A Double-blind, Randomized, Placebo-controlled Multicenter Study to Investigate Efficacy and Safety of Elinzanetant for the Treatment of Vasomotor Symptoms Induced by Adjuvant Endocrine Therapy, Over 52 Weeks and Optionally for an Additional up to 2.5 Years in Women With Hormone-receptor Positive Breast Cancer:
Phase: PHASE3
Conditions: Vasomotor Symptoms Caused by Adjuvant Endocrine Therapy in Women With, or at High Risk for Developing Hormone-receptor Positive Breast Cancer, Hot Flashes
Sponsor: Bayer

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Title Page
Protocol Title:
A double-blind, randomized, placebo-controlled multicenter study to investigate efficacy and 
safety of elinzanetant for the treatment of vasomotor symptoms caused by adjuvant endocrine
therapy, over 52 weeks and optionally for an additional 2 years in women with, or at high risk 
for developing hormone-receptor positive breast cancer
Protocol Number:
21656
Protocol Version: 
3.0
Amendment Number
Amendment 2 (Global)
Compound Number:
BAY 3427080 / elinzanetant
Short Title:
Overall Assessment of efficacy and Safety of elinzanetant In
patients with vasomotor Symptoms in women with, or at high 
risk for developing hormone-receptor positive breast cancer
(OASIS-4)
Study Phase:
3
Acronym:
OASIS 4
Sponsor Name and 
Legal Registered Address: Bayer Consumer Care AG, 
Peter-Merian-Strasse 84, 4052 Basel, Switzerland
Regulatory Agency 
Identifier Number(s):
EudraCT: 2022-000095-18
Amendment Date: 
10 MAY 2023
Medical Monitor name and contact information will be provided separately.
Name:
 MD, PhD
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
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

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Document History Table 
DOCUMENT HISTORY 
Document
Version  
Date
Comments (if 
applicable) 
Amendment 2 (Global) 
3.0 
10 MAY 2023 
 
Amendment 1 (Global) 
2.0 
09 DEC 2022 
 
GBR-1 
GBR-1 
21 OCT 2022 
To include changes 
specific to United 
Kingdom 
ITA-1 
ITA-1 
30 SEP 2022 
To include changes 
specific to Italy 
Original Clinical Study 
Protocol 
1.0 
06 JUN 2022
 
 
Protocol Amendment Summary of Changes Table 
Amendment 2 (10 MAY 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC and Article 2(2)(13) of the REGULATION (EU) 
No 536/2014 of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
There are no effective treatment options for vasomotor symptoms (VMS) caused by 
adjuvant endocrine therapy since hormone treatment is contraindicated in patients with or 
at high risk for developing hormone receptor (HR)-positive breast cancer. It is expected 
that elinzanetant will reduce the frequency and severity of VMS caused by adjuvant 
endocrine therapy. If these benefits are confirmed, patients will benefit from the continued 
treatment in the extension period of this study. Study participants who have completed the 
originally planned 52 weeks of treatment and who need to continue the intake of adjuvant 
endocrine therapy will be offered two additional years of treatment with elinzanetant.  
A description of changes and a brief rationale is outlined in the table below. 
 
Key Changes 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 1.2 Schema 
Section 1.3.2 Treatment 
and follow-up 
Section 1.3.3 Treatment 
extension 
Section 4.1 Overall Design 
Section 4.4 End of Study 
Definition 
Section 6.1 Study 
Intervention(s) 
Administered 
Section 6.6 Continued 
Access to Study 
Intervention after the End 
of the Study 
Extension period was 
added. Participants who 
have completed 52 weeks 
of treatment and need to 
continue intake of their 
adjuvant endocrine 
therapy beyond the 
original treatment period 
of 52 weeks will be offered 
to continue with the study 
and study drug intake for 2 
additional years. 
There are no effective treatment 
options for VMS caused by adjuvant 
endocrine therapy since hormone 
treatment is contraindicated in 
patients with or at high risk for 
developing HR-positive breast 
cancer. It is expected that 
elinzanetant will reduce the frequency 
and severity of VMS caused by 
adjuvant endocrine therapy. If these 
benefits are confirmed, patients will 
benefit from the continued treatment 
in the extension period of this study 
that is expected to cover the period of 
regulatory approval for the extended 
indication until launch.  

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Section 6.8.1 Background 
therapy
Section 7 Discontinuation 
of Study Intervention and 
Participant
Discontinuation/Withdrawal
Section 8.1 Efficacy 
Assessments
Section 8.1.2 Investigator 
collected Patient Reported 
Outcomes (RAVE)
Section 8.2.5 Pregnancy 
Testing
Section 9.5 Interim 
Analysis
Section 10.1.5 Informed 
Consent Process
Section 5.1 Inclusion 
Criteria
Footnote was added to 
explain that according to 
the prescription 
information of tamoxifen, 
females of reproductive 
potential need to be 
advised to use highly 
effective non-hormonal 
contraception during 
treatment with tamoxifen 
and for 9 months following 
the last dose of tamoxifen.
To follow a request from the German 
HA (BfArM) to address the need for
long-lasting contraceptive methods 
after the last dose of tamoxifen.
Section 5.4 Screen 
Failures
Added wording to allow for
rescreening in particular
cases.
To follow practice used in Phase 3
studies of other Bayer compounds.
Section 6.8.3 Other 
Treatment Considerations
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
The content of drug-drug 
interaction with P-gp
substrates was updated.
Based on study 22081 P-gp 
substrates can be removed from the 
list of prohibited concomitant 
medications. No clinically relevant 
drug-drug interaction was observed.
Section 10.6 Appendix 6:
Prohibited concomitant 
medications
The content of drug-drug 
interaction 
were 
wrongly listed in the table.
Section 8.1.1.6 Beck 
Depression Inventory (BDI-
II)
Instructions on AE
reporting were updated. 
Scores provide information and 
should be interpreted in connection 
with the clinical presentation. As the 
investigator sees the participant the
interpretation of the score should be 
left to the discretion of the 
investigator. 
Section 8.2.11 Suicidal 
thoughts or wishes: Beck's 
Depression Inventory (BDI-
II)
Instructions on AE 
reporting were updated
Responses to item 9 with a 2 or a 3 
should be interpreted in connection 
with the clinical presentation. As the 
investigator sees the participant the
interpretation of the responses should 
be left to the discretion of the 
investigator.
CCI
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Clarifications to the protocol 
Section #  
and Name 
Description of Change 
Section 1.1 Synopsis 
Section 3 Objective, 
Endpoints and Estimands 
Clarification for the reduction in frequency of moderate to severe 
HF was added.  
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications 
Classification of drugs was added. 
 
Corrections of inconsistencies and minor corrections (editorial corrections not detailed):  
Section #  
and Name 
Description of Change 
Section 2.3.1 Risk 
Assessment 
Subjects are also required to avoid pregnancy and to use highly-
effective contraception during the study. 
Section 10.1.7 
Dissemination of Clinical 
Study Data 
Bayer Trial Finder and EU Clinical Trials Register for 
interventional studies have been renamed to Bayer Clinical Trials 
Explorer and EU Clinical Trials Information System. 
 

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Table of Contents 
Title Page .......................................................................................................................... 1
Document History Table ................................................................................................. 2
Protocol Amendment Summary of Changes Table ...................................................... 2
Table of Contents ............................................................................................................ 5
Table of Tables ................................................................................................................ 8
Table of Figures ............................................................................................................... 8
1.
Protocol Summary ................................................................................................... 9
1.1
Synopsis .................................................................................................................. 9
1.2
Schema .................................................................................................................. 12
1.3
Schedule of Activities (SoA) ................................................................................ 12
1.3.1
Screening ........................................................................................................... 12
1.3.2
Treatment and follow-up ................................................................................... 14
1.3.3
Treatment extension .......................................................................................... 15
1.3.4
PK sampling schedule ....................................................................................... 16
2.
Introduction ............................................................................................................ 17
2.1
Study Rationale ..................................................................................................... 17
2.2
Background ........................................................................................................... 17
2.3
Benefit/Risk Assessment ...................................................................................... 18
2.3.1
Risk Assessment ................................................................................................ 18
2.3.2
Benefit Assessment ........................................................................................... 20
2.3.3
Overall Benefit: Risk Conclusion ...................................................................... 21
3.
Objectives, Endpoints and Estimands .................................................................. 21
4.
Study Design ........................................................................................................... 24
4.1
Overall Design ...................................................................................................... 24
4.2
Scientific Rationale for Study Design .................................................................. 25
4.2.1
 ................................................................................ 26
4.3
Justification for Dose ............................................................................................ 26
4.4
End of Study Definition ........................................................................................ 27
5.
Study Population .................................................................................................... 28
5.1
Inclusion Criteria .................................................................................................. 28
5.2
Exclusion Criteria ................................................................................................. 30
5.3
Lifestyle Considerations ....................................................................................... 32
5.4
Screen Failures ...................................................................................................... 32
5.5
Criteria for Temporarily Delaying Randomization .............................................. 33
6.
Study Intervention(s) and Concomitant Therapy ............................................... 33
6.1
Study Intervention(s) Administered ...................................................................... 34
6.2
Preparation/Handling/Storage/Accountability ...................................................... 35
6.3
Measures to Minimize Bias: Randomization and Blinding .................................. 35
6.4
Study Intervention Compliance ............................................................................ 36
6.5
Dose Modification ................................................................................................ 36
6.6
Continued Access to Study Intervention after the End of the Study .................... 37
6.7
Treatment of Overdose ......................................................................................... 37

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6.8
Concomitant Therapy ........................................................................................... 37
6.8.1
Background therapy ........................................................................................... 38
6.8.2
Prohibited concomitant medications ................................................................. 38
6.8.3
Other Treatment Considerations ........................................................................ 39
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ................................................................................. 39
7.1
Discontinuation of Study Intervention .................................................................. 39
7.1.1
Pregnancy .......................................................................................................... 39
7.1.2
Liver Chemistry Stopping Criteria .................................................................... 39
7.1.3
Platelet count Stopping Criteria ......................................................................... 40
7.1.4
Temporary Discontinuation ............................................................................... 40
7.1.5
Rechallenge ....................................................................................................... 40
7.1.5.1
Study Intervention Restart or Rechallenge After Liver Stopping Criteria Met
 ........................................................................................................................ 40
7.2
Participant Discontinuation/Withdrawal from the Study ...................................... 41
7.3
Lost to Follow Up ................................................................................................. 41
8.
Study Assessments and Procedures ...................................................................... 42
8.1
Efficacy Assessments ........................................................................................... 42
8.1.1
Electronic Participant-Reported Outcomes (ePROs) ........................................ 43
8.1.1.1
Hot Flash Daily Diary (HFDD) ...................................................................... 45
8.1.1.2
Patient-reported Outcomes Measurement Information System Sleep 
Disturbance Short Form 8b (PROMIS SD SF 8b) ......................................... 45
8.1.1.3
Menopause Specific Quality of Life Scale (MENQOL) ................................ 46
8.1.1.4
European Quality of Life 5-dimension 5-level questionnaire (EQ-5D-5L) ... 46
8.1.1.5
Insomnia Severity Index (ISI) ........................................................................ 46
8.1.1.6
Beck Depression Inventory (BDI-II) .............................................................. 47
8.1.1.7
Short Form-36 Health Survey Acute (SF-36 acute) ....................................... 47
8.1.1.8
Vaginal bleeding diary ................................................................................... 48
8.1.2
Investigator collected Patient Reported Outcomes (RAVE) ............................. 48
8.2
Safety Assessments ............................................................................................... 48
8.2.1
Physical Examinations ....................................................................................... 48
8.2.2
Vital Signs ......................................................................................................... 49
8.2.3
Electrocardiograms ............................................................................................ 49
8.2.4
Clinical Safety Laboratory Assessments ........................................................... 49
8.2.5
Pregnancy Testing ............................................................................................. 50
8.2.6
Mammogram ..................................................................................................... 51
8.2.7
Cervical cytology ............................................................................................... 51
8.2.8
Transvaginal ultrasound (TVU)......................................................................... 51
8.2.9
Endometrial biopsy ............................................................................................ 52
8.2.10
Sleepiness Scale ................................................................................................. 53
8.2.11
Suicidal thoughts or wishes: Beck's Depression Inventory (BDI-II) ................ 54
8.3
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting .............................................................................................................. 54
8.3.1
Time Period and Frequency for Collecting AE and SAE Information.............. 54
8.3.2
Method of Detecting AEs and SAEs ................................................................. 55
8.3.3
Follow-up of AEs and SAEs ............................................................................. 55
8.3.4
Regulatory Reporting Requirements for SAEs ................................................. 55
8.3.5
Pregnancy .......................................................................................................... 55

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8.3.6
Adverse Events of Special Interest .................................................................... 56
8.4
Pharmacokinetics .................................................................................................. 57
8.5
Genetics ................................................................................................................ 58
8.6
Biomarkers ............................................................................................................ 58
8.7
Immunogenicity Assessments ............................................................................... 59
8.8
Health Economics ................................................................................................. 59
9.
Statistical Considerations ...................................................................................... 59
9.1
Statistical Hypotheses ........................................................................................... 59
9.2
Sample Size Determination .................................................................................. 59
9.3
Analysis Set .......................................................................................................... 61
9.4
Statistical Analyses ............................................................................................... 62
9.4.1
General Considerations...................................................................................... 62
9.4.2
Primary Endpoint ............................................................................................... 63
9.4.2.1
Calculations related to the frequency and severity of HF .............................. 63
9.4.2.2
Primary analysis of the primary efficacy endpoints ....................................... 64
9.4.3
Secondary Endpoints ......................................................................................... 65
9.4.4
Exploratory / Other Endpoints ........................................................................... 65
9.4.5
Other Safety Analysis ........................................................................................ 65
9.4.6
Other Analysis ................................................................................................... 65
9.5
Interim Analysis .................................................................................................... 66
10. Supporting Documentation and Operational Considerations ........................... 66
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 66
10.1.1
Regulatory and Ethical Considerations ............................................................. 66
10.1.2
Data Safety Monitoring Board .......................................................................... 67
10.1.3
Liver Safety Monitoring Board ......................................................................... 67
10.1.4
Financial Disclosure .......................................................................................... 67
10.1.5
Informed Consent Process ................................................................................. 67
10.1.6
Data Protection .................................................................................................. 68
10.1.7
Dissemination of Clinical Study Data ............................................................... 68
10.1.8
Data Quality Assurance ..................................................................................... 69
10.1.9
Source Documents ............................................................................................. 69
10.1.10 Study and Site Start and Closure ....................................................................... 70
10.1.11 Publication Policy .............................................................................................. 71
10.2
Appendix 2: Clinical Laboratory Tests ................................................................. 72
10.3
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .................................................................. 73
10.3.1
Definition of AE ................................................................................................ 73
10.3.2
Definition of SAE .............................................................................................. 74
10.3.3
Recording and Follow-Up of AE and/or SAE ................................................... 75
10.3.4
Reporting of SAEs ............................................................................................. 77
10.4
Appendix 4: Collection of Pregnancy Information ............................................... 78
10.4.1
Definitions ......................................................................................................... 78
10.4.2
Contraception Guidance .................................................................................... 79
10.4.3
Collection of Pregnancy Information: ............................................................... 80
10.5
Appendix 5: Liver Safety Actions and Follow-up Assessments .......................... 80
10.5.1
Liver safety -related monitoring and discontinuation criteria ........................... 80
10.5.2
Close observation of participants with liver function test findings ................... 81
10.6
Appendix 6: Prohibited concomitant medications ................................................ 85

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10.7
Appendix 7: Additional information on scoring and measurement properties of 
the HFDD, the PROMIS SD SF 8b and the MENQOL........................................87
10.7.1
HFDD ................................................................................................................87
10.7.2
PROMIS SD SF 8b............................................................................................87
10.7.3
MENQOL..........................................................................................................87
10.8
Appendix 8: Country/region-specific Requirements ............................................88
10.8.1
Italy....................................................................................................................88
10.8.1.1
ITA-1: Country/region-specific Changes Valid for Italy only.......................88
10.8.2
United Kingdom ................................................................................................89
10.8.2.1
GBR-1: Country/region-specific Changes Valid for United Kingdom only..89
10.9
Appendix 9: Protocol Amendment History ..........................................................90
10.10 Appendix 10: Abbreviations and Definitions .......................................................93
11. References ...............................................................................................................96
Table of Tables
Table 1-1: Schedule of Activities - Pre-Screening and Screening.......................................13
Table 1-2: Schedule of Activities - Treatment and follow-up .............................................14
Table 1-3 Treatment extension (for participants who completed the 52 weeks treatment 
phase, optionally) ..............................................................................................15
Table 1-4: PK sampling schedule for elinzanetant and tamoxifen or Aromatase Inhibitors
...........................................................................................................................16
Table 2-1: Risk assessment for elinzanetant ........................................................................18
Table 3-1: Objectives and endpoints....................................................................................21
Table 3-2 : Primary Estimand: ICEs and Strategies to Address Them ................................23
Table 6-1: Study Intervention(s) Administered ...................................................................34
Table 6-2: Study Arm(s) ......................................................................................................34
Table 9-1: Sample size justification.....................................................................................61
Table 9-2: Definition of the analysis sets.............................................................................61
Table 10-1: Clinical laboratory tests ....................................................................................72
Table 10-2: Liver Safety-Related Monitoring and Discontinuation Criteria .......................81
Table 10-3: Samples during close observation for liver safety............................................83
Table 10-4: Prohibited concomitant medication potentially confounding efficacy.............85
Table of Figures
Figure 1-1: Study Schema for participants not entering the 2 year treatment extension .....12
Figure 1-2: Study Schema for participants entering the 2 year treatment extension ...........12
CCI
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1. 
 
1.1 
Synopsis 
Protocol Title:  A double-blind, randomized, placebo-controlled multicenter study to 
investigate efficacy and safety of elinzanetant for the treatment of 
vasomotor symptoms caused by adjuvant endocrine therapy, over 52 
weeks and optionally for an additional 2 years in women with, or at high 
risk for developing hormone-receptor positive breast cancer 
Short Title: 
Overall Assessment of efficacy and Safety of elinzanetant In patients 
with vasomotor Symptoms in women with, or at high risk for developing 
hormone-receptor positive breast cancer (OASIS-4) 
Rationale: 
This is a phase 3 study to assess the efficacy and safety of elinzanetant 
for the treatment of vasomotor symptoms (VMS) caused by adjuvant 
endocrine therapy in women with, or at high risk for developing 
hormone-receptor positive breast cancer. 
 
Objectives and Endpoints: 
Objectives 
Endpoints  
Primary 
 
 To evaluate the efficacy 
of elinzanetant for the 
treatment of VMS caused
by adjuvant endocrine 
therapy in women with, 
or at high risk for 
developing hormone-
receptor positive breast 
cancer   
Primary endpoints  
 Mean change in frequency of moderate to severe HF from baseline to Week 
4 (assessed by HFDD) 
 Mean change in frequency of moderate to severe HF from baseline to 
Week 12 (assessed by HFDD) 
 
Secondary endpoints  
 Mean change in severity of moderate to severe HF from baseline to Week 4 
(assessed by HFDD) 
 Mean change in severity of moderate to severe HF from baseline to Week 
12 (assessed by HFDD) 
Exploratory endpoints: 
 Proportion of participants with at least 50% reduction in frequency of 
moderate to severe HF at Week 4 
  Proportion of participants with at least 50% reduction in frequency of 
moderate to severe HF at Week 12 
 

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Objectives 
Endpoints  
Secondary 
 
 To evaluate the onset of 
efficacy of elinzanetant 
for the treatment of VMS 
caused by adjuvant 
endocrine therapy in 
women with, or at high 
risk for developing 
hormone-receptor 
positive breast cancer  
Secondary endpoints 
 Mean change in frequency of moderate to severe HF from baseline to Week 
1 (assessed by HFDD) 
 Mean change in frequency of moderate to severe HF from baseline over 
time (assessed by HFDD) 
Exploratory endpoints: 
Time to treatment response 
 
 To evaluate the efficacy 
of elinzanetant in women 
with, or at high risk for 
developing hormone-
receptor positive breast 
cancer on: 
 sleep quality  
 menopause related 
quality of life 
 
 
Key secondary endpoints: 
 Mean change in PROMIS SD SF 8b total score from baseline to Week 12 
 Mean change in MENQOL total score from baseline to Week 12 
Exploratory endpoints: 
 Absolute values and changes from baseline in the PROMIS SD SF 8b over 
time 
 Absolute values and changes from baseline in MENQOL total score over 
time 
 Absolute values and changes from baseline in the ISI total score over time 
 Absolute values and changes from baseline in EQ-5D-5L single dimensions 
and health state VAS score over time. 
 Absolute values and changes from baseline in SF-36 acute domain, 
physical component summary (PCS) and mental component summary 
(MCS) scores over time 
 Absolute values and changes from baseline in the BDI-II total score over 
time 
 
 To evaluate the safety of 
elinzanetant for the 
treatment of VMS caused
by adjuvant endocrine 
therapy in women with, 
or at high risk for 
developing hormone-
receptor positive breast 
cancer  
Other endpoints: 
 
Number of participants with TEAEs 
 
Number of participants with abnormal laboratory parameters  
 
Mean change in Sleepiness Scale, at Week 1, Week 4, Week 12, Week 
26, Week 36 and Week 50 compared to baseline 
 
The full list of exploratory endpoints will be presented in the SAP. 
BDI-II=Beck Depression Inventory, EQ-5D-5L=European Quality of Life 5-dimension 5-level questionnaire, HF 
= Hot Flash, HFDD=Hot Flash Daily Diary, ISI=Insomnia Severity Index, MENQOL=Menopause Specific 
Quality of Life Scale, PROMIS SD SF 8b=Patient-reported Outcomes Measurement Information System Sleep 
Disturbance Short Form 8b, SAP = Statistical analysis plan, SF-36 acute = Short Form-36 Health Survey 
acute, TEAE = treatment emergent adverse event, VAS = Visual analog scale, VMS = Vasomotor symptoms 
Overall Design: 
This is a Phase 3 multi-center, multi-country, placebo-controlled, double blind, parallel 
group intervention study, in women with, or at high risk for developing hormone-receptor 
positive breast cancer. 
Short Summary: 
The purpose of this study is to investigate efficacy and safety of elinzanetant for the 
treatment of VMS caused by adjuvant endocrine therapy in women with, or at high risk for 
developing hormone-receptor positive breast cancer. 

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Study details include: 
 Total study duration for an individual participant: approximately 62 weeks (plus 
potential washout period), including 
 Pre-screening / Washout period (if applicable) 
 Screening: approximately 6 weeks 
 Treatment: 52 weeks  
 Follow-up: 4 weeks 
 Visit Frequency: Every 4 weeks until Week 16, then every 10 weeks until week 36 
and end of treatment visit at week 52, including 6 phone call visits. See Section 
1.3.2 for more details. 
 Treatment extension (part C): Participants who complete the 52 weeks treatment 
phase will be offered to continue treatment for another 2 years. Visit frequency: 
every 24 weeks until week 156. See Section 1.3.3 for more details 
Number of Participants: 
Approximately 810 participants will be screened to achieve 405 participants randomly 
assigned to study intervention in a 2:1 ratio, resulting in estimated 365 participants 
evaluable for the primary efficacy analysis (243 and 122 evaluable participants in 
respectively the elinzanetant and placebo arm) after 12 weeks. The randomization will be 
stratified by women with breast cancer or high-risk for developing breast cancer and by 
type of treatment for the pre-existing condition at baseline (participants on tamoxifen and 
participants on aromatase inhibitors). See Section 9.2 for more details. 
Intervention Groups and Duration: 
All participants will receive either 120 mg of elinzanetant or matching placebo orally once 
daily, while staying on their current treatment, including their adjuvant endocrine therapy. 
There will be 2 arms in the study  
 Elinzanetant for 52 weeks and optionally additional 2 years  
 Placebo for 12 weeks, followed by elinzanetant for 40 weeks and optionally 
additional 2 years 
Data Monitoring/Other Committee: 
Yes 
 

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1.2
Schema
Figure 1-1: Study Schema for participants not entering the 2 year treatment 
extension
Figure 1-2: Study Schema for participants entering the 2 year treatment extension
Approx. = approximately, ICF = Signing of informed consent form, Rand. = randomization
After completion of Part A the final efficacy analysis and a preliminary safety assessment can be performed.
1.3
Schedule of Activities (SoA)
1.3.1
Screening
The 3 visits in the table below can be combined, if possible, according to 
organizational set-up at the study center. 
Depending on prior medication a wash-out period may be necessary and needs to 
be performed between Pre-SCR and SCR-1 (See Section 4.1 for further details). 
All screening evaluations should typically be completed within 6 weeks after 
SCR-1 (see Section 5.5 for exceptions). The time required for central reading of 
endometrial biopsy samples needs to be considered for visit planning.

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Table 1-1: Schedule of Activities - Pre-Screening and Screening 
Visit name 
Pre-SCR 
SCR-1 
SCR-2 
In person or phone visit 
in person 
in person 
in person 
Baseline characteristics 
Informed consent  
( )a 
 
Demography, including tobacco use and education level
( )a
 
Medical history and concomitant medications  
 
 
Gynecological and reproductive history including number 
of pregnancies and births 
( )a 
 
eDiary and eCOA instruments  
Dispensation and training of 
-held 
device 
 
 
Background medication intake documentation (see 
Section 6.8.1) 
 
 
------------------>
HFDD (twice daily) 
 
 
------------------>
Sleepiness Scale (daily in the evening) 
------------------>
BDI-II 
 
 
Screening and randomization 
Inclusion/exclusion criteria 
 
Safety 
Complete physical examination (including height and 
weight, see section 8.2.1) 
 
 
 
Vital signs  
 
 
 
12-lead ECG 
 
 
 
Mammogram (if applicable, see Section 8.2.6) 
Cervical cytology (if applicable, see Section 8.2.7) 
 
 
Transvaginal ultrasound (if applicable, see Section 
8.2.8) 
 
 
b
Endometrial biopsy (if applicable, see Section 8.2.9) 
 
 
b
Laboratory (including safety) 
Blood sampling (safety) 
 
Urine pregnancy test (if applicable, see Section 8.2.5)  
 
b 
Urinalysis 
 
 
ECG = electrocardiogram, eCOA = Electronic clinical outcome assessment, Pre-SCR = pre-screening Visit, SCR=Screening Visit  
Questionnaires: BDI-II=Beck Depression Inventory, HFDD=Hot Flash Daily Diary 
a Only if Pre-screening visit is not performed 
b A pregnancy test (unless participant has been confirmed post-menopausal or women of nonchildbearing potential (WONCBP)) and 
ultrasound must be performed before an endometrial biopsy is taken.  

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1.3.2 
Treatment and follow-up 
Table 1-2: Schedule of Activities - Treatment and follow-up 
 
 
Part A 
Part B 
 
Visit name 
BL
T1
T2
T3
T4
T5
T6
T7
T8
T9
T10 T11
T12
T13/ 
EoT a
FUe
In person (IP) or phone visit 
IP
IP
IP
IP 
IP 
IP 
IP 
 
IP 
IP 
Visit Week 
1 
2 
4 
6 
8 
10
12
16
20
26
30
36 
42 
52 
56 
Visit window in days 
1 
8-
14
22-
28
36-
42
50-
56
64-
70
85-
90
106-
112
127-
140
176-
182
197
-
210
246-
252
281-
294
351-
364 
386-
399
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
(
)f
 
f 
eDiary and eCOA instruments  
HFDD (twice daily, Section 
8.1.1.1) 
------------------------>
Week 25 & 26, Week 35 & 36 and 
Week 49 & 50  
Sleepiness scale (reported in 
the evening) 
7 consecutive days during Weeks 1, 4, 12, 26, 36 and 50
PROMIS SD SF 8b  
once weekly
 
 
ISI 
 
 
MENQOL 
 
 
BDI-II 
 
 
EQ-5D-5L 
once weekly
 
 
SF-36 acute 
 
 
 
 
Vaginal bleeding diary (if 
applicable, see Section 
8.1.1.8) 
------------------------> 
 
Study drug/background 
medication intake 
documentation 
----------------------------------------------------------------> 
Check completeness of eDiary 
via web report 
----------------------------------------------------------------> 
Collection of hand-held device 
 
 
 
 
 
 
 
 
 
 
 
 
 
f 
Screening and randomization 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety/Laboratory 
AEs / concomitant 
medications 
------------------------------------------------------------------------------------> 
Symptom-based physical 
examination (including weight) 
 
 
Complete physical 
examination (including weight) 
 
 
Vital signs  
 
 
 
 
 
 
 
 
 
Mammogram (if applicable, 
see Section 8.2.6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
b 
 
Transvaginal ultrasound (if 
applicable, see Section 8.2.8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endometrial biopsy (if 
applicable, see Section 8.2.9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample (safety) 
 
 
 
 
 
 
 
 
 
 
Blood samples (E2) 
 
 
 
 
Blood samples (biomarker) 
 
 
 
 
Blood sample (PK 
elinzanetant/placebo) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample (PK tamoxifen 
or Aromatase Inhibitor) 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample CYP2D6 
genetics only from participants 
receiving tamoxifen (see 
Section 8.5 and 8.6)d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (if 
applicable, see Section 8.2.5)c 
 
 
---------------------------> 
 
 

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Table 1-2: Schedule of Activities - Treatment and follow-up 
 
 
Part A 
Part B 
 
Visit name 
BL
T1
T2
T3
T4
T5
T6
T7
T8
T9
T10 T11
T12
T13/ 
EoT a
FUe
In person (IP) or phone visit 
IP
IP
IP
IP 
IP 
IP 
IP 
 
IP 
IP 
Visit Week 
1 
2 
4 
6 
8 
10
12
16
20
26
30
36 
42 
52 
56 
Visit window in days 
1 
8-
14
22-
28
36-
42
50-
56
64-
70
85-
90
106-
112
127-
140
176-
182
197
-
210
246-
252
281-
294
351-
364 
386-
399
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention and study exit 
Study drug dispensing/training 
 
 
 
 
 
 
 
f 
 
Supervised study drug intake at 
site 
 
 
 
 
Study drug collection (if 
applicable) 
 
 
 
 
 
 
 
 
 
Study drug compliance 
 
 
 
 
Participant feedback survey 
 
 
AEs = adverse events, BL = baseline, CYP2D6 = Cytochrome P450 2D6, E2 = estradiol, eCOA = Electronic clinical outcome 
assessment, EoT = End of treatment Visit; FU = follow up, IP = In person; PK = pharmacokinetics, T = treatment 
Questionnaires: BDI-II = Beck Depression Inventory, EQ-5D-5L= European Quality of Life 5-dimension 5-level questionnaire, 
HFDD = Hot Flash Daily Diary, ISI = Insomnia Severity Index, MENQOL = Menopause Specific Quality of Life Scale, PROMIS 
SD SF 8b = Patient-reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b; SF-36 acute = 
Short Form-36 Health Survey acute  
a If a participant discontinues prematurely from treatment after the baseline visit, an EoT visit will be performed as soon as 
possible. It will comprise the same assessments as the Week 52 visit, and should be scheduled at the latest within 14 days 
after the discontinuation of the study drug. If the participant in addition decides to withdraw from the study, the EoT visit will be 
followed after 4 weeks by the FU visit. If a participant discontinues from treatment but agrees to stay in the study, the next 
scheduled in person visit will cover the assessments expected to be performed during the FU visit, and therefore no FU visit is 
needed after T13. The handheld device will be collected at the last scheduled IP visit. 
b Mammogram should be performed if the time that has elapsed since the previous mammogram is in line with local medical 
guidelines for the frequency of mammograms in the respective age and patient group. In case a non-study mammogram was 
conducted during the time of study participation, the result should be documented. In this case the mammogram will not be 
done at Visit T13 or EoT. 
c Urine pregnancy test will be performed at site at BL, T2, T4, T6, T7, T9, T11, T13/EoT and FU, and at home at week 20, 24, 
30, 34, 40, 44 and 48. Home testing results will be documented in eDiary. 
d If the blood sample for CYP2D6 genetics was not collected at BL visit it can be also collected at a later visit. 
e Not applicable for participants continuing with the treatment extension (part C). 
f Only applicable for participants continuing with the treatment extension (part C). 
1.3.3 
Treatment extension 
Table 1-3 Treatment extension (for participants who completed the 52 weeks treatment 
phase, optionally) 
Part C
Visit name 
T14 
T15 
T16 
T17 
EoT part C 
FU part 
C
In person (IP)  
IP 
IP 
IP 
IP 
IP 
IP 
Visit Week
58
82
107
131
156
160
Visit window in days 
402-
409 
573-
580 
744-
751 
915-
922 
1088-1095 
1116-1123
Safety 
AEs / concomitant medications 
------------------------------------------------------------------------------> 
Question on adherence to adjuvant 
endocrine therapy 
 
 
 
 
Dispensation of urine pregnancy test 
(if applicable, see Section 8.2.5) 
Study intervention
Study drug dispensing 
Study drug collection 
Study drug compliance 

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Table 1-3 Treatment extension (for participants who completed the 52 weeks treatment 
phase, optionally) 
 
Part C 
Visit name 
T14 
T15 
T16 
T17 
EoT part C 
FU part 
C 
In person (IP)  
IP 
IP 
IP 
IP 
IP 
IP 
Visit Week 
58 
82 
107 
131 
156 
160 
Visit window in days 
402-
409 
573-
580 
744-
751 
915-
922 
1088-1095 
1116-1123
AEs = adverse events, EoT = End of treatment Visit; FU = follow up, IP = In person; T = treatment
 
1.3.4 
PK sampling schedule 
Table 1-4: PK sampling schedule for elinzanetant and tamoxifen or Aromatase Inhibitors 
Visit 
BL 
T2 
T4 
T6 
T9 
EoT 
Week 
1 
4 
8 
12 
26 
52 
Study 
interventiona 
intake on visit 
days 
at site 
at home the 
evening before 
at home the 
evening 
before 
at home the 
evening 
before 
at site and no 
dosing on the 
day before  
at home the 
evening 
before  
Documentation 
of date and time 
of study 
interventiona 
 
on visit day 
on the previous 
dosing days 
on the 
previous 
dosing days 
on the 
previous 
dosing days 
on visit day 
and the 
previous 
dosing days 
on the 
previous 
dosing days 
PK sampling 
elinzanetant 
post dose at: 
0.5-3 hours 
 
any time during 
the visit 
any time 
during the 
visit 
any time 
during the 
visit 
pre-dose, and 
two samples 
between 0.5-4 
hours post 
dose, at least 
1 hour apart 
any time 
during the visit
PK sampling 
tamoxifen 
OR 
Aromatase 
Inhibitor 
prior to first 
elinzanetant 
dose 
 
any time during 
the visit 
any time 
during the 
visit 
any time 
during the 
visit 
prior to 
elinzanetant 
dose and two 
samples 
between 0.5-4 
hours post 
dose, at least 
1 hour apart 
any time 
during the visit
BL= baseline, EoT = end of treatment, T = treatment, PK = Pharmacokinetics 
a Tamoxifen OR Aromatase Inhibitor will be taken as prescribed by the doctor and the last intake (date and 
time) should be documented. Elinzanetant intake and documentation should be followed as described in this 
table. 
 
When PK samples must be taken pre-dose at Visit T9, the previous evening dose of study 
intervention will not be taken at home. On the day of BL visit and visit T9 with supervised 
study drug intake at the clinical site, the participant should not take any further study 
medication in the evening at home. Tamoxifen or aromatase inhibitors with or without the 
use of GnRH analogues 
oncologist, gynecologist, or general practitioner) and no change to this schedule should be 
made.  
If the participant has mistakenly taken the evening dose prior to Visit T9 instead of intake 
at the clinical site, the participant will not receive a supervised study drug intake, and 
should take the study drug in the evening as usual. In this case, PK sampling for all three 

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samples, to be taken at least 1 hour apart (between each sampling), will be done at any 
time during Visit T9.  
For participants prematurely discontinuing study treatment, a PK sample is neither required 
for elinzanetant nor for background treatment (tamoxifen or aromatase inhibitor) as part of 
the EoT activities.  
 
2. 
 
2.1 
Study Rationale 
This is a phase 3 study to assess the efficacy and safety of elinzanetant for the treatment of 
VMS caused by adjuvant endocrine therapy in women with, or at high risk for developing 
hormone-receptor positive breast cancer. 
 
2.2 
Background  
are not only related 
to menopause. VMS are very common adverse reactions in women treated with adjuvant 
endocrine therapy such as tamoxifen and aromatase inhibitors (Arimidex SmPC 2021, 
Berkowitz et al. 2021, Biglia et al. 2003, Nolvadex SmPC 2021, Tamoxifen SmPC 2021).  
Women with hormone receptor (HR)-positive breast cancer are treated for at least 5 years 
(up to 10 years) with adjuvant endocrine therapy, which substantially reduces the rate of 
disease recurrence and mortality (Davies et al. 2011, Davies et al. 2013). Tamoxifen is 
approved for the treatment of HR-positive breast cancer in both pre- and post-menopausal 
women. In post-menopausal women, aromatase inhibitors (such as anastrozole) have 
shown superior efficacy and safety over tamoxifen and are usually preferred (Cuzick et al. 
2010). This strong benefit is reflected in current treatment guidelines, with all patients with 
HR-positive breast cancer being offered adjuvant endocrine therapy (Cardoso et al. 2019). 
Ovarian function suppression with gonadotropin-releasing hormone (GnRH) analogues or 
ovarian ablation may also be offered to premenopausal patients in combination with 
tamoxifen or an aromatase inhibitor (Cardoso et al. 2019).  
Adjuvant endocrine therapy is also used for breast cancer prevention in women at high risk 
for developing breast cancer as clinically indicated although the level of evidence is weak 
(Paluch-Shimon et al. 2016). The use of adjuvant endocrine therapy for the prevention of 
breast cancer varies between countries and within countries. 
Treatment-related side effects of adjuvant endocrine therapy negatively affect health-
related quality of life and adherence to treatment and these side effects are often discussed 
by participants in online breast cancer forums (Berkowitz et al. 2021, Cella and 
Fallowfield 2008, Knobf 2006, Murphy et al. 2012, Runowicz et al. 2016). 
Effective treatment options for VMS caused by adjuvant endocrine therapy are not 
available since hormone treatment is contraindicated in HR-positive breast cancer patients. 
Most self-management strategies for VMS such as relaxation, behavioral strategies, weight 
loss, and physical activity lack efficacy and are often based on weak or inconclusive 
evidence (Hall et al. 2021).  

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Elinzanetant (formerly NT-8141) is a dual neurokinin (NK)-1,3 receptor antagonist. Data 
indicate that VMS are triggered by hyperactivation of the KNDy neurons, which are part of 
the thermoregulatory pathway, due to withdrawal of estradiol caused by decreasing ovarian 
function in natural menopause or as a side effect of medical intervention (bilateral 
oophorectomy, antiestrogen treatments) (Rance et al. 2013, Zhang et al. 2021).
Two previous studies, RELENT-1 (NCT02865538 2020) and SWITCH-1 (814-PM-02)
(NCT03596762 2020), have shown elinzanetant to be significantly better than placebo in 
reducing the frequency of HF in post-menopausal women. Furthermore, the SWITCH-1
study showed that the reduction in frequency of HF was associated with marked 
improvements on participant reported outcomes of sleep, mood and quality of life.  
It is expected that elinzanetant will reduce the frequency and severity of VMS caused by 
adjuvant endocrine therapy. If these benefits are confirmed in this study, it is anticipated 
that elinzanetant will be available for the treatment of VMS in a high medical need 
population. Based on the phase 2 data elinzanetant has a quick onset of action and is 
expected to treat bothersome VMS. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of elinzanetant 
is provided in the Investigator brochure (IB).
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of elinzanetant may be found in the IB.
2.3.1
Risk Assessment
Table 2-1: Risk assessment for elinzanetant
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention elinzanetant
Somnolence or 
fatigue
Mild to moderate somnolence and fatigue 
identified as common (1-10% of participants) in 
the previous studies.
Participants will be generally 
dosed in the evening to limit the 
occurrence of these reactions 
and will be advised to avoid 
driving or use of machinery if 
affected.
with narrow 
therapeutic range
Will be managed through 
exclusion of participants taking 
the interacting concomitant 
medications during clinical trials.
                                                
1 The compound was initially developed by GSK, then NeRRe Therapeutics Ltd. on behalf of KaNDy 
Therapeutics Ltd. On 08 SEP 2020 Bayer AG acquired KaNDy Therapeutics Ltd. and continues 
development of elinzanetant.
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Table 2-1: Risk assessment for elinzanetant
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Increase in plasma 
concentration of 
tamoxifen
Based on the available in-house PK data on the 
drug-drug interaction (DDI) of elinzanetant and 
midazolam and available literature, co-
administration of elinzanetant and tamoxifen 
might lead to a maximum 2-fold increase of the
tamoxifen plasma concentrations.
DDI study elinzanetant and 
tamoxifen is completed.
The results from this DDI study 
together with the multiple dose 
simulations indicate no clinically 
relevant interaction between 
tamoxifen and its metabolites 
when continuously co-
administered with elinzanetant 
with respect to safety and 
efficacy supporting the combined 
use in the ongoing Phase 3 study
OASIS 4. Further PK data is 
being collected in the OASIS 4 
study.
Phototoxicity
Preclinical safety finding. The in vitro 3T3 
Neutral Red Uptake (NRU) phototoxicity assay 
showed a potentially phototoxic effect. 
However, this test has a high rate of false-
positives and poor positive predictive value.
One participant in the SWITCH-1 study who 
received 160 mg of elinzanetant reported a mild 
skin reaction that was potentially consistent with 
photosensitivity. The event resolved after 15 
days despite continued treatment with 
elinzanetant. No particular precautions to avoid 
sunlight had been taken.
Investigators and participants will 
be advised of the potential for 
skin sensitivity and to be vigilant 
to any possible reactions. 
Measures are to be taken to 
avoid strong sunlight should such 
reactions occur.
Increase in liver 
enzymes
Two participants were withdrawn from the 
SWITCH-1 study because of increased liver 
enzymes, although both were subsequently 
found to be noncompliant with the elinzanetant 
treatment. There was one further participant in 
the 814-1-05 study who was found to have 
increased transaminases. The participant had 
abnormal GGT at screening and fatty liver.
Defined exclusion criteria. 
Regular monitoring of liver 
parameters during the study. 
Defined strategy for close 
observation and defined stopping 
criteria for participants with 
increased liver parameters during 
the study.
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Table 2-1: Risk assessment for elinzanetant
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Arrhythmias
A possible signal with respect to an increased 
incidence of arrhythmias was identified in Phase 
1 studies in healthy male volunteers but has not 
been substantiated in subsequent studies, 
including through Holter monitoring conducted 
over an extended period in all participants in the 
RELENT-1 study.
12 lead ECG will be performed
during screening for all 
participants to exclude relevant 
preexisting arrhythmias.
If clinically indicated, 
unscheduled 12-lead ECGs can 
be performed at any point during 
the study. Unscheduled ECGs 
must be recorded in the 
database.
Effects on 
reproductive
function
There was no evidence of developmental or 
reproductive toxicity in embryo-fetal toxicity
studies at doses up to 
 in rats or 
up to 
 in rabbits representing
 the human exposure in rats 
or rabbits, respectively. In a female rat fertility 
and early embryonic development study, 
increased percentage of pre-implantation and 
post-implantation embryo loss, reduced litter 
size and lower fetal body weights were seen at 
the dose of
, which exceeds 
human exposure at the anticipated therapeutic 
dose of 120 mg/day 
. The dose 
free of findings represents 
the human 
exposure.
Elinzanetant reduced plasma estradiol,
progesterone and luteinizing hormone in pre-
menopausal females. These effects
were correlated in one of the studies with
delayed or irregular menses
Subjects are informed of these
effects on reproductive function. 
Subjects are also required to 
avoid pregnancy and to use 
highly-effective contraception 
during the study.
Study Procedures
No relevant risks are 
expected related to 
the study procedures
All study procedures are routine medical 
procedures in this participant population.
All study procedures will be 
conducted by appropriately 
trained staff.
Other
Non-effective 
treatment for 
participants who are 
randomized to 
placebo.
Participants who are randomized to placebo will 
not receive active treatment for VMS during the 
first 12 weeks of treatment. After 12 weeks 
participants randomized to placebo will be 
switched to active treatment.
Participants are not expected to 
suffer undue medical 
consequences from absence of 
treatment during the first 12 
weeks. Participants who 
discontinue study treatment will 
be encouraged to remain in the 
study for further data collection.
AE = Adverse event, AST = Aspartate-aminotransferase, CK = Creatinine Kinase,
 3A4, DDI = drug-drug interaction, ECG = Electrocardiogram, GGT = Gamma glutamyl 
transferase, LDH = Lactate dehydrogenase, PK = Pharmacokinetics, VMS = Vasomotor symptoms
2.3.2
Benefit Assessment
Based on the mode of action, pre-clinical, and clinical data it is expected that treatment 
with elinzanetant will provide relevant clinical benefits to women with VMS caused by 
endocrine adjuvant therapy. These benefits may include 
reduction in frequency of VMS,
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 sleep-related benefits, 
 improvement of mood and health-related quality of life. 
Participants who are randomized to the placebo group are expected to benefit from 
participation in the study since after 12 weeks all participants will receive active treatment. 
2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with elinzanetant are justified by the anticipated 
benefits that may be afforded to participants with VMS caused by adjuvant endocrine 
therapy. 
 
3. 
 
Objectives and endpoints are listed in Table 3-1.  
Table 3-1: Objectives and endpoints 
Objectives 
Endpoints  
Primary 
 
 To evaluate the 
efficacy of elinzanetant 
for the treatment of 
VMS caused by 
adjuvant endocrine 
therapy in women with, 
or at high risk for 
developing hormone-
receptor positive breast 
cancer   
Primary endpoints  
 Mean change in frequency of moderate to severe HF from baseline to Week 4 
(assessed by HFDD) 
 Mean change in frequency of moderate to severe HF from baseline to Week 12 
(assessed by HFDD) 
 
Secondary endpoints  
 Mean change in severity of moderate to severe HF from baseline to Week 4 
(assessed by HFDD) 
 Mean change in severity of moderate to severe HF from baseline to Week 12 
(assessed by HFDD) 
Exploratory endpoints: 
 Proportion of participants with at least 50% reduction in frequency of moderate 
to severe HF at Week 4 
  Proportion of participants with at least 50% reduction in frequency of moderate 
to severe HF at Week 12 
 

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Objectives 
Endpoints  
Secondary 
 
 To evaluate the onset 
of efficacy of 
elinzanetant for the 
treatment of VMS 
caused by adjuvant 
endocrine therapy in 
women with, or at high 
risk for developing 
hormone-receptor 
positive breast cancer  
Secondary endpoints 
 Mean change in frequency of moderate to severe HF from baseline to Week 1 
(assessed by HFDD) 
 Mean change in frequency of moderate to severe HF from baseline over time  
(assessed by HFDD) 
Exploratory endpoints: 
Time to treatment response 
 
 To evaluate the 
efficacy of elinzanetant 
in women with, or at 
high risk for developing 
hormone-receptor 
positive breast cancer 
on: 
 sleep quality  
 menopause related 
quality of life 
Key secondary endpoints: 
 Mean change in PROMIS SD SF 8b total score from baseline to Week 12 
 Mean change in MENQOL total score from baseline to Week 12 
Exploratory endpoints: 
 Absolute values and changes from baseline in the PROMIS SD SF 8b over time 
 Absolute values and changes from baseline in MENQOL total score over time 
 Absolute values and changes from baseline in the ISI total score over time 
 Absolute values and changes from baseline in EQ-5D-5L single dimensions and 
health state VAS score over time. 
 Absolute values and changes from baseline in SF-36 acute domain, physical 
component summary (PCS) and mental component summary (MCS) scores 
over time 
 Absolute values and changes from baseline in the BDI-II total score over time 
 
 To evaluate the safety 
of elinzanetant for the 
treatment of VMS 
caused by adjuvant 
endocrine therapy in 
women with, or at high 
risk for developing 
hormone-receptor 
positive breast cancer  
Other endpoints: 
 
Number of participants with TEAEs 
 
Number of participants with abnormal laboratory parameters  
 
Mean change in Sleepiness Scale, at Week 1, Week 4, Week 12, Week 26, 
Week 36 and Week 50 compared to baseline 
Other pre-specified
 To evaluate variability 
in exposure in relation 
to the efficacy and 
safety for elinzanetant  
Systemic exposure of elinzanetant in plasma via sparse PK sampling 
 
 To further investigate 
elinzanetant (e.g., 
mode-of-action-related 
effects, safety) and to 
further investigate 
pathomechanisms 
deemed relevant to 
VMS caused by 
adjuvant endocrine 
therapy and associated 
health problems
Various biomarkers (e.g., diagnostic, safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers) 
The full list of exploratory endpoints will be presented in the SAP. 
BDI-II=Beck Depression Inventory, EQ-5D-5L=European Quality of Life 5-dimension 5-level questionnaire,  
HF = Hot Flash, HFDD=Hot Flash Daily Diary, ISI=Insomnia Severity Index, MENQOL=Menopause Specific 
Quality of Life Scale, PK = Pharmacokinetics, PROMIS SD SF 8b=Patient-reported Outcomes Measurement 
Information System Sleep Disturbance Short Form 8b, SAP = Statistical analysis plan, SF-36 acute = Short 
Form-36 Health Survey acute, TEAE = treatment emergent adverse event, VAS = Visual analog scale,  
VMS = Vasomotor symptoms 

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Estimands 
The attributes of the main estimand for the primary endpoints are as following: 
 Population:
as 
described by the inclusion/exclusion criteria detailed in the protocol.  
 Variable: Efficacy will be assessed based on 2 primary endpoints as listed below: 
 Change in frequency of moderate to severe HFs from baseline to Week 4  
 Change in frequency of moderate to severe HFs from baseline to Week 12. 
 Treatment: 120 mg elinzanetant, placebo  
 ICEs: see Table 3-2  
Table 3-2 : Primary Estimand: ICEs and Strategies to Address Them 
ICEsa 
Reason for ICE 
Strategy 
Data handling method  
Temporary 
Treatment 
interruption b 
 
AEs  
(treatment 
related/unrelated) 
 
COVID-19 and 
administrative 
reasons 
Treatment policy  
 
 
 
Treatment policy  
 
Utilise the collected data 
after ICE.  
 
 
Utilise the collected data 
after ICE.  
 
 
 
 
 
Permanent 
discontinuation of 
randomized 
treatment  
AEs  
(treatment 
related/unrelated) or 
Lack of efficacy 
 
 
 
 
 For participants 
who remained 
untreated/on 
background 
therapy. 
 
 
For participants 
who initiate 
alternative VMS 
treatment  
Treatment policy 
 
 
 
 
 
Treatment policy  
 
Utilise the collected data 
after ICE.  
 
 
 
 
Utilise the collected data 
after ICE.  
 
 
 
 
 
 
Other treatment-
unrelated reasons, 
including COVID-19 
 
Treatment policy  
 
Utilise the collected data 
after ICE.  
 
 
 
Intake of 
prohibited 
concomitant 
medication having 
impact on efficacy 
All reasons 
Treatment policy  
 
Utilise the collected data 
after ICE.  
 
 
 
Interruption/ 
discontinuation in 
intake of adjuvant 
endocrine 
therapyc
 
All reasons 
 
Treatment policy 
 
Utilise the collected data 
after ICE.  
 
AE = Adverse event, COVID-19 = Coronavirus disease of 2019, ICE = Intercurrent event, VMS = 
Vasomotor symptoms 
a) ICEs will be reviewed at the Blinded Review Meeting prior to the study unblinding 

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Table 3-2 : Primary Estimand: ICEs and Strategies to Address Them 
ICEsa 
Reason for ICE 
Strategy 
Data handling method  
b) Definition of temporary treatment interruption: 
Week 1 = Treatment taken on <5/7 days during week 1. 
Week 4= Treatment taken <80% during weeks 1-4 OR treatment taken on <5/7 days during 
either Week 3 or 4. 
Week 12= Treatment taken <80% during weeks 1-12 OR treatment taken on <5/7 days during 
either Week 11 or 12. 
c) Definition of interruption/discontinuation in intake of adjuvant endocrine therapy: 
For participants using tamoxifen: reduction of at least 50% of planned daily dosage taken during 
weeks 3 and 4 OR weeks 11 and 12 compared to baseline  
For participants using aromatase inhibitor: reduction of at least 30% of planned daily dosage 
taken during weeks 3 and 4 OR weeks 11 and 12 compared to baseline  
 
 Population level summary:  
 Mean change in frequency of moderate to severe HFs from baseline to 
Week 4.  
 Mean change in frequency of moderate to severe HFs from baseline to 
Week 12.  
The key secondary endpoints will be handled using similar attributes except for the 
variables and population summary that are listed below: 
 Variable: 
 Change in PROMIS SD SF 8b total score from baseline to Week 12 
 Change in MENQOL total score from baseline to Week 12 
 Population level summary:  
 Mean change in PROMIS SD SF 8b total score from baseline to Week 12  
 Mean change in MENQOL total score from baseline to Week 12. 
 
4. 
 
4.1 
Overall Design 
This is a multi-center, multi-country, double-blind, randomized, parallel-group, placebo-
controlled, Phase 3 intervention study in women with, or at high risk for developing 
hormone-receptor positive breast cancer. 
Main study (part A+B): The study includes a wash-out period (if applicable), 
approximately 6-week screening, a 52-week treatment and a 4-week follow-up period. 
Treatment extension (part C): Participants who completed the 52 weeks treatment phase 
are offered to continue treatment for 2 additional years.  
 
Wash-out: After giving informed consent, participants will be withdrawn from prohibited 
concomitant medications (see Section 10.6) at Pre-SCR visit if needed. 

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Screening: The screening period starts at SCR-1 Visit. The screening period may also be 
used to obtain a mammogram, if required. 
Randomization: After screening, eligible participants will be randomized with a 2:1 ratio 
in a stratified way into 2 arms, as depicted below.  
 elinzanetant  
 placebo for 12 weeks, followed by elinzanetant for 40 weeks 
The randomization will be stratified by women with breast cancer or high-risk for 
developing breast cancer and by type of treatment for the pre-existing condition at baseline 
(participants on tamoxifen and participants on aromatase inhibitors). 
The investigator will receive an email notification if a participant responded to item 9 of 
the BDI-II 
3 
randomized. If this happens after randomization the participant can continue in the study at 
the discretion of the investigator. Any suicidal ideation should be reported as an adverse 
event and treated according to local clinical practice. 
Treatment: Participants will receive either 120 mg (2x 60 mg soft gel capsules) of 
elinzanetant or matching placebo orally once daily. More details are provided in Section 6. 
Participant surveys will be conducted to evaluate their experience with study assessments 
and overall satisfaction of participating in the study. These surveys will be conducted at 
timepoints defined in the SoA, and in addition may be conducted throughout the study. 
Follow-Up: The treatment phase will be followed by a 4-week safety follow-up period in 
participants who do not continue with the treatment extension (part C) and completed with 
the FU visit. 
Treatment extension (part C): Participants who completed 52 weeks of treatment and 
decide to continue in the study will receive 120 mg (2x 60 mg soft gel capsules) of 
elinzanetant orally once daily. Treatment in part C will start the day after last medication 
intake in the main study, i.e., without interruption of treatment.  
Follow-Up (part C): The treatment extension (part C) will be followed by a 4-week safety 
follow-up period and completed with the FU part C visit. 
 
4.2 
Scientific Rationale for Study Design 
A double-blind placebo-controlled design up to the primary endpoint at week 12 is 
considered necessary to differentiate drug effects from the natural course of disease, the 
effects of study participation, and background safety findings. Experience from multiple 
studies of women with postmenopausal VMS have shown that a placebo response of up to 
60% can be expected (Newton et al. 2014). Therefore, comparison to placebo is relevant to 
describe the true treatment effect of elinzanetant. 
A placebo-controlled period of 12-weeks to assess efficacy at week 4 and week 12 is 
considered acceptable because VMS caused by adjuvant endocrine therapy negatively 
affect health-related quality of life and adherence to treatment. The use of placebo is also 
considered adequate by both the EU Committee for Medicinal Products for Human Use 
(CHMP) and US FDA disease-specific guidelines (EMA 2005, FDA 2003). For women 

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experiencing VMS caused by adjuvant endocrine therapy, no approved active comparator 
is available.   
Participants will remain on the treatment regimen for the underlying condition, i.e. 
adjuvant endocrine therapy.  
The study includes multiple efficacy and safety endpoints in a population of patients with 
different degrees of moderate to severe VMS caused by adjuvant endocrine therapy, with 
the intention of reflecting the future patient population. These assess relevant aspects for 
the treatment of women with VMS and safety topics that were identified based on the 
mode of action of elinzanetant as well as available pre-clinical and clinical data. 
Study participants who have completed the originally planned 52 weeks of treatment and 
who need to continue the intake of adjuvant endocrine therapy will be offered two 
additional years of treatment with elinzanetant. There are no effective treatment options for 
VMS caused by adjuvant endocrine therapy since hormone treatment is contraindicated in 
patients with or at high risk for developing HR-positive breast cancer. It is expected that 
elinzanetant will reduce the frequency and severity of VMS caused by adjuvant endocrine 
therapy. If these benefits are confirmed, patients will benefit from the continued treatment 
in the extension period of this study.  
 
4.2.1 
Patient  Input into Design 
Feedback was collected from patient population through a patient Insights and patient 
surveys with the intent to: 
 Identify potential hurdles to recruitment, adherence with the study procedures, and 
participant retention  
 Confirm the relevance of the investigated endpoints for patients with VMS 
 Seek input on the content and visual design of study-related awareness and 
educational materials 
 
4.3 
Justification for Dose 
The clinical development program has broadly evaluated doses ranging from 1.5 mg to 
300 mg. The free base form of elinzanetant in a soft-gel capsule formulation was evaluated 
at doses between 25 mg and 160 mg once daily. A dose of 120 mg per day has been shown 
to be optimal with respect to efficacy, safety and receptor pharmacology.  
The 120 mg once daily dose was effective on a range of measures in the SWITCH-1 study 
that included post-menopausal women and was more effective than the two lower doses 
studied (40 mg and 80 mg once daily). There was no relevant additional benefit from a 
higher dose (160 mg once daily).   
The plasma concentrations achieved with the 120 mg dose are associated with full 
occupancy of central NK1 receptors throughout a dose interval at steady state as 
demonstrated in a human PET study. Although it is not possible to assess NK3 receptor 
occupancy directly, as a suitable NK3 PET ligand does not exist, the achieved 
concentrations are also very likely to fully occupy central NK3 receptors.  

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VMS are triggered by hyperactivation of the KNDy neurons, which are part of the 
thermoregulatory pathway, due to withdrawal of estradiol caused by decreasing ovarian 
function in natural menopause or as a side effect of medical intervention (bilateral 
oophorectomy, antiestrogen treatments). Based on the full receptor occupancy the 
hyperactivation of the KNDy neurons causing VMS can be antagonized by elinzanetant in 
both post-menopausal women and in women who are treated with adjuvant endocrine 
therapy. 
For details, refer to the IB. 
 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last scheduled visit of the last participant 
in the study globally. 
The primary completion date is the date when the last participant completes Visit T6. 
A participant is considered to have completed the main study if she  
has completed all phases of part A+B (including EoT visit at week 52) and the FU 
IP visit at week 56 or  
has completed all phases of part A+B (including EoT visit at week 52) and 
continues in part C.  
A participant is considered to have completed the study if she has completed all phases 
including the last visit. 
 

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5. 
 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Females aged 18 to 70 years, inclusive, at signing of informed consent. 
Type of Participant and Disease Characteristics  
2. Women experiencing VMS caused by adjuvant endocrine therapy that they are 
expected to use for the duration of the study  
a. Tamoxifen with or without the use of GnRH analogues or 
b. Aromatase inhibitors with or without the use of GnRH analogues 
The participant should be on stable adjuvant endocrine therapy at least 6 weeks 
prior to baseline.   
Switching or dose modification of adjuvant endocrine therapy is only allowed after 
Visit T6. 
3. Women must have  
a. a personal history of hormone-receptor positive breast cancer or 
b. a high risk for developing breast cancer  
 
4. Negative urine pregnancy test at Screening and at Baseline if participant has not 
been confirmed post-menopausal or WONCBP. 
5. In good general health (apart from the condition that resulted in adjuvant endocrine 
therapy), in the opinion of the investigator, based on the results of the assessments 
completed during screening.  

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6. Normal or clinically insignificant cervical cytology not requiring further follow-up: 
a. A cervical cytology sample has to be obtained during screening, or  
b. A documented normal result has to be available from cervical cytology 
conducted within 12 months prior to signing of informed consent.  
c. Human papilloma virus (HPV) testing in participants with atypical 
squamous cells of undetermined 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. 
d. HPV testing in participants with 
 endocervical/transformation 
 will be used as an adjunctive test automatically. 
Participants can be included if they are negative for high-risk HPV strains. 
7. BMI between 18 and 38 kg/m2 at screening. 
8. Participant has completed HFDD for at least 11 days during the two weeks 
preceding baseline visit, and participant has recorded at least 35 moderate to severe 
HF (including night-time HF) over the last 7 days that the HFDD was completed 
(assessed at the Baseline Visit). 
Sex and Contraceptive/Barrier Requirements 
9. Contraceptive use by women (except for post-menopausal women or WONCBP) 
should be consistent with local regulations regarding the methods of contraception 
for those participating in clinical studies. 
 A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and one of the following conditions applies: 
 Is a WONCBP as defined in Section 10.4.1  
OR 
 Is a WOCBP and using a highly effective contraceptive method 
as described in Section 10.4.2 during the study intervention 
period (the contraceptive methods must be used through the end 
of exposure [for at least 8 days after the last dose of 
elinzanetant2]). The investigator should evaluate the potential for 
contraceptive method failure (e.g., noncompliance, recently 
initiated) in relationship to the first dose of study intervention. 
                                                 
2 Tamoxifen can cause fetal harm when administered to a pregnant woman. Therefore, according to the 
prescription information of tamoxifen, females of reproductive potential need to be advised to use highly 
effective non-hormonal contraception during treatment with tamoxifen and for 9 months following the last 
dose of tamoxifen. 

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 A WOCBP must have a negative highly sensitive urine pregnancy 
test within 4 weeks before the first dose of study intervention, see 
Section 8.2.5.  
 If a urine test performed at site cannot be confirmed as negative 
(e.g., an ambiguous result), a serum pregnancy test is required. 
In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.  
 Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.2.5. 
 The investigator is responsible for review of medical history, 
menstrual history, and recent sexual activity to decrease the risk for 
inclusion of a woman with an early undetected pregnancy. 
Informed Consent 
10. Capable of giving signed informed consent as described in Section 10.1.5 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Initial diagnosis of metastatic hormone-receptor positive breast cancer (stage IV) or 
recurrence under adjuvant endocrine therapy of hormone-receptor positive breast 
cancer. 
2. Current or history (except complete remission for 5 years or more prior to signing 
informed consent) of any malignancy, except for hormone-receptor positive breast 
cancer (Stage 0-III), basal and squamous cell skin tumours. 
3. Surgery or non-surgical (e.g., chemotherapy, radiotherapy, immunotherapy) 
treatment for breast cancer within the last 3 months prior to signing informed 
consent (except use of tamoxifen, aromatase inhibitors, GnRH analogues). 
4. Planned surgery, chemotherapy, radiotherapy, or immunotherapy within the 
duration of the study (reconstructive breast surgery allowed after week 12). 
5. Current pregnancy or less than 3 months since delivery, abortion or stop of 
lactation prior to signing informed consent. 
6. Any clinically significant prior or ongoing history of arrhythmias, heart block and 
QT prolongation either determined through clinical history or on ECG evaluation.  
7. Any active ongoing condition that could cause difficulty in interpreting VMS such 
as: infection that could cause pyrexia, pheochromocytoma, carcinoid syndrome. 
8. Any unexplained vaginal bleeding. 

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9. Mammogram with clinically relevant malignant or suspicious findings that will 
require surgery, radiotherapy or chemotherapy as per local guidelines 
(mammogram should not be older than 12 months prior to signing informed 
consent). If a mammogram is not possible after partial mastectomy an ultrasound 
could be performed instead. 
10. Any clinically significant abnormal laboratory test result(s) measured during 
screening (single re-test allowed, except for tests listed in exclusion criterion 113).  
11. Abnormal liver parameters (presence of at least one of the following criteria):  
 AST > 2 x ULN,  
 ALT > 2 x ULN, 
 AP > 2 x ULN,  
 TBL > ULN 
syndrome, 
 INR > ULN unless explained by, e.g. intake of anti-coagulants3, 
 Diagnosis of hepatitis B infection, i.e., Hbs-antigen positive at screening, 
 Diagnosis of hepatitis C infection, i.e., hepatitis C-antibodies and HCV-
RNA positive at screening. 
12. Untreated hyperthyroidism or hypothyroidism.  
 Treated hyperthyroidism with no abnormal increase of thyroid function 
laboratory parameters and no relevant clinical signs for > 6 months before 
signing of informed consent is acceptable. 
 Treated hypothyroidism with normal thyroid function test results during 
screening and a stable (for > 3 months before signing of informed consent) 
dose of replacement therapy is acceptable. 
13. Renal impairment greater than moderate (i.e. estimated glomerular filtration rate 
< 30 mL/min/1.73m2) at screening. 
14. Disordered proliferative endometrium, endometrial hyperplasia, polyp, or 
endometrial cancer diagnosed based on endometrial biopsy during screening (see 
Section 8.2.9). 
15. Current arterial or venous vascular event (e.g. MI, TIA, stroke, DVT), i.e. within 
the last 6 months prior to signing informed consent. 
16. Any other history, condition, therapy, or intercurrent illness which could in the 
opinion of the investigator affect compliance with study requirements.  
17. Women with an ovarian cyst/cysts that need further diagnostic procedures to 
exclude the possibility of malignancy during screening. 
                                                 
3 Re-test of INR will be allowed once. 

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Prior/Concomitant Therapy 
18. Any other contraindication listed in the local labeling for medication used as 
adjuvant endocrine therapy. 
19. Has used and is unwilling to wash-out use of any of the prohibited concomitant 
medications, as specified in Section 10.6. 
20. Intake of medication prohibited due to potential drug-drug interaction, see 
Sections 6.8.2 and 10.6. 
Prior/Concurrent Clinical Study Experience 
21. Concurrent (or within the 2 months prior to signing of informed consent) 
participation in a clinical study with an investigational medicinal product (including 
medical devices). 
Other Exclusions 
22. At screening a response of 2 (I would like to kill myself) or 3 (I would kill myself if 
I had the chance) on BDI-II item 9 (Suicidal thoughts or wishes). 
23. Clinically relevant recreational/illicit drug or alcohol abuse within 12 months of 
signing of informed consent4. 
24. Dependent on the investigator, the contract research organisation(s) or Sponsor for 
education or employment (e.g. family members, employees, people who receive 
grants/education). 
25. Known hypersensitivity to elinzanetant or any of the excipients in the formulation. 
26. Inability to comply with the study procedures for any reason, including the 
following examples: language comprehension, psychiatric illness, general inability 
to get to the study site. 
27. Wish for pregnancy during the study period. 
 
5.3 
Lifestyle Considerations 
No restrictions to lifestyle are required. 
 
5.4 
Screen Failures 
A screen failure occurs when a participant consents to participate in the clinical study but 
is 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, date of informed consent, date of last visit, screen failure details, 
and eligibility criteria based on completed procedures. 
                                                 
4 Clinically relevant alcohol or drug abuse is behavior that meets the DSM-5 criteria for substance use 
disorder (DSM-5:Diagnostic and Statistical Manual of Mental Disorders). 

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Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once. Rescreening will not be allowed in participants who failed because of 
any of the following criteria: 
 Inclusion criterion 8 
 Exclusion criteria: 1, 6, 9, 10, 11, 13, 14, 18, 22, and 25. 
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 ICF for re-screening, even if the content was not changed 
after the previous consenting. Re-screened participant will be assigned a new participant 
number. 
 
5.5 
Criteria for Temporarily Delaying Randomization 
If a participant is otherwise eligible, acute intercurrent conditions (e.g. current febrile 
illness, quarantine for suspicion of COVID-19) may allow to postpone start of study 
intervention in a participant to a time when the condition has resolved.  
A delayed assessment or report of procedures required for assessment of eligibility (e.g., 
post-vaccine delay for mammogram, delayed result or repeated endometrial biopsy, 
technical ePRO issues) would constitute a reason for postponing randomization. Under 
these circumstances and to keep the treatment-free screening period as short as possible, 
the baseline visit will be scheduled as soon as reasonably possible, once the issue or 
condition is resolved and all screening results available. In case the screening period is 
extended to more than 8 weeks, a new blood sample has to be taken for assessment of 
eligibility.  
 
6. 
 
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. 

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6.1 
Study Intervention(s) Administered 
Table 6-1: Study Intervention(s) Administered 
Intervention Label 
Elinzanetant 
Placebo 
Intervention Name 
BAY 3427080 / elinzanetant 
Placebo 
Intervention Description 
60 mg capsule, 120 mg, qd 
two capsules, qd 
Type  
Drug 
N/A 
Dose Formulation 
soft gel capsule 
soft gel capsule 
Unit Dose Strength(s) 
60 mg 
N/A 
Dosage Level(s) 
two capsules daily (120 mg) 
two capsules daily 
Route of Administration 
oral 
oral 
Use 
experimental 
placebo 
Packaging and Labeling 
Study Intervention will be 
provided in an Alu-Alu blister 
with 12 soft gel capsules. 5 
blisters will be placed into 1 
box containing capsules for 
treatment of one month. Each 
box will be labeled as required 
per country requirement 
Study Intervention will be 
provided in an Alu-Alu blister 
with 12 soft gel capsules. 5 
blisters will be placed into 1 
box containing capsules for 
treatment of one month. 
Each box will be labeled as 
required per country 
requirement 
Current 
Former Name 
BAY 3427080  
NT-814 
N/A 
Alu = Aluminium; N/A = Not applicable; qd = Once daily 
Table 6-2: Study Arm(s) 
 
Study intervention will be dispensed at the study visits summarized in the SoA.  
The first dose should be taken supervised during the Baseline Visit on the day of 
randomization. In general, study treatment will be taken once daily before going to bed in 
both treatment arms, with or without food. For requirements on drug intake for PK 
sampling, please refer to Section 1.3.4. 
If a participant forgets to take a dose in the evening, then the dose can be taken at any time 
up to 2AM the same night. After this time, the dose should not be taken and will be 
considered a missed dose. 
Returned study intervention may not be re-dispensed to a different participant. 
 
Arm Title 
Elinzanetant 
Placebo 
Arm Type 
experimental 
placebo 
Arm Description 
Participants will receive 
120 mg elinzanetant orally 
once daily for 52 weeks and 
optionally for additional 2 
years. 
Participants will receive 
placebo orally once daily for 
the first 12 weeks. 120 mg 
elinzanetant will be 
administered from week 13 to 
52 and optionally for 
additional 2 years. 
Associated Intervention 
Labels 
Elinzanetant 
Placebo or Elinzanetant 

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6.2 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants randomized in the study may receive study intervention and only 
authorized site staff 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). Drug returns, accountability, 
reconciliation and destruction return information will be captured in IxRS. 
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 of child bearing 
potential after ruling out pregnancy (urine pregnancy test with negative result). 
Local destruction (if any) of the study drug must be properly documented consistent with 
destruction will be made available to affected parties as applicable. 
 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Participants who meet all eligibility criteria will be centrally assigned to randomized study 
intervention using an IxRS. Before the study is initiated, the log in information and 
directions for the IxRS will be provided to each site. The randomization schedule will be 
computer generated by the sponsor or delegate. Once a randomization number has been 
assigned it must not be re-assigned. 
Participants will be randomly assigned to receive study intervention as described in 
Section 9.2
intervention throughout the course of the study.  
Unblinding 
The IxRS will be programmed with blind-breaking instructions. In case of an emergency, 
intervention assignment is warranted.  
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 24 hours/7-day service. Participant safety must always be the 
first consideration in making such a determination.  
If the investigator decides that unblinding is warranted, the investigator should make every 
unless this could delay emergency treatment of the participant.  

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24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and case report form, as applicable. 
In case of unblinding, only those individuals who are required to know treatment allocation 
may be given this information. All others must remain blinded to treatment, including the 
participant.  
Pharmacometrics staff may be unblinded according to Bayer standard operating 
procedures. Pharmacokinetic and exposure-response analysis might be performed using 
population approaches (popPK and popPK/PD, e.g., by non-linear mixed effect modeling). 
Analysis and report will be done under a separate cover. This evaluation might 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. 
Sponsor global pharmacovigilance staff may unblind the intervention assignment for any 
participant with an SAE/SUSAR. If the SAE/SUSAR requires that an expedited regulatory 
report be sent to one or more regulatory agencies, a copy of the report, identifying the 
regulations and/or sponsor policy. 
An independent data analysis center will provide unblinded safety data to the independent 
Data Safety Monitoring Board. A Liver Safety Monitoring Board will assess the blinded 
cases that enter Close Liver Observation. 
 
6.4 
Study Intervention Compliance 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by review of daily 
diary entries and confirmatory capsule counts during study visits and documented in the 
source documents and relevant form. Deviation(s) from the prescribed dosage regimen 
should be recorded. 
A record of the quantity of study intervention dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays will also 
be recorded. If the participant is unable to continue taking the study intervention as 
required, she should contact the study site. 
Study drug intake documenting 
Participants will document the number of study medication capsules taken, together with 
hand-held device during the treatment period as indicated 
in the SoA. 
 
6.5 
Dose Modification 
Not applicable, all participants receiving active treatment will stay on the same dose. 
 

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6.6 
Continued Access to Study Intervention after the End of the Study 
Study participants who have completed the main study of 52 weeks of treatment will be 
offered to continue with the study and study drug intake for 2 additional years (treatment 
extension). No general access to study intervention is planned after the end of the study. 
Investigators can request post trial access for their study participants, if deemed necessary.  
 
6.7 
Treatment of Overdose 
For this study, any dose of elinzanetant greater than 240 mg within a 24-hour time period 
will be considered an overdose. 
There is no known specific treatment (no antidote) for an overdose with elinzanetant. 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: 
 
Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
 
Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until stabilization and/or resolution. 
 
Obtain a plasma sample for PK analysis as soon as possible from the date of the 
last dose of study intervention if requested by the Medical Monitor (determined 
on a case-by-case basis). 
 
Document the quantity of the excess dose as well as the duration of the 
overdose in the eCRF. 
Decisions regarding dose interruptions will be made by the investigator in consultation 
with the Medical Monitor 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 
 Dates 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 
Background therapy 
As per inclusion criterion 2, all participants experience VMS caused by adjuvant endocrine 
therapy
amoxifen 
inhibitors with or without the use of GnRH analogues
 
These background therapies are considered as Auxiliary Medicinal Products (not an 
Investigational Product) and are authorized in all participating countries. Please refer to the 
current prescribing information / Summary of Product Characteristics (SmPC).  
These drugs will be used as prescribed by the 
e.g., oncologist, 
gynecologist, or general practitioner) for the treatment of breast cancer or for the 
prevention of developing breast cancer. The European Society for medical oncology 
clinical practice guideline for breast cancer prevention and screening says that adjuvant 
endocrine therapy should be administered as clinically indicated although the level of 
evidence is weak (Paluch-Shimon et al. 2016). The use of adjuvant endocrine therapy for 
the prevention of breast cancer varies between countries and within countries.  
These drugs will be supplied locally (by the site or local pharmacy) during the course of 
the study as per local laws and regulations. In case of local shortages the sponsor may 
supply background medication as a risk mitigation to ensure that participants can continue 
the study as planned. 
These Auxiliary Medicinal Products will be recorded in the prior and concomitant 
medication pages of the eCRF. 
Participants will document these background medication intakes on a daily basis in the 
eDiary (using hand-held device) as indicated in the SoA, i.e. until EoT visit (week 52). A 
participant who completed the 52 weeks treatment period will be offered 2 additional years 
of treatment extension (part C). During the part C the intake will not any longer need to be 
documented on a daily basis. Instead some general information will be collected during the 
visits (see Section 8.1.2).  
The participant should be on stable adjuvant endocrine therapy at least 6 weeks prior to 
baseline and, until the week 12 visit (T6), it is not permitted to switch or to modify dose of 
adjuvant endocrine therapy (e.g., switch from tamoxifen to an aromatase inhibitor, or 
switch from one aromatase inhibitor to another aromatase inhibitor). 
6.8.2 
Prohibited concomitant medications 
Section 10.6 presents a comprehensive (but not exhaustive) list of prohibited concomitant 
medications (recently approved drugs may not be included in the list and should be 
checked on a case-by-case basis). The Medical Monitor should be contacted if there are 
any questions regarding concomitant or prior therapy. 

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6.8.3 
Other Treatment Considerations 
Based on preclinical data, an increase in exposure of drugs that are sensitive substrates of 
OATP1B1/1B3, P-glycoprotein or breast cancer resistance protein (BCRP) during co-
administration of elinzanetant due to inhibition of those transporters by elinzanetant could 
not be excluded. Results from a clinical drug-drug interaction study with the BCRP and 
OATP1B1/B3 substrate rosuvastatin showed no clinically relevant effect on the 
pharmacokinetics of rosuvastatin when administered together with elinzanetant. Therefore, 
medications that are substrates of BCRP and/or OATP1B1/1B3 can be administered 
together with elinzanetant without restrictions. Results from a clinical drug-drug 
interaction study with the sensitive P-gp substrate dabigatran etexilate (study 22081) 
showed no clinically relevant interaction. Therefore, medications that are substrates of P-
gp can be administered together with elinzanetant without restrictions. 
7. 
 
7.1 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue study intervention. If 
study intervention is permanently discontinued, and if the investigator considers it 
medically justified, the participant may remain in the study without receiving the study 
intervention. As a general rule, all procedures scheduled for the end-of-treatment visit 
should be performed at the time of premature discontinuation of study intervention and 
documented. In case this is considered not medically appropriate for certain procedures 
(e.g. for invasive procedures if only short time has elapsed since the last scheduled 
assessment) this should be documented by the investigator. All scheduled study visits and 
procedures, except for study intervention, should continue if agreed by the participant. PK 
sampling is also not required. For participants who agree to continue in the study, any 
medication used after discontinuation of study intervention must be documented. 
Treatment extension (part C): 
Participants who prematurely discontinue from treatment during part C are asked to return 
to the EoT part C and FU part C visit. 
For withdrawal from study see Section 7.2. 
7.1.1 
Pregnancy 
The participants must discontinue study intervention in case of pregnancy (See 
Section 8.3.5). 
7.1.2 
Liver Chemistry Stopping Criteria 
Discontinuation of study intervention for abnormal liver tests is required by the 
investigator when a participant meets one of the conditions outlined in Section 10.5 or in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if 
the investigator believes that it is in best interest of the participant. See Section 10.5 for 
further details. 
No lab samples are taken during part C. In case the participant meets one of these 
thresholds in lab samples taken outside of the study these criteria apply. 
 

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7.1.3 
Platelet count Stopping Criteria 
In the case of platelet counts below 50,000/mm3, study intervention must be discontinued 
immediately.  
In the case of platelet counts between 50,000/mm3 and 75,000/mm3, a retest should be 
performed within 72 hours of the initial test results. If values do not normalize within 7 
days, study intervention must be discontinued. 
No lab samples are taken during part C. In case the participant meets one of these 
thresholds in lab samples taken outside of the study these criteria apply. 
 
7.1.4 
Temporary Discontinuation  
In the event that a participant experiences an AE which the investigator believes is 
treatment related and which the participant finds intolerable, a break in dosing of up to one 
week is permitted. If, on reintroduction of the study medication, the AE recurs and remains 
intolerable, the study drug will be permanently withdrawn. A break in dosing will not 
result in extension of the overall dosing period. 
Temporary discontinuation is also allowed in the following two cases: 
 Temporary discontinuation of study intervention for an intercurrent illness, at the 
discretion of the investigator.  
 In the event of a trial-continuity issue (e.g. caused by a pandemic), the sponsor may 
provide additional guidance in study-specific communication. 
7.1.5 
Rechallenge 
Study intervention may be restarted after a temporary interruption if deemed clinically 
appropriate by the investigator in collaboration with the 
 representative (e.g. 
medical monitor). 
7.1.5.1 
Study Intervention Restart or Rechallenge After Liver Stopping 
Criteria Met 
Section 7.1.5.1 is not applicable for the treatment extension (part C). 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
 

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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.  
 If a participant is tested positive for SARS-CoV-2 infection while on 
study, the investigator will have to decide whether staying in the 
study is compatible with participant and site personnel safety and 
wellbeing. In most cases, temporary discontinuation (see section 
7.1.4) may be an appropriate solution. The decision should also take 
into account possible interaction between the study intervention and 
potential treatment for SARS-CoV-2 infection. 
 If a participant discontinues treatment with tamoxifen/aromatase 
inhibitors in the main study (part A+B), the investigator will decide 
whether the participant should be withdrawn from the study. 
 If a participant discontinues treatment with 
tamoxifen/aromatase inhibitors during treatment extension 
(part C), she should be withdrawn from the study. 
 At the time of discontinuing from the study, if possible, End of 
Treatment visit (either EoT or EoT part C visit) procedures should be 
conducted, followed by a FU visit as shown in the SoA and in particular 
described in footnote a) in Table 1-2. 
 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. 
 For withdrawal during the follow-up period, the participant should 
undergo the assessments scheduled for the next visit (FU Visit). 
 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. 
For withdrawal from study intervention see Section 7.1. 
 
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. 

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 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 
methods). These contact attempts should be documented in the 
 
 Should the participant continue to be unreachable, she will be 
considered to have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
 
8. 
 
 Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
 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 screen failure, as applicable.  
 
e.g., 
cervical smear or mammogram) and obtained before signing of the ICF may be 
utilized for screening or baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within the time frame defined in the 
SoA. 
 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. 
 In the event of a significant trial-continuity issue (e.g. caused by a pandemic), 
alternate strategies for participant visits, assessments, medication distribution and 
monitoring may be implemented by the sponsor or the investigator, as per local 
health authority / ethics requirements. 
 
8.1 
Efficacy Assessments 
In this clinical trial, efficacy will be assessed using clinical outcome assessments. As these 
are responded to by the study participants themselves, they are considered PROs. The 
PROs used in the study are described in Section 8.1.1 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
The efficacy assessments described in Section 8.1.1 are not conducted during treatment 
extension (part C) of the study.  

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8.1.1 
Electronic Participant-Reported Outcomes (ePROs)  
During the study visits, ePROs are to be completed prior to any other procedure. An ePRO 
is an electronically applied measurement based on a report that comes directly from the 
participant about the status of the 
 health condition without interpretation of 
the response by a clinician or anyone else. In this trial ePROs will be used for the 
assessment of different endpoints. These endpoints will be collected using an electronic 
participant hand-held device during the entire study duration both for entries at home 
(including days of the study visits), and at study visits at the study site, as indicated in the 
SoA. Web-based back-up versions may be applied in addition. 
ePROs collected on the 
 hand-held device 
The following ePROs will be collected on a hand-held device in the following sequence: 
 Morning HFDD 
 PROMIS SD SF 8b 
 ISI 
 MENQOL 
 BDI-II 
 EQ-5D-5L 
 SF-36 acute  
 Evening HFDD  
 Sleepiness Scale (See Section 8.2.10) 
 Study drug intake documentation (See Section 6.4) 
 Background medication intake documentation (See Section 6.8.1) 
 Vaginal bleeding diary5 
 Result of home urine pregnancy test (independent of above sequence) 
After BL visit up to Visit T6 (inclusive) the PROMIS SD SF 8b, the MENQOL, the 
BDI-II, the EQ-5D-5L and the SF-36 acute will be open for completion by the participant 
at pre-defined days in the study, as roughly reflected in the SoA. Exact days will be 
described in a participant guidance document. From Visit T7 onwards these ePROs will be 
completed by the participant during the study visits. 
Time for completion 
Time for completion of each item of the different ePROs is conservatively estimated with 
approximately 30 seconds per individual item. The daily completion time, therefore, ranges 
from approximately 6 min during normal days during the study without study visits to a 
maximum of 60 min on the one day when all/most questionnaires are to be completed.  
                                                 
5 Only to be completed by women who use tamoxifen monotherapy as adjuvant endocrine therapy and who 
had in addition a menstrual bleeding in the 3 months prior to the Baseline Visit. 

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Data entry into the electronic devices during the visits at the study sites must be performed 
prior to any other study related activity. 
Dispense of the 
 hand-held device, data entry and transmission 
The device will be dispensed at the time point specified in the SoA.  
The specific time window for data entry into the participant hand-held device is ePRO-
specifically technically regulated and alarms will be set as appropriate to remind the 
participant to complete the ePROs respectively. The participants will be asked to fill in the 
questionnaires at specified time intervals as detailed in the SoA. 
P
ata entries from the hand-held device will be transmitted automatically by 
wireless connectio
, and later by the vendor to 
Data Management. Automatic continuous checking of the data transfer will be 
performed, and completeness of diary entries will be monitored, so that a failure to make 
entries is detected by the data-logging system and a warning will be sent to the study site. 
The ePRO device will be returned to the site when a participant leaves the study. 
Training of participants 
During screening, participants will be trained on the use of the hand-held device. 
Retraining will be performed as needed during the course of the study. The participants 
will be asked to confirm their understanding on the use of the device and completion of the 
ePRO before data entry on the hand-held device is activated. Participants will be educated 
regarding the importance of their timely and accurate completion of the ePROs during all 
study visits. The participants will be instructed to complete the ePROs on their own 
without any input from others at the pre-specified time points, in a quiet place in one 
sitting, following the instructions on the ePROs. 
Ongoing technical support during the entire study duration will be provided by the study 
site staff to prevent missing data entry to the extent possible. Beyond this technical 
support, no other help should be given to participants regarding the completion of the 
ePROs at home and at the study site.  
Training of and by study site staff, 24-hour help desk 
The study site staff will be instructed to explain the importance of completing the ePROs 
to the participants. 
The study site staff will be trained regarding the use of the participant hand-held device, 
and in resolving technical issues with these devices during the Investigator Meeting and 
site initiation process. Educational material will be available in the ePRO portal and the 
Investigator Site File. The study site staff will provide a standardized technical training on 
the handling of the participant hand-held device to the participants during SCR-2, and 
retraining will be performed as needed during the course of the trial. The study site staff 
will assist the participants in case of any technical queries during the entire study duration. 
In addition to the technical support by the study site staff, a 24-hour help desk by the ePRO 
provider will be available during the entire study duration to respond urgent technical 
questions. 

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Measures to further prevent missing 
 hand-held device entries 
In case one entry on the HFDD, the Sleepiness Scale, the Study/background medication 
intake or the vaginal bleeding diary was missed (for morning diaries in case this was not 
completed when getting up in the morning; for evening diaries, Sleepiness Scale, 
study/background medication intake and vaginal bleeding diary in case this was not 
completed in the evening when going to bed), retrospective data entry is possible for a 
limited time. For the morning diary these retrospective entries will be allowed on the same 
day between 11:00 AM and 11:59 PM. For the evening diary, the Sleepiness Scale, the 
Study/background medication intake documentation, and the vaginal bleeding diary, the 
entry option will be available between midnight until 10:59 AM on the day after the 
missed entry.  
When the study site becomes aware of missing participant hand-held device entries, the 
study site staff will contact the participants who have missed a defined number of 
consecutive entries (provided separately) immediately, and ask for reasons for failure in 
data entry and transfer. The study site staff will remind the participants of the importance 
of the twice daily eDiary entry. 
Further to the automatic continuous checking of completeness of the participant hand-held 
device entries, at all the study visits following SCR-2, the participant hand-held device 
entries will be checked, and the checks documented by the study site personnel for 
completeness. 
8.1.1.1 
Hot Flash Daily Diary (HFDD) 
HF will be recorded electronically twice daily using the 
Sponsor developed HFDD. The HFDD will be completed in the morning after waking up 
(morning diary) and each evening at bedtime (evening diary) on the hand-held device at 
time points indicated in the SoA. The HFDD items assess the number of mild, moderate, 
and severe HF experienced during the day and during the night. In addition, the number of 
awakenings during the night and disturbance of sleep due to HF will be documented in the 
morning diary. 
Mild HF ar
, moderate HF are defined as 
, and severe HF are 
 
8.1.1.2 
Patient-reported Outcomes Measurement Information System Sleep 
Disturbance Short Form 8b (PROMIS SD SF 8b) 
The PROMIS SD SF 8b includes 8 items assessing sleep disturbance over the past 7 days 
(Yu et al. 2011). Items assess sleep quality, sleep depth and restoration associated with 
sleep, perceived difficulties with getting to sleep or staying asleep and perceptions of the 
adequacy of and satisfaction with sleep. Participants respond to the items on a 5-point scale 
from not at all, never or very poor to very much, always or very good. Four of the items are 
scored reversely. Total scores range from 8 to 40, with higher scores indicating greater 
severity of sleep disturbance. The individual items for a respondent can be summed and 
raw scores can be converted into T-scores for comparison with population norms. 
In this study the PROMIS SD SF 8b will be applied electronically and responded to by the 
participants at home and during selected in person visits using the handheld device at the 
time points indicated in the SoA. 

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8.1.1.3 
Menopause Specific Quality of Life Scale (MENQOL) 
The MENQOL questionnaire is comprised of 29 items assessing the presence of 
menopausal symptoms and the impact of menopause on health-related quality of life over 
the past week (Hilditch et al. 2008). The items assess four domains of symptoms and 
functioning: VMS, psychosocial functioning, physical functioning, and sexual functioning. 
For each item, the participants indicate if they have experienced the symptom (yes/no). If 
they select yes, they rate how bothered they were by the symptom using a six-point verbal 
descriptor scale, with response options ranging from 0 'not at all bothered' to 6 'extremely 
bothered'.  
Based on the individual responses, item scores, domain scores, and a total MENQOL score 
are calculated. Each score ranges from 1-8, higher scores indicate greater bother. 
In this study the MENQOL will be applied electronically and responded to by the 
participants at home and during selected in person visits at time points indicated in the 
SoA. 
8.1.1.4 
European Quality of Life 5-dimension 5-level questionnaire 
(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. For the EQ-5D-5L descriptive system, participants provide a rating for 
each question on a five-point 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".  
In this study the EQ-5D-5L will be applied electronically and responded to by the study 
participants at home and during selected in person visits at the timepoints indicated in the 
SoA.  
8.1.1.5 
Insomnia Severity Index (ISI) 
The ISI is a seven item instrument that quantifies the participant perception of insomnia 
severity, along with the impact of insomnia on daytime functioning in adults in the last two 
weeks (Bastien et al. 2001). The items refer to: severity of sleep onset, sleep maintenance 
and early morning wakening problems, satisfaction with sleep pattern, noticeability of 
sleep problems by others, distress caused by the sleep difficulties and interference of sleep 
difficulties with daytime functioning. It is scored on a five point Likert scale from 0 to 4 
-
total score (maximum 28). 

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Total score categories: 
0 7 = No clinically significant insomnia 
8 14 = Subthreshold insomnia 
15 21 = Clinical insomnia (moderate severity) 
22 28 = Clinical insomnia (severe) 
In this study the ISI will be applied electronically and responded to by the study 
participants at home and during selected in person visits at timepoints indicated in the SoA. 
8.1.1.6 
Beck Depression Inventory (BDI-II) 
The BDI-II is an established and widely used measure for assessment of depression. 
Additionally, it provides conceptual coverage and some concepts in the emotional 
experience of postmenopausal women.  
The BDI-II consists of 21 items to assess the severity of depression over the past 2 weeks 
(Beck et al. 1996). Each item is a list of four statements arranged in increasing levels of 
severity about a particular symptom of depression. Items use a 4-point verbal response 
scale ranging from 0 (not at all) to 3 (extreme form of each symptom); specific response 
options are tailored to the aspect of depression being measured in each item. A total score 
ranging from 0 to 63 is calculated with scores of 0  13 indicating mild minimal range, 14 
 19 mild depression, 20  28 indicating moderate and 29  63 severe depression (higher 
score = greater depression).  
The investigator will receive an email notification if a BDI of >19 is reported. The 
investigator may consider reporting an adverse event based on the clinical presentation. 
The participant can be enrolled in the study when in the opinion of the investigator the 
depression does not affect compliance with study requirements. In addition, any depression 
should be treated according to local clinical practice. See details in Section 8.2.11 for 
eligibility criteria based on BDI-II. 
In this study the BDI-II will be applied electronically and responded to by the study 
participants during selected in person visits at timepoints indicated in the SoA.  
8.1.1.7 
Short Form-36 Health Survey Acute (SF-36 acute) 
The SF-36 acute is a widely used measure of general health status with well-documented 
reliability, validity, and responsiveness in the general population as well as in various 
disease indications. It consists of 36 items which are responded to using item specific 1-5 
or 1-3 Likert scales. The acute version has a recall period of 1 week. The items are 
comprising 8 domains: physical function, role physical, bodily pain, general health, 
vitality, social functioning, role of emotional and mental health and two composite scores, 
the physical component score (PCS) and mental component score (MCS). Scores from 
individual items of each subscale are combined to form a subscale rating and are 
transformed to a 0 to 100 scale. Higher scores indicate better quality of life. Reference 
values derived in a healthy population, distributed by age and gender, are available.  
In this study the SF-36 acute will be applied electronically and responded to by the study 
participants at home and during selected in person visits at the timepoints indicated in the 
SoA.  

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8.1.1.8 
Vaginal bleeding diary 
The vaginal bleeding diary will be completed only by pre-menopausal women who use 
tamoxifen monotherapy as adjuvant endocrine therapy and who had in addition a vaginal 
bleeding in the 3 months prior to the Baseline Visit. The vaginal bleeding diary will be 
completed only during the placebo-controlled period of 12 weeks. It will be filled in daily 
using the electronic hand-held device. 
The vaginal bleeding diary is a frequently used PRO instrument designed to assess the 
participant
 vaginal bleeding symptoms. The vaginal bleeding diary will be 
completed daily by the participant each evening in the electronic hand-held device, when 
the participant is to reflect on her experiences in the past 24 hours. Participants will be 
asked to rate their vaginal bleeding as follows: 
 None (no vaginal bleeding) 
 Spotting (less than associated with normal menstruation relative to the participant
experience, with no need for sanitary protection (except for panty liners)) 
 Light (less than associated with normal menstruation relative to the participant
experience, with need for sanitary protection) 
 Normal (like normal menstruation relative to the participant
) 
 Heavy (more than normal menstruation relative to the participant
xperience) 
Findings from the vaginal bleeding diary data only need to be documented as an AE, if 
they lead to a special diagnosis, treatment or to a drop-out. 
8.1.2 
Investigator collected Patient Reported Outcomes (RAVE)  
Only applicable for treatment extension (part C) of the study. 
During each visit, the investigator will ask the participant about adherence to the 
prescribed intake schedule of the adjuvant endocrine therapy (tamoxifen/aromatase 
inhibitor) during the past 6 months by use of a five-point Likert scale: none of the time, a 
little of the time, some of the time, most of the time, all the time. 
The investigator will document the participant  responses in her patient file and enter the 
response in the eCRF.  
 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Physical Examinations 
 A complete physical examination will be performed at visits indicated in the SoA. 
It will include, at a minimum, gynecological examination, and assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Gynecological examination is to be done according to local guidelines/common 
clinical practice. 
 A symptom-based physical examination will be performed as indicated in the SoA, 
in a response to new symptoms, or changes in symptoms. 
 Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 

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 Height will be measured at Screening Visit only. 
 Weight will be recorded at all in person visits. 
 Abnormal physical examination findings, including overweight/obesity when 
BMI > 30, are to be recorded either as medical history or as adverse events. 
8.2.2 
Vital Signs 
 Pulse rate, and systolic and diastolic blood pressure will be assessed. 
 Vital signs measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).  
 Vital signs should be taken before blood collection for laboratory tests. 
 Blood pressure and pulse rate measurements will be assessed once in a sitting 
position with a completely automated device. Manual techniques will be used only 
if an automated device is not available. 
 In case of abnormal results, repeat measurements should be performed to 
adequately document potential findings, e.g. hypertension.6  
8.2.3 
Electrocardiograms 
 ECGs should be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals according to Bazett's 
formula and/or Fridericia's formula.   
 A single 12-lead ECG will be obtained for eligibility check only at screening. If 
clinically indicated, unscheduled 12-lead ECGs can be performed at any point 
during the study. Unscheduled ECGs must be recorded in the eCRF. 
 The interpretation of the tracing must be made locally by a qualified physician. 
 Each ECG tracing should be labeled with the study number, participant number, 
and date and kept in the source documents at the study site. 
 Clinically relevant abnormalities should be reported as AEs as appropriate (e.g. 
new onset atrial fibrillation). 
8.2.4 
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. 
                                                 
6 Hypertension is defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg over 
three readings on at least two different occasions. 

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 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or the medical monitor. 
 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. 
 All protocol-required laboratory tests, as defined in Section 10.2, 
must be conducted in accordance with the laboratory manual and the 
SoA.  
 If laboratory values from non-protocol specified laboratory tests 
ry require a change in 
participant management or are considered clinically significant by 
the investigator (e.g., SAE or AE or dose interruption), then the 
results must be recorded according to the eCRF completion 
guideline. 
8.2.5 
Pregnancy Testing 
All women who are not confirmed post-menopausal or who are WOCBP should have 
pregnancy tests performed according to the SoA. See Section 10.4.1 for definitions. 
In these participants a urine pregnancy test will be performed to confirm eligibility at 
Screening and at Baseline prior to the first study drug intake. Afterwards, urine pregnancy 
tests will be performed during all site visits. Additionally, the participant is asked to 
conduct home urine pregnancy testing as indicated in the SoA and document the results in 
the eDiary. If the home urine pregnancy test is positive or cannot be confirmed as negative 
(e.g., an ambiguous result) after repeating at home, the participant should contact the site 
immediately. Further investigations will be performed at the discretion of the investigator. 
Reference is made to Section 8.3.5 in the unlikely event that a pregnancy is detected during 
the study. The home pregnancy tests will be provided by the sponsor. 
Treatment extension (part C): 
No urine pregnancy tests will be performed during the site visits. The participant is asked 
to conduct home urine pregnancy testing once a month, e.g., when starting a new package. 
If the home urine pregnancy test is positive or cannot be confirmed as negative (e.g., an 
ambiguous result) after repeating at home, the participant should contact the site 
immediately. Further investigations will be performed at the discretion of the investigator. 
Reference is made to Section 8.3.5 in the unlikely event that a pregnancy is detected during 
the study. The home pregnancy tests will be provided by the sponsor. 

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8.2.6 
Mammogram 
Mammogram will be performed at time points indicated in Section 1.3.  
 Prior mammogram results may be used for eligibility if obtained no more than 12 
months prior to signing informed consent and the results should be documented in 
the eCRF.  
 Women with bilateral mastectomy do not have to provide a mammogram provided 
that all breast tissue has been removed. If a mammogram is not possible after 
partial mastectomy an ultrasound could be performed instead. 
 Mammograms should be obtained during the study in alignment with local medical 
guidelines for the follow up of the specific participant and the results should be 
documented in the eCRF. 
 At the end of treatment, a mammogram should be performed if the time that has 
elapsed since the previous mammogram is in line with local medical guidelines for 
the follow up of the specific participant and the results should be documented in the 
eCRF. 
 Since unilateral axillary lymphadenopathy is a frequent mild side effect of 
COVID-19 vaccination, it is recommended to perform the mammogram at the 
screening visit prior to any planned COVID-19 vaccination or to delay the 
screening visit for a certain period according to local guidance. In addition, it is 
recommended to schedule any planned COVID-19 vaccination after the EoT 
mammogram (if a mammogram is required, see above). 
8.2.7 
Cervical cytology 
 Cervical smear will only be performed before randomization to ensure eligibility 
and is not a safety endpoint. 
 Cervical smear will be performed only if the participant has an intact cervix. 
 Cervical smear performed during the last 12 months prior to signing of informed 
consent 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. 
 If cervical smear and endometrial biopsy are scheduled for the same day, cervical 
smear should be conducted first. 
 Cervical smear is not required in participants with total hysterectomy (condition 
needs to be recorded in the eCRF). 
8.2.8 
Transvaginal ultrasound (TVU) 
 Transvaginal ultrasound should be performed as indicated in the SoA or if the 
participant has symptoms (e.g. unexplained vaginal bleeding) and endometrial 
biopsy will be considered depending on the endometrial thickness (see 
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 Ultrasound examination should be performed by a physician/examiner well 
experienced in the procedure or with corresponding qualification based on local 
clinical practice. TVU is not required in participants who had both a total 
hysterectomy and a bilateral salpingo-oophorectomy. 
 If TVU is not possible due to vulvo-vaginal atrophy (e.g. in women who use 
aromatase inhibitors) an abdominal or transrectal ultrasound is allowed.  
 The following safety parameters will be measured and recorded:  
 Endometrial thickness (measured in the medio-sagittal section as double-
layer in millimeters) 
 Overall assessment of the pelvic organs, especially for evaluation of the 
uterus, ovaries (including diameters as well as details of cyst like structures, 
if applicable) and fallopian tubes (abnormalities to be reported as AE/SAE) 
 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 electronic format with 
images from the ultrasound machine showing the endometrium in sagittal section 
and both ovaries. The 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. 
 TVU is not required in participants with total hysterectomy and bilateral salpingo-
oophorectomy (these conditions need to be recorded in the eCRF).  
8.2.9 
Endometrial biopsy 
Timing and sampling of endometrial biopsy 
 Endometrial biopsy is to be performed only when applicable as outlined below at 
time points indicated in the SoA.  
 Endometrial biopsy should be performed by a physician/examiner well experienced 
in the procedure or with corresponding qualification based on local clinical practice 
 Endometrial biopsy should be performed if the participant has an intact uterus and 
has symptoms (e.g. unexplained vaginal bleeding)  
 Endometrial biopsy should be considered if:  
 the endometrial thickness assessed by TVU 
7 mm for pre-menopausal 
women. According to the Royal College of Obstetricians and Gynaecologists 
guidance (Royal College of Obstetricians and Gynaecologists 2016), 
endometrial hyperplasia is unlikely if the endometrial thickness <7 mm. The 
final decision to perform an endometrial biopsy should be based on the 
 
 the endometrial thickness assessed by TVU is 4 mm for post-menopausal 
women.  
 If an endometrial biopsy was taken at screening, the result should be normal in 
order for the participant to be randomized (disordered proliferative endometrium, 
hyperplasia, polyp and malignant findings will be considered as abnormal).  

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If postmenopausal status has not been confirmed prior to the endometrial biopsy, a 
urine pregnancy test and a transvaginal ultrasound must be performed before 
conducting the biopsy.  
 
If a cervical smear sample is collected at the same visit, it must be performed before 
performing the biopsy. 
 
Unscheduled biopsy should be performed in case of an abnormal finding in the 
TVU and/or if the participant has unexplained bleeding during the study.  
 
If necessary for pain prophylaxis or relief relating to the endometrial biopsy 
procedure, the use of an analgesic is permitted and will be documented as 
concomitant medication.  
Assessment of endometrial biopsies 
All biopsy samples will be processed via the central laboratory and will be evaluated 
independently by three pathologists who are blinded with regard to treatment assignment.   
If the baseline biopsy is interpreted by at least one of the reviewing pathologists to contain 
findings that constitute an exclusion criterion, the participant must be excluded from the 
study. Details can be found in the Operational Manual for Pathology Reads. 
Study sites will be informed about the individual diagnoses of the three pathologists to 
allow for clinical follow-up.  
sample will be requested by the central laboratory. 
 Women with a diagnosis of disordered proliferative endometrium, endometrial 
hyperplasia, polyp or malignant neoplasm by any of the three pathologists will not 
be included in the study. 
 At end-of-treatment, the requirement for a repeat biopsy after a non-evaluable 
sample is at the discretion of the investigator. The decision should take into account 
endometrial thickness and clinical findings. 
 Any abnormal endometrial biopsy findings should be followed-up and treated 
according to local clinical practice.  
8.2.10 
Sleepiness Scale 
The sleepiness scale is a Sponsor developed questionnaire containing 3 items assessing the 
degree of sleepiness experienced by the participant in the morning, in the afternoon and in 
the evening of the same day. The Sleepiness Scale will be assessed together with the 
HFDD evening diary at bedtime during selected time periods, using the electronic hand-
held device. In case one entry on the Sleepiness Scale was missed, retrospective data entry 
is possible for a pre-defined period of time (see Section 8.1.1
-
).  
Participants respond to the items using a 5-
-day averages of daily individual single 
item scores and 7-day averages of an aggregated overall sleepiness score will be used.  
During the screening period assessments will be done daily in the evenings together with 
the HFDD assessment.  

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During the treatment period the assessment will be done on 7 consecutive evenings at time 
points indicated in the SoA. 
8.2.11 
Suicidal thoughts or wishes: Beck's Depression Inventory (BDI-II)  
Suicidal thoughts or wishes will be assessed at screening by the BDI-II item 9. For further 
details regarding the BDI-II, please refer to Section 8.1.1.6. 
See Exclusion Criterion 22 for information on when the participant should not be 
randomized based on suicidal ideation.  
The investigator will receive an email notification if a participant responded to item 9 with 
a 2 (I would like to kill myself) or a 3 (I would kill myself if I had the chance). If this 
happens after randomization the participant can continue the study at the discretion of the 
investigator. The investigator has to consider reporting an adverse event based on the 
clinical presentation. In addition, any suicidal ideation should be treated according to local 
clinical practice. 
 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting 
The definitions of adverse events (AEs) and serious adverse events (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 all AEs (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 
(S)AEs will be collected from the start of study intervention until the last follow-up visit at 
the time points specified in the SoA (Section 1.3). (S)AEs which are related to protocol-
required study procedures (eg, (S)AE related to invasive study procedures) will be 
recorded as (S)AEs from the signing of the ICF. 
Any medical occurrences/conditions that begin in the period between signing ICF and the 
start of study intervention, and which are not related to a protocol-required study 
procedure, will be recorded on the Medical History/Current Medical Conditions, not as 
AEs. 
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 being available. 

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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, and AEs of special interest (as defined 
in Section 8.3.6), 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, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
 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 
 will 
notify the IRB/IEC, if appropriate according to local requirements. 
 For all studies except those using medical devices, investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
8.3.5 
Pregnancy 
In case of a suspected pregnancy, a pregnancy test should be performed. In the unlikely 
event of a pregnancy the following applies: 
 Details of all pregnancies in participants will be collected after the start of study 
intervention and until end of Follow-up. 
 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. 

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 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. 
 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. 
See Section 10.4 for details on collection of pregnancy information. 
8.3.6 
Adverse Events of Special Interest  
The following are defined as AESI in this study, if the event takes place after the first 
intake of study intervention:  
 Any condition triggering close liver observation according to Section 10.5. 
Any increase in liver enzymes meeting the following criteria needs to be reported 
as an adverse event to the sponsor within 24 hours 
 
for expedited reporting to the health authorities: 
 ALT and/or AST >8x ULN OR 
 ALT and/or AST >3x ULN with total bilirubin >2x ULN 
The investigator may consider whether the observed increase in liver values would 
qualify as SAE. 
 Somnolence or fatigue: Mild somnolence has been identified as a possible adverse 
reaction to elinzanetant. Participants will be instructed neither to drive nor operate 
machinery if they experience somnolence or fatigue. As a precautionary measure, 
participants are dosed before going to bed. 
 Phototoxicity: A signal with respect to potential phototoxicity warrants monitoring 
of participants for skin reactions to sunlight. In case such a reaction occurs, 
exposure to strong sunlight should be avoided. 
 Post-menopausal uterine bleeding: Any participants experiencing post-menopausal 
bleeding after randomization should undergo a transvaginal ultrasound with 
subsequent investigation and management (including endometrial biopsy, if 
practice 
(unexplained post-menopausal bleeding prior to randomization will exclude the 
participant from the study). 

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8.4 
Pharmacokinetics 
Blood samples for measurement of elinzanetant and its main metabolites, for tamoxifen 
and its metabolites and for the aromatase inhibitors (i.e. anastrozole) in plasma for PK are 
to be collected at the time points given in Table 1-4. The date and time of study drug intake 
and adjuvant endocrine therapy on the previous dosing days prior to the PK sampling as 
indicated in Table 1-4, the time of the supervised intake of elinzanetant, and the time of all 
blood samples are to be documented. 
If, for any reason, PK samples are taken outside of the pre-specified time window, the 
exact time that the sample was taken has to be recorded. These time deviations are not to 
be considered as important deviations. 
If a participant discontinues study treatment permanently, no blood sampling for PK is 
required. PK analyses are based on a population modeling approach. Blood samples are 
considered valid for the population PK analysis under the following conditions: 
 The dose amount and time of study drug intake and adjuvant endocrine therapy 
prior to the blood sample is known 
 The time of the blood sample collection is known. 
The samples are to be collected and processed as described in detail in the respective 
Sample Handling Sheets as a part of a separate Laboratory manual.  
Plasma concentrations of elinzanetant, tamoxifen and its metabolites or aromatase 
inhibitors (i.e. anastrozole) are determined using a validated liquid chromatography-tandem 
mass spectrometry (LC-MS/MS). Quality control (QC) and calibration samples are 
analyzed concurrently with study samples. The results of calibration samples, QC samples, 
and study samples will be reported in the Bioanalytical Reports, which will be included in 
the Clinical Study Report for this study. A re-opening of the database may become 
necessary in order to include the results of the PK measurements. In addition, selected 
metabolites may be quantified in plasma using a validated analytical method and evaluated 
and reported as described for elinzanetant. 
The bioanalyst will be unblinded for analysis of study samples. Placebo samples will not 
be analyzed. 
Plasma concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Pharmacometric analysis of elinzanetant 
Based on the plasma concentrations, the variability in elinzanetant PK will be analyzed 
using population PK modeling. Optionally, a population PK/PD model could be used to 
describe the effect of elinzanetant exposure on PD data related to efficacy and safety such 
as frequency of VMS and endocrine hormone levels. This analysis might start prior to 
database lock (eg, at the moment that approximately 80% of the expected PK samples have 
been measured). The final population PK model that will be applied to describe the PK of 
elinzanetant in the study population will be linked to relevant PD parameters (eg, 
frequency of VMS, endocrine hormone levels) obtained in this study to investigate the 
relationship between elinzanetant exposure and response.   

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The PK data and the relationship of the elinzanetant exposure parameters (e.g. Cmax, AUC) 
with treatment effects might be evaluated using pharmacometric approaches (e.g. non-linear 
mixed effect modeling) including potential influence of relevant subject co-variables. Analysis 
and report will be done under a separate cover. This evaluation might be started prior to 
database lock: if this is applicable, appropriate measures will be taken to maintain blinding of 
the study team.   
 
8.5 
Genetics 
In this study a CYP2D6 genotyping analysis will be performed in all participants treated 
with tamoxifen. The CYP2D6 enzyme is one of the main enzymes involved in converting 
tamoxifen into its major active metabolite, endoxifen. Genetic variation in the CYP2D6 
gene (various CYP2D6 alleles 
enzyme activity. 
 
8.6 
Biomarkers 
In this study, non-genetic biomarkers (e.g., related to the mode of action or the safety of 
the study intervention and similar drugs) may be investigated after End of Study. This 
applies to further biomarkers deemed relevant to VMS caused by adjuvant endocrine 
therapy and associated health problems. These investigations may include e.g., diagnostic, 
safety, pharmacodynamic, monitoring, or potentially predictive biomarkers. 
PD /safety biomarkers from blood  
BM samples (see below) will be collected within the first 12 weeks of the study.  
The following table gives an overview on sample types collected: 
Sample type 
Description 
Biomarker plasma 
Blood sample to provide plasma for 
biomarker analyses 
Biomarker serum 
Blood sample to provide serum for 
biomarker analyses 
Biomarker whole blood
For CYP2D6 polymorphism (only 
collected from tamoxifen participants)  
 
 Timing  see the SoA planned time points of sample collection.  
Sampling time points may also be moved or removed. 
 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. 
 Reporting  the results of biomarker investigations may be reported separately 
(e.g. in a biomarker evaluation report). 
 

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8.7 
Immunogenicity Assessments 
Not applicable. 
 
8.8 
Health Economics 
EQ-5D-5L data will be collected; VAS and single-dimensions will be assessed 
descriptively (see Section 8.1.1.4). A preference weighted or utility score with the aim to 
support economic models can be calculated in a further step independent of this study, 
using statistical algorithms producing utility values ranging from dead (0 or depending on 
the algorithm used lower than 0) to full health (1). 
 
9. 
 
9.1 
Statistical Hypotheses 
The hypotheses for the primary efficacy endpoints are defined as: 
H1-  
: 
 versus 
 where 
 and 
 stand for the mean 
change from baseline in the placebo (P) and verum (V) group in HF frequency at week 
4. 
H2- 
: 
 versus 
 where 
 and 
 stand for the mean 
change from baseline in the placebo (P) and verum (V) group in HF frequency at week 
12. 
 
The hypotheses for the key secondary efficacy endpoints are defined as: 
H3- 
: 
 versus 
 where 
 and 
 stand for the mean 
change from baseline in the placebo (P) and verum (V) group in PROMIS SD SF 8b 
total score at week 12. 
H4- 
: 
 versus 
 where 
 and 
 stand for the mean 
change from baseline in the placebo (P) and verum (V) group in MENQOL total score 
at week 12. 
For the confirmatory efficacy analysis, a hierarchical testing approach will be applied, 
involving the two primary efficacy variables and the two key secondary variables. 
The type I error rate will be controlled at a one-
 For a positive study 
outcome, both tests for primary variables need to be significant. As the hierarchical testing 
procedure follows a fixed sequence, it stops as soon as any of these tests cannot be rejected 
at an alpha level of 0.025 and all further tests after failing to reject one null hypothesis in 
the testing sequence will be considered exploratory. This fixed sequence procedure 
accounts for the multiplicity created by carrying out multiple tests. Moreover, all other 
endpoints will be summarized descriptively and therefore no multiplicity adjustment is 
needed. 
 
9.2 
Sample Size Determination  
Approximately 405 participants will be randomly assigned to study intervention in a 2:1 
ratio. Of these, 270 participants will be randomly assigned to elinzanetant and the other 

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135 participants will be randomly assigned to the placebo arm. The randomization will be 
stratified by women with a personal history of hormone-receptor positive breast cancer or 
women at high-risk for developing breast cancer (maximum of 10% of participants for 
high-risk developing breast cancer) and by type of treatment of pre-existing condition at 
baseline (at least 40% of participants on tamoxifen and at least 40% of participants on 
aromatase inhibitors in both population groups, i.e. breast cancer and high-risk for 
developing breast cancer). Assuming a drop-out rate of 10 % in the first 3 months, this will 
result in approximately 243 evaluable participants in the elinzanetant arm and 
approximately 122 participants in the placebo arm who completed 12 weeks of treatment. 
Assuming a yearly drop-out rate of 30% in the elinzanetant arm, approximately 189 
participants will be available that were treated for 1 year. 
The number of participants needed for this study is based on the total number of 
participants needed for the safety evaluation. Following the ICH E1 guideline (EMA 
1995), a total of 1,500 participants are required that were exposed to at least one dose of 
elinzanetant 120 mg. Of these 1,500 participants 300-600 should have been treated for at 
least 6 months and approximately 100 for 1 year. Based on the number of participants that 
are available from previous phase 1 and phase 2 studies, together with the number of 
participants that are planned to be enrolled in ongoing and upcoming phase 3 studies, the 
number of participants needed for the elinzanetant arm in this study is 270, also taking into 
account that participants in the placebo arm receive elinzanetant after 3 months and the 
drop-out rates described above. 
Screen failures are defined in Section 5.4. Assuming a screen failure rate of 50% 
approximately 810 participants need to be enrolled to achieve the required number of 405 
randomized participants. More participants might be enrolled in case the screen failure rate 
is higher than anticipated. Additionally, further patients may be enrolled in case of an 
exceptionally high drop-out rate due to a trial-continuity issue. 
A formal sample size justification was performed for the primary efficacy endpoints using 
the one-sided two-Sample T-test (equal variance) assuming at least approximate normal 
distribution and taking into account the drop-out rate of 10% in the first 3 months as 
described above. The power with treatment differences (i.e. mean change in frequency of 
moderate to severe HF from baseline to Week 4 or 12), with N=243 in the elinzanetant arm 
and N=122 in the placebo arm and assumed standard deviations are provided in Table 9-1. 
The data from placebo arm in SWITCH-1 study (NCT03596762 2020) was used for 
assumption of standard deviation. 

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Table 9-1: Sample size justification 
 
Primary efficacy 
endpoint 
Standard deviation 
Treatment difference  
Elinzanetant vs. placebo 
Power % 
Mean change in 
frequency of moderate to 
severe HF from baseline 
to Week 4 
3.632 
 
-1.00 
-1.50 
-2.00 
69.67 % 
96.01% 
>99.9 % 
 
 
-1.00 
55.38 % 
Mean change in 
frequency of moderate to 
severe HF from baseline 
to Week 12 
4.29 
 
-1.50 
-2.00 
88.16 % 
98.71 % 
 
 
 
 
Mean change in 
PROMIS SD SF 8b total 
score from baseline to 
Week 12 
 
1.00 
-0.4 
94.90 % 
Mean change in 
MENQOL total score 
from baseline to Week 
12 
 
1.00 
-0.4 
94.90 % 
nQuery Version 9.1.0.0 was used for sample size calculation. 
HF = Hot Flash, MENQOL=Menopause Specific Quality of Life Scale, PROMIS SD SF 8b=Patient-reported 
Outcomes Measurement Information System Sleep Disturbance Short Form 8b 
 
9.3 
Analysis Set 
For the purposes of analysis, the following analysis sets are defined in Table 9-2. 
Table 9-2: Definition of the analysis sets. 
Analysis Set
Description
Enrolled 
All participants who sign the informed consent form. 
Full Analysis Set (FAS) 
All randomized participants.  
Safety Analysis Set (SAF) 
All participants who receive at least one dose of study intervention.  
 
Efficacy analyses will be based on the FAS and participants will be analyzed according to 
the randomized intervention. Safety analyses will be performed on the SAF and 
participants will be analyzed according to the intervention received.  
Documentation of validity findings and assignment of participants to analysis sets will be 
performed according to the spon
. 
Details on additional subsets which may be of interest will be provided in the statistical 
analysis plan (SAP). 
 

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9.4 
Statistical Analyses 
9.4.1 
General Considerations 
SAP will be finalized prior to database lock and 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 and secondary endpoints. 
If not otherwise indicated, the statistical analyses will be performed using SAS; the version 
used will be specified in the SAP. 
The endpoints/variables collected in the study will be analyzed using descriptive statistics 
as appropriate. Continuous variables will be analyzed using at least the following 
descriptive statistics: number of non-missing observations, arithmetic mean and standard 
deviation, median, minimum and maximum. Where appropriate 95 % confidence intervals 
will be provided. Discrete data will be analyzed using frequency tables. Further details will 
be described in the SAP. 
Intercurrent Events 
Important Intercurrent Events (ICEs) for this study are defined as: 
a. Temporary treatment interruption in the week 4 defined as treatment taken <80% 
during weeks 1-4 OR treatment taken on <5/7 days during either week 3 or 4. 
Temporary treatment interruption in the week 12 defined as treatment taken <80% 
during weeks 1-12 OR treatment taken on <5/7 days during either week 11 or 12. 
b. Permanent treatment discontinuation of randomized treatment. 
c. Intake of prohibited concomitant medications having impact on efficacy. 
d. Interruption/discontinuation in intake of adjuvant endocrine therapy defined as 
follows: 
 For participants using Tamoxifen: reduction of at least 50% of planned 
daily dosage taken during weeks 3 and 4 OR weeks 11 and 12 compared to 
baseline  
 For participants using Aromatase inhibitor: reduction of at least 30% of 
planned daily dosage taken during weeks 3 and 4 OR weeks 11 and 12 
compared to baseline  
The impact of these ICEs on the study results and its interpretation is addressed in Table 
3-2 where the primary estimand for the primary endpoint is defined. 
A low impact of the COVID-19 pandemic on missing assessments of the frequency and 
severity of HFs is considered due to the use of eDiary. The eDiary should be completed at 
home and therefore, there is no need for participants to attend the clinic for the assessment 
of HFs related endpoints. 
COVID-19 is included as a reason for occurrence of the important ICEs in the study 
estimand strategy (Table 3-2). 

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The number of deaths are considered to be small and therefore the impact of death as a 
potential ICEs is expected to be negligible. That will be monitored throughout the trial 
until the blind review and if deemed necessary, the estimand will be adjusted in the SAP 
before the study unblinding. 
The number of observed intercurrent events will be summarized by treatment group and 
overall, for each intercurrent event.  
9.4.2 
Primary Endpoint 
The primary efficacy endpoints for this study are:  
 Mean change in frequency of moderate to severe HF from baseline to 
Week 4 (assessed by HFDD) 
 Mean change in frequency of moderate to severe HF from baseline to 
Week 12 (assessed by HFDD) 
9.4.2.1 
Calculations related to the frequency and severity of HF 
A diary day for the calculation of the frequency and severity of HF consists of the evening 
entry and the morning entry of the subsequent day. A day will be considered available for 
the calculation of the frequency and severity of HF, if at least the evening or the morning 
entry (of the subsequent day) is not missing. The daily number of hot flashes per day will 
be calculated as the sum of the evening and morning entries (of the subsequent day). If 
only the evening or morning entry is available, then only this will be used for that 
particular day. 
The baseline value of frequency and severity of moderate to severe HF will be calculated 
using the available data assessed via the HFDD during the 14 days prior to the baseline 
visits. As per inclusion criterion 8, at least 11 days will be available for the derivation of 
the baseline value. 
Baseline value of frequency of moderate to severe HF:  
The baseline value will be calculated by aggregating the available days during the 14 days 
prior to start of treatment to a mean daily frequency as (total number of moderate to severe 
HF during the 14 days prior to start of treatment) / (total number of available days with 
data). 
Frequency of moderate to severe HF during treatment:  
The frequency of moderate to severe HF for each week during the treatment period will be 
calculated using the available data during that particular week. Specifically, for Week 4 
Days 22-28 will be used and for Week 12, Days 78-84 will be used (Day 1 corresponds to 
start of treatment). These data will be aggregated to a mean daily frequency as (total 
number of moderate to severe HF during that week) / (total number of available days with 
data during that week). In case data is not available for more than 2 days within a week, the 
value for that particular week will be set to missing. Further details will be specified in the 
SAP.  

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Mean change in frequency of moderate to severe HF from baseline to Week 4 and 
Week 12: 
This will be calculated as the difference in the frequency of moderate to severe HF at 
Week 4 or Week 12, respectively, from the baseline value of the frequency of moderate to 
severe HF.  
Baseline value of severity of moderate to severe HF: 
The mean daily severity during baseline will be calculated as [(2 x number of moderate 
HF) + (3 x number of severe HF)] / (total number of moderate to severe hot flashes on that 
day). When no moderate or severe HF are reported for a particular day, the mean severity 
for that day will be set to 0. The baseline value will be calculated by averaging the mean 
daily severity of the available days during the 14 days prior to start of treatment. 
Severity of HF during treatment:  
The mean daily severity during treatment will be calculated as [(1 x number of mild HF) + 
(2 x number of moderate HF) + (3 x number of severe HF)] / (total number of mild, 
moderate and severe hot flashes on that day). When no HF are reported for a particular 
day, the mean severity for that day will be set to 0.  
Similar to the frequency, the severity of moderate to severe HF for each week during the 
treatment period will be calculated using the available data during that particular week. 
Specifically, for Week 4 Days 22-28 will be used and for Week 12, Days 78-84 will be 
used (Day 1 corresponds to start of treatment). To obtain the post-baseline severity of HF 
during a particular week, the weekly data will be aggregated by averaging the mean daily 
severity of HF of the available days during that week. In case data is not available for more 
than 2 days within a week, the value for that particular week will be set to missing. Further 
details will be specified in the SAP. 
Mean change in severity of moderate to severe HF from baseline to Week 4 and Week 
12: 
This will be calculated as the difference in the severity of HF at Week 4 or Week 12, 
respectively, from the baseline value of the severity of moderate to severe HF.  
9.4.2.2 
Primary analysis of the primary efficacy endpoints 
The primary estimand to be applied to primary efficacy endpoints is described in Table 
3-2.  
The primary endpoint will be analyzed using a mixed model with repeated measures 
(MMRM) model on the change from baseline scores at various weeks including Week1, 
Week 4, Week 8 and Week 12. Baseline, treatment, week, population type (women with a 
personal history of hormone-receptor positive breast cancer or women at high-risk for 
developing breast cancer) and the type of treatment of pre-existing condition at baseline 
(stratification factors for randomization) will be included as covariates in the model. The 
interaction terms baseline*week and treatment*week will also be included. More details on 
model diagnostics, alternative modeling approaches, main and sensitivity analysis, and 
details of the missing data handling/imputation will be given in the SAP. 

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9.4.3 
Secondary Endpoints 
The key secondary efficacy endpoints in this study are: 
 Mean change in PROMIS SD SF 8b total score from baseline to Week 12 
 Mean change in MENQOL total score from baseline to Week 12 
The secondary efficacy endpoints in this study are: 
 Mean change in severity of moderate to severe HF from baseline to Week 4 
(assessed by HFDD) 
 Mean change in severity of moderate to severe HF from baseline to Week 12 
(assessed by HFDD) 
 Mean change in frequency of moderate to severe HF from baseline to Week 1  
 Mean change in frequency of moderate to severe HF from baseline over time 
(assessed by HFDD) 
The calculation of the total scores for the PROMIS SD SF 8b and for the MENQOL will 
be done according to the respective questionnaire guidelines. Details will be provided in 
the SAP. 
The same clinical questions are posed in respect of each primary and key secondary 
endpoint, and hence the same estimand strategy applies to the key secondary endpoints 
(detailed in Table 3-2). 
The key secondary endpoints will be analyzed using a similar modeling approach as the 
primary endpoints (see Section 9.4.2.2). 
The calculation of the mean change in severity of moderate to severe HF from baseline to 
Week 4 and 12 will be done as described in Section 9.4.2.1 The calculation of the mean 
change in frequency of moderate to severe HF from baseline to Week 1 will be done 
analogously to the calculations for Week 4 and 12 described in Section 9.4.2.1. The 
calculation of the frequency of moderate to severe HF for Week 1 will be based on Days 2-
8 on treatment, where Day 1 corresponds to start of treatment. 
Details for the analysis of the secondary endpoints will be provided in the SAP. 
9.4.4 
Exploratory / Other Endpoints 
The analysis of the exploratory / other safety and efficacy endpoints will be described in 
the SAP. Additional exploratory endpoints may be specified in the SAP. 
9.4.5 
Other Safety Analysis 
All safety analyses will be descriptive and will be performed on the SAF. Safety data will 
be summarized descriptively for each treatment group.  
All AEs will be coded using the latest version prior to database lock of the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Further details on safety analyses will be described in the SAP. 
9.4.6 
Other Analysis 
Subgroup analyses may be specified in the SAP. 

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9.5 
Interim Analysis 
Blinded data may be used for evaluation of psychometric and other measurement 
properties of PRO instruments. 
The analysis of part A is planned after the last participant completed part A. This will be 
the final analysis for efficacy and safety of part A data based on cleaned and final data and 
will be reported together with part B data. No multiplicity adjustment is needed since the 
primary efficacy analysis will be final after the evaluation of part A data. Part B data will 
be analyzed for available endpoints and reported together with the data from part A in one 
report. Treatment extension (part C) will be analyzed and reported separately from parts A 
and B. Further details will be given in the SAP. 
 
10. 
 
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 (CIOMS) International Ethical 
Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
 
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 

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 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 
Data Safety Monitoring Board 
An independent data safety monitoring board (DSMB) has been established for the 
elinzanetant development program to perform ongoing safety surveillance. The DSMB will 
monitor the general safety of the ongoing Phase 3 trials and relevant additional data at an 
appropriate frequency as provided in the DSMB charter and make recommendations to the 
sponsor regarding steps to ensure the safety of the trial participants. Details are described 
in the DSMB charter. 
10.1.3 
Liver Safety Monitoring Board 
An independent liver safety monitoring board (LSMB) has been established for the 
elinzanetant development program to perform ongoing surveillance regarding hepatic 
safety. Independent hepatologists experienced in the assessment of drug induced liver 
injury (DILI) will conduct an independent review of available clinical data, i.e. blinded 
individual cases pertaining to elevated transaminases or other liver health markers on a 
regular basis. The LSMB will advise the DSMB and the sponsor whether the individual 
cases meet the criteria of a potential DILI, and whether any other actions are necessary to 
ensure participant safety. Details are described in the LSMB charter. Case evaluations of 
the LSMB will be included in the ongoing safety surveillance of the DSMB (see 
section 10.1.2). 
10.1.4 
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. 
10.1.5 
Informed Consent Process 
Detailed description of the recruitment strategy will be provided in country-specific 
documentation as required. 
 The investigator or his/her representative will explain the nature of the 
study to the participants 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 (HIPAA) 
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. 

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 Participants must be re-consented to the most current version of the 
ICF(s) during their participation in the study.  
 A copy of the ICF(s) must be provided to the participants.  
 It may be considered to apply an eConsent process in some countries. 
The consenting will still take place at the site (no remote consenting). 
Instead of a paper version the informed consent information will be 
provided in an electronic format. 
 If the participant decides to take part in the treatment extension, she will 
sign a separate ICF. 
Participants who are rescreened are required to sign a new ICF. 
10.1.6 
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. 
 The participant must be informed that 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 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. 
 The contract between sponsor and study sites specifies responsibilities 
of the parties related data protection, including handling of data security 
breaches and respective communication and cooperation of the parties. 
 Information technology systems used to collect, process, and store 
study-related data are secured by technical and organizational security 
measures designed to protect such data against accidental or unlawful 
loss, alteration, or unauthorized disclosure or access. 
10.1.7 
Dissemination of Clinical Study Data 
Result Summaries of Bayer's sponsored clinical studies in drug development phases 2, 3 
and 4 and Phase 1 studies in patients are provided in the Bayer Clinical Trials Explorer  
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 Information System (CTIS) in line with the 
applicable regulations. 
In accordance with the current EU regulation, result summaries will be submitted within 
one year from the end of the studies in adult populations in all participating countries. No 

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preliminary data analysis (e.g., on EU data only) will be performed, as this might 
compromise data integrity and the scientific validity of the study. 
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 (US) and 
European Union (EU) on or after January 01, 2014 as necessary for conducting legitimate 
research.  
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.
10.1.8 
Data Quality Assurance 
 All participant data relating to the study will be recorded on 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 
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.  
10.1.9 
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 
 

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 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. 
 Definition of what constitutes source data can be found in the Source Data Location 
List. 
 The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF, excluding ePRO data.  
 Study monitors will perform ongoing source data verification and source data 
review according to the monitoring plan to confirm that data entered into the eCRF 
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.  
10.1.10 
Study and Site Start and Closure 
Study Start 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The start of a clinical study in EU is defined as the date on which the first site is declared 
by the sponsor to be ready to enroll in a country and clinical study will be open for 
recruitment of participants.  
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 
 Recommendation by the DSMB (see Section 10.1.2) to stop the 
development program or an individual trial within the program. 

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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. 
10.1.11 
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 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. 
 

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10.2 
Appendix 2: Clinical Laboratory Tests 
 The tests detailed in Table 10-1 will be performed by the central 
laboratory, unless otherwise indicated.  
 Protocol-specific requirements for inclusion or exclusion of participants 
are detailed in Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local 
regulations. 
 
Table 10-1: Clinical laboratory tests 
Panel 
Parameters (by category)  
Safety parameter 
Hematology:  
 
red blood cell count, white blood cell count, hematocrit, hemoglobin, mean 
corpuscular volume, platelet count and WBC differentials. 
Clinical chemistry:  
 
sodium, potassium, glucose, urea (blood urea nitrogen), creatinine, creatine kinase 
(CK), albumin, calcium, phosphate, bilirubin (total and direct), alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), gamma 
glutamyl transferase (GGT), total cholesterol, high density lipoprotein (HDL) 
cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, magnesium, 
chloride, total protein, hemoglobin A1c, lactate dehydrogenase (LDH), Estimated 
Glomerular Filtration Rate (eGFR, only at screening) 
Coagulation:  
prothrombin time (Quick), INR, activated partial thromboplastin time (aPTT)  
Hormones: 
thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free 
triiodothyronine (fT3), free thyroxine (fT4), estradiol (E2) only at BL, T2, T4, T6.           
Bone markers  
bone-specific alkaline phosphatase (BALP),  
Urine analysis 
pH, urobilinogen, blood/hemoglobin, total protein, ketone, bilirubin, nitrite, glucose, 
leukocytes 
Screening/Start of Intervention parameters 
Urine pregnancy test 
-hCG)a 
Virology 
Hepatitis B virus surface antigens and hepatitis C antibodies, HCV-RNA (HCV-
mRNA automatically tested if anti-HCV is positive) 
Endometrial Biopsy 
Histological analysis of endometrium 
Cervical cytology 
Cervical smear (HPV-DNA automatically tested if ASCUS is reported from cervical 
cytology) 
High risk HPV-DNA 
BM, PK & PG  
Pharmacogenetics  
CYP2D6 genotyping (only from participants treated with tamoxifen) 
Pharmacokinetics  
pre-and post-dose PK samples 
Biomarkers  
For biomarkers, serum and plasma samples needed 
ASCUS = atypical squamous cells of undetermined significance; BM = biomarker, CYP2D6 = Cytochrome 
P450 2D6, DNA = Deoxyribonucleic acid; HCV = Hepatitis C virus; HPV-DNA = Human papilloma virus; INR = 
International normalized ratio; mRNA = Messenger ribonucleic acid; PG = pharmacogenomics, PK = 
Pharmacokinetics, RNA = ribonucleic acid; WBC = White blood cell count  
a Only if the urine pregnancy test does not show a final conclusive negative result a serum pregnancy test is 
required. 
 
See section 10.5 for additional parameters to be assessed in case of increased ALT or AST.  
Investigators must document their review of each laboratory safety report. 
 

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10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a clinical study participant, 
associated with the use of study intervention, 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., ECG, 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 
sequelae. 
 Sign, symptoms, or the clinical sequelae of suspected medication errors, misuse 
and abuse of either study intervention or a concomitant medication. Medication 
errors, misuse and abuse per se will not be reported as an AE/SAE, unless it is 
resulting in AE/SAE. Such medication errors, misuse and abuse should be 
reported regardless of sequelae. 
  
not be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, 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. 
 

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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 disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
 
 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. 
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 
 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 
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. 

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d. 
Results in persistent or significant disability/incapacity 
 The term disability means a su
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. 
 
medical records to the sponsor in lieu of completion of the AE/SAE eCRF page. 
 There may be instances when copies of medical records for certain cases are 
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 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. 

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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. 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. 
 
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. 
 
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 
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 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. 

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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 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 or during a 
recognized follow-up period, the investigator will provide 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. 
 
10.3.4 
Reporting of SAEs 
SAE Reporting to sponsor via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE to 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. 
 

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SAE Reporting to 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 
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 not replace the need for the 
investigator to complete and sign the SAE data collection tool within 
the designated reporting time frames. 
 Contacts for SAE reporting can be found in the Investigator Site File.
 
10.4 
Appendix 4: Collection of Pregnancy Information 
10.4.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are considered WOCBP (fertile) 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below). 
A postmenopausal state is defined as:   
 
12 months of spontaneous amenorrhea in the absence of other physiological or 
pathological causes (e.g. pregnancy, thyroid disease, hyperprolactinemia) or 
 Surgical menopause as a result of bilateral oophorectomy with or without 
hysterectomy at least 6 weeks prior to signing of informed consent 
Permanent sterilization methods (for the purpose of this study) include: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
Note
medical records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in athletes, post-chemotherapy amenorrhea) and a 
menstrual cycle cannot be confirmed before first dose of study intervention, additional 
evaluation should be considered. 
 
Woman of Nonchildbearing Potential (WONCBP) 

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Women in the following categories are considered WONCBP: 
1. Pre-menopausal female with permanent infertility due to one of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 For individuals with permanent infertility due to an alternate medical 
cause other than the above, (e.g., Mullerian agenesis, androgen 
insensitivity, gonadal dysgenesis), investigator discretion should be 
applied to determining study entry. 
2. Postmenopausal women (see definition above) 
Note
medical records, medical examination, or medical history interview 
10.4.2 
Contraception Guidance 
This study does include Woman of Childbearing Potential (WOCBP) and accordingly 
these women must use highly effective contraception during the entire study participation. 
Reference is made to Section 10.4.3 in the unlikely event that a pregnancy is detected 
during the study. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year when used 
consistently and correctly. 
 Intrauterine device without hormonal release (IUD) 
 Bilateral tubal occlusion 
 Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days. 
Note: documentation of azoospermia for a male partner can come from the s
 
Highly Effective Methodsb That Are User Dependent Failure rate of < 1% per year when used 
consistently and correctly. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
 
The table below presents contraceptive methods that are not considered highly effective 
and these should not be used during the study. 

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CONTRACEPTIVES NOT ALLOWED DURING THE STUDY INCLUDE: 
Effective Methods That Are Not Considered Highly Effective 
 1% per year when used 
consistently and correctly. 
 Male or female condom with or without spermicide 
 Cervical cap, diaphragm, or sponge with spermicide 
 A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods 
of contraception.  
 
10.4.3 
Collection of Pregnancy Information: 
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information 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.  
 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 female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 
10.5 
Appendix 5: Liver Safety Actions and Follow-up Assessments 
10.5.1 
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. 

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 Information on these symptoms should be asked for in case of abnormal 
liver laboratory values (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 
 In the case of increased liver values as defined in Table 10-2, a retest should 
be performed within 72 hours of the initial test results. If the abnormal liver 
values are confirmed in the retest, liver safety monitoring should be 
initiated. 
 
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 10.5.2.  
Consider withdrawal of study intervention if the participant 
does not adhere to procedures required for close observationa  
AP > 2 x ULNb  
 
 
 
Initiate close observation as defined in Section 10.5.2. 
Consider withdrawal of study intervention if the participant 
does not adhere to procedures required for close observation 
ALT or AST > 3 x ULN and TBL > 2 x ULN  
Withdraw study intervention and initiate close observation as 
defined in Section 10.5.2.  
ALT or AST > 3 x ULN and INR > 1.5 x ULN 
Withdraw study intervention and initiate close observation as 
defined in Section 10.5.2.  
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 and initiate close observation as 
defined in Section 10.5.2. 
ALT or AST > 5 x ULN for more than 2 
weeks 
Withdraw study intervention and initiate close observation as 
defined in Section 10.5.2. 
ALT or AST > 8 x ULN 
Withdraw study intervention and initiate close observation as 
defined in Section 10.5.2. 
ALT = alanine aminotransferase; AP = Alkaline phosphatase; 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  
b Close observation can be stopped if bone AP value is reported as abnormal 
 
10.5.2 
Close observation of participants with liver function test findings 
 Abnormal laboratory results and clinical signs and symptoms resulting in close 
liver observation should be reported as adverse event. 
 Any increase in liver enzymes meeting the following criteria needs to be 
reported as an adverse event to the sponsor within 24 hours of the 
 
 ALT and/or AST >8x ULN OR 
 ALT and/or AST >3x ULN with total bilirubin >2x ULN 
 The investigator may consider whether the observed increase in liver values 
would qualify as SAE (see Section 8.3.6). 

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 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 (FDA Guidance for 
Industry 2009). Objectives are to: 
 Ensure participant safety 
 Identify possible non-study-intervention-related causes of liver injury 
 A close observation has to be initiated during intervention or follow-up phase if 
liver function tests meet the criteria in Table 10-2. Close observation includes: 
 Sampling for the first batch of laboratory parameters (Table 10-3). 
 Repeating follow-up samplings (Table 10-3) 2 to 3 times per week. 
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize. 
 Obtaining a detailed history of the symptoms and prior or concurrent diseases   
 Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets.  
 Ruling out acute viral hepatitis, autoimmune or alcoholic hepatitis, 
nonalcoholic steatohepatitis, hypoxic/ischemic hepatology and biliary tract 
disease. Unless an obvious and firm non-drug induced liver injury diagnosis 
has already been made additional procedures, e.g. ultrasound examinations 
should be performed. If requested, tests will be done retrospectively using 
residual blood/serum samples collected at visits before laboratory 
abnormalities occurred. 
 Obtaining a history of exposure to environmental chemical agents 
 Obtaining additional tests to evaluate liver function as required (e.g. INR, 
direct bilirubin measurements) 
 Considering gastroenterology or hepatology consultations  
 Data for any findings are to be recorded in the corresponding eCRF pages 
 Stopping criteria for close observation: 
 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 
 a confirmed clinical diagnosis explaining the elevated liver enzymes, or 
 if fragmentation reveals abnormal bone AP as reason for the increase of 
AP>2 x ULN. 
Table 10-3 lists the samples to be taken during close observation for liver safety. The 
samples are to be taken as needed.

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Table 10-3: Samples during close observation for liver safety 
First batch of parameters to be taken when initiating close observation for liver safetya 
Albumin 
Alkaline phosphatase (AP) 
Alanine-aminotransferase (ALT) 
Aspartate-aminotransferase (AST) 
Bone-specific alkaline phosphatase (BALP) 
Complete blood count including WBC with differentials 
Cholinesterase 
Conjugated (direct) bilirubin 
Creatine kinase (CK) 
GGT 
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) 
- 
HDV antibodies (if positive, automatically test HDV RNA) 
Anti-HCV antibodies  
Hepatitis C RNA 
Anti-HDV antibodies (if positive, automatically test HDV RNA) 
Anti-HEV IgM (if positive, automatically test HEV RNA) 
Anti-cytomegalovirus IgM antibodies 
Anti-Epstein-Barr Virus IgM antibodies 
HSV IgM (anti-HSV IgM) 
IgG level (gamma globulins) 
IgA 
IgM 
c-Antineutrophil cytoplasmic antibodies  
c-Antineutrophil perinuclear antibodies  
Anti-mitochondrial antibodies 
Anti-nuclear antibodies  
Anti-Smooth muscle antibodies  
A1AT level 
Ceruloplasmin 
Ferritin 
Iron 
Total iron binding capacity  
 
Follow-up samples during close observation for liver safetyb
Albumin 
Alkaline phosphatase  
Alanine-aminotransferase  
Aspartate-aminotransferase  
WBC with differentials 
Cholinesterase 
Creatine kinase 
Conjugated (direct) bilirubin 

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Table 10-3: Samples during close observation for liver safety 
Total bilirubin 
Gamma-glutamyl transferase 
INR 
LDH 
a) First sample after AST or ALT > 3 X ULN or AP>2xULN 
b) Additional parameters/tests may be added as medically justified 
A1AT = Alpha-1 antitrypsin; GGT = Gamma-glutamyl transferase; INR = International 
normalized ratio; HBV = hepatitis B virus; HCV = Hepatitis C 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 cell count 
 

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10.6
Appendix 6: Prohibited concomitant medications
Table 10-4: Prohibited concomitant medication potentially confounding efficacy
Prohibited from the time shown until 1 week after the last dose of study drug
Hormonal therapies
From 1 week prior to 
Baseline Visit 
Vaginal hormonal products (rings, creams, gels)
From 4 weeks prior to 
Baseline Visit
Transdermal estrogen alone or estrogen/progestin products
From 8 weeks prior to 
Baseline Visit
Oral estrogen and/or progestin therapy
Intrauterine progestin therapy  
From 12 weeks prior to 
Baseline Visit
Progestin implants and estrogen alone injectable drug therapy
From 24 weeks prior to 
Baseline Visit
Estrogen pellet therapy or progestin injectable drug therapy 
Non-hormonal therapies
From 12 weeks prior to 
Baseline Visit
adjuvant endocrine therapy other than tamoxifen, aromatase inhibitors or GnRH 
analogues (e.g., CDK 4/6 inhibitor, toremifene, fulvestrant). The participant is 
allowed to switch to CDK 4/6 inhibitors
after 12 weeks of treatment with the study intervention 
(i.e., after the placebo-controlled period ends).
From 4 weeks prior to 
Baseline Visit
Antidepressant drugs:
Participants are permitted to continue to use antidepressant drugs and over the 
counter/herbal treatments (see details below) when the dose has been stable for at 
least 4 weeks and when it is anticipated to be stable for the duration of the study. In 
addition, the drug has been prescribed solely for the management of another 
disorder (e.g., neuropathic pain, depression). 
Participants are not allowed to start with these drugs during the study:
Anti-depressant drugs with effect on vasomotor symptoms (e.g., paroxetine, other 
including selective serotonin reuptake inhibitors, serotonin norepinephrine 
reuptake inhibitors and tri-cyclic antidepressants, alpha agonists [clonidine], 
methyldopa, gabapentin, pregabalin, medicinal cannabis or derivatives)
Over the counter/herbal treatments including traditional Chinese medicine for 
treatment of vasomotor symptoms.
Others:
Oxybutynin/ Oxybutynin hydrochloride
CDK = Cyclin-dependent kinases, CYP2D6 = Cytochrome P450 2D6, GnRH = Gonadotropin-releasing 
hormone
CCI

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Table 10-6 and Table 10-7 list examples of the most common medication regarded as 
CCI
CCI

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)
10.7
Appendix 7: Additional information on scoring and measurement 
properties of the HFDD, the PROMIS SD SF 8b and the MENQOL
10.7.1
HFDD
Rules for assessment of eligibility and efficacy using scores from the HFDD are detailed in 
section 9.4
The HFDD was acknowledged for use by regulatory agencies to appropriately assess 
frequency and severity of HF. Instruments similar to the HFDD are well established and 
have been used in competitive clinical trials. 
10.7.2
PROMIS SD SF 8b
The mean of the total PROMIS SD SF 8b score will be used for assessing a key secondary 
efficacy endpoint.
The PROMIS SD SF 8b is a generic measure of sleep disturbances which showed good 
measurement properties in conditions other than VMS. It also has appropriate conceptual 
coverage of concepts relevant for VMS as the cause of sleep disturbance and it currently 
supports secondary endpoints in other development programs assessing VMS.
10.7.3
MENQOL
The mean of the total MENQOL score will be used for assessing a key secondary efficacy 
endpoint. For each item, the participant indicates if they have experienced the symptom 
(yes/no). If they select yes , they rate how bothered they were by the symptom using a 
six-point verbal descriptor scale, with response options ranging from 0 'not at all bothered' 
to 6 'extremely bothered'. 
Item scores are converted to a score ranging from 1 to 8 in the following manner: 
Response
Converted Score
experience the problem
1
The participant experienced the problem and 
2
The participant experienced the problem and 
3
The participant experienced the problem and 
4
The participant experienced the problem and 
5
CCI

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Response 
Converted Score 
The participant experienced the problem and 
 
6 
The participant experienced the problem and 
rated it as 
 
7 
The participant experienced the problem and 
 
8 
Domain scores are calculated by averaging the converted individual item scores (range 1-
8) related to the respective domain. For a total MENQOL score the aggregated mean of the 
mean domain scores is calculated. Higher scores indicate greater bother. 
The MENQOL is widely used in menopausal clinical trials. There is some evidence 
available for content validity and other measurement properties in postmenopausal 
populations. 
 
10.8 
Appendix 8: Country/region-specific Requirements  
10.8.1 
Italy 
10.8.1.1 
ITA-1: Country/region-specific Changes Valid for Italy only 
Overall Rationale 
This section implements country-specific modifications of the original protocol, dated 30 
SEP 2022, to meet local requirement in Italy. 
10.8.1.1.1 Overview of Changes 
A description of changes and a brief rationale is outlined in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 4.1 Overall design 
Section 5.1 Inclusion Criteria 
Only women treated with 
adjuvant endocrine therapy 
for hormone receptor-positive 
breast cancer are included in 
the study. 
To follow the request from the 
Italian Medicines Agency AIFA.  
Only women treated with adjuvant 
endocrine therapy for hormone 
receptor-positive breast cancer 
should be included in the study. 
 
10.8.1.1.2 Changes to the Protocol Text 
10.8.1.1.2.1 
Section 1.1 Synopsis 
Protocol Title:  A double-blind, randomized, placebo-controlled multicenter study to 
investigate efficacy and safety of elinzanetant for the treatment of 
vasomotor symptoms caused by adjuvant endocrine therapy, over 52 
weeks in women with, or at high risk for developing hormone-receptor 
positive breast cancer  
Short Title: 
Overall Assessment of efficacy and Safety of elinzanetant In patients 
with vasomotor Symptoms in women with, or at high risk for developing 
hormone-receptor positive breast cancer (OASIS-4) 
Rationale: 
This is a phase 3 study to assess the efficacy and safety of elinzanetant 
for the treatment of vasomotor symptoms (VMS) caused by adjuvant 

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endocrine therapy in women with, or at high risk for developing 
hormone-receptor positive breast cancer. 
Note: 
In Italy only women with hormone-receptor positive breast cancer are 
allowed to participate in the study. 
 
10.8.1.1.2.2 
Section 4.1 Overall Design 
This is a multi-center, multi-country, double-blind, randomized, parallel-group, placebo-
controlled, Phase 3 intervention study in women with, or at high risk for developing 
hormone-receptor positive breast cancer. 
The study includes a wash-out period (if applicable), approximately 6-week screening, a 
52-week treatment and a 4-week follow-up period.  
Note: In Italy only women with hormone-receptor positive breast cancer are allowed to 
participate in the study. 
 
10.8.1.1.2.3 
Section 5.1 Inclusion Criteria 
 
Type of Participant and Disease Characteristics  
 
3. Women must have a personal history of hormone-receptor positive breast cancer 
 
10.8.2 
United Kingdom 
10.8.2.1 
GBR-1: Country/region-specific Changes Valid for United Kingdom 
only 
Overall Rationale 
This section implements country-specific modifications of the original protocol, dated 21 
OCT 2022, to meet local requirement in United Kingdom. 
10.8.2.1.1 Overview of Changes 
A description of changes and a brief rationale is outlined in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion Criteria 
The contraceptive methods 
must be used through the 
end of exposure (for at least 
8 days after the last dose of 
elinzanetant). 
To follow the request from 
Medicines and Healthcare 
products Regulatory Agency 
(MHRA). The contraceptive 
methods must be used through 
the end of exposure (for at least 8 
days after the last dose of 
elinzanetant).  
 

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10.8.2.1.2 Changes to the Protocol Text 
10.8.2.1.2.1 
Section 5.1 Inclusion Criteria 
 
Sex and Contraceptive/Barrier Requirements  
9. Contraceptive use by women (except for post-menopausal women or WONCBP) 
should be consistent with local regulations regarding the methods of contraception 
for those participating in clinical studies. 
 
 
  
 
OR 
 Is a WOCBP and using an acceptable contraceptive method as 
described in Section 10.4.2 during the study intervention period 
(the contraceptive methods must be used through the end of 
exposure (for at least 8 days after the last dose of elinzanetant)). 
 
 
10.9 
Appendix 9: Protocol Amendment History 
 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the table of contents (TOC). 
Amendment 1 (09 DEC 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 because it impacts the safety of participants of the study. 
Below is a description of the change and a brief rationale. 
 
Key Changes 
Section # and 
Name 
Description of 
Change 
Brief Rationale 
Section 1.3.2 
Treatment and 
follow-up 
Add blood sample 
(safety) at T9 
In the original version of the clinical study protocol a 
T9 in week 26 was missing in the schedule of 
activities (Table 1-2). 
Section 1.3.2 
Treatment and 
follow-up 
Section 1.3.3 PK 
sampling 
schedule 
Add PK sampling at 
T4 and T6 
Longitudinal PK data of tamoxifen/aromatase 
inhibitors in relation to elinzanetant exposure is 
required to be able to detect potential drifts in the 
exposure. 
Section 1.3.3 PK 
sampling 
schedule 
PK sampling at BL 
was updated to prior 
to first elinzanetant 
dose 
True baseline PK values for tamoxifen/aromatase 
inhibitors in the absence of elinzanetant are 
required in order to quantify the influence of 
elinzanetant on the exposure of these 
comedications. 

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Section 2.3.1 Risk 
Assessment 
Section 5.1 
Inclusion Criteria  
DDI study 
elinzanetant and 
tamoxifen is 
completed. The 
results from this DDI 
study together with 
the multiple dose 
simulations indicate 
no clinically relevant 
interaction between 
tamoxifen and its 
metabolites when 
continuously co-
administered with 
elinzanetant with 
respect to safety and 
efficacy supporting 
the combined use in 
the ongoing Phase 3 
study OASIS 4. 
Further PK data is 
being collected in the 
OASIS 4 study. 
Maximum daily dose 
of 20mg was 
removed for 
tamoxifen. 
Tamoxifen is indicated for treatment of adult 
patients with estrogen receptor-positive metastatic 
breast cancer in doses of 20 and in some countries 
up to 40 mg daily. Based on the results of the DDI 
interaction study with elinzanetant and tamoxifen 
there is no need to exclude women using 40 mg 
tamoxifen from participation in this study. 
Section 5.1 
Inclusion Criteria 
To ensure that 
contraceptive 
protection is used 
throughout the entire 
time of exposure, it 
was requested that a 
highly effective 
contraceptive 
method is to be used 
until at least 8 days 
after the last dose of 
elinzanetant. 
To follow the request from Medicines and 
Healthcare products Regulatory Agency (MHRA). 
The contraceptive methods must be used through 
the end of exposure (for at least 8 days after the 
last dose of elinzanetant). 
Section 6.6 
Continued Access 
to Study 
Intervention after 
the End of the 
Study 
No general access to 
study intervention is 
planned after the end 
of the study. 
Investigators can 
request post trial 
access for their 
patients, if deemed 
necessary. 
There is no treatment available for VMS in this 
patient population. If it is in the interest of the study 
participant to continue with study drug the 
investigator can request post-trial access.  
 

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Clarifications to the protocol
Section # 
and Name
Description of Change
Section 5.5 Criteria for 
Temporarily Delaying 
Randomization
In case the screening period is extended to more than 8 weeks, a 
new blood sample has to be taken for assessment of eligibility.
Section 10.6 Prohibited 
concomitant medications 
after 12 
weeks of treatment with the study intervention is allowed.
Corrections of inconsistencies and minor corrections (editorial corrections not detailed): 
Section # 
and Name
Description of Change
Section 5.1 Inclusion 
Criteria
The contraceptive method was updated to a highly effective 
contraceptive method, in accordance with Section 10.4.2 
Contraception Guidance.
Section 1.3.1 Screening
Section 8.2.5 Pregnancy 
Testing
Footnote b was removed at SCR-1 in Table 1-1. The text of in all 
participants except those who have undergone total hysterectomy 
and/or bilateral oophorectomy was removed in Section 8.2.5 since 
the scope of the pregnancy tests was described above.
CCI

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10.10
Appendix 10: Abbreviations and Definitions
Definitions:
Throughout this document, terms study drug and study intervention are used 
interchangeably.
Abbreviations:
A1AT
Alpha-1 antitrypsin
AE(s)
Adverse event(s)
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
ASCUS
Atypical squamous cells of undetermined significance
AST
Aspartate-aminotransferase
AUC
Area under the concentration vs. time curve from zero to infinity after 
single (first) dose
BCRP
Breast Cancer Resistance Protein
BDI
Beck Depression Inventory
BL
Baseline
BM
Biomarker(s)
BMI
Body mass index
CD
Compact disc
CHMP
Committee for Medicinal Products for Human Use
CK
Creatinine kinase
COVID-19
Coronavirus disease of 2019
CYP2D6
Cytochrome P450 2D6
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
DSM-5
DSMB
Diagnostic and Statistical Manual of Mental Disorders
Data Safety Monitoring Board
DVT
Deep vein thrombosis
EC(s)
Ethics committee(s)
ECG
Electrocardiogram
eCOA(s)
Electronic clinical outcome assessments
eCRF(s)
Electronic case report form(s)
EMA
European Medicines Agency
EoT
End of treatment
ePRO(s)
Electronic patient reported outcome(s)
EQ-5D-5L
European Quality of Life 5-dimension 5-level questionnaire
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FU
Follow up
GCP
Good clinical practice
GGT
Gamma glutamyl transferase
GnRH
Gonadotropin-releasing hormone
HA
Health authority
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HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL  
High density lipoprotein 
HDV 
Hepatitis D virus 
HEV 
Hepatitis E virus 
HF(s) 
Hot flash(es) 
HFDD 
Hot Flash Daily Diary 
HPV 
Human papilloma virus 
HSV 
Herpes simplex virus 
IB 
Investigator brochure 
ICE(s) 
Intercurrent event(s) 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International normalized ratio 
IRB 
Institutional review board 
ISI 
Insomnia Severity Index 
IUD 
Intrauterine device 
IxRS 
Interactive voice  web response system 
LC-MS/MS 
Liquid chromatography and tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LDL
Low density lipoprotein
LH 
LSMB
Luteinizing hormone (once) 
Liver Safety Monitoring Board
MCS
Mental component summary
MedDRA
Medical dictionary for drug regulatory affairs
MENQOL
Menopause-specific quality of life questionnaire
MI
Myocardial infarction
MMRM
Mixed model repeated measures
mRNA
Messenger RNA
N/A
Not applicable
NK / NK1 / 
NK3
Neurokinin / neurokinin 1 / neurokinin 3 
OATP
Organic-anion-transporting polypeptide
OCT
Organic cation transporter
PCR
Polymerase chain reaction
PCS
Physical component summary
PD
Pharmacodynamic(s)
PET
Positron emission tomography
PK
Pharmacokinetic(s)
PopPK
Population pharmacokinetics
pre-SCR
Pre-screening visit
PRO
Participant reported outcome
PROMIS SD 
SF 8b
Patient-Reported Outcomes Measurement Information System Sleep 
Disturbance short-form 8b

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PT 
Prothrombin time 
QC 
Quality control 
QTc 
Corrected QT value 
QTL(s) 
Quality tolerance limit(s) 
RNA 
Ribonucleic acid 
SAE(s) 
Serious adverse event(s) 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus -2 
SAS 
Statistical analysis software 
SCR-1 
Screening visit 1 
SCR-2 
Screening visit 2 
SF-36 acute 
Short Form-36 Health Survey Acute 
SoA 
Schedule of activities 
SUSAR 
Suspected unexpected serious adverse reaction(s) 
TBL 
Total bilirubin 
TEAE(s) 
Treatment-emergent adverse event(s) 
TIA 
Transient ischemic attack 
TMF 
Trial master file 
TSH 
Thyroid stimulating hormone 
TVU 
Transvaginal ultrasound 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
VMS 
Vasomotor symptoms 
WBC
White blood cell count
WOCBP
Women of childbearing potential
WONCBP
Women of Nonchildbearing potential
 

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