR 
formula will be used for participants enrolled at sites in Japan in this study (See 
Section 10.9).
Other Exclusions
26.
Wish for pregnancy during the study period
27.
Close affiliation with the study site, e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the site, or sponsor’s staff)
28.
Inability to cooperate with the study procedures for any reason, e.g. language 
comprehension, or inability to get to the study site
                                                
8 Laboratory tests may be repeated once prior to Visit 1b in case it is medically justified and the investigator 
expects a non-exclusionary result, with the exception of ALT, AST, AP and hepatitis B and C related tests.


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29.
Abuse of alcohol or medicines, or use of recreational/illicit drugs, as evaluated by 
the investigator
30.
Otherwise vulnerable patients. Patients who are in custody by order of an 
authority or a court of law.
5.3
Lifestyle Considerations
Not applicable
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria and date 
of last visit.
Re-screening is allowed once only. Re-screening can be performed in the following cases:

If the inclusion/exclusion criteria preventing participant’s initial attempt to participate 
have been changed via a protocol amendment.

Screening failures may undergo re-screening within 4 weeks from first screening
(counting since Visit 1a) if the eligibility issue that caused the screening failure can be 
resolved during this period. The 4-week limit is not valid in case inclusion/exclusion
criteria have been changed via a protocol amendment

Re-screening will not be allowed in participants who failed because of any of the 
following criteria:
o
inclusion criterion “Type of Participant and Disease Characteristics” 
number 2
o
inclusion criterion “Type of Participant and Disease Characteristics” 
number 6
o
exclusion criterion “medical conditions” number 10
o
exclusion criterion “diagnostic assessments” number 23

In participants who failed to fulfill exclusion criterion “diagnostic assessments” 
number 22 it will be decided on a case by case basis whether or not a re-screening 
is allowed.
The investigator should ensure that the repeated screening procedures do not expose the 
participant to an unjustifiable health risk. 
The participant must sign a new informed consent form for re-screening, even if the content 
was not changed after the previous consenting. Re-screened participant will be assigned a new 
participant number. 


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5.5
Criteria for Temporarily Delaying Enrollment
Not applicable
6.
Study Intervention(s) and Concomitant Therapy
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
Table 6–1: Study interventions administered
Group Name
BAY 1817080
BAY 1817080 Placebo
Elagolix
Intervention 
Name
BAY 1817080
placebo for BAY 
1817080
elagolix
Type 
drug
placebo
drug
Dose 
Formulation
tablet
tablet
tablet
Unit Dose 
Strength(s)
25 mg and 100 mg
N/A
150 mg
Dosage Level(s)
25 mg, 75 mg and 150 
mg BID
N/A
150 mg QD
Route of 
Administration
oral
oral
oral
Use
experimental
placebo
active comparator
Packaging and 
Labeling
Study Intervention will 
be provided in blisters. 
Study Intervention will 
be labeled as required 
per country 
requirement
Study Intervention will be 
provided in blisters. 
Study Intervention will be 
labeled as required per 
country requirement
Study Intervention will be 
provided in blisters. 
Study Intervention will be 
labeled as required per 
country requirement
[Current/Former 
Name(s) or 
Alias(es)]
N/A
N/A
Orilissa ®

Participants will take study intervention:
o
BAY 1817080 or matching placebo twice daily (morning and evening doses) 
at approximately the same time each day 12 hours apart, OR
o
Elagolix once daily at approximately the same time each day 24 hours apart.
o
To the effect that they will receive (according to assigned treatment groups):

Treatment group 1: 2 tablets of 25 mg BAY 1817080, 1 tablet of 
100mg BAY 1817080 and one tablet of 25 mg placebo to BAY 
1817080

Treatment group 2: 3 tablets of 25 mg BAY 1817080 and one tablet of 
100mg placebo to BAY 1817080 


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
Treatment group 3: 1 tablet of 25mg BAY 1817080, 2 tablets of 25mg 
placebo to BAY 1817080 and one tablet of 100mg placebo to BAY 
1817080 

Treatment group 4: 3 tablets of placebo for 25mg, and 1 tablet of 
placebo for 100mg placebo to BAY 1817080 

Treatment group 5: One tablet of elagolix 150mg
For Treatment groups 1-4 participants will receive Placebo for BAY 1817080 due to blinding 
reasons. Participants are recommended to take the tablets at approximately the same time each 
day with or without food. 

Participants from China and Japan will only be randomized to treatment groups 1 to 4.

Study interventions are not to be broken, halved or crushed; they should be swallowed 
as a complete unit with water.

Study intervention can be taken with food or without food. See Section 8.4 for detailed 
instructions regarding recording of the drug intake and the food intake before or after 
the drug intake in relation to blood sampling for PK.

If a dose of study intervention has been missed: 
o
Treatment groups 1-4:

If ≤ 6 hours has passed since the dose was due, it should be 
taken immediately 

If > 6 hours have passed since the dose was due, the dose 
should be skipped and the next dose should be taken according 
to the regular schedule. 
o
Treatment group 5:
Instruct the participant to take the missed dose on the same day as soon as she 
remembers and then resume the regular dosing schedule. Not more than 1 
tablet should be taken each day.
6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm that study interventions have been received 
and appropriate temperature conditions, if applicable, have been maintained during 
transit. Any discrepancies are to be reported and resolved before use of the study 
intervention.
2. Only participants assigned to treatment in the study may receive study intervention,
and only authorized site personnel or delegates may supply or administer study 
intervention. All study intervention must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.
3. The investigator or the head of the institution (where applicable) is responsible for 
study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Study intervention returns, reconciliation 
and removal for destruction information will be captured in IWRS.


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4. Further guidance and information for the final disposition of unused study 
interventions are provided in Investigator Site File. 
5. Study intervention may only be dispensed to a study participant after ruling out 
pregnancy (urine pregnancy test with negative result).
6.3
Measures to Minimize Bias: Randomization and Blinding

Participants who meet all eligibility criteria will be centrally randomized by assigning 
a unique randomization number on Visit 1b using an IWRS system.

Once a randomization number has been assigned it must not be re-assigned.

The randomization number encodes the participant’s assignment to one of the five 
treatment groups of the study, according to the randomization plan.

Randomization plan is a computer-generated list produced prior to the study start by 
the sponsor or delegate, and provided to the IWRS provider. Scrambled randomization 
plan will be used in this study.

Site personnel will be trained for the use of the IWRS during the Investigator’s 
Training and/or during the Site Initiation. The instructions for the use of the IWRS 
will be provided in the Investigator Site File. 

Double-blinded and open-label study intervention will be dispensed to all randomized 
participants according to the instructions by the IWRS as summarized in the SoA.

Returned study interventions may not be re-dispensed

The blinding will be maintained by the following measures:
o
Tablets containing 25 mg of BAY 1817080 and corresponding placebo are 
identical in appearance (size, color, shape) 
o
Tablets containing 100 mg of BAY 1817080 and corresponding placebo are 
identical in appearance (size, color, shape) 
o
The route of administration, will be the same for all participants within Japan
and China and the rest of the world, respectively.
o
The study intervention packages will be labeled with a unique number, and 
assigned to a participant through the IWRS 
o
The randomization number will be unavailable for either the site personnel or
the study team until unblinding.
Unblinding

Unblinding during the study conduct can be done using the IWRS, according to the 
blind-breaking instructions.

The investigator has the responsibility for determining if unblinding of a participant’s 
study intervention assignment is warranted when knowledge of the actual treatment is 
absolutely essential for further medical management of the participant. Participant’s 
safety must always be the first consideration in making such a determination. 


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
If the investigator decides that unblinding is warranted, the investigator should contact 
the sponsor prior to unblinding unless this could delay emergency treatment of the 
participant.

If the investigator is unavailable, and a treating physician not associated with the study 
requests emergency unblinding, the emergency unblinding requests are forwarded to 
the emergency medical advice service that is available 24 hours/7 days (applying the 
same criteria for unblinding as described above, country-specific emergency contact 
information provided in the participant card).

If a participant’s intervention assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason for unblinding must be 
recorded in the source documentation and the eCRF.

For regulatory reporting purposes, sponsor’s Global Pharmacovigilance is permitted to 
unblind individual cases.

In compliance with applicable regulations, in the event of a SUSAR, the participant’s 
intervention is unblinded before reporting to the health authorities and IECs.

Participants who are unblinded to the study team and/or to the investigators may be 
withdrawn from the study intervention.

Sponsor’s bioanalytical, pharmacometrics and pharmacokinetics personnel will be 
unblinded prior to the database lock, and/or interims analyses according to the 
corresponding sponsor’s Standard Operating Procedures. Appropriate measures are 
taken to maintain blinding of the study team, e.g. data will be stored separately, and 
members of the study team will neither have access to the randomization list nor to 
individual data.
6.4
Study Intervention Compliance

Participant compliance with use of study drug intervention will be assessed based on 
accountability: 
o
Study intervention will be dispensed according to the SoA.
o
Participants are asked to return all unused study interventions and empty 
packages to the study site according to the SoA for accountability purposes.
o
Compliance will be assessed by direct questioning, and counting the number of 
returned tablets (recordings in the eDiary will not be used as a source).
o
Investigator or delegate is requested to document all dispensed and returned 
study intervention per study participant.
o
Any discrepancy between expected and actual number of tablets used/returned 
should be discussed with the study participant. Deviation(s) from the 
prescribed dosage regimen should be recorded. 

Concentration of the study intervention will be measured from the participant’s PK 
samples as summarized in the SoA.

Special attention should be paid to follow compliance at the beginning of intervention 
to ensure correct understanding of the instructions.


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6.5
Dose Modification
Not applicable in this study.
6.6
Continued access to Study Intervention after the End of the Study

Study participants will not be given further access to the study intervention 
(BAY 1817080 or the active comparator).

After end of the study, participants will receive routine medical care based on local 
medical practice. No restrictions regarding the choice of medical care apply after 
completion of the study.
6.7
Treatment of Overdose
In this study, an overdose is defined as an intentional or accidental administration of 
investigational drug, to or by a study participant, at a dose which is higher than the dose 
assigned to that individual participant according to the study protocol.
There is no known specific treatment (no antidote) for an overdose with BAY 1817080 or 
elagolix. An overdose should be treated as clinically indicated based on signs and symptoms. 
Overdose per se will not be reported as an AE and/or SAE unless it is associated with 
clinically relevant signs and/or symptoms, or an intentional overdose taken with possible 
suicidal and/or self-harming intent (see Sections 10.3.1 and 10.3.2). 
In the event of an overdose, the investigator should:

Contact the Sponsor as soon as possible.

Evaluate the participant to determine, in consultation with the Sponsor, if needed, 
whether study intervention should be interrupted.

Closely monitor the participant for any AE/SAE and laboratory abnormalities for 
at least 14 days.

Document the quantity of the excess dose as well as the duration of the overdose.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor, if needed, based on the clinical evaluation of the participant.
6.8
Concomitant Therapy
Any medications (including over-the-counter or prescription medicines, contrast media, 
vaccines), vitamins and/or herbal supplements that the participant uses during the study 
participation must be recorded along with:

Reason for use

Time of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.


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6.8.1
Standardized Rescue Pain Medication
Participants will be instructed to use standardized rescue medication only when relief of 
pelvic pain currently being experienced is required, i.e. not prophylactically.
Standardized rescue pain medication for endometriosis-associated pain will be prescribed for 
participants by the investigator and limited to ibuprofen tablets (containing 200mg or 400 mg 
ibuprofen per tablet, depending on local country regulations). In addition to ibuprofen, 
alternatively acetaminophen/paracetamol 500 mg and/or Tramadol 50 mg may be prescribed 
to participants who do not obtain sufficient relief from the study intervention and ibuprofen. 
The standardized rescue medication is considered an authorized auxiliary medicinal product 
(not an investigational medicinal product). The maximal single and daily dose and dosing 
interval should be approved by the investigator and be in line with the product prescribing 
information for that particular dosage form in that country. 
Investigators will prescribe these standardized rescue pain medications for participants at the 
time of entry into the screening phase, taking into consideration their preference and/or 
historical use of analgesics. The same rescue pain medication (type and dose preparation) 
used during the screening phase should be used as needed for rescue during the entire study.
Participants will be instructed to contact the site if an escalation (in dose, frequency or 
category) in their analgesic medication from what was last prescribed by the investigator is 
needed, so that appropriate adjustments can be made. Participants will be instructed not to 
increase their total daily dose or frequency of rescue pain medication or to escalate the 
category of analgesic used (i.e., from ibuprofen or acetaminophen to a narcotic containing 
medication) unless it is necessary, after a discussion between the participant and the 
investigator.  
Daily use of standardized rescue pain medication will be recorded by the participant in the 
hand-held device during the entire study. This will include specific dosing information of the 
permitted rescue pain medication, including dose and total number of pills/tablets within a 24-
hour period and the information whether it was taken for pain in the target area or not. Local 
pharmacy or sites have responsibility for documentation e.g., in case of recall  according to 
their local requirements. 
If the rescue pain medication is used for pain related to other conditions (e.g. headache, joint 
pain), these conditions must be recorded as AEs, and the pain medication used for their 
treatment documented as concomitant medication in the corresponding eCRFs.
6.8.2
Prohibited Medications 
6.8.2.1
Pain Medication other than permitted standardized rescue medication

Use of all other analgesics beyond the permitted rescue pain medication is discouraged 
during the study since it potentially disturbs the study outcome 

If any other pain medication is taken, for any reason (including EAPP), it must be 
recorded in the eCRF


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6.8.2.2
Hormonal Medications

Hormonal medications listed in Table 6–2 are prohibited during participation in this 
study

Participants using hormonal treatment at Visit 1a must be willing to stop this at the 
next suitable time point at or following Visit 1a as outlined in Table 6–2
Table 6–2: Discontinuation of Hormonal Medications
Hormonal medications 
before the study
Timing of stopping hormonal 
medications 
Bleeding which counts as the 1st
menstrual bleeding after Visit 1a
Cyclic combined 
contraceptives (oral, 
vaginal, or
transdermal)
Complete the current cycle ongoing 
at Visit 1a
Withdrawal bleeding which occurs at 
the end of the cycle ongoing at Visit 
1a
Short-acting progestins or 
extended regimen of COC Stop at Visit 1a
Withdrawal bleeding after stopping 
treatment
Hormone-releasing IUDs 
(Jaydess™, Kyleena™, 
Liletta™ and Mirena™) or 
subdermal implants
Not allowed during the study, users 
are only eligible if IUD/implant was 
coincidentally removed shortly 
before Visit 1a and normal menses 
have resumed before Visit 1a, and 
participant is willing to defer restart 
of IUD/implant use until after study 
participation. Removal of the 
IUD/implant for study participation 
only is not allowed.
First menstrual bleeding after Visit 1a
(as participants entering the study 
without hormonal treatment) 
GnRH-agonists or long-
acting hormonal 
contraceptive (injectables)
Not allowed during the study, users 
are only eligible if the last injection 
was administered more than one 
application interval before Visit 1a
and normal menses have resumed 
before Visit 1a. 
First menstrual bleeding after Visit 1a
(as participants entering the study 
without hormonal treatment)
GnRH-antagonists and 
progesterone receptor 
modulators
Not allowed during the study, users 
are only eligible if it has been 
stopped at least 28 days before 
Visit 1a and normal menses have
resumed before Visit 1a
First menstrual bleeding after Visit 1a
(as participants entering the study 
without hormonal treatment)
Hormonal replacement 
treatments (e.g. add-back 
therapy for menopausal 
symptoms from GnRH-
analogues)
Not allowed during the study, users 
are only eligible if it has been 
stopped 
before Visit 1a and normal menses 
have resumed before Visit 1a
First menstrual bleeding after Visit 1a
(as participants entering the study 
without hormonal treatment)
COC = combined oral contraceptive, IUD = intrauterine device, GnRH-a = Gonadotropin-releasing hormone 
agonists


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6.8.2.3
Medication Prohibited Due to Potential Drug-Drug Interaction
Strong CYP3A4 inducers and strong CYP3A4 inhibitors
The following strong CYP3A4 inducers and strong CYP3A4 inhibitors are prohibited within 
the last 4 weeks before start of study intervention and during the intervention period of this 
study:

CYP3A4 inducers: e.g. St. John's wort, rifampicin, carbamazepine, phenytoin

CYP3A4 inhibitors: e.g. itraconazole, posaconazole, voriconazole, ritonavir, 
nelfinavir or other inhibitors of human immunodeficiency virus protease, 
clarithromycin, telithromycin, nefazodone, telaprevir, boceprevir
For examples of common inducers and inhibitors of CYP3A4 see Section 10.7.
Note: ketoconazole and other triazole antifungal drugs are allowed for topical/local use 
(including vaginal application).
Strong OATP1B1 inhibitors

Strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine 
and gemfibrozil) during the intervention period of this study.
OATP1B1/1B3, BCRP and P-gp substrates
Based on preclinical data, an increase in exposure of OATP1B1/1B3, P-gp and BCRP 
substrates during co-administration of BAY 1817080 due to inhibition of those transporters 
by BAY 1817080 cannot be excluded.

Apixaban, dabigatran, edoxaban, digoxin: prohibited within the last 2 weeks prior to start 
of treatment and until 2 weeks after end of intervention period of this study.

Participants receiving a combination of BAY 1817080 and OATP1B1/1B3, BCRP and P-
gp substrates should be closely monitored for signs and symptoms of adverse events due 
to increased exposure of co-administered OATP1B1/1B3, BCRP and P-gp substrates.

Dose modification of OATP1B1/1B3, BCRP and P-gp substrates should be considered 
based on the prescriber information or such compounds should be avoided. Typical 
OATP1B1, OATP1B3, BCRP and P-gp substrates include but are not limited to the 
following: fexofenadine, sulfasalazine, rosuvastatin, atorvastatin, cerivastatin, glyburide, 
pravastatin, repaglinide, simvastatin.
A clinical DDI study investigating the effect of BAY 1817080 on the sensitive 
OATP1B1/1B3 and BCRP substrate rosuvastatin is ongoing.
Please refer to the current version of the IB for further information.
Additional information can be found in Table 5-1 of the FDA DDI guidance (19).


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study, receive the procedures scheduled for the end of intervention visit (i.e. visit 5) as 
soon as possible, and then be evaluated for the whole follow-up phase. See the SoA for data 
to be collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed.

Participants must discontinue study intervention if any of the following occurs:
o
In the investigator's opinion, continuation of the study intervention would be 
harmful to the participant's well-being
o
Surgical treatment of endometriosis9
o
Liver safety-related discontinuation criteria are met (see Section 10.6)
o
Pregnancy (see Sections 8.3.5 and 10.4)
o
At the specific request of the sponsor and in liaison with the investigator (e.g. 
obvious non-compliance, safety concerns)

Participants may be withdrawn from study intervention if any of the inclusion criteria 
are no longer fulfilled or if any of the exclusion criteria apply during treatment.
7.1.1
Rechallenge
Study intervention may be restarted after a temporary interruption if deemed clinically 
appropriate by the investigator in collaboration with the Bayer Medical Monitor.
7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral or
compliance reasons. This is expected to be uncommon.
o
If a participant becomes SARS-CoV-2 virus RNA test positive while on study, 
the investigator will have to decide whether staying in the study is compatible 
with participant and site personnel safety and wellbeing. The decision should 
also take into account possible interaction between the test drug and potential 
antiviral medication.

At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed.
                                                
9 If possible, Visit 5 should be performed as close to the timeframe in the SoA as possible but before surgery


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o
Participants who have been randomized but not yet started study intervention 
do not need to undergo further study procedures other than return of supplies, 
before their study participation terminates.
o
For withdrawal during the intervention phase, the participant should undergo 
assessments scheduled for the end of intervention visit (Visit 5) plus physical 
examination and return of supplies
o
For withdrawal during the follow-up period, the participant should undergo the 
assessments scheduled for the next visit (Visit 6 or 7)

The participant will be permanently discontinued both from the study intervention and 
from the study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.
A participant is called “dropout” if she was randomized and discontinues study participation 
prematurely for any reason.
7.3
Lost to Follow Up
A participant will be considered lost to follow-up if she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, she will be considered to have 
withdrawn from the study.

If the participant is reached, the site personnel must:
o
Ascertain whether or not the participant wishes to continue in the study
o
Counsel the participant on the importance of maintaining the assigned visit 
schedule and 
o
Reschedule the missed visit as soon as possible 
o
In case study intervention was interrupted, the investigator should check 
whether permanent withdrawal from study intervention was required (see 
Section 7.1) 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

MRI, ultrasound (in Japan only) and cervical smear conducted as part of the 
participant’s routine clinical management and obtained before signing of the ICF may 
be utilized for screening or baseline purposes provided the procedures were performed 
within the time frame defined in Section 5.1 (inclusion criteria #2 and #7).

Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
approximately 350 mL

Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Efficacy Assessments
Planned time points for all efficacy and immunogenicity assessments are provided in the SoA.
8.1.1
Patient-Reported Outcomes (PROs)

PROs will be responded to by the study participants themselves without any 
assistance. 

PROs will be collected using an electronic handheld diary (eDiary) except for the PCS
and painDETECT, which are collected as paper questionnaires. Paper questionnaires 
will not be used as replacement for the eDiary device. 

Site personnel as well as study participants will receive validated training (20, 21) to 
ascertain accurate and reliable reporting of pain scores, proper use of pain scales and 
minimization of placebo response. Training will be provided at study start and 
retraining will be performed at regular intervals and as needed during the course of the 
trial.


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
Site personnel will be trained for the PROs, use of eDiary device and related internet 
portal (used for review of data) during the Investigator’s Training and/or during the 
Site Initiation. The paper PROs, instructions for the use of the eDiary and portal will 
be provided in the Investigator Site File.

Site personnel will provide technical guidance for the study participants. In addition, a 
24-hour help desk in local languages will be available. No other help than technical 
support will be given to study participants regarding the completion of the PROs. 
Study participants will be asked to confirm their understanding on the use of the 
eDiary device and completion of the questionnaires. 

When study participants complete PROs at the site, they should do so before other 
study procedures. The questionnaires should be completed independently by the 
participant herself in a quiet, private area. The site should allocate adequate time for 
completion of all PROs at respective visits.

At no time is the site personnel allowed to respond to other than technical questions.

The site personnel should check the ePRO entries via the internet portal/reports.

Allowed ePRO data changes are described in the Vendor documentation.
8.1.1.1
Endometriosis Symptom Diary (ESD)

The ESD v 9.0 is a multi-item PRO instrument designed to assess the patient’s 
experience of endometriosis symptoms.

Item 1 of the ESD serves as the primary endpoint in this study.

This PRO was first used in a validation study (22) and subsequently in a treatment 
study with an aromatase inhibitor (23). Regarding the rationale for developing the 
ESD, see Gerlinger et al. 2012 (24). In order to evaluate psychometric properties, ESD 
pain items will be complemented by pain recordings using 4-week recall VAS. 

The ESD will be completed by the study participant each evening (between 18:00 and 
24:00 preferably after intake of the evening dose), when she is to reflect on her 
experiences during the past 24 hours.

Participants will be asked to record their: 
o
endometriosis pain at its worst (single items 1-3)
o
vaginal bleeding (single item 4)
o
sexual intercourse and dyspareunia (single items 5-7)
o
use of study intervention (single item 8) 
o
use of standardized rescue medication and other pain medication (single items 
9-11).

Single items rating symptoms (1, 2, 3, and 6) are reported using a 0 to 10 NRS.


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
Items concerning having or avoiding sexual intercourse (5 and 7) and intake of pain 
medications (9, and 10) use a dichotomous yes/no scoring system (in addition, the 
number of each of the pain medications taken will also be recorded). The item for 
study intervention (8) quantifies the number of tablets taken. 

Vaginal bleeding intensity (item 4) will be assessed; the response that best describes 
the vaginal bleeding during the past 24 hours is to be selected on a categorical 
response scale (5 levels of increasing intensity: none, spotting, light, normal, heavy).
8.1.1.2
Endometriosis Impact Scale (EIS)

EIS version 5.0 is a multi-item PRO instrument designed to assess the impact of 
endometriosis symptoms on the patients’ lives.

EIS was used in a validation study (22) and subsequently in a treatment study with an 
aromatase inhibitor (17). Regarding the rationale of developing the EIS, see Gerlinger 
et al. 2012 (24). 

The EIS will be completed by the study participant once a week (between 18:00 and 
24:00), when she is to reflect on her experiences during the past 7 days. In case a study 
participant misses to enter data, EIS will be available for data entry the next day. 

Participants are to reflect on the effect of endometriosis pain on their daily lives during 
the past 7 days. Participants will be asked to describe impacts on:
o
physical activities (physical subscale; contains 7 single items)
o
emotional effect (emotional subscale; contains 7 single items)
o
sexual activities (sexual activities subscale; contains 3 single items)
o
ability to concentrate
o
ability to sleep
o
household activities
o
paid work or study
o
social and leisure activities

Participants will be asked to rate on a 5- to 6-point scale (6-point scales are used for 
items which allow for the rating of a “does not apply” option) where 0 represents 
“does not apply”, 1 represents “not at all” and 5 represents “extremely”.
8.1.1.3
Visual Analogue Scale (VAS) for Pelvic Pain 

VAS is commonly used for the assessment of pain in various indications. It has been 
used for development of Visanne (dienogest) in endometriosis and hence allows for 
comparison with historical data (25). 

VAS consists of a straight line offering 101 positions/dots to choose from, with verbal 
anchors at either end, representing a continuum of pain intensity. One end of the line 
has the anchor “no pain” while the other end of the line has the anchor “unbearable 
pain”. 

Study participants will be asked to indicate their level of pelvic pain over the last 4 
weeks with a single vertical mark on the line. Pelvic pain refers to endometriosis pain 
in the lower abdomen and surrounding areas.


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
VAS will be completed during the site visits in the eDiary. 
8.1.1.4
Patient Global Impression of Severity (PGI-S) and Change (PGI-C)

PGI-S and PGI-C are self-administered instruments used in former endometriosis 
trials. Inclusion into this study will contribute to the investigation of psychometric 
properties of ESD and EIS.

PGI-S asks the participant to rate severity of the endometriosis pain over past 4 weeks
using a 6-point verbal single-item rating Likert scale (no pain, very mild, mild, 
moderate, severe, and very severe).

PGI-C measures change in the participants’ endometriosis pain since the start of the 
study intervention on a single-item 5-point Likert scale ranging from “much better” to 
“much worse”.

PGI-S and PGI-C will be completed during the site visits in eDiary.
8.1.1.5
PainDETECT

The painDETECT PRO was developed and its properties were originally tested on a 
sample of lower-back pain patients; additional PRO and clinical research is 
summarized by Freynhagen et al. (26). There is limited evidence for applicability and 
validity of painDETECT in endometriosis, hence it will be used and data evaluated as 
an explorative endpoint. 

PainDETECT data will be collected on paper questionnaire in this study to explore 
and describe potential presence of neuropathic pain and the change under intervention.

The painDETECT is a self-administered 13-item paper questionnaire to screen the 
patients with neuropathic pain (26). It includes 3 domains: 
o
pain course pattern
o
pain radiation
o
sensory symptoms.

A painDETECT score is generated for each participant by assigning a value to items 
7–13 (0 = “never” to 5 = “very strongly”) and summating the result. This score is then 
adjusted, based on responses to items about pain course pattern and pain radiation. 

The final score range is from -1 to 38. For screening purposes, the below cut-off 
points have been suggested in other indications and will be used in this study
exploratively, as there is limited evidence on using painDETECT and validity of these 
thresholds for endometriosis indication. 
o
score ≤ 12, a neuropathic component is unlikely (< 15%)
o
score ≥ 19, a neuropathic component is likely (> 90%) 
o
Between these, the result is uncertain, i.e. a neuropathic pain component can be 
present.


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8.1.1.6
EuroQoL 5-dimension 5-level (EQ-5D-5L)
The EQ-5D-5L is a self-administered preference-based generic measure of health status which 
includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (27). Patients provide a rating for each question on a five-level Likert 
scale: having no problems, having slight problems, having moderate problems, having severe 
problems and being unable to do/having extreme problems. In addition, patients are asked to 
self-rate their own health today on a vertical 0-100 unit visual analogue scale (VAS), with 0 
corresponding to "the worst health you can imagine", and 100 corresponding to "the best 
health you can imagine".
EQ-5D-5L will be collected on eDiary and programmed after EIS data collection weekly 
during screening phase before treatment and monthly (every 4 weeks) during the treatment 
phase and follow up. 
The reported data will be analyzed descriptively. The utility analyses based on collected EQ-
5D-5L data are planned to be conducted in separate post-hoc analyses.
8.1.1.7
Modified Work Productivity and Activity Impairment questionnaire 
(mWPAI)
Work Productivity and Activity Impairment Questionnaire is commonly used to assess the 
impact of different health conditions including gynecological indications on absenteeism, 
presenteeism and activity impairment (28). Modified version for Endometriosis (mWPAI)
with 6 items with recall over past 4 weeks will be used. The items will be analyzed 
descriptively, there is no total score. The data will be collected on eDiary during the site visits
as indicated in the SoA (29, 30).
8.1.1.8
Pain Catastrophizing Scale (PCS)
The Pain Catastrophizing Scale (PCS) is a 13-item instrument derived from concepts of
catastrophizing described in the literature (Chaves & Brown, 1987; Spanos et al., 1979) as 
well as items from the catastrophizing subscale of the Coping Strategy Questionnaire (31). 
The PCS instructions ask patients to reflect on past painful experiences, and to indicate the 
degree to which they experienced each of 13 thoughts or feelings when experiencing pain, on 
5-point scales with the end points (0) not at all and (4) all the time. The PCS yields a total 
score and three subscale scores assessing rumination, magnification and helplessness. The
total score is computed by summing responses to all 13 items. PCS total scores range from 0 –
52 (32).
The PCS data will be collected on paper at baseline as an explorative endpoint to better 
understand pain-related distress experienced by women with endometriosis. The results will 
be reported descriptively without applying any cut-off points or thresholds. 


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8.1.1.9
Additional daily symptom items
Three additional items will be asked and reported daily by patient on eDiary to assess 
dyschezia (pain associated with bowel movement), dysuria (pain associated with urination) 
and number of hot flushes. These questions will be completed by the study participant each 
evening (between 18:00 and 24:00) together with the ESD.
The patients will be asked to report pain at its worst during the past 24 hours on 0-10 NRS 
scale to assess dyschezia and dysuria. These items were derived from previous qualitative 
research and development of ESD. 
In addition, the number of hot flushes (sensation of heat with sweating) in the past 24 hours 
will be reported to assess tolerability of different active treatments. 
8.2
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical and Gynecological Examinations

Physical examination includes, at a minimum, assessments of the skin, the lungs, 
cardiovascular system and abdomen (liver and spleen).

Gynecological examination is to be done according to local guidelines/common 
clinical practice.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

In the event of any suspicious finding during examinations, further diagnostic 
investigations should be performed at the discretion of the investigator.

Abnormal examination findings are to be recorded either as medical history or as AEs 
(see Section 8.3.1).
Height and weight will be measured and recorded. For weight measurement the 
participant may wear indoor clothing with no shoes. The clothing should be alike at all 
measurements.
8.2.2
Vital Signs
Blood pressure and heart rate will be assessed. Measurements should be:

Preceded by at least 5 minutes of rest for the participant in a quiet setting without 
distractions

Assessed in a sitting position

1 heart rate and 1 blood pressure reading. The readings will be recorded in the eCRF, 
as well as corresponding AEs or medical history, if clinically relevant.
8.2.3
Ultrasound 

Ultrasound examination should be performed by a physician well experienced in 
gynecology or with corresponding qualification based on local clinical practice

Preferably the evaluation should be performed by transvaginal ultrasound. However, if 
deemed appropriate, transabdominal or transrectal ultrasound examinations can be 
performed in addition or instead. The chosen method (s) should be used consistently 
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
The following safety parameters will be measured and recorded: 
o
Endometrial thickness (measured in the medio-sagittal section as double-layer 
in millimeters)
o
Evaluation of the ovaries 
o
Endometriosis
o
Adenomyosis
o
Any other pathology detected during the examination

In case of any suspicious finding, further diagnostic investigations should be 
performed at the discretion of the investigator.

The minimum documentation will include printouts and/or CDs with images from the 
ultrasound machine showing the endometrium in sagittal section and both ovaries. The 
printouts and/or CDs with images have to be labeled unambiguously, containing at 
least the study number, participant number, time point, endometrial thickness, and 
laterality (left/right) for ovaries. If the printouts are on thermo-sensitive paper, they 
need to be copied as they will fade over time.
8.2.4
Cervical cytology

Cervical smear should be obtained at Visit 1a or shortly after Visit 1a.

Cervical smear performed during the last 12 months prior to Visit 1a can be used for 
the screening assessment.

Participants with ASCUS are eligible for the study if they have negative result for 
high-risk HPV strains from an HPV deoxyribonucleic acid test.

Cervical smear can be repeated once in case of insufficient material in the sample.

Cervical smear will only be performed before randomization to ensure eligibility and 
is not a safety endpoint.
8.2.5
Clinical Safety Laboratory Assessments

See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents. 

Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more 
severe than expected for the participant's condition.
o
If clinically significant values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified,
and the sponsor notified.
o
All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
o
If laboratory values from non-protocol specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE), then 
the results must be recorded.


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
Laboratory tests may be repeated once prior to Visit 1b in case it is medically 
justified, and the investigator expects a non-exclusionary result, with the 
exception of ALT, AST, AP and hepatitis B and C related tests

For information regarding laboratory assessments related to liver safety, see 
Section 10.6.
8.2.6
Pregnancy Testing
All participants of the study are women of childbearing potential, thus should receive 
pregnancy tests according to the SoA. Additionally, the participant is asked to conduct home 
urine pregnancy testing whenever there is suspicion of a pregnancy (See Section 10.4)
8.2.7
Suicidal Ideation and Behavior Risk Monitoring
Suicidal ideation and behavior have been reported in patients treated with the active 
comparator (elagolix) (please see section 2.3.1). Therefore, after the start of study 
intervention, participants should be 

Monitored for new or worsening depression, anxiety or other mood changes, as well 
as any unusual changes in behavior. Participants with such signs should be referred to 
a mental health professional, as appropriate.

Advised to seek immediate medical attention for suicidal ideation or behavior.

Put through a risk assessment where all possible factors contributing to suicidal 
ideation and behavior are evaluated and discontinuation of the study intervention is 
considered.
8.3
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting
The definitions of AEs and SAEs can be found in Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Section 7).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit, i.e., 
Visit 6 or 7, respectively, at the time points specified in the SoA (Section 1.3).
Additional details on smell and taste related AEs will be collected once at the end of an 
individual’s study participation via dedicated eCRF pages. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in Section 
10.3. The investigator will submit any updated SAE data to the sponsor within 24 hours of it 
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Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor. 
8.3.2
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in Section 
10.3. 
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/ IECs, and investigators.

For all studies except those utilizing medical devices investigator safety reports must 
be prepared for SUSAR according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5
Pregnancy

Details of all pregnancies will be collected after the start of study intervention and 
until the end of study. Time period for reporting pregnancies should align with the 
time period for post-intervention contraception determined in Section 5.1.

If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
pregnancy.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.


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
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported as 
such.

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor.

Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting.

Any participant who becomes pregnant while participating in the study will 
discontinue study intervention.
8.3.6
Taste Related AEs

Taste-related AEs will be recorded if reported by the participant 

At the EoT visit, there will be additional questions posed to those participants who
spontaneously reported a taste-related AE which occurred during the intervention 
period:
o
Question for frequency
o
Question on how bothersome the taste effect was

Additional details on smell and taste related AEs will be collected once at the end of 
an individual’s study participation via dedicated eCRF pages.
8.3.7
Adverse Events of Special Interest
Adverse events of special interest have to be reported to the sponsor along the timelines 
set for SAEs, i.e. within 24 hours of the investigator’s awareness, as described in Section 
8.3.1.
Declaration of an event as serious should only occur if one or more of the serious criteria 
is applicable. Non-serious adverse events of special interest should not automatically be 
upgraded to serious by the reporting investigator.
Adverse events of special interest are liver enzyme increases meeting the following 
criteria:

ALT and/or AST >8x ULN OR

ALT and/or AST >3x ULN with total bilirubin >2x ULN.
8.4
Pharmacokinetics

PK samples will be collected from participants in treatment groups 1-4 to maintain
blinding; however, PK samples from the placebo treatment group will not be 
analyzed (placebo samples might be analyzed e.g. in case of suspected treatment 
errors).  


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
Sparse blood PK samples will be collected for measurement of plasma 
concentrations of BAY 1817080 as specified in the SoA:
o
Pre-dose sample will be taken at Visits 2, 3 and 5, at least 10 hours after the 
previous dose (NA for Visit 2). Study intervention will be administered at the 
study site after the pre-dose sample at these visits. The following must be 
recorded: 

Time of the last dose taken at home before the site visit

Time of the closest food intake before or after that last dose taken at 
home

Time of the closest food intake before or during dose taken at the site.
o
Two post-dose samples will be taken at Visit 2 and 5: first sample 2 (±1) hours 
and the second sample 4 (±1) hours after the first daily dose, with at least 1 
hour between. Time of the closest food intake before or after the dose must be 
recorded.
o
One post-dose sample will be taken at Visit 4, at least 5 hours after the 
previous dose taken at home. The following must be recorded: 

Time of the previous dose taken at home before the site visit

Time of the closest food intake before or after that first dose taken at 
home

It is of importance that the actual date and time (24-hour clock time) of blood 
sampling are documented in the eCRF because PK calculations will be based on 
the actual sampling times relative to dosing times.

A maximum of 2 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling, may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 

Plasma concentrations of BAY 1817080 from sparse PK sampling will be 
determined using validated analytical methods.

Samples will be used to evaluate the PK of BAY 1817080 as an exploratory 
endpoint in this study.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Detailed instructions about the collection, processing, storage and shipment of biological 
samples will be provided separately (e.g. sample handling sheets or laboratory manual).
Population pharmacokinetic (popPK) analysis
The systemic exposure of BAY 1817080, drug-related PD biomarker and/or safety and 
efficacy measurements collected during the trial might be analyzed using nonlinear mixed 
effects modeling.
Mixed effects models, e.g., popPK models, describe the relationship between dose and time 
and variables such as drug plasma concentrations. Both structural and random effects are 
involved in this relationship. A preliminary popPK compartmental model will be further 
developed using the concentration of the drug as the dependent variable.


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The potential influence of relevant participant covariates (e.g., body weight) and optionally 
efficacy, PD biomarkers or safety laboratory parameter can be included in the PK/PD 
modeling using population approaches. A separate evaluation plan, providing details of the 
model building process and evaluation will be provided prior to the beginning of the 
popPK/PD analysis. Results obtained by popPK/PD modeling will be presented in a separate 
report that may also include PK data from other studies with BAY 1817080 or published PK 
data on elagolix.
The modeling analyses may be started prior to database lock. If this is applicable, appropriate 
measures will be taken to maintain blinding of the study team, e.g., data will be stored 
separately, and members of the study team will neither have access to the randomization list 
nor to individual data.
Plasma concentration data for all participants will be listed in the clinical study report.
Pharmacodynamic parameters are not evaluated in this study.
8.5
Genetics 
Genetic as well as non-genetic analyses may be part of the biomarker investigations in this 
study if approved by local IECs / IRBs and competent authorities, in all countries except for 
China. Genetic investigations may be of any kind, except for the whole genome sequencing. 
A sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. Details on sample handling will be provided separately. See Section 8.6 for details.
8.6
Biomarkers
In this study, genetic as well as non-genetic biomarkers will be investigated in participants 
from all countries except for China.

Timing – see SoA for planned time points of sample collection.

Sample handling and storage – details on the collection, processing, shipment and 
storage of samples will be provided in separate documents (e.g. sample handling 
sheets or lab manual). Samples may be stored for a maximum of 15 years (or 
according to local regulations) following the end of the study at a facility selected by 
the sponsor to enable further analyses.

Medical history information – if any additional information about the status of 
disease was collected in the course of treatment prior to entry of the participant in the 
study, the results may be collected in order to include this data in biomarker analyses.

Reporting – the results of biomarker investigations may be reported separately (e.g. in 
a biomarker evaluation report).
8.6.1
Biomarkers Monitoring Disease Activity
Serum and plasma will be investigated for e.g. interleukins, high sensitivity C-reactive 
protein, and neurotrophins:

Endometriosis is an inflammatory condition with significantly altered local cytokine 
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
Concentrations of selected immune- and neurotrophin related BMs have been 
described as being altered not only locally but also systemically in serum/plasma

Serum concentrations of CA125, CA19-9 and B2M will be investigated within lab 
parameters to evaluate their diagnostic and monitoring value in endometriosis patients
(see Section 10.2).
Analysis of key steroids (estrogen and progesterone) may be conducted in BM samples and 
utilized for the analysis of disease activity BMs:

Many inflammatory BMs undergo cyclical modulation during the menstrual cycle, 
resulting data will need to be investigated in a cycle-controlled manner

Study visits are scheduled to reflect the intervention period and do not reflect 
individual cycle lengths and characteristics
8.6.2
Biomarkers Related to Ovarian Activity
Regular menstrual cycles are considered relevant indicators of reproductive health in women 
and changes may impact the quality of life. In order to demonstrate that BAY 1817080 has no 
effect on the menstrual cycle and ovarian activity, parameters indicative of ovarian activity 
will be assessed in this study.
Following parameters will be taken into account to assess ovarian activity:

Regular menstrual bleeding

Serum progesterone >3 ng/mL
8.6.2.1
Bleeding Pattern 

Menstrual bleeding pattern can be seen as a noninvasive marker for endocrine status in 
the studied cycle (33).

The information on menstrual bleeding will be derived from Item 4 in the ESD (see 
Section 8.1.1.1).

Cycle length and bleeding duration as well as an average intensity will be calculated.
8.6.2.2
Diameter of Ovarian Follicles

Throughout the cycle, the diameter of the largest healthy follicles, with the exception 
of the dominant follicle, does not exceed on average 6 mm during the follicular phase 
and 4 mm during the luteal phase. The dominant follicle has a linear daily diameter 
growth of 2–3 mm per day, and at the moment of ovulation, the diameter of the 
dominant follicle is 18–27 mm.

During the ultrasound examination (see Section 8.2.1), ovarian follicles should be 
monitored. The size of the largest follicle (if mean diameter > 10 mm) as well as 
presence of a ruptured follicle or corpus luteum should be recorded in the eCRF.

Follicles larger than 18 mm, ruptured follicles, as well as structures identified as 
corpus luteum will be indicative of an ovulatory cycle.


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8.6.2.3
Serum Progesterone
Serum progesterone will be investigated from blood samples at each visit. Progesterone level 
≥ 3 ng/mL (9.5 nmol/L) will be considered indicative of a recent ovulation (33, 34).
8.6.3
Sleep Quality and Activity Measurement
Investigation of sleep quality and activity is considered as an option for an additional,
objectively assessed, marker demonstrating improvement of patient outcome; further, the
degree of baseline sleep disturbance could predict the response to treatment.
Optional participation in a sleep quality and activity substudy will be offered to a subset of 
participants. This will be limited to certain countries at the sponsor’s discretion.
In an exploratory biomarker analysis, different parameters characterizing sleep quality (e.g. 
total sleep time, sleep onset latency, sleep efficiency) and daily activity (e.g. number of steps 
taken, physical activity intensity, sedentary bouts) will be investigated retrospectively (see 
Section 10.8 for details).
In addition to the objective sleep monitoring by wearable, all participants will be provided a 
sleep questionnaire developed to assess pain associated sleep disturbance (for time points, 
refer to SoA).
Pain and Sleep Questionnaire three-item index (PSQ3)
PSQ3 is a three-item PRO assessing ‘trouble falling asleep because of pain’, ‘frequency of 
awakenings by pain during the night’ and ‘frequency of awakenings by pain in the morning’ 
on the visual analogue scale with one week recall period. The items of PSQ3 are also part of 
the Pain and Sleep Questionnaire (PSQ) and Chronic Pain Sleep Inventory (CPSI). The 
assessment of selected psychometric properties of PSQ-3 using the data from clinical studies 
in different chronic pain indications is reported by Ayearst et al (35). PSQ-3 questionnaire 
will be completed during the site visits in eDiary.
8.6.4
Other Biomarkers
In addition to the biomarkers described above, further biomarkers related to, e.g., the mode of 
action or the safety of the study intervention and similar compounds may be investigated. The 
same applies to further biomarkers deemed relevant to endometriosis and associated health 
problems. These investigations may include e.g. diagnostic, safety, pharmacodynamic, 
monitoring, or potentially predictive biomarkers.
8.7
Immunogenicity Assessments
Not applicable
8.8
Health Economics
Health-economic parameters are evaluated through PROs EQ-5D-5L and mWPAI (Section 
8.1.1) to assess utility and activity/productivity impairment. Descriptive PRO analyses will be 
part of clinical report, additional economic analyses including country-specific cost and utility 
estimation are planned in a separate HEOR analysis and report.  


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9.
Statistical Considerations 
9.1
Statistical Hypotheses
The objective of the primary analysis is the detection of a trend in the relationship between 
the dose of BAY 1817080 and the primary efficacy endpoint, and describing the dose-
response-relationship to provide a dose for possible phase III studies. Thus, only the placebo 
group (0 mg of BAY 1817080) and the three active intervention groups of BAY 1817080 
with corresponding doses ,  = 1, … , 4, will be used for the primary efficacy assessment.
The objective will be pursued through the application of the MCP-Mod approach, because 
there is not enough prior knowledge to decide on a specific dose-response-model (, ). The 
MCP-Mod method makes “use [of] multiple comparison techniques to choose the most likely 
[parametric model among a set of candidates] to represent the underlying dose-response 
curve” (36). It combines the flexibility of modeling with the robustness to model 
misspecification associated with multiple comparison procedures.
For the so-called proof of activity of BAY 1817080, at least one of the null hypotheses
:   , 


= 0, 
∑



= 0, belonging to model  has to be rejected. The contrast coefficients  are 
chosen such that they maximize the local power, i. e. the probability for rejecting the null 
hypothesis  under the one-sided alternative hypothesis
:   , 


> 0.
Consequently, the null hypothesis  states no trend in the dose-response-relationship
(implying the overall null hypothesis of no trend in even one model) since the chosen dose-
response-curves described in Section 9.4 are monotonically decreasing. The optimal contrast 
coefficients depend on the sample sizes in the end. 
A more detailed description of the multiple comparison procedure modelling (MCP-Mod) 
approach and the models used will be given in Section 9.4.
9.2
Sample Size Determination 
Approximately 840 participants will be screened to start study intervention in about 420 
randomized participants for at least 50 participants evaluable for the primary analysis (i.e. 
included in the pPPS) per intervention group. The primary analysis will not include the 
participants enrolled based on visually-confirmed diagnosis, i.e. about half of the women 
randomized in Japan, nor all the participants randomized in China, who are mainly included 
to generate further data using the ESD in this population. Refer to Section 9.3 for further 
information of inclusion of participants into analysis sets.
If blinded data reviews indicate an unexpected high number of screening failures due to the 
COVID-19 pandemic, enrollment may be increased.


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Sample size calculations were performed for establishing evidence of a drug effect across the 
doses, that is, detecting a statistically significant dose response signal for the primary efficacy 
outcome in this study using the MCP-Mod approach. They are based on the following 
assumptions:

change in mean EAPP under placebo after 12 weeks of -2.3

maximum change in mean EAPP of -1.2 for BAY 1817080 over placebo

standard deviation of 2.5 for all dose groups 

a set of plausible dose-response shapes including Emax and sigmoidal Emax models 
(chosen based on literature review and historic in-house data) 

random allocation of participants to dose groups according to a 1:1:1:1 ratio, 
A sample size of 50 participants per dose groups will have appr. 90% power (averaged across 
the set of dose-response shapes) to demonstrate a dose- response relationship, using a one-
sided test at a type I error rate of α=0.10. 
Approximately 70 participants for primary analysis will be randomized to each treatment 
group to achieve 50 evaluable participants for each treatment group.
In addition, 28 participants from Japan with clinical diagnosis, as well as 28 participants from 
China will be randomized 1:1:1:1, but will not be included in the primary analysis.
Although not formally included in the sample size determination, the exploratory 
elagolix 150mg treatment group is planned to be of about the same size as the other treatment
groups. As participants from Japan and China cannot be randomized to the elagolix 150mg 
arm, the randomization ratio outside of Japan and China will be 3:3:3:3:4 (Placebo:25 mg:75 
mg:150 mg:elagolix). This will provide similar sizes of all treatment groups overall.
9.3
Analysis Sets
Final decisions regarding the assignment of subjects to analysis sets defined in table 1 will be 
made during the review of study data and documented in the final list of important deviations, 
validity findings and assignment to analysis set(s).


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Table 9–1: Definition of the analysis sets.
Analysis set
Description
Enrolled
All participants who signed the informed consent 
form
Full Analysis Set (FAS)
All randomized non-Chinese participants
Primary full Analysis Set (pFAS)
All randomized non-Chinese participants with 
surgically-confirmed endometriosis
Per Protocol Set (PPS)
All randomized non-Chinese participants without 
any validity findings impacting the primary 
efficacy variable
Primary Per Protocol Set (pPPS)
All randomized non-Chinese participants with 
surgically-confirmed endometriosis and no 
validity finding impacting the primary efficacy 
variable
Safety Analysis Set (SAF)
All participants who took at least 1 dose of study 
drug
Pharmacokinetic Analysis Set (PKS)
All participants who took at least 1 dose of study 
drug and had at least 1 available 
pharmacokinetic sample
The primary analysis will be based on the pPPS. The PPS will be used for other non-safety 
analyses and the separate pharmacodynamics analyses. Safety analyses will be performed on 
the SAF. If and only if the SAF is used, the subjects will be analyzed as treated instead of as 
randomized. In selected cases, the (p)FAS will be used for sensitivity analyses. PK analysis 
will be performed on the PKS. Data from screening failures will only be shown in separate
listings.
9.4
Statistical Analyses
The statistical analysis plan will be finalized prior to unblinding and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. If not otherwise indicated, the statistical 
analyses will be performed using SAS; the version used will be specified in the statistical 
analysis plan.
9.4.1
General Considerations
According to the statistical hypotheses above, the detection of a trend in the dose-response 
relationship between BAY 1817080 and EAPP will be of a one-sided nature. The level of 
significance for statistical testing is set to 10 % to control the overall type I error, i.e. the 
type I error will be controlled for the primary analysis only. No multiplicity problem arises 
from the interim analyses. This study will be independent from their conduct and results, 
including different teams in order to maintain the blind of the study team.
In general, CIs will be two-sided. Thus, the CIs belonging to or directly linked with the 
primary analysis will have a coverage probability of 80 %. In addition, 95 %-CIs will be 
provided. Otherwise only 95 %-CIs will be calculated.
Baseline will be the last measurement or the measurements of the last 28 days before 
randomization.


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The four study periods are defined in section 1.3.
9.4.2
Primary Endpoint(s)
The primary estimand, including the primary efficacy variable, is described in section 3. The 
handling of missing values unrelated to the ICEs mentioned there will be described in the 
SAP.
The dose-response effect-capturing parameters  !" of the probability model assumed for the 
participant responses are assumed to follow the statistical model
 !" = ,  + $,       = 1, … , 4,  
where $ ~&(', () and (, ) = −2.3 + ,-./ ,01
/ + /
⁄
defining the dose-response
models in the candidate set, where  is the dose ranging from 0 mg to 150 mg. The different 
models are characterized by the parametrization  listed in Table 9–2. Figure 9–1 illustrates
them.
Table 9–2: Parameters of the dose-response-curves in the candidate set.
Model
Parameters
Abbreviation
Indicator 3
456'
4378
Hill factor 9
emax1
1
25
-1.4
1
emax2
2
100
-2.0
1
sigEmax1
3
35
-1.2
3
sigEmax2
4
75
-1.2
5


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Figure 9–1: Candidate set of dose-response-curves.
The null hypothesis of no trend in even one model will be investigated by means of the 
maximum of the test-statistics belonging to one-sided single contrast tests challenging . 
The critical value will be chosen such that the multiple significance level of 0.1 will be met.
If at least one local test-statistic is greater than the global critical value, the model ∗with the 
highest Akaike’s Information Criterion among the significant models will be fitted for 
determining the smallest dose which shows a clinically relevant and a statistically significant 
effect, i.e.
;,0 =
argmin
!∈{D1,1,…,1}
{(, ∗) > (, ∗) + F},
where F is the smallest relevant difference, by which a dose is expected to be better than 
placebo. The smallest relevant difference will be defined in the SAP prior to un-blinding to 
account for the most up-to-date research.
9.4.3
Secondary Endpoint(s)
For the identification of at least 1 superior effective dose of BAY 1817080 compared to 
placebo in terms of the absolute change in mean worst EAPP from baseline to end of 
intervention, pairwise p-values and 80 % as well as 95 % CIs will be derived from an
ANCOVA. The mean worst EAPP at baseline and the region (Japan vs. ROW excluding 
China) are set as covariates.
The secondary endpoint of TEAEs will be analyzed by descriptive statistics, such as 
frequency tables. A TEAE is defined as any event arising or worsening after the start of study 
drug administration until 14 days after the last study medication intake. All TEAEs will be 
tabulated according to the affected system organ class and preferred term, as coded by the 


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Medical Dictionary for Regulatory Affairs. Further tables will be provided for serious and/or 
drug related TEAEs. 
Summaries will be provided by intervention group and overall.
9.4.4
Other Endpoints
The analysis of the exploratory endpoints will be described in the SAP.
9.4.5
Safety Analysis
All safety analyses will be descriptive, and will be performed on the SAF. Details on safety 
analyses will be described in the SAP.
9.4.6
Other Analysis
BAY 1817080 plasma concentrations will be summarized by group, visit and planned 
sampling time. The statistical analysis will be described in the SAP. 
Population PK/PD and selected biomarker exploratory analyses will be described in separate 
analysis plans. The population PK/PD analysis will be presented separately from the main 
clinical study report.
PRO data will be used for psychometric analyses of ESD and EIS, which will be conducted 
and reported outside of clinical analyses and report.
Any other pre-specified analyses will be described in the SAP finalized before database lock.
9.5
Interim Analysis
Interim analyses may be performed after approximately 50% of the study participants have 
completed the 12-week intervention period in order to plan subsequent studies. This study 
will be independent from their conduct and results, including different teams in order to 
maintain the blind of the study team. For this, even if some interim analyses may be described 
in the main SAP, separate table, listings and figures documents will be created.
The Statistical Analysis Plans, including the Biomarker SAP and the HEOR SAP, will 
describe the planned interim analyses in greater detail. No formal interim report will be 
written.
The results of the biomarker investigation and of the HEOR analysis may be reported 
separately (see Section 8.6 and Section 8.8 for details)  
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations


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
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH Good Clinical 
Practice and national and international regulations.

Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants will 
be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study 
center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 


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
A copy of the ICF(s) must be provided to the participants. 

Participants who are rescreened are required to sign a new ICF.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records datasets or biological samples that are transferred to the sponsor will 
contain the identifier only; participant names or any information which would 
make the participant identifiable will not be transferred.

Participants will be asked to register with their contact information (email address) 
as users for the eDiary. This information is managed by the service provider and
data is transferred to the sponsor using identifier only. 

The service provider(s) will treat participants’ personal data in a confidential 
manner according to the regulations.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Committees Structure
A Study Steering Committee will be established to provide medical consultancy. The full 
description of the Steering Committee structure and tasks is provided in the Steering 
Committee charter.
10.1.6
Dissemination of Clinical Study Data

Result Summaries of Bayer's sponsored clinical trials in drug development Phases 2, 3 
and 4 and Phase 1 studies in patients are provided in the Bayer Trial Finder 
application after marketing authorization approval in line with the position of the 
global pharmaceutical industry associations laid down in the "Joint Position on the 
Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases". 
In addition, results of clinical drug trials will be provided on the publicly funded 
website www.ClinicalTrials.gov and EU Clinical Trials Register in line with the 
applicable regulations.

Bayer commits to sharing, upon request, from qualified scientific and medical 
researchers’ patient-level clinical trial data, study-level clinical trial data, and 
protocols from clinical trials in patients, for medicines and indications approved in the 
United States and European Union on or after January 01, 2014 as necessary for 
conducting legitimate research. 


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
All Bayer-sponsored clinical trials are considered for publication in the scientific 
literature irrespective of whether the results of the clinical trials are positive or 
negative.
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

Guidance on completion of CRFs will be provided in the CRF Completion Guidelines.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

Quality tolerance limits (QTLs) will be pre-defined in the integrated data review plan
to identify systematic issues that can impact participant safety and/or reliability of 
study results. These pre-defined parameters will be monitored during the study and 
important deviations from the QTLs and remedial actions taken will be summarized in 
the clinical study report.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g.,
Contract Research Organizations).

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor. 
10.1.8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
o
Definition of what constitutes source data can be found in Source Data 
Location List.


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
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
10.1.9
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first subject screened in the study and will be the study start 
date.
Study/Site Termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:

Discontinuation of further study intervention development
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator

Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
10.1.10
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 


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sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10–1 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be recorded.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Blood samples for testing of liver parameters, i.e., AP, ALT (GPT), AST (GOT), 
Gamma-GT, and total bilirubin, should be taken as specified in the SoA.
These visits are not to be performed in participants randomized to the active 
comparator elagolix.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

For pregnancy tests, see the SoA Section 1.3 and Section 8.3.5

ATIII activity: Increases up to 30% above baseline value were observed in healthy 
subjects and chronic cough patients in study 18184. Since there is no established 
clinical relevance linked to increased ATIII activity in medical literature, it is 
concluded that at this stage of development, the increase in ATIII activity can be 
considered as not clinically relevant. Screening ATIII results will be available to 
the investigator/sites as soon as measured and reported by the central laboratory. 
Considering the potential for unblinding participants receiving active treatment 
with BAY 1817080, the results of ATIII measures at the following visits will not 
be communicated to study teams nor investigators until after unblinding of the 
study.  


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Table 10–1: Protocol-Required Safety Laboratory tests 
Panel
Parameters
Time point(s)
Comment
Safety parameter
Biochemistry
Albumin
Visits 1a, 2-7
eGFR (MDRD 
formula) calculation 
needed for Visit 1a
only
Calcium
Magnesium
Creatinine
Cystatin C
Phosphorus
Potassium 
Sodium
Total protein
Blood urea nitrogen
Alkaline phosphatase 
ALT
AST
GGT
Total bilirubin
Total bile acids
Lipase
Pancreatic α-amylase
Non-fasting glucose
Total cholesterol
HDL-cholesterol
LDL-cholesterol
Triglycerides
β-hCG
Ferritin
Hematology
Erythrocytes
Visits 1a, 2-7
Hematocrit
Hemoglobin
Leukocytes with differentials 
(neutrophils, lymphocytes, 
monocytes, eosinophils, 
basophils)
Platelets
Hemoglobin A1c 
Visits 1a, 2-7
Coagulation
aPTT
Fibrinogen
INR
PT (Quick)
Antithrombin III (ATIII)
Visits 1a, 2-7
Reporting of the 
results at the 
screening phase only, 
other results reported 
to sites after the 
database lock
Hormones
Estradiol
Progesteronea
Visits 1a-7
SARS-CoV-2
SARS-CoV-2 viral antibody test
(IgM, IgG)
Visits 1a, 6/7
Depending on which 
is the last Follow-up
visit for the participant
SARS-CoV-2
RNA test
if needed
in case of symptoms, 
see below
Highly sensitive serum 
pregnancy test
β-hCG
Visits 1a, 2


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Table 10–1: Protocol-Required Safety Laboratory tests 
Panel
Parameters
Time point(s)
Comment
Highly sensitive urine 
pregnancy test
β-hCG
Visits 1a, 2-7
Screening/Start of Intervention parameters
Virology
Hepatitis B virus surface 
antigen 
Visit 1a
HCV-mRNA 
automatically tested if
anti-HCV is positive
Hepatitis C virus antibodies 
Hepatitis C virus mRNA 
Cervical cytology
Cervical smear
Visit 1a
HPV-DNA 
automatically tested if
ASCUS is reported 
from cervical cytology
High risk HPV-DNA
Hormones
Thyroid stimulating hormone 
Visit 1a
Luteinizing hormone
Visit 1a
Follicle-stimulating hormone 
Visit 1a
BM, PK & PG 
Biomarker (BM)
Biomarkers
Visits 1a, 2-6
Delivered from the 
central laboratory to 
the BM laboratory
Endometriosis biomarkers
Cancer antigen 125 (CA125), 
Carbohydrate antigen 19-9 
(CA19-9), Beta-2-Microglobulin 
(B2M)
Visits 1a, 2-6
Delivered to central 
laboratory
Pharmacokinetics (PK)
Pre-dose PK
Visits 2-5
Delivered from the 
central laboratory to 
the PK laboratory
Post-dose PK at 2h & 4 h after 
study intervention
Visits 2 and 5
at Visit 4 5h 
after study 
intervention
Pharmacogenetics (PG)
Genetics
One sample at 
Visit 2 or 3
Only consented 
participants 
Delivered from the 
central laboratory to 
the PG laboratory
Supplies to be provided to study participants
Urine pregnancy tests
To be used at home
Per need
Spermicide-coated condoms
To be used at home 
Per need
Per need triggered parameters
Repeated test triggered by 
abnormal (out of range) test 
result
Dependent on result
Per need
Repeat once
a
Blood samples should be taken at least 72 hours after the intake of high doses of biotin, since the 
laboratory results of ferritin and progesterone may be affected, if a participant had biotin intake at a 
concentration higher than 5 mg per day which occurred less than 72 hours before the sample is taken.
Abbreviations: A1AT = alpha-1 antitrypsin; ALT = alanine-aminotransferase; aPTT = Activated partial 
thromboplastin time; ASCUS = Atypical squamous cells of unknown significance; AST = aspartate-
aminotransferase; β-hCG = β-human chorionic gonadotropin; BM = biomarker; CK = creatine kinase; DNA = 
deoxyribonucleic acid; eGFR = estimated glomerular filtration rate; GGT = gamma-glutamyl transferase; HCV 
= hepatitis C virus; HDL = high-density lipoprotein; HPV = human papilloma virus; IgA = immunoglobulin A; 
IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized ratio; LDH = lactate 
dehydrogenase; LDL = Low-density lipoprotein; MDRD = Modification of Diet in Renal Disease; mRNA = 
messenger ribonucleic acid; PCR = polymerase chain reaction; PG = pharmacogenetics; PK = 
pharmacokinetics; PT = prothrombin time; ULN = upper limit of normal; WBC = white blood cells
Investigators must document their review of each laboratory safety report.


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SARS-CoV-2 Testing
Testing for SARS-CoV-2 virus RNA is to be performed in case a participant reports Covid-19 
associated symptoms, including fever or chills, cough, shortness of breath or difficulty 
breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, 
congestion or running nose, nausea or vomiting, diarrhea, during the study.
RNA tests will be provided centrally to ensure that they can actually be performed and to 
avoid unnecessary efforts by participants/sites in countries where there is no easy access to 
the test, even if symptoms are present. 
If required by local guidelines/practice for SARS-CoV-2 infection screening/diagnosis, 
additional laboratory or imaging examinations can be done, e.g. chest computed tomography. 
The results should be documented in the medical records.
10.3
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
Time period and frequency for collecting AEs and SAEs can be found in Section 8.3.1
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, that 
occurs after providing written informed consent, whether or not considered related 
to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., electrocardiogram, radiological 
scans, vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the 
investigator (i.e., not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected intervention-
intervention interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 


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sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
“Lack of efficacy” or “failure of expected pharmacological action” also 
constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
An SAE is defined as any AE that, at any dose:
a.
Results in death
b.
Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant 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

In general, hospitalization signifies that the participant has been admitted
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d.
Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse.
10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to sponsor in lieu of completion of the required form.

There may be instances when copies of medical records for certain cases are 


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requested by the sponsor. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the 
medical records before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals.

If a participant dies during participation in the study, the investigator will 
provide the sponsor with a copy of any post mortem findings including 
histopathology

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.


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10.3.4
Reporting of SAEs
SAE Reporting to the Sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to the local pharmacovigilance contact person by 
telephone.

Contacts for SAE reporting can be found in the Investigator Site File.
SAE Reporting to the Sponsor via Paper Data Collection Tool

Email transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the sponsor’s Pharmacovigilance department.

In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does data collection tool pages within the 
designated reporting time frames.

Contacts for SAE reporting can be found in the Investigator Site File.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Contraceptive Guidance

All participants in this study are considered to be of child-bearing potential, and 
accordingly must use contraception during the entire study participation 

Participants must be willing to use a non-hormonal barrier method for contraception 
(spermicide-coated condoms for their partners) from screening visit until the end of 
the study (or for at least 2 weeks after the last dose of study intervention in case of 
withdrawal from the study). This is not required if adequate contraception is achieved 
by at least one of the following options:
o
vasectomy of male partner(s)
o
female sterilization through bilateral salpingectomy or tubal ligation/occlusion 
o
use of copper IUD for at least 6 months at Visit 1a, provided that the copper IUD 
is planned to be worn without replacement for the entire study duration
o
total abstinence from heterosexual intercourse, which is only to be chosen if this 
method of contraception is consistent with the preferred and usual lifestyle of the 
participant; periodic abstinence and coitus interruptus (withdrawal) are not 
meant by total sexual abstinence

For discontinuation of hormonal contraceptives, see Section 6.8.2.2.
Collection of Pregnancy Information:

The investigator will collect pregnancy information on any participant who becomes 
pregnant while participating in this study (or within 2 weeks of the last dose of study 
intervention, in the case of premature discontinuation during the intervention phase). 
The initial information (at a minimum: participant identification, description of study 
intervention and report source) will be recorded on the appropriate form and submitted 
to the sponsor within 24 hours of learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 


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
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
Any participant who becomes pregnant while participating in the study will 
discontinue study intervention.
10.5
Appendix 5: Genetics

Genetic predisposition has been proposed to correlate with disease severity and pain 
processing in endometriosis (37). In needs to be explored whether some of the recently 
discovered genetic variants contribute to pain experience and response to therapy in 
endometriosis.

Genetic predisposition that might be associated with treatment response to 
BAY 1817080 and/or pain experience in endometriosis will be investigated as a 
voluntary substudy.

The participation in the pharmacogenetic (PG) substudy is voluntary and has no 
influence on the participation in the main study.

A whole blood sample will be obtained from those participants, who have signed a 
separate informed consent form (ICF) for PG substudy. The sample may be used as 
source of germline DNA. 

DNA will be utilized for genotyping of candidate genes suggested to play a role in 
endometriosis and/or pain processing.

Analyses may include targeted sequencing of the candidate genes and allele-specific 
polymerase chain reaction analyses, for example. The methods will be chosen 
according to current state of the art.

Details on the collection and handling of samples will be provided in separate 
documents (sample handling sheets and laboratory manual), available at the 
Investigator Site File.

Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the end of the study at a facility selected by the sponsor to enable further 
analyses.

The results of PG analyses may be reported separately (e.g. in a Biomarker Evaluation 
Report).
10.6
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 


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10.6.1
Liver safety -related monitoring and discontinuation criteria
Investigators and participants should pay special attention to non-specific symptoms
which may be associated with liver dysfunction; including anorexia, nausea, fatigue, 
right upper abdominal discomfort, vomiting, malaise, jaundice, fever, and rash.

Information on these symptoms should be asked for in case of abnormal liver 
laboratory values (see Table 10–2) or any other suspicion of liver dysfunction.

Participants should be regularly reminded to contact the investigator 
immediately if they are concerned about such symptoms, and unscheduled 
visits for evaluation should be considered
Table 10–2: Liver Safety-Related Monitoring and Discontinuation Criteria
Lab result
Measures
ALT or AST ＞3 x ULN
Initiate close observation as defined in Section 10.6.2. 
Consider withdrawal of study intervention if the 
participant does not adhere to procedures required for 
close observationa
ALT or AST > 3 x ULN and TBL > 2 x 
ULN 
Withdraw study intervention
ALT or AST > 3 x ULN and INR > 1.5 x 
ULN
Withdraw study intervention
ALT or AST > 3 ULN with appearance 
of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, 
fever, rash and/or eosinophilia (>5%)
Withdraw study intervention
ALT or AST > 5 x ULN for more than 2 
weeks
Withdraw study intervention
ALT or AST > 8 x ULN
Withdraw study intervention
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR= international 
normalized ratio, TBL = total bilirubin, ULN = upper limit of normal (all referring to serum/plasma)
a
in case visits for close observation could not be arranged with a frequency deemed adequate by the investigator, despite of 
reasonable efforts
10.6.2
Close observation of participants with ALT or AST ＞3 x ULN 

Abnormal laboratory results and clinical signs and symptoms resulting in close liver 
observation should be reported as adverse event.

Abnormal laboratory results meeting the criteria of transaminases (ALT and/or AST) 
>8x ULN or >3x ULN with total bilirubin >2x ULN will be reported as AEs of special 
interest (see Section 8.3.7).

It is critical to initiate close observation immediately upon detection and confirmation 
of early signals of possible drug-induced liver injury, and not to wait until the next 
scheduled visit or monitoring interval

Procedures to be taken resemble workup/ documentation along the guideline of the US 
FDA for assessment of potential drug-induced liver injury (38). Objectives are to:


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o Ensure participant safety
o Identify possible non-study-intervention-related causes of liver injury

A close observation has to be initiated during intervention or follow-up phase if ALT 
or AST reaches >3 x ULN. Close observation includes:
o Sampling for the first batch of laboratory parameters (see Table 10–3).
o Repeating follow-up samplings (see Table 10–3).2 to 3 times per week. 
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize.
o Obtaining a detailed history of the symptoms and prior or concurrent diseases  
o Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 
o Ruling out acute viral hepatitis, autoimmune or alcoholic hepatitis, nonalcoholic 
steatohepatitis, hypoxic/ischemic hepatology and biliary tract disease. This may 
require performing additional procedures, e.g. ultrasound examinations. If 
requested, tests will be done retrospectively using residual blood/serum samples 
collected at visits before laboratory abnormalities occurred.
o Obtaining a history of exposure to environmental chemical agents
o Obtaining additional tests to evaluate liver function as required (e.g. INR, direct 
bilirubin measurements)
o Liver imaging
o Considering gastroenterology or hepatology consultations

Data for any findings are to be recorded in the corresponding eCRF pages

Stopping criteria for close observation:
o
2 consecutive normal/baseline results for liver enzymes in addition to 
availability of results from detailed close liver observation lab panel, related 
procedures, relevant medical and medication history and the reporting of signs 
and symptoms related to elevated liver enzymes, or
o
A confirmed clinical diagnosis explaining the elevated liver enzymes.
Table 10–3: Samples during close observation for liver safety 
Parameters
Time point(s)
Comment
First batch of parameters to be taken when initiating close observation for liver safety
Albumin
Per need
First sample after AST or ALT > 3 X ULN
Alkaline phosphatase (AP)
Alanine-aminotransferase (ALT)
Aspartate-aminotransferase (AST)
Complete blood count including 
WBC with differentials
Cholinesterase
Conjugated (direct) bilirubin
Creatine kinase (CK)
GGT


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Table 10–3: Samples during close observation for liver safety 
Parameters
Time point(s)
Comment
Hemoglobin
INR
Lactate dehydrogenase (LDH)
PT
Total bilirubin
HDL-cholesterol
LDL-cholesterol
Total cholesterol
Triglycerides
Anti-hepatitis A virus IgM antibodies.
Hepatitis B virus surface antigen (if 
positive, automatically test below 
antibodies related to HBV and HDV)
-
Anti-hepatitis B surface 
antibodies
-
Anti-hepatitis B core total 
antibodies
-
Anti-hepatitis B IgM antibodies
-
Hepatitis B PCR (viral copies)
-
Hepatitis D virus antibodies (if 
positive, automatically test HDV 
RNA)
Anti-hepatitis C virus antibodies (if 
positive, automatically test Hepatitis 
C viral copies)
HCV RNA
Anti-Hepatitis D virus antibodies (if 
positive, automatically test HDV 
RNA)
Anti-hepatitis E virus IgM (if positive, 
automatically test HEV RNA)
Anti-cytomegalovirus (CMV) IgM 
antibodies
Anti-Epstein-Barr Virus (EBV) IgM 
antibodies
Herpes simplex IgM (anti-HSV IgM)
IgG level (gamma globulins)
IgA
IgM
c-Antineutrophil cytoplasmic 
antibodies 
c-Antineutrophil perinuclear 
antibodies 
Anti-mitochondrial antibodies
Anti-nuclear antibodies (ANA)
Anti-Smooth muscle antibodies
(ASMA)
A1AT level
Ceruloplasmin
Ferritin
Iron
Total iron binding capacity 
Follow-up samples during close observation for liver safety
Albumin
Per need
Additional parameters/tests may be added as 
medically justified
Alkaline phosphatase (AP)
Alanine-aminotransferase (ALT)
Aspartate-aminotransferase (AST)
WBC with differentials
Cholinesterase


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Table 10–3: Samples during close observation for liver safety 
Parameters
Time point(s)
Comment
CK
Conjugated (direct) bilirubin
Total bilirubin
GGT
INR
LDH
A1AT = Alpha-1 antitrypsin; CK = Creatine kinase; DNA = deoxyribonucleic acid; GGT = Gamma-glutamyl 
transferase; INR = International normalized ratio; HBV = hepatitis B virus; HDL = high-density lipoprotein; HDV 
= hepatitis D virus; HEV = hepatitis E virus; HSV = herpes simplex virus; IgA = immunoglobulin A; IgG = 
immunoglobulin G; IgM = immunoglobulin M; LDH = lactate dehydrogenase; LDL = low density lipoprotein; 
PCR = Polymerase chain reaction; PT = prothrombin time; RNA = ribonucleic acid; ULN = upper limit of 
normal; WBC = white blood cells
10.7
Appendix 7: Examples of Most Common Medication Regarded as 
Strong CYP3A4 Inhibitors or Inducers
Table 10–4 lists the most common prohibited medication regarded as 
strong CYP3A4 inhibitors or inducers.
Table 10–4: Cytochrome P450 (CYP) 3A4: List of most common prohibited 
concomitant medication
Strong CYP3A4 inducers, e.g.
Strong CYP3A4 inhibitors, e.g.
apalutamide
boceprevir
avasimibe
clarithromycin
carbamazepine
cobicistat
carbamazepine
conivaptan > 20 mg
enzalutamide
danoprevir / ritonavir
fosphenytoin
elvitegravir / ritonavir
hypericum perforatum / St John's wort
grapefruit juice
mephenytoin
indinavir, indinavir / ritonavir
mitotane
itraconazole
phenytoin
ketoconazole
rifapentine
lopinavir / ritonavir
rifampicin / rifampin
nefazodone
nelfinavir
posaconazole
ritonavir
saquinavir, saquinavir / ritonavir
telaprevir
telithromycin
tipranavir / ritonavir
troleandomycin
voriconazole
Source: Drug Interaction Solutions by University of Washington, July 2020 (39)


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Weak or moderate inducers or inhibitors of CYP3A4 are allowed. Table 10–5 gives examples 
of the most relevant antibiotics, antimycotics and antidepressants regarded as weak or 
moderate CYP3A4 inhibitors or inducers. For further information contact the sponsor.
Table 10–5: Cytochrome P450 (CYP) 3A4: List of most common allowed concomitant 
medication
Weak or Moderate CYP3A4 inducers, e.g.
Weak or Moderate CYP3A4 inhibitors, e.g.
dicloxacillin
alprazolam
clobazam
azithromycin
isavuconazole
casopitant
oritavancin
ciprofloxacin
rifabutin
clotrimazole
nafcillin
erythromycin
flucloxacillin
fluconazole ≤ 200 mg
fluvoxamine
isoniazid
lefamulin
norfloxacine
rimegepant
roxithromycin
Source: Drug Interaction Solutions by University of Washington, July 2020 (39)
10.8
Appendix 8: Actigraphy Substudy

Studies suggest that 50% to 70% of chronic pain patients suffer from a sleep 
disturbance. Little is known about sleep in endometriosis patients, but individual 
studies hint towards reduced sleep quality.

Participants in this study suffer from chronic pain due to endometriosis with high pain 
score at the begin of the intervention. Investigation of sleep quality is considered as 
option for an additional variable demonstrating improvement of patient outcomes.

Participants will be offered a possibility to participate in an optional actigraphy 
substudy on sleep quality in endometriosis, potential associations with pain symptoms 
and intervention-related improvement of bad sleep.

The participation in the substudy is voluntary and has no influence on the participation 
in the main study. For this substudy approximately 125 evaluable participants 
(approximately 25 per treatment group) are required. For this reason, the sponsor 
reserves the right to limit participation in this substudy to certain countries. Such 
limitation will be communicated to the relevant authority at the time of submission of 
the study.

Actigraphy will be monitored at defined time points during screening and study 
intervention periods as specified in the SoA with a medical-grade wearable monitoring 
device. This wrist worn wearable is a Class I non-measuring medical device within the 
European Union and an FDA cleared Class II medical device within the United States.


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
The actigraphy monitoring device will capture and record raw accelerometer data, 
which will be used to derive markers of mobility during sleep and daily activity, such 
as but not limited to:

total minutes asleep

sleep effectiveness

sleep onset latency

awakenings

physical activity intensity

activity bouts

sedentary bouts

Site personnel will be trained for the use of the wearable actigraphy monitoring device 
during the Investigator’s Meeting and/or during the Site Initiation. The instructions for 
the use of the device will be provided in the Investigator Site File.

Site personnel will provide technical support for the study participants. In addition, 
help desk will be available.

Study participants will be asked to use the actigraphy monitoring device for two 
periods of time (24-hours/day) during the study:
o
During screening period (baseline measurement) for all days between Visits 1a
and 2
o
During the third month of intervention, for all days between Visits 4 and 5.

In an exploratory BM analysis, different parameters characterizing sleep quality will 
be investigated retrospectively (e.g. total sleep time, sleep onset latency, sleep 
efficiency) and daily activity (e.g. number of steps taken, physical activity intensity, 
sedentary bouts)

The results will be reported separately (e.g. in a Biomarker Evaluation Report).
10.9
Appendix 9: Country-specific Requirements 
10.9.1
Japan

Limited to no more than half of all randomized Japanese participants: For inclusion in 
the study visually-confirmed endometriosis diagnosis can be based on previous 
imaging (i.e. endometriosis lesion detected by ultrasound or MRI). If the participant 
was diagnosed by ultrasound, the lesion must be visualized again by ultrasound at the 
screening visit. If the participant was diagnosed by MRI, the diagnosis must have been 
made within 12 months before Visit 1a.

The estimation of GFR is limited by differences in creatinine generation among 
ethnicities. Thus, the MDRD GFR equation is less accurate for Asians, with greater 
bias at eGFR less than 30 mL/min/1.73 m2. In Japan, the equation recommended by 
the Japanese Society of Nephrology (40) will be used for participants enrolled at Japan 
site in this study.


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o
eGFRcreat(mL/min/1.73m2) = 194×Cr-1.094×age-0.287×0.739

The investigator must report immediately all non-approved medical device failures 
which 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.

Participants in Japan will not be randomized to receive elagolix.
10.9.2
China

Participants in China will not be randomized to receive elagolix.

Genetic and non-genetic biomarkers samples will not be performed in China. 


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10.10
Appendix 10: Abbreviations
A1AT
Alpha-1 antitrypsin
AE(s)
Adverse event(s)
AG
Aktiengesellschaft, public limited company
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
ASCUS
Atypical squamous cells of unknown significance
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
ATIII
Antithrombin III
BCRP
Breast cancer resistance protein
BID
Bis in die (twice daily)
B2M
Beta-2-Microglobulin Biomarker
BM(s)
Biomarker(s)
CA125
Cancer antigen 125 biomarker
CA 19-9
Carbohydrate antigen 19-9
CD(s)
Compact disc(s)
CI(s)
Confidence interval(s)
CK
Creatine kinase
COC(s)
Combined oral contraceptive(s)
COVID-19
Coronavirus disease of 2019
CRF(s)
Case report form(s)
CTFG
Clinical Trial Facilitation Group
CYP3A4
Cytochrome P450 isoenzyme 3A4
DBP
Diastolic blood pressure
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
EAPP
Endometriosis associated pelvic pain
eCRF(s)
Electronic case report form(s)
eDiary
Electronic patient diary
eGFR
Estimated glomerular filtration rate
EIS
Endometriosis Impact Scale
ePRO
Electronic patient report outcome
EQ-5D-5L
EuroQoL 5-dimension 5-level questionnaire
ESD
Endometriosis Symptom diary
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
GnRH
Gonadotropin-releasing hormone


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GnRH-a
Gonadotropin-releasing hormone agonist
HbA1G
Hemoglobin A1c
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HCV-mRNA
Hepatitis C virus mRNA
HDL
high-density lipoprotein
HDV
Hepatitis D virus
HEOR
Health economics and outcomes research
HEV
hepatitis E virus
HFHC
high fat, high calorie
HPV
Human papilloma virus
HR
Heart rate
HSV
Herpes simplex virus
i.e.
id est, (that is)
IB
Investigator’s Brochure
ICE(s)
Intercurrent event(s)
ICF(s)
Informed consent form(s)
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC(s)
Independent Ethics Committee(s)
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IND
Investigational new drug
INR
international normalized ratio
IRB(s)
Institutional Review Board(s)
IUD
Intrauterine device
IWRS
Interactive web response system
LDH
lactate dehydrogenase
LDL
Low-density lipoprotein
MCP-Mod
Multiple Comparison Procedures – Modelling
MD
Medical Doctor 
MDRD
Modification of Diet in Renal Disease
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
mWPAI
Modified Work Productivity and Activity Impairment questionnaire
NA
Not applicable
NCT
ClinicalTrials.gov identifier
NRS
Numerical rating scale
OATP
Organic anion transporting polypeptide
OATP 1B1
Organic anion transporting polypeptide B1
OATP 1B3
Organic anion transporting polypeptide B3
P2X
Purinergic receptor
P2X2/3
Purinergic receptor 2/3
P2X3
Purinergic receptor 3
P2Y
Purinergic receptor Y


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PCR
Polymerase chain reaction
PCS
Pain catastrophizing score
PD
Pharmacodynamic(s)
pFAS
Primary full Analysis Set
PG
Pharmacogenetic
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PIF
Photoirritation factor
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic Analysis Set
PopPK
Population pharmacokinetics
pPPS
Primary Per Protocol Set
PPS
Per protocol set
PRO(s)
Patient reported outcome(s)
PSQ3
Pain and Sleep Questionnaire three-item index
PT
Prothrombin time
QD
quaque die,  daily
QTLs
Quality tolerance limits
RNA
Ribonucleic acid
RO
Receptor occupancy
SAE(s)
Serious adverse event(s)
SAF
Safety analysis set
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 of the genus Betacoronavirus
SoA
Schedule of activities
SUSAR(s)
Suspected, unexpected, serious adverse reaction(s)
TBL
total bilirubin
TEAE(s)
Treatment emergent adverse event(s)
TMF
Trial master file
ULN
Upper limit of normal
US(A)
United States
UV
Ultraviolet
VAS
Visual Analogue Scale
WBC
White blood cells
WHO
World Health Organization


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10.11
Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC).
10.11.1
Amendment 1
Amendment 1 (22 JUN 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
As of the date of this amendment, three cases of close liver observation (ALT> 3 x ULN 
(upper limit of norm)), have been reported within the ongoing phase 2 program of 
BAY1817080, with about 500 patients randomized overall so far. One of these cases was 
assessed as moderate liver injury seen 4 weeks after start of treatment, with the study drug as 
most likely cause. The study participant discontinued treatment and recovered from the 
condition. 
Based on this case Bayer has decided to implement testing of liver parameters every two 
weeks during the treatment period in the ongoing Phase 2 studies as a precautionary measure.
The implementation of the intensified monitoring will ascertain an early identification of 
potential increases in transaminases and allow for swift initiation of appropriate measures.
Following are the description of change and a brief rationale.
Section # and Name
Description of Change
Brief Rationale
Title page
Header throughout the 
document
Protocol version number is 
included in the Title page and 
removed from the header. 
Date is added in the header.
To reflect the current convention of 
the company
1.2 Schema
1.3
Schedule of Activities (SoA)
2.3.1
Risk Assessment
10.2 
Appendix 2: Clinical 
Laboratory Tests
3 new visits are added for 
taking blood samples for liver 
monitoring (not applicable for 
participants randomized to 
active control elagolix)
Text updated regarding one 
case of moderate liver injury
Text on blood samples for 
liver monitoring added.
Testing of liver parameters every 
two weeks during the treatment 
period is added as a precautionary 
measure.
5.2
Exclusion criteria
Addition of extremely low 
body weight as an example 
to criterion #7
To support investigator decisions 
on patient selection in light of the 
recent liver test results.


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11.
References
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Bodin P, Burnstock G. Increased release of ATP from endothelial cells during acute 
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Burnstock G. Purinergic receptors and pain. Curr Pharm Des. 2009;15(15):1717-35.
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Lazarowski ER, Shea DA, Boucher RC, Harden TK. Release of cellular UDP-glucose 
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Burnstock G. Purinergic signalling in the reproductive system in health and disease. 
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Investig Drugs. 2003;4(7):833-40.
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Ford AP, Undem BJ. The therapeutic promise of ATP antagonism at P2X3 receptors 
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Burnstock G. Purinergic signalling in the gastrointestinal tract and related organs in 
health and disease. Purinergic Signal. 2014;10(1):3-50.
10.
Ding S, Zhu L, Tian Y, Zhu T, Huang X, Zhang X. P2X3 receptor involvement in 
endometriosis pain via ERK signaling pathway. PLoS One. 2017;12(9):e0184647.
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NCT03310645. Repeat Doses of BAY 1817080 in Healthy Males & Proof of Concept 
in Chronic Cough Patients. Bayer. 2017. ClinicalTrials.gov.
12.
Morice A, Smith JA, McGarvey L, Birring SS, Parker SM, Turner A, et al. Eliapixant 
(BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a 
randomised, placebo-controlled, crossover phase 2a study. Eur Respir J. 2021;58(5).
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FDA. Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical 
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Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
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CTFG. Clinical Trials Facilitation and Coordination Group. Recommendations related 
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ORILISSA TM (Elagolix) Prescribing information. FDA Prescribing information for 
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PH-39016. 15832 (ESPARIOS) Dose Finding / POC Study, Bay 98-7196.  2017; 
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PH-40439. A Study to Test Whether Study Drug BAY1128688 Brings Pain Relief to 
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FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
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labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table5-1. Accessed date: 05NOV2019. 2020.
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minimal clinically important difference for endometriosis-associated pelvic pain 
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Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.


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38.
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Evaluation. Available online: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation. 
Accessed date 11Nov2019. 2009.
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https://www.druginteractionsolutions.org/. 2020.
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Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised Equations 
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2009;53(6):982-92.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A randomized, double-blind, open for active comparator, parallel-
group, multicenter Phase 2b study to assess the efficacy and safety 
of three different doses of P2X3 antagonist (BAY 1817080) versus 
placebo and elagolix 150 mg in women with symptomatic 
endometriosis 
NCT Number: 
NCT04614246  
Document Date: 
01-JUL-2022 
 


Statistical Analysis Plan
BAY 1817080/20584
Page: 1 of 32
Title page
A randomized, double-blind, open for active comparator, parallel-group, 
multicenter Phase 2b study to assess the efficacy and safety of three 
different doses of P2X3 antagonist (BAY 1817080) versus placebo and 
elagolix 150 mg in women with symptomatic endometriosis
Assess safety and efficacy of three different doses of P2X3 antagonist in 
women with symptomatic endometriosis
Bayer study drug
BAY 1817080
Study purpose:
dose-finding
Clinical study 
phase:
IIb
Date:
01 JUL  2022
Study No.:
20584
Version:
3
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 1817080/20584
Page: 2 of 32
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 4
1.
Introduction....................................................................................................................... 5
2.
Study Objectives................................................................................................................ 5
3.
Study Design ...................................................................................................................... 6
4.
General Statistical Considerations .................................................................................. 8
4.1
General Principles............................................................................................................ 8
4.2
Handling of Dropouts ...................................................................................................... 8
4.3
Handling of Missing Data................................................................................................ 9
4.3.1
COVID-19 pandemic-related missing data .................................................................. 9
4.3.2
Diary data ..................................................................................................................... 9
4.3.3
Partially missing start/stop dates ................................................................................ 10
4.4
Interim Analyses and Data Monitoring ......................................................................... 10
4.5
Data Rules...................................................................................................................... 10
4.6
Blind Review ................................................................................................................. 13
5.
Analysis Sets .................................................................................................................... 13
5.1
Assignment of analysis sets ........................................................................................... 13
6.
Statistical Methodology .................................................................................................. 14
6.1
Population characteristics .............................................................................................. 14
6.1.1
Subject disposition and validity.................................................................................. 15
6.1.2
Demographics and Baseline Characteristics............................................................... 15
6.1.3
Medical history........................................................................................................... 16
6.1.4
Prior and concomitant medication.............................................................................. 16
6.2
Efficacy.......................................................................................................................... 17
6.2.1
Primary Efficacy Endpoint ......................................................................................... 17
6.2.2
Secondary efficacy endpoint ...................................................................................... 21
6.2.3
Other endpoints .......................................................................................................... 22
6.3
Pharmacokinetics/pharmacodynamics (PK/ PD)........................................................... 23
6.4
Safety ............................................................................................................................. 23
6.4.1
Adverse events (AEs)................................................................................................. 23
6.4.2
Study Treatment Duration and Exposure ................................................................... 25
6.4.3
Liver Function Laboratory Parameters....................................................................... 27
6.4.4
Other safety variables ................................................................................................. 27
7.
Document history and changes in the planned statistical analysis............................. 29
8.
References ........................................................................................................................ 31


Statistical Analysis Plan
BAY 1817080/20584
Page: 3 of 32
Table of Tables
Table 1: Parameters of the dose-response-curves in the candidate set .................................... 19
Table 2: Outcomes of Interest Based on Accelerometer MeasurementsError! Bookmark not defined.
Table 3: Daily Aggregates for Sleep Outcomes........................Error! Bookmark not defined.
Table 4: Daily Aggregates for Physical Activity Outcomes.....Error! Bookmark not defined.
Table of Figures
Figure 1: Schema........................................................................................................................ 6


Statistical Analysis Plan
BAY 1817080/20584
Page: 4 of 32
Abbreviations
AE
ALT
AP
AST 
BEP
Adverse event
Alanine-aminotransferase
Alkaline Phosphatase
Aspartate aminotransferase
Biomarker Evaluation Plan 
CI
Confidence Interval
COI
Concept of Interest
CSR
Clinical Study Report
EAPP
Endometriosis-Associated Pelvic Pain
EIS
eDiary
Endometriosis Impact Scale
electronic diary
ESD
EQ-5D-5L
Endometriosis Symptom Diary
European Quality of Life 5 Dimension 5 Level Scale
FAS
pFAS
FUP
Full Analysis Set
Primary Full Analysis Set
Follow-Up Period
HEOR
HRQoL
Health Economics and Outcome Research
Health-related Quality of Life
IE
Intercurrent Event
IQR
Inter-quartile range
LOS
Listing only set
MAH
Meaningful Aspect of Health
MCP-Mod
Multiple Comparison Procedures – Modelling
MedDRA
MMRM
mWPAI
Medical Dictionary for Regulatory Activities
Mixed Model Repeated Measurement
modified Work Productivity and Activities Impairment
N/A
NMPP
Not applicable
Nonmenstrual pelvic pain
NRS
P2X3
PCS
PGI-C
PGI-S
PK
Numerical rating scale
Purinergic receptor P2X 
Pain Catastrophizing Score
Patient Global Impression of Change
Patient Global Impression of Severity
Pharmacokinetic(s)
PPS
PRO
pPPS
Per-protocol set
Patient report outcome
Primary Per-protocol set
SAE
SAF
Serious adverse event
Safety analysis set
SAP
SARS-CoV-2
SAS
SFU
STD
TBL
TEAE(s) 
ULN 
VAS
WHO-DD
Statistical Analysis Plan
Severe Acute Respiratory Syndrome Coronavirus 2
Statistical Analysis System
Safety Follow-Up
Standard Deviation
total bilirubin
Treatment emergent adverse event(s)
upper limit of normal (all referring to serum/plasma)
Visual Analogue Scale
WHO Drug Dictionary


Statistical Analysis Plan
BAY 1817080/20584
Page: 5 of 32
1.
Introduction
Endometriosis is a hormone-dependent gynecological disease characterized by painful
symptoms like dysmenorrhea, chronic and non-cyclic pelvic pain, and dyspareunia.
Considering all available treatment modalities, recent data confirm a significant degree of 
unmet medical need, since up to 70 % of treated patients have persistent symptoms like 
chronic pelvic pain that are not sufficiently managed (Bayer market research, 2009; 21,700 
women in 8 countries).
Pathologically the disease is defined by the presence of endometrial tissue outside the uterine 
cavity (endometriotic lesions). The endometrial lesions exhibit signs of inflammation.
BAY 1817080 demonstrated robust efficacy in different in vivo and in vitro models including 
effects on neurogenic inflammation with high relevance for endometriosis. BAY 1817080 is 
an antagonist for the P2X3 receptor that is an important mediator of nociception and other 
disorders with an over-activation of sensory nerve fibers and can be found in nerve fibers of 
endometriotic lesions. Thus, BAY 1817080 is believed to carry the potential to relieve 
endometriosis-associated pelvic pain and improve quality of life of women with 
endometriosis.
This Statistical Analysis Plan (SAP) is based on:

the clinical study protocol BAY 1817080 / 20584, version 3.0, amendment number 2
dated 27 JAN 2022.
2.
Study Objectives
The objective of this study was to identify the optimal dose of P2X3 receptor antagonist BAY 
1817080 in women with symptomatic endometriosis and further assess efficacy and 
characterize safety and tolerability profile of BAY 1817080. 
The primary study objective was to 

assess the dose-response relationship and demonstrate efficacy of BAY 1817080 
compared to placebo in women with symptomatic endometriosis
The secondary study objectives were to 

identify at least 1 superior effective dose of BAY 1817080 compared to placebo

evaluate the safety and tolerability of 3 doses of BAY 1817080 compared to placebo 
and elagolix 150mg in women with symptomatic endometriosis
Other objectives were to

assess efficacy of BAY 1817080 compared to placebo and elagolix 150mg in the 
treatment of EAPP at weeks 4 / 8 and end of intervention period

assess efficacy of BAY 1817080 compared to placebo and elagolix 150mg in the 
treatment of EAPP during days with vaginal bleeding (dysmenorrhea/menstrual 
pelvic pain) at weeks 4/ 8 and end of intervention period

assess efficacy of BAY 1817080 compared to placebo and elagolix 150mg in the 
treatment of EAPP during days without vaginal bleeding (‘non-menstrual pelvic 
pain’) at weeks 4 / 8 / and of intervention period

further describe the patient population, efficacy profile of BAY 1817080 and change 
during the study period using the data collected by patient reported outcomes

assess sustainability of treatment effect and recurrence of symptoms


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
describe sleep and physical activity associated measurements collected with 
accelerometer
A table that lists all primary, secondary, and exploratory objectives with the corresponding 
endpoints can be found in section 3 of the CSP. Additional other objectives listed in the CSP 
refer to analyses that are outside the scope of this SAP, and thus are not described in this 
document.
3.
Study Design
This study is a placebo and active-controlled, double-blind, but open-label for the active 
comparator, randomized, parallel-group multi-center study. The study will be conducted in 
multiple clinical centers across Europe, North America, China, and Japan who take care of 
women with symptomatic endometriosis. An overview of the study design is shown in Figure 
1.
Figure 1: Schema
*Follow-up 2 will be performed additionally in the 1st 50 % of randomized participants only. 
Follow-up 2 will extend to 90±3 days after the last administration of study intervention
Five treatment groups will be investigated: 25 mg, 75 mg, and 150 mg BAY 1817080 
(referred to as low, mid, and high dosage group), placebo group and Elagolix group. The 
subjects will take 4 tablets twice daily (thus, 8 per day), containing BAY 1817080 or 
matching placebo, or 1 capsule once daily, containing 150 mg Elagolix. The treatment 
duration will be 12 weeks (84+3 days).
To achieve 50 evaluable participants for the primary analysis in each treatment arm, 840 
participants were planned to be screened to start study intervention in about 420 randomized 
participants. Among them approximately 28 subjects from Japan with clinically confirmed 
instead of visually confirmed endometriosis and approximately 28 participants from China
were planned to be randomised. None of the two groups will be included in the primary 
analysis.


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The Japanese women with clinical confirmation will not be included as they are deviating 
from the overall population who is included with a surgically confirmed diagnosis. Women 
from China are mainly included to generate further data using the ESD in this population.
All participants that were found to be eligible according to the eligibility criteria assessable at 
screening visit (Visit 1a) will enter the screening period. Eligibility criteria related to the 
endometriosis symptom diary (ESD) will be calculated on the basis of the 28 consecutive 
days starting on the first day with menstrual bleeding (according to the definition given in 
Section 4.5) at or after Visit 1a. Thus, the screening period will last 28 to 70 days to allow for 
slightly irregular menstrual cycles and menstrual bleeding started immediately before the 
screening visit1.
Re-screening is allowed once and only under the conditions stated in the CSP. Repeating the 
28-day period for pain evaluation by the ESD is not explicitly excluded, because of many 
possible special cases that could justify a repetition. Not meeting the pain criteria per se 
provides no justification. Re-screened participant will be assigned a new participant number. 
Eligible subjects will be randomized at Visit 1b. Participants from China and Japan are not
randomized to the Elagolix group. The randomization ratio for the other treatment groups is
set to 1:1:1:1 in China and Japan. A randomization ratio outside of China and Japan of
3:3:3:3:4 (Placebo:25 mg:75 mg:150 mg:elagolix) yields similar sizes of all treatment groups 
overall.
The follow-up period will last for 38±3 days and 90±3 days after the last dose of study 
intervention for all of the randomized participants, respectively.
3.1
Sample Size Determination
Approximately 840 participants will be screened to start study intervention in about 420
randomized participants for at least 50 participants evaluable for the primary analysis (i.e.
included in the pPPS) per intervention group. The primary analysis will not include the
participants enrolled based on visually-confirmed diagnosis, i.e. about half of the women
randomized in Japan, nor all the participants randomized in China, who are mainly included
to generate further data using the ESD in this population. Refer to Section 9.3 for further
information of inclusion of participants into analysis sets.
If blinded data reviews indicate an unexpected high number of screening failures due to the
COVID-19 pandemic, enrollment may be increased.
Sample size calculations were performed for establishing evidence of a drug effect across the
doses, that is, detecting a statistically significant dose response signal for the primary efficacy
outcome in this study using the MCP-Mod approach. They are based on the following
assumptions:

change in mean EAPP under placebo after 12 weeks of -2.3

maximum change in mean EAPP of -1.2 for BAY 1817080 over placebo

standard deviation of 2.5 for all dose groups

a set of plausible dose-response shapes including Emax and sigmoidal Emax models
                                                
1 The investigators are advised to schedule the screening visit during the second half of the menstrual cycle to 
keep the screening period as short as possible.


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(chosen based on literature review and historic in-house data)

random allocation of participants to dose groups according to a 1:1:1:1 ratio,
A sample size of 50 participants per dose groups will have appr. 90% power (averaged across
the set of dose-response shapes) to demonstrate a dose- response relationship, using a 
onesided test at a type I error rate of α=0.10. Approximately 70 participants for primary 
analysis will be randomized to each treatment group to achieve 50 evaluable participants for 
each treatment group.
In addition, 28 participants from Japan with clinical diagnosis, as well as 28 participants from
China will be randomized 1:1:1:1, but will not be included in the primary analysis.
Although not formally included in the sample size determination, the exploratory
elagolix 150mg treatment group is planned to be of about the same size as the other treatment
groups. As participants from Japan and China cannot be randomized to the elagolix 150mg
arm, the randomization ratio outside of Japan and China will be 3:3:3:3:4 (Placebo:25 mg:75
mg:150 mg:elagolix). This will provide similar sizes of all treatment groups overall.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software SAS (release 9.4 or higher; 
SAS Institute Inc., Cary, NC, USA) and ValidR (version 3.5.2 or higher; Mango Solutions 
Ltd., UK)[1].
All variables will be analyzed by descriptive statistical methods. The number of data available 
and missing data, arithmetic mean, standard deviation, minimum, quartiles, median, and 
maximum will be calculated for metric data. Frequency tables will be generated for 
categorical variables. Where appropriate, the individual change from baseline will also be 
analyzed.
Unscheduled/extra assessments (e.g. laboratory data or vital signs) associated with non-
protocol visits will be included in listings, but not in any visit-based summary tables.
In general, confidence intervals (CIs) will be two-sided with a confidence level of 95 %. For 
the primary analysis of the primary efficacy variable only, 80% CIs will be reported in 
addition for consistency with the one-sided α-level of 10%.
4.2
Handling of Dropouts
A randomized participant who 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 participants who prematurely discontinue the study and study intervention for 
any reason, as well as the reasons for premature discontinuation of study and study 
intervention will be reported. 
All dropouts will be carefully evaluated with respect to baseline characteristics. If necessary, 
additional sensitivity analyses may be performed.
The handling of missing data is described in section 4.3.


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4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listings as they are recorded in 
the Case Report Form (CRF), electronic diary (eDiary) or device.
Subjects with missing baseline assessments will be excluded from all analyses that require the 
respective baseline assessment.
If the treatment end date is missing from the eCRF, the last documented exposure date in the 
ESD e-Diary will be used instead.
4.3.1
COVID-19 pandemic-related missing data
Efficacy Variables
Data collected during an active COVID-19 infection (confirmed by a positive SARS-CoV-2 
test by PCR or an AE confirming COVID-19 infection) will be used in the primary efficacy 
analysis as they are not expected to be biased. 
Treatment interruptions and additional pandemic-related reasons for treatment interruption 
will be collected and the time of the interruption will be subtracted from the exposure 
duration (for details see Section 6.4.2).
The number of participants who prematurely discontinue the study and study intervention for 
any pandemic-related reason, as well as the reasons for premature discontinuation of study 
and study intervention will be reported. 
The number of subjects with missed visits and the number of subjects with missing e-diary 
data due to COVID-19 pandemic will be displayed as well as the reason why the visit/ 
assessment was not performed.
4.3.2
Diary data
28-day mean of ESD single items on pain
According to the ESD manual, the 28-day mean of an item asking for pain can be derived if at 
least 15 non-missing entries2 are available (i. e., the number of missing entries is < 50 %).
For calculating the primary efficacy variable only, missing entries on days during a severe
COVID-19 infection as recorded on the adverse event (AE) case report form (CRF) (this 
means in particular that the severity is not missing) will be imputed as described in 
Section 6.2.1 first. Thus, the 28-day will be derived only if the number of observed and 
imputed daily values add up to 15 or more.
Vaginal bleeding intensity
Missing bleeding diary data will be imputed following the sponsor’s instruction on the 
evaluation of bleeding data. 
4-week mean of Endometriosis Impact Scale (EIS) single items
A 4-week average score for a respondent will only be calculated if there are at least 2 not 
necessarily consecutive weeks of non-missing PRO data. This is consistent with the 
                                                
2 By design of the eDiary (ESD and EIS), if one item is missing, all items are missing. The respondents have to 
select an answer for an item in order to move on to the next item.


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requirement of (at least) 50 % of the data to be available for calculating the 28-day mean of 
the ESD single items on pain.
4.3.3
Partially missing start/stop dates
Partially missing start dates/stop dates allow for the true date lying within a certain time 
window that is restricted by the respective stop date/start date and the reporting date. The
partially missing date/s will be imputed by the middle of the related time window in which the 
true date is located.
For partially/completely missing start or end dates of prior/ concomitant medication, a worst-
case assumption is made, i.e. if there is the possibility that the medication was taken during 
the intervention period, it will be classified as “concomitant”.
This worst case assumption will be used analogously for imputing partially missing start dates
and stop dates of AEs. AEs will be classified as treatment-emergent, if possible. On that basis, 
the duration of an AE being classified as severe will be set as long as possible. Thereafter, the 
duration of the classification as moderate will be maximized. Missing intensities will not be 
imputed.
For calculating the primary variable only, the duration of a COVID-19 infection being 
classified as severe will be kept to a minimum of at least 1 day to avoid unjustified 
imputations (see Section 4.3.2).
4.4
Interim Analyses and Data Monitoring
Two interim analysis were planned during the course of the study.
The first interim analyses was to be performed on blinded data and after approximately 50% 
of the study participants had completed the 12-week intervention period in order to further 
validate the PRO instruments used in this study.
The second interim analysis was to be performed on unblinded data once the last participant
had started treatment. These interim results were to be used for planning of Phase 3 studies. 
No final dose decision were to be made at this point in time.
Neither of the interim analyses were planned for stopping for efficacy or futility.
The final analysis for the study will occur at the conclusion of the study. No Type-I error 
adjustment will be made.
As the study was terminated early, none of these interim analyses will be carried out.
4.5
Data Rules
Definition of Baseline
In general, baseline is defined as the last available measurement before start of treatment.
The 28-day baseline period for the ESD items is the last 28 days before start of treatment (e.g. 
-1 to -28). In case these contain less than 15 available entries, the baseline value will be given 
by the last 28 consecutive days before the start of treatment with at least 15 non-missing 
values (e.g. -2 to -29, -3 to -30, -4 to -31 and so on).


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In addition, for daily measurements, if baseline and screening periods overlap, all the 
overlapping measurements will be considered as baseline data.
Definition of Post Baseline
In general, post baseline is defined as the first available measurement after start of treatment.
Intervention period is 84 days, capturing 3 menstrual cycles of 28 days on average. As 
defined in Section 4.3.2, the 28-day mean of an item asking for pain can be derived if at least 
15 non-missing entries are available. 
Therefore, a post baseline value will be given by 28 consecutive days starting from end of 
treatment and counting backwards (e.g. day 84 to day 57 will be cycle 3). If a participant does 
not have 3 full available cycles, the count will start from the last available full cycle with at 
least 15 non-missing entries available (e.g. if two cycles are available, the count will start 
from day 56 to 29).
If a participant has 87 days of measurements, the first 3 measurements on day 1,2 and 3 will 
be discarded. 
In addition, if a participant has more than 87 days of measurement, each data collected after 
day 87 will be discarded.
(Absolute change from) Baseline
To calculate the absolute change from baseline, the baseline value will be subtracted from the 
post-baseline value of interest, i. e.,
Absolute change = post baseline value – baseline value.
PROs data rules
If the weekly EIS questionnaire is administered less than 3 days after starting either Week 1, 
Week 5, 9 or 13 after start of treatment, the collected questionnaires will be counted for the 
previous 28-day cycle. 
For example if a participant has the questionnaire pushed on day 3 after starting her treatment 
period, the responses will be counted as baseline.
If the monthly EQ5D questionnaire is administered less than 3 days after starting either Week 
1, Week 5, 9 or 13 after start of treatment, the collected questionnaires will be counted for the 
previous 28-day cycle.
For example if a participant has the EQ5D questionnaire pushed on day 3 after starting her 
treatment period, the responses will be counted as baseline.
The above rule for the EQ5D will also apply to the follow-up cycles.
Bleeding episode  
The sponsor’s standard procedures defines a bleeding episode as “day(s) with 
bleeding/spotting of which at least one day is of intensity “light” or higher, preceded and 
followed by at least 2 bleed-free days” [2] . Bleeding episodes will be derived from the ESD.
An episode is left censored if it starts at or before day 2 of the diary. Left censored episodes 
are expected to count to the previous cycle / reference period and are therefore ignored in all 


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episode related evaluations. Bleeding / spotting days of left censored episodes are evaluated in 
all day related evaluations as they would for not left censored episodes.
Likewise, for bleeding/spotting on the second last or last study day, the unobservable 
following two bleed-free days will be assumed to be given.
The reason for this is that each bleeding/spotting episode, spotting only episode, or bleeding 
free interval is attributed to the reference period in which it begins.
In addition, if a participant does not experience any bleeding days during the 28-day cycle, 
the observations collected will not be assessed for the dysmenorrhea endpoint.
Numerical coding of ESD values when response is not expected by design
The ESD device is programmed such that items 2 (worst constant pain) and 3 (worst short-
term pain) are not administered if the participant reports no pain for item 1 (pain at its worst). 
Based on the logical relation of the questions, the values for items 2 and 3 will be set to 0
when item 1 = 0.
COVID-19 infection
The start of an active COVID-19 infection is defined as the date of the first positive SARS-
CoV-2 RNA test or the start date of the AE confirming the COVID-19 infection, whichever is 
earliest. For participants with documented vaccination against COVID-19 during the study, 
positive serology IgG tests post vaccination will not be considered an active COVID-19 
infection.
For the relevant MedDRA preferred terms see Appendix 3 [3]
The distinguishment of P2X3 related taste AEs from COVID-19 related smell/taste symptoms 
will be done by individual patient review based on the details of smell/taste disturbance 
assessments, the SARS-CoV-2/serology IgG test results, the AEs confirming COVID-19 and 
the timing information. 
Rescue Medication
Ibuprofen rescue medication will be reported as 400mg. For the country in which this is 
collected as 200mg (Japan and USA), the number of tablets collected will be divided by 2.
Repeated measurements at the same visit
If more than one measurement flagged as valid for analysis is available for a given visit, the 
valid measurement closest to the start of treatment will be used in the data summaries. This is 
the last valid measurement before and the first valid measurement after the start of treatment
visit. In the data listings, all observations will be presented.
Data Rules for laboratory measurements
For lab values reported as “<x”, “<x.x”,“ <x.xx” or etc. the value for analysis used will be 
derived by “x/2”, “x.x/2”,“ x.xx/2” etc . For lab values reported as “>x”, “>x.x”,“ >x.xx” or 
etc. the value for analysis used will be derived by increasing the last digit by 1.


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4.6
Blind Review
The purpose of the blind review is to provide documentation of important deviations from the 
protocol and validity findings and the resulting assignment of subjects to the analysis sets (see 
section 5.1). This will be done according to the sponsor’s applicable operational instruction
[4][2]. The definition for important deviations and validity findings will be set down in the 
specification of assessment criteria and identification requirements before the blind review’s 
closure.
Any changes to the statistical analysis prompted by the results of the review of study data will 
be documented in an amendment and, if applicable, in a supplement to this SAP before 
unblinding the data.
The blind review includes the continued monitoring of the number of participants who 
contracted COVID-19 (see Section 4.5), those otherwise affected by the pandemic (i. e., 
pandemic- related administrative reasons), and the related amount of missing data relevant for 
the primary analysis, including premature discontinuations of the study (treament). The 
impact of the amount of missing data on the power of the primary analysis may be assessed 
by running simulations. Patient characteristics of participants with pandemic-related missing 
data may be compared with those of participants with observed data. The latter two analyses 
will not be reported.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of participants to analysis sets will be made during 
the blinded 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).
Enrolled
                        
All participants who sign the Informed consent form (ICF).
Full analysis set (FAS)
All participants randomly assigned to study intervention. Participants will be analyzed 
according to the intervention they were randomized to.
Safety analysis set (SAF)
All participants randomly assigned to study intervention and who take at least 1 tablet of 
study intervention. Participants will be analyzed according to the intervention they actually 
received. If participants received different interventions throughout the course of the study, it 
will be decided in the assessment meeting on a case-by-case decision which group they will 
be assigned to for the final analysis. These participants will be excluded from the unblinded
interim analysis. 
Primary full analysis set (pFAS)
Subset of FAS, containing all participants with surgically confirmed endometriosis and 
outside China randomly assigned to study intervention. Participants will be analyzed 
according to the intervention they were randomized to. 
Per protocol set (PPS)


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All participants randomly assigned to study intervention, who take at least 1 tablet of study 
intervention, and who have no validity findings affecting efficacy. 
A list of potential validity findings will be provided in a separate important deviations and 
validity specifications document (Assessment Criteria and Identification Requirement 
(ACIR)) which will be finalized before unblinding. The assignment of participants to this 
analysis set will be based on the assessment meetings. 
The participants with missing baseline ESD item 1 (as defined in 4.5) or no valid post-
baseline 28-day average of ESD item 1 will be excluded from the PPS.
Due to the repeated measurements design of the study a participant dropping out of the study 
may still be evaluable for efficacy and will therefore not be automatically excluded from PPS.
Participants will be analyzed according to the intervention they actually received. If 
participants received different interventions throughout the course of the study, they will be 
excluded from the PPS.
Primary Per Protocol Set (pPPS)
Subset of the PPS containing all participants in the PPS with surgically confirmed 
endometriosis and outside China.  The analyses performed on the pPPS are chosen to be the 
primary one.
The PPS and pPPS will be used for all non-safety analyses and the separate 
pharmacodynamics analyses. 
Pharmacokinetic Analysis Set (PKS)
All participants who took at least 1 dose of study drug and had at least 1 available 
pharmacokinetic sample.
Listing Only Set (LOS)
This set contains all screening failures. It will be used for listing purposes only.
The primary and secondary efficacy endpoints will be analyzed using the pPPS. The safety 
endpoints will be analyzed using the SAF. All other endpoints will be analyzed on the FAS, 
unless specified otherwise.
digitalBIO Analysis Set (DAS)
All participants who consented to take part in the actigraphy sub-study with any amount of 
actigraphy data available will be included in the Digital Measures Analysis Set. Participant 
may be included or excluded from particular analyses depending on the extent of available 
data. Participants will be analyzed according to the intervention they were randomized to.
6.
Statistical Methodology
6.1
Population characteristics
All variables in this section will be analyzed descriptively. The analyses will be based on the 
FAS and pPPS, unless otherwise specified. 
Any table displaying demographics and baseline characteristics will be repeated for the 
following COVID-19 pandemic related subgroups:


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all randomized subjects affected by COVID-19 pandemic related study disruption 
all randomized subjects with COVID-19 adverse event and/or positive SARS-CoV-2 PCR test 
and/or positive serology IgG test after start of treatment
6.1.1
Subject disposition and validity
All except one table in this section will be based on all enrolled subjects.
For each investigator, the number of screening failures and the number of protocol deviations 
and prematurely discontinuations of randomized subjects will be presented in total and per 
individual treatment group. The screening failures, discontinued subjects and protocol 
deviations will be listed along with the reasons, where applicable, each. In particular, the 
number of participants who prematurely discontinue the study for any COVID-19 pandemic-
related reason, as well as the reasons for premature discontinuation of study will be reported. 
An additional listing will show the inclusion and exclusion criteria not met.
Participants who completed the study will be summarized. A participant completed the study 
if she completed all phases of the study including the last visit.
In addition, a disposition summary by study period (epoch), i.e. screening, treatment, and 
follow-up, will show the number of subjects completing the respective epoch and the number 
of subjects discontinuing it prematurely including information of the reasons for 
discontinuation. The table will include COVID-19 pandemic associated reasons for 
discontinuation, i.e. the information whether decision for discontinuation was made by the 
participant, the physician or was due to logistical reasons. An overview of the subject 
disposition including the number of participants who received at least one dose of study drug 
will be given overall and by treatment group.
For each investigator, the number of randomized participants valid for the SAF, the FAS, the 
PPS and the PKS will be presented in total and per treatment group. 
An overview of the subject validity and the primary reasons for exclusion from the respective 
analysis set will be given overall and by treatment group for the FAS only. A listing of the 
subjects’ assignment to the (p)FAS, (p)PPS, SAF and PKS and the reasons for exclusion will 
also be provided by treatment group.
6.1.2
Demographics and Baseline Characteristics
The following demographic data and baseline characteristics will be summarized:
Age at baseline (years);
Age category (<30years vs 30-40years vs >40-55years);
Race;
Ethnicity;
Height (cm);
Subject rescreened;
Natural hair color (at age 18);
Main eye color;
Weight (kg) at baseline;
BMI (kg/m²) at baseline;
Reproductive and menstrual history;


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Endometriosis history/characteristics

Age at first endometriosis treatment (medical or surgical whatever is 
earlier);

Previous medical treatments;

Number of surgeries;
Baseline pain

Mean worst pain;

Nonmenstrual pelvic pain (NMPP);

Dysmenorrhea;
Bleeding characteristics;
Baseline scores of EIS.
Demographic variables and baseline characteristics will be summarized using descriptive 
statistics and will be reported for the FAS and PPS.
6.1.3
Medical history
Medical history findings will be coded according to the latest effective version of the Medical 
Dictionary for Regulatory Activities (MedDRA), Medical history findings (id est, previous 
diagnoses, diseases or surgeries starting before signing of the informed consent) considered 
relevant to the study will be summarized by primary system organ class (SOC) and preferred 
term overall and per treatment group. The table will be calculated based on the SAF and the 
FAS, respectively. 
6.1.4
Prior and concomitant medication
The number of participants that used prior and concomitant medication will be analyzed using 
frequency tables based on classified data. The classification will be done according to the 
World Health Organization Drug Dictionary (WHO-DD) and Bayer Drug Grouping (BDG).
This includes a classification of the substances which will be used for presentation, such as 
medication prohibited due to potential drug-drug interaction (E.g. Analgesia producing opiods 
and Nonsteroidal anti-inflamatory drugs (NSAIDs).
The tables will display the following three categories: prior, prior/concomitant and post-
treatment.
Regarding medication data collected during the study course, the following rules will be 
implemented: 
If the stop time of medication is before the time of the first study drug administration, then 
medication is considered to be prior medication.
If the start time of medication is before or at the time of the first study drug administration 
and the stop time of medication is after or at the time of the first study drug administration 
then the medication is considered to be concomitant medication.
If the start time of medication is at or after the time of the first study drug administration and 
earlier than 14 days after or at the time of the last study drug administration, then the 
medication is considered to be concomitant medication.
If the start time of medication is later than 14 days after the time of the last study drug 
administration, then the medication is considered to be post-treatment medication.


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If time information is missing but only date information is given, then classification of 
medication as prior or concomitant will be done by date information only. In such case, if the 
start day of medication is the same date as the first study drug administration, then the 
medication will be classified as concomitant medication.
Analysis of prior and concomitant medication will be performed on the SAF. Prior, 
concomitant and post-treatment medication will be shown by treatment group and total. 
6.2
Efficacy
6.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined below along with other attributes of the primary 
estimand.
Primary Estimand
Endpoint: The primary efficacy variable will be the absolute change in mean worst EAPP 
from baseline (last 28 days before the first intake of study drug) to end of intervention (last 28 
days ending with the last intake of study drug planned on Day 84 (+3)). The worst EAPP will 
be measured daily on the NRS by item 1 of the ESD. The time frame of 28 days captures a 
menstrual cycle on average. For more details on how to derive the mean values over 28 days 
see Section 4.5.
Summary measure: A population-level treatment group summary is an estimated model-
based group mean of the primary endpoint’s values adjusted for region (Japan vs. ROW 
excluding China) and a baseline EAPP. Treatment effect will be evaluated as a difference 
between group means.
Treatment: The investigated treatments will be BAY 1817080 25 mg or 75 mg or 150 mg or 
placebo, plus standardized rescue medication taken for any reason.
Population: The target population is comprised of women with surgically confirmed
symptomatic endometriosis as further defined by the inclusion/exclusion criteria described in 
the study protocol.
Intercurrent events (IEs):
a) Early discontinuation of study intervention: 
o
The IEs of premature discontinuation of study treatment due to a non-COVID-
19-related AE and a premature discontinuation of study treatment due to a lack 
of efficacy will be considered as treatment failure and as such addressed by the 
composite strategy. The baseline value and the pre-discontinuation value will 
be considered as representative of the unfavorable outcomes associated with
these events, respectively. Returning to baseline pain level is considered to be
a clinically plausible outcome for participants not being able or willing to take 
the study treatment because of an AE and is considered to be an unfavorable 
outcome. The pre-discontinuation value reflects the pain level that the 
participant feels unfavorable enough to discontinue the study treatment due to 
a lack of efficacy.
For premature discontinuation of study treatment due to a non-COVID-19-
related AE, the baseline value will be imputed as:


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a) If at least 15 observations are collected in the cycle in which the IE 
occurs: a weighted average of the observed values and the baseline 
value will be calculated for the current cycle, with the weights being
number of available days divided by 28 days and number of missing 
days divided by 28 days. The baseline value will be used for the 
subsequent cycles.
b)
If less than 15 observations are collected in the cycle in which the IE 
occurs: the baseline value will be used for this and the subsequent 
cycles.
For premature discontinuation of study treatment due to a lack of efficacy the 
last observation will be carried forward.
o
The IEs of early discontinuation of the study intervention due to any other 
reason, including COVID-19 related reasons, will be addressed by the 
hypothetical strategy. The assumed hypothetical scenario is that participants 
would not discontinue the study treatment at that time and would have similar 
outcomes as other ptextarticipants in the study. If a participant continues
completing the e-diary, the information included after the IE will be discarded.
b) The IEs of non-compliance with study intervention will be addressed using the 
treatment policy strategy: compliance will be calculated for each period between two 
consecutive visits. If the compliance is too low (i.e. below 80%), or too high (i.e. 
>120%, which is highly unlikely) for some but not all post-baseline cycles, the data 
collected during these no-compliant periods will be used as observed. 
c) Increased and decreased intake of standardized rescue medication taken for EAPP and 
taken for any other reason than EAPP will be addressed by the treatment policy 
strategy. Earlier trials suggest that the intake of standardized rescue medication taken 
for EAPP is expected to be low. Any change in intake of standardized rescue 
medication taken for either EAPP or other reasons is considered as part of a general 
background treatment. Consequently, the treatment policy strategy will be used, and 
the standardized rescue medication is specified as part of the treatment attribute.
Other potential IEs (e. g. pregnancy or death due to any cause, including COVID-19 infection,
or surgery) are considered to be unlikely. The occurrence of unexpected IEs will be evaluated 
during the blinded review and the estimand definition will be amended if needed.
6.2.1.1
Primary efficacy Analysis 
The primary analysis will be performed on the pPPS analysis set as defined in Section 5.1.
For the primary efficacy variable, it is planned to perform a test for a dose-response signal in 
the study population, under the assumption of a monotone dose-response relationship in the 
dose range considered. The MCP-Mod method [5] combining multiple comparison 
procedures principles with modeling techniques (MCP-Mod) will be used for the primary 
analysis of the primary efficacy variable. This method allows the flexibility of modeling for 
dose estimation, while preserving the robustness to model misspecification associated with 
MCP procedures. More specifically, it is planned to use a generalization of the original MCP-


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Mod method which allows to perform dose-response testing and modeling in conjunction with 
the response variable being described by a parametric model [6].The key idea of this 
generalization is to decouple the dose-response model from the expected response so that the 
dose response can be characterized using a suitable parameter in the probability distribution 
of the response.
Assumptions
It is assumed that the primary efficacy variable, denoted as , is measured at the patient level 
for the 4 parallel groups corresponding to dose levels: (placebo =) 1 < 2 < … < K, where 
K = 4.
Furthermore, assume that the probability model for the patient responses  includes 
parameters , . . . ,  for the changes from baseline in the primary endpoint capturing the 
dose-response effect for the doses 1, 2 , … , K. This probability model may depend on 
other (nuisance) parameters and covariates and is described in detail further below. 
Subsequently, it is assumed that the dose-response parameters ,  = 1, … ,  are related 
through a dose-response model  = (d, ) where (. ) is parameterized by a vector of 
parameters .  
Let  = (̂, . . . , ̂) denote the vector of estimated dose-response parameters obtained 
from a parametric model of . The key assumption for the generalized MCP-Mod method is 
that  has an approximate distribution (, ), where  denotes the variance-covariance of . 
The estimates for  and  are obtained first, while the estimation of  is done in a separate,
second stage based on  and . 
The candidate set of models consists of the  = 4 models given by
(, ) =  ! +  #!(, !) = −2.3 + '()*+ ,'-.!
+ + +/
⁄
,
where  is the dose ranging from 0 mg to 150 mg,  ! is a location parameter, and  # is a scale 
parameter such that only ! determines the shape of the model function,  where ! is used to 
denote parameters associated with !(. ) component. Guestimates for parameters  assumed 
at the trial design stage are listed in Table 1. The two '()* models and the two sigmoidal 
'()* models assume a strictly monotonically decreasing dose-response, the illustration of 
which is provided in the Figure 9–1 in the clinical study protocol.
Table 1: Parameters of the dose-response-curves in the candidate set
Model
Parameters
Abbreviation
Indicator 1
2345
2167
Hill factor 8
emax1
1
25
-1.4
1
emax2 
2
100
-2.0
1
sigEmax1
3
35
-1.2
3
sigEmax2
4
75
-1.2
5
Analysis
Step 1: Estimation of  and  from a mixed model for repeated measures with covariate 
adjustment


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The expected dose response at the tested dose levels will be captured by the adjusted model-
based treatment group means of the primary variable’s values obtained from a mixed model 
for repeated measures (MMRM). Absolute change in mean worst EAPP from baseline to each 
post-baseline time point will be modeled as the dependent variable. The model will include 
fixed effects for treatment group (four treatment groups: placebo group and 25 mg, 75 mg, 
and 150 mg BAY 1817080), time point (Visits 3, 4, and 5), time point by treatment group 
interaction, region (Japan vs. ROW excluding China), and baseline EAPP as continuous 
covariate. An unstructured variance-covariance pattern will be used to model variance-
covariance of the within-subject errors. This variance-covariance matrix will be estimated 
across treatment groups. In case the model does not converge, alternative variance-covariance 
structures will be considered. Variance-covariance parameters will be estimated using 
Restricted Maximum Likelihood (REML) with the Newton-Raphson algorithm and using 
Kenward-Roger method for calculating the denominator degrees of freedom and adjusting 
standard errors. 
Least squares means for each treatment group at Visit 5 will be estimated from the time point 
by treatment group interaction term together with their variance-covariance matrix and will 
represent  and , respectively. The 80% CIs will also be estimated. 
Absolute change in mean worst EAPP from baseline to post-baseline Visits 3, 4, and 5 may be 
missing for some participants due to a lack of compliance with eDiary completion. All such
missing data and data that are unobservable after IEs intended to be addressed by a 
hypothetical strategy, as described in the primary estimand definition in Section 6.2.1, will be 
assumed to be Missing at Random (MAR) and will be modeled as such using the MMRM 
described above. That is, values of subjects with missing and unobservable data will be 
assumed to be distributed similarly to subjects with observed data in their treatment group 
conditional on the covariates included in the model and on partially observed data.
MMRM analysis will be implemented using SAS Proc MIXED.
Step 2: Detection of dose-response signal
For detecting an overall trend, or a dose-response signal, each of the M = 4 dose-response 
shapes in the candidate set will be tested, using a single contrast test.
For each model m in the candidate set 
the null hypothesis
9!(: (;()< = 0
will be tested against 
the respective 1-sided alternative hypothesis,
9#(: (;()< > 0
where ;( = (?(#, … , ?(@)< is the optimal contrast vector representing model m. 
The optimum contrast coefficients and critical values for the four contrast tests on the dose-
response shapes will be derived based on the guestimates for parameters ! of standardized 
versions of the models in the candidate set specified at the design stage, the actual sample size 
for each treatment group after study completion, and the covariance matrix  estimated from 
actual data using the MMRM described above [6].
Each dose-response model m will be tested using a single contrast test: 


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A( = (;()< /C(;()<;(D1,1
E/F
where [H]1,1 denotes the mth diagonal element of the matrix H.
The final detection of a dose-response signal is based on the maximum contrast test statistic 
A()* = max(A# , … , AM) and can be concluded if A()* > N#OP, where N#OP is the multiplicity 
adjusted critical value at level Q = 0.1. The MCP-Mod method takes multiplicity into 
account, and no further multiplicity adjustments are needed. 
If no candidate model is statistically significant, the procedure stops indicating that a dose-
response relationship cannot be established from the observed data. If, on the other hand,
there is one or more models with a significant adjusted p value, these significant models will 
be retained and fitted as described in the next step. 
Step 3: Modeling and estimation of target doses
The selected dose-response models (with a significant dose-response trend detected at the 
previous step) will be fitted to  and  to estimate the model parameters  using a generalized 
least squares (GLS) estimation criterion [6].
If multiple models have significant adjusted p-values at Step 2 and can be successfully fitted 
(without convergence or numerical stability issues), final inference will be based on the model 
with the best fit as determined by the AIC criterion. 
To estimate the target dose(s) of interest the minimal effective dose (MED) will be 
determined: 
'- = RSTUVW(XYX#,XM)Zf\,,  ]/ > f\,#,  ]/ + ∆}
where f\(,  ]) is the best estimated model and ` is the smallest relevant difference, by which a 
dose is expected to be better than placebo in terms of efficacy measured by the primary 
efficacy variable.
The MED will be provided for the following smallest relevant differences:
∆= clinically meaningful threshold (e.g. -1)
∆= the observed effect of Elagolix in the study
The final choice of the target dose will be based on the analyses of the primary, secondary,
and other efficacy variables, as well as safety considerations
MCP-Mod related steps 2 and 3 will be performed using the R “DoseFinding” package 
(version 0.9-17 or higher) [7].
The level of significance for statistical testing is set to 10 % one-sided. The type I error will 
be controlled for the primary analysis only. 
In consistency with the one-sided level of significance given the generally two-sided reporting 
of CIs, 80 % CIs will be reported for the primary analysis and its related 
sensitivity/supplementary analyses in addition to 95 % CIs.
6.2.2
Secondary efficacy endpoint
The same estimand as the primary efficacy estimand - except the endpoint - will be used for 
the secondary efficacy endpoints analyses. The IEs a), b) and c) will be handled as described
in section 6.2.1.


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For the identification of at least 1 superior effective dose of BAY 1817080 compared to 
placebo in terms of the absolute change in mean worst EAPP from baseline to end of 
intervention, estimates and CIs will be derived from MMRM. The mean worst EAPP at 
baseline, the region (Japan vs. ROW excluding China) visit and treatment*visits are set as 
covariates.
Summaries will be provided by treatment group and overall. Analyses will be performed 
including the Elagolix population arm.
6.2.3
Other endpoints
The descriptive analyses of the other endpoints described in the following subsections will be 
based on the FAS and presented by treatment group.
6.2.3.1
Endpoints on the worst EAPP
Absolute change in mean worst EAPP from baseline to the first 4 weeks/8 weeks of 
intervention/end of intervention (measured daily on the NRS by item 1 of the ESD)
Absolute change in mean worst EAPP from end of intervention to non-overlapping, 
consecutive 28-day intervals during follow-up (measured daily on the NRS by item 1 of the 
ESD)
Absolute change in mean worst EAPP on bleeding days from baseline to the first 4 weeks/8 
weeks of intervention/end of intervention (measured on the NRS by item 1 and item 4 of the 
ESD)
Absolute change in mean worst EAPP on bleeding days from end of intervention to non-
overlapping, consecutive 28-day intervals during follow-up (measured on the NRS by item 1 
and item 4 of the ESD)
Absolute change in mean worst EAPP on non-bleeding days from baseline to the first 4 
weeks/8 weeks of intervention/end of intervention (measured on the NRS by item 1 and item 
4 of the ESD)
Absolute change in mean worst EAPP on non-bleeding days from end of intervention to non-
overlapping, consecutive 28-day intervals during follow-up (measured on the NRS by item 1 
and item 4 of the ESD)
6.2.3.2
Rescue medication
The overall amount of rescue medication during the days considered for pain evaluation will 
be summarized by treatment group and by 28-day time window.
6.2.3.3
Other HRQoL and PRO associated endpoints

Descriptive assessment will be done on the basis of the VAS and on dimension level 
assessment basis. 
Frequency tables providing the number and percentages of the different response 
options to individual questions will be displayed. In addition, changes from baseline 
for the single questions will be displayed with shift tables by treatment.
The EQ visual analogue scale (VAS) values of the EQ-5D-5L and their changes to ue 
baseline will be summarized by treatment as continuous variable; arithmetic mean, 
SD, minimum, quartiles, median and maximum will be displayed by treatment.
The scoring algorithm described in the EQ-5D-5L manual will be used.

EIS single items, EIS physical subscale, EIS emotional subscale, and the eight
remaining EIS individual items during baseline, at weeks 4/8/end of 


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intervention/FUP1/FUP2 and absolute change from each week after start of 
intervention to baseline. Full details of scoring algorithms and transformation of 
domain scores and single item scores are provided in Section 8 Appendix 1.

VAS for pelvic pain at baseline, at weeks 4/8/end of intervention/FUP1/FUP2 and 
absolute change from each visit after start of intervention to baseline

Patient Global Impression of Change (PGI-C) and change from baseline in Patient 
Global Impression of Severity (PGI-S), at visit 3, 4 and 5. Frequency tables providing 
the number and percentages of the different response options to individual questions 
will be displayed for PGI-S and PGI-C. In addition, changes from baseline for PGI-S 
and changes from Visit 3 for PGI-C will be displayed using shift tables for the single 
questions.

PAQ (Productivity Activity Questionnaire). single items at screening and end of 
intervention; absolute change of PAQ individual items from end of intervention to 
screening

PainDETECT single items and total score at baseline, end of intervention/FUP1/FUP2
and absolute change from end of intervention/end of follow-up to baseline for numeric 
items and shift tables for categorical items.

PCS single items, subscales, and total score at baseline

Absolute change in PSQ3 single items from end of intervention to baseline
These summary statistics and difference to baseline will be presented by treatment.
6.3
Pharmacokinetics/pharmacodynamics (PK/ PD)
BAY 1817080 plasma concentrations will be summarized by intervention group, visit, and 
planned sampling time. Box-plots showing  plasma concentration vs timepoint will be created
for each intervention, highlighting patients who fullfil the criteria for close liver observation.
6.4
Safety
All variables in this section will be analyzed descriptively based on the SAF.
6.4.1
Adverse events (AEs)
All AEs will be collected from signing the informed consent until the SFU visit.
A treatment-emergent AE (TEAE) is defined as any event arising or worsening after the start 
of study drug administration until 14 days after the last study medication intake.
The incidence of TEAEs will be assessed as secondary safety endpoint. The incidence of AEs 
and TEAEs will be analyzed by descriptive statistics, such as frequency tables. 
An overall summary of the number and percentage of participants with AEs and TEAE will 
be presented. In addition, all AEs and TEAEs will be tabulated according to the affected 
system organ class and preferred term, as coded by the Medical Dictionary for Regulatory 
Affairs (MedDRA). 
The frequency of the AEs related to potential and identified risks of Eliapixant will be 
displayed. Regarding the identification specifications for these AEs, the following SMQs and 
PTs will be applied:
1. SMQ “Taste and smell disorders”


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2. SMQ “Hemorrhages”
3. MLG Hypotension

PT: Blood pressure ambulatory decreased;

PT: Blood pressure decreased;

PT: Blood pressure diastolic decreased

PT: Blood pressure systolic decreased;

PT: Diastolic hypotension

PT: Hypotension; 

PT: Mean arterial pressure decreased 

PT: Heart rate decreased

PT: Bradyarrhythmia

PT: Bradycardia

PT: Sinus bradycardia

PT: Dizziness

PT: Dizziness postural

PT: Dizziness exertional

PT: Syncope

PT: Presyncope

PT: Loss of consciousness

PT: Blood pressure orthostatic decreased;

PT: Orthostatic hypotension;
4. SMQ “Drug related hepatic disorders - comprehensive search”
Further tables will be provided for serious and/or drug related TEAEs. Tables for non-serious 
TEAEs will also be provided.
In addition, a separate table summarizing TEAEs that occurred in more than 5% of the 
subjects will be provided.  
The incidence of all AEs during pre-treatment and during post-treatment (that is, AEs 
occurring more than 14 days after end of treatment with study drug) will be tabulated 
separately.
The summaries will be tabulated by intervention group and overall.
Serious adverse events, deaths and adverse events leading to discontinuation will be listed. 
The date, relative day (to study intervention) and treatment-emergent flag will be included.
Further summaries of adverse events by intensity and worst outcome, may be provided, 
consistent with Bayer Global Medical Standards.
6.4.1.1
Taste-related and smell-related AEs
Impairment or loss of smell and/or taste is a common symptom of COVID-19. Taste-related/ 
smell-related AEs as well as the responses to the questions of the taste/smell disturbance 
assessments will be analyzed using descriptive statistics.


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To distinguish P2X3 related taste AEs from COVID-19 related smell/taste AEs the details of 
smell/taste disturbance assessments will be evaluated together with the SARS-CoV-
2/serology IgG test results, the AEs confirming COVID-19 and the timing information by 
individual patient review.
SMQ “Taste and smell AEs” has 14 MedDRA PTs, these will be devided in two cateogires 
one for “Taste AEs” and one for “Smell-Related AEs” as follows:
The following preferred terms will be combined into the “Taste AE” - category: 
PT: Ageusia
PT: Dysgeusia
PT: Gustometry abnormal
PT: Hallucination, gustatory
PT: Hypergeusia
PT: Hypogeusia
PT: Taste disorder
The following preferred terms will instead be included in the “Smell-related AEs” category: 
PT: Anosmia
PT: Congenital anosmia
PT: Hallucination, olfactory
PT: Hyposmia
PT: Olfactory nerve disorder
PT: Olfactory test abnormal
PT: Parosmia
Taste- and smell-related AEs, along with responses about frequency and bothersomeness, will 
be analyzed using descriptive statistics.
In addition, the dose-dependency of taste-related AEs will be assessed using a logistic 
regression model with treatment as factor. The odds ratio and its 80% and 95% confidence 
intervals, and the p-value for treatment comparisons from the logistic regression model will 
be provided. Only taste-related AEs that cannot be attributed to a SARS-CoV-2 infection will 
be considered for the model.
6.4.2
Study Treatment Duration and Exposure
Study treatment duration and the average daily dose will be summarized overall for SAF. The 
duration of study treatment (in days) is derived by the following formula:  
last dose date – first dose date + 1- number of days treatment was interrupted due to COVID-
19 pandemic-related reasons.
Descriptive statistics of treatment duration will be presented.
The number of tablets taken will be summarized descriptively by treatment group and overall. 
Using the drug accountability data, the average daily dose for overall study is calculated for 
subjects on active treatment based on the following formulas depending on the treatment arm:
For the 25mg treatment arm


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25mg ·
1
3 · Total Number of 25mg tablets taken
min(last tablets returned date, last treatment intake date) − first tablets dispensed date
For the 75mg treatment arm
25mg ·
Total Number of 25mg tablets taken
min(last tablets returned date,   last treatment intake date) − first tablets dispensed date
For the 150mg treatment arm
25mg ·
2
3 · Total Number of 25mg tablets taken
min(last tablets returned date,   last treatment intake date) − first tablets dispensed date
+100mg ·
Total Number of 100mg tablets taken
min(last tablets returned date,   last treatment intake date) − first tablets dispensed date
For the Elagolix arm
150m ·
Total Number of 150mg Elagolix tablets taken
[min(last tablets returned date,   last treatment intake date) − first tablets dispensed date) + 1]
Overall Compliance will be calculated as
Total Number of 25mg tablets taken +  4 · Total Number of 100mg tablets taken
14 · (min(last tablets returned date,   last treatment intake date) − first tablets dispensed date) .
In addition, overall Compliance for the Elagolix arm will be calculated as
Total number of 150mg  Elagolix tablets taken
[min(last tablets returned date,   last treatment intake date) − first tablets dispensed date) + 1] .
Compliance between visits will be calculated as
Number of 25mg tablets taken between visits +  4 · Number of 100mg tablets taken between visits.
14 · (min(tablets returned date; last treatment intake) at Visit x − tablets dispensed date at Visit (x −1))
If compliance between two consecutive visits cannot be determined (e.g., if a participant does 
not return medication at the scheduled time), then compliance will be averaged across the 
periods that are affected.
For between-visit compliance, periods from unscheduled visits are assigned to nearest 
scheduled between visit periods.
The compliance will be summarized descriptively by treatment group and overall. In addition, 
compliance will be categorized into three groups (< 80%, 80-120%, > 120%) and summarized 
by treatment group and overall.


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6.4.3
Liver Function Laboratory Parameters
The number of participants with laboratory abnormalities will be provided for SAF for the 
following liver function laboratory parameters. The table will be provided for both baseline 
and post-baseline measurements. The measurements from both scheduled / unscheduled visits 
will be used. The ratio to the upper limits of normal (ULN) will be used for these parameters.

Alanine aminotransferase (ALT): > 2xULN – ≤3xULN, > 3xULN – ≤ 5xULN, > 
5xULN – ≤ 8xULN, > 8xULN

Aspartate aminotransferase (AST): > 2xULN – ≤3xULN, > 3xULN – ≤ 5xULN, > 
5xULN – ≤ 8xULN, > 8xULN

Total bilirubin (TBL): > 2xULN

alkaline phosphatase (AP): ≥ 1.5xULN

γ-GT (gamma GT): ≥ 2xULN

International normalized ratio (INR): > 1.5xULN
In addition, frequency tables based on categories above and box plot for measurements over 
time by visit will be provided.
The number of participants with postbaseline elevated liver values according to the following 
criteria will be provided:

> 3xULN of ALT or AST accompanied (using the values taken from the same serum 
sample) by > 2xULN of TBL, or

> 3xULN of ALT or AST accompanied by > 1.5xULN of INR, or 

participants who reported unspecific symptom (fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever, rash and/or eosinophilia) with the CRF 
pages: Clinical Signs and Symptoms with elevated liver enzymes / Clinical Signs and 
Symptoms with elevated liver enzymes (Follow-up) 

For participants with eosinophilia, only the case if their measurement of 
laboratory parameter of Eosinophils/Leukocytes > 5% will be included into the 
analysis.
A subject listing will be provided for those participants.
The eDISH plot (maximum of ALT postbaseline value × maximum of TBL postbaseline 
value) will be provided. A line plot of AP, ALT, AST and TBL over time will be provided for 
participants with liver injury (ALT>5xULN).
6.4.4
Other safety variables
6.4.4.1
Laboratory parameters
Quantitative data (e.g. laboratory parameters) will be described by the following summary 
statistics: arithmetic mean, standard deviation, quartiles, median, minimum, and maximum.  
Safety parameters with categorical data will be summarized by reporting number and percent 
of participants under such categories.
These summary statistics and the difference to baseline (i.e. pre-dose measurements, 
performed before the first administration of the study medication) will be presented by 
intervention.  


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Subjects with abnormal laboratory values (values out of the reference range) will be 
summarized using shift tables comparing the baseline to post-baseline measurements by 
timepoint and also for the worst post-baseline measurement. The worst post baseline 
measurement includes all post baseline values including laboratory values from unscheduled 
visits.
Frequency tables will be provided for qualitative data. Laboratory data outside the reference 
range will be listed and flagged with ‘L’ for low and ‘H’ for high.  Additional tables with all 
abnormal values will be presented.
The results of the SARS-CoV-2 tests will be displayed descriptively.
6.4.4.2
Menstrual bleeding pattern
For the analysis of bleeding pattern, the following measures will be derived based on ESD 
item 4 and analyzed using descriptive statistical methods overall and by treatment group: 
1) number of bleeding / spotting days 
Number of days where ESD item 4 is spotting, light, normal, or heavy within the respective 
28-day reference period. 
2) number of bleeding days (excluding spotting-only days) 
Number of days where ESD item 4 is light, normal, or heavy within the respective 28-day 
window. 
3) number of spotting-only days 
Number of days where ESD item 4 is spotting within the respective 28-day window. 
4) number, mean length, and maximal length of bleeding / spotting episodes 
According to (2), an episode is defined as consecutive days where ESD item 4 is spotting, 
light, normal, or heavy, preceded and followed by at least 2 days without bleeding, i.e. ESD 
item 4 is none. The number, mean length and maximal length for the respective 28-day 
window will be calculated. 
5) number, mean length, and maximal length of spotting-only episodes 
According to (2), an episode is defined as consecutive days where ESD item 4 is spotting, 
preceded, and followed by at least 2 days without bleeding, i.e. ESD item 4 is none. Episodes 
of length 1 are possible. The number, mean length and maximal length for the respective 28-
day window will be calculated.
6.4.4.3
Cervical smear
A frequency table for cervical smear findings will be produced by treatment group and visit 
(Visit 1 and FUP). A listing will be provided with the cytology Cervical smear High risk 
HPV-DNA results at screening visit and at FUP visit for each participant. 
6.4.4.4
Pregnancy testing
Both Highly sensitive urine pregnancy test (β-hCG) and urine pregnancy tests will be 
summarized by the number of women taking a pregnancy tests and the test results.
A listing of pregnancy tests which summarizes the date of pregnancy test, the type (i. e.,
urine, serum, or home pregnancy test) and the result will be summarized. Listing of 
participants with positive pregnancy tests will be provided.


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6.4.4.5
Vital signs
Vital signs (heart rate, systolic blood pressure, diastolic blood pressure and weight) will be 
summarized by treatment group and visit grouped by treatment period, including absolute 
change from baseline where appropriate. Boxplots for absolute change from baseline at each 
visit will be presented by treatment group.
7.
Document history and changes in the planned statistical analysis
SAP V 1.0 dated 31 MAR 2021.
Approval of the SAP V 1.0 dated 08 APR 2021.
SAP final version 2.0 dated 23 MAY 2022. SAP was updated to take into consideration 
project and study early termination. For this reason, study objectives were corrected. Interim 
analyses section was modified to reflect the early termination of the study. 
Handling and Missing data sections was updated to reflect missing end treatment date in 
eCRF.  Data Rules section was updated to reflect ePRO questionnaires being pushed to 
participants not in line with start of treatment date. Data rules for laboratory parameters were 
also modified to reflect observing values higher and lower than the preselected limits.
In the primary efficacy analysis, the estimand section was expanded to provide more 
clarification on how to impute values after the occurrence of an intercurrent event. Subgroup 
analyses and sensitivity analyses were removed from the SAP. The actigraphy associated 
endpoint analyses were removed from the SAP.
SMQs for the specification of AEs were modified to be aligned on compound level. 
SAP was also updated to correct categories for liver function laboratory parameters and add 
analyses of close liver observations. In addition, the list of preferred MedDRA terms relevant 
to COVID-19 has been updated. The compliance calculation has been adapted to cover 
specific cases. In addition, the compliance definition for overall compliance and between-visit 
compliance was updated to be aligned on compound level.
Finally, an appendix section containing the derivation and the scoring of the EIS 
questionnaire was also included.
SAP V 2.0 dated 23 MAY 2022.
Approval of the SAP V 2.0 dated 23 MAY 2022.
SAP final version 3.0 dated 01 JULY 2022. SAP was updated to correct typos. All corrections 
included in this updated version of the SAP did not affect the primary and secondary analyses.
8.
Supporting Documentation
8.1
Appendix 1: Scoring and Transformation of EIS
The following sections are taken from the EIS User Manual Version 3_0 [6].
8.1.1
Summary of EIS scoring algorithms

EIS Physical activities domain score (based on EIS items 1-7)

EIS Emotional well-being domain score (based on EIS items 8-14)

EIS single-item scores, including: 
o
Impact on sexual activities (EIS item 15)


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o
Limited enjoyment of sexual intercourse (EIS item 16)
o
Guilt about avoidance of sexual intercourse (EIS item 17)
o
Difficulty concentrating (EIS item 18)
o
Difficulty sleeping (EIS item 19)
o
Impact on household activities (EIS item 20)
o
Impact on paid work or study  (EIS item 21)
o
Impact on social and leisure activities (EIS item 22)
All EIS domain and individual item scores range from 0 (indicating no impact) and 
100 (indicating maximum impact). A summary of EIS scoring algorithms is provided
in the table below.
Score
Item(s) 
employed
Calculation of score
EIS Physical Activity 
score
EIS items 1-7
When all 7 items are completed and item 7 is applicable (i.e., > 0):  
(100x((SUM EIS 1, 2, 3, 4, 5, 6, 7)-7)/28)
When all 7 items are completed but item 7 is not applicable 
(100x((SUM EIS 1, 2, 3, 4, 5, 6)-6)/24);
summed over the 4-week window, divided by the number of non-
missing weeks within that 4-week window
EIS Emotional Well-
being score
EIS items 8-14
(100x ((Sum EIS 8, 9, 10, 11, 12, 13, 14)-7)/28) summed over the 4-
week window, divided by the number of non-missing weeks within 
that 4-week window
4 week mean of 
impact on sexual 
activities
EIS item 15
When item 15 is applicable (i.e., > 0): (100x (EIS item 15 -1)/4) 
summed over the 4-week window, divided by the number of non-
missing (or applicable) weeks within that 4-week window.
4 week mean of 
limited enjoyment of 
sexual intercourse
EIS item 16
When item 16 is applicable (i.e., > 0): (100x (EIS item 16 -1)/4), 
summed over the 4-week window, divided by the number of non-
missing (or applicable) weeks within that 4-week window.
4 week mean of guilt 
about avoidance of 
sexual intercourse
EIS item 17
When item 17 is applicable (i.e., > 0): (100x (EIS item 17-1)/4), 
summed over the 4-week window, divided by the number of non-
missing (or applicable) weeks within that 4-week window.
4 week mean of 
difficulty 
concentrating 
EIS item 18
(100x (EIS item 18 -1)/4), summed over the 4-week window, divided 
by the number of non-missing weeks within that 4-week window.
4 week mean of 
difficulty sleeping 
EIS item 19
(100x (EIS item 19 -1/4), summed over the 4-week window, divided 
by the number of non-missing weeks within that 4-week window.
4 week mean of 
impact on household 
activities
EIS item 20
(100x (EIS item 20 -1)/4), summed over the 4-week window, divided 
by the number of non-missing weeks within that 4-week window.
4 week mean of 
impact on paid work 
or study
EIS item 21
When item 21 is applicable (i.e., > 0): (100x (EIS item 21 -1)/4), 
summed over the 4-week window, divided by the number of non-
missing (or applicable) weeks within that 4-week window.


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Score
Item(s) 
employed
Calculation of score
4 week mean of 
impact on social or 
leisure activities
EIS item 22
(100x (EIS item 22 -1)/4), summed over the 4-week window, divided 
by the number of non-missing weeks within that 4-week window
8.1.2
Transformation of scores
The sum of all responses given to a set of items is referred to as a score. For the EIS, scores 
are transformed to a 0-100 scale (where 0 represents no impact and 100 represents maximum 
impact) so to facilitate comparison across domains and items. 
The general formula for transformation of multi-item domain scores (physical activities and 
emotional well-being) for each respondent is as follows: 
(100 x (sum of participant responses to all applicable items – number of applicable 
items)) / (maximum potential sum of responses to all applicable items – number of 
applicable items)
The general formula for transformation of single item scores (EIS items 15-22) for each 
respondent, where applicable (i.e., scores > 0) is as follows: 
(100 x (item response - 1)) / (maximum potential item response-1)
9.
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