A Double-blind, Randomized, Placebo-controlled Multicenter Study to Investigate Efficacy and Safety of Elinzanetant for the Treatment of Vasomotor Symptoms Over 52 Weeks in Postmenopausal Women
Phase: PHASE3
Conditions: Vasomotor Symptoms Associated With Menopause, Hot Flashes
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
A double-blind, randomized, placebo-controlled multicenter 
study to investigate efficacy and safety of elinzanetant for 
the treatment of vasomotor symptoms over 52 weeks in 
postmenopausal women 
NCT Number: 
NCT05030584 
Document Date: 
22-Jun-2022 
 

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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 over 52 weeks in 
postmenopausal women
Protocol Number:
21810
Protocol Version:
4.0
Amendment Number:
2
Compound Number:
BAY 3427080 / elinzanetant
Brief Title:
Overall Assessment of efficacy and Safety of elinzanetant In 
patients with vasomotor Symptoms (OASIS-3)
Study Phase:
3
Acronym:
OASIS 3
Sponsor Name and 
Legal Registered Address:
Bayer Consumer Care AG, 
Peter-Merian-Strasse 84, 4052 Basel, Switzerland
Regulatory Agency 
Identifier Number(s):
EudraCT: 2021-000059-38 
Protocol Date: 
22 JUN 2022
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 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation.  Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD

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Document History Table
DOCUMENT HISTORY
Document
Version
Date
Comments (if applicable)
Amendment 2
4.0
22 JUN 2022
Amendment 1
3.0
10 FEB 2022
Clinical Study Protocol
2.0
04 JUN 2021
Version addressing feedback from 
FDA from Special Protocol 
Assessment
Clinical Study Protocol
1.0
17 MAR 2021
Version submitted to FDA Special 
Protocol Assessment
Protocol Amendment Summary of Changes Table
Amendment 2 (22 JUN 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for Amendment 2: 
Changes consist of three types, (i) they address comments from FDA, (ii) will help to clarify 
certain aspects of the protocol or (iii) they are minor corrections. 
Key changes
Section # 
and Name
Description of Change
Brief Rationale
Section 1.3.1 Schedule of 
activities, Table 1-1
Demography and baseline 
characteristics were updated to 
include educational level, and 
gynecological and reproductive 
history including numbers of 
pregnancy and birth.
Since start of the study, data 
have already been collected in 
the CRF as they are relevant for 
the analysis. 
Revised the study protocol to 
match information collected in 
the CRF.
Section 5.1 Inclusion criterion 6
A new sub-bullet was added: HPV 
testing in participants with “absence 
of endocervical/transformation zone 
component” will be used as an 
adjunctive test automatically. 
Participants can be included if they 
are negative for high-risk HPV 
strains.
Sub-criterion added to comply 
with ASCCP guidelines
Section 5.2 Exclusion Criteria
Re-test is allowed once in case of an 
abnormal INR value
Intake of concomitant medication 
may lead to abnormal INR 
values. 
INR can be repeated once in 
participants for whom no INR 
prolonging anticoagulant is 
recorded as prior and 
concomitant medication.

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Section # 
and Name
Description of Change
Brief Rationale
Section 10.6 Prohibited 
concomitant medications
All vaginal hormonal products are 
prohibited from 4 weeks prior to 
Baseline, and not only those with 
systemic exposure.
Requested by FDA
Clarifications to the protocol
Section # 
and Name
Description of Change
Section 1.3.1 Schedule of 
activities
Instructions on wash-out of prior medication were clarified to ensure that 
hormonal therapies possibly affecting laboratory measurements of follicle-
stimulating hormone and estradiol are washed out prior to SCR-1 visit.
Section 1.3.2 Treatment and 
Follow-up
Footnote a was reworded to clarify which Visits should be performed in 
case of premature discontinuation of study intervention.
Section 2.3.1 Risk Assessment
A new section on effects on reproductive function was added for 
completeness.
Section 5.1. Inclusion criteria
Inclusion criteria 9 was modified to add “and is showing eligibility with 
respect to inclusion criterion 3 during this time period”
Section 5.4 Screen Failures
It was clarified that re-screening is allowed once if the inclusion/exclusion 
criteria, including related footnotes, have been changed via a protocol 
amendment.
Section 7.1 Discontinuation of 
Study intervention
Clarification was added that participants who discontinue study intervention
early will be asked to remain in the study without receiving the study 
intervention until Visit T9 has been reached.
Section 7.1.3 Temporary 
Discontinuation
Wording on permanent discontinuation of study intervention was clarified.
Section 7.2 Participant 
Discontinuation/Withdrawal from 
the Study
At the time of discontinuing from the study, if possible, End of Treatment 
visit procedures should be conducted, followed by FU visit as shown in the 
SoA and in particular described in footnote a) in Table 1–2.
Section 8.2.5 Pregnancy testing
Pregnancy testing will not be performed in participants who have 
undergone total hysterectomy and/or bilateral oophorectomy
Section 8.2.6 Mammogram
Women with bilateral mastectomy do not have to provide a mammogram 
provided that all breast tissue has been removed.
Section 8.2.6 Mammogram
A clarification was added that mammogram should be performed before 
any planned COVID-19 vaccination.
Section 8.2.7 Transvaginal 
ultrasound
TVU is not required in participants who have both a total hysterectomy as 
well as bilateral salpingo-oophorectomy since the organs that are meant to 
be assessed are absent.
The assessment of ovaries should include diameters as well as details of 
cyst like structures, if applicable.
Section 8.2.9 Cervical cytology
Cervical smear will be performed only if the participant has an intact cervix.

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Section # 
and Name
Description of Change
Section 10.5.2 Close observation 
of participants with liver function 
test findings
In accordance with Table 10-2, a bullet point was added stating that close 
liver observation can be stopped if fragmentation reveals abnormal bone 
AP as reason for the increase of AP>2 x ULN.
Corrections of inconsistencies and minor corrections (editorial corrections not detailed):
Section # 
and Name
Description of Change
Section 1.3 Schedule of Activities
Weight, hip and waist circumference were added to the screening 
safety assessments, in accordance with Section 8.2.1 Physical 
examinations.
Section 2.3.1 Risk Assessment
Information on abnormal involuntary muscle contractions and skeletal 
muscle toxicity were divided onto two separate rows.
Section 6.8.2 Other Treatment 
Considerations
Correction of a typo in OATP1B1/ B3
Section 10.6 Appendix 6: Prohibited 
concomitant medications
An erroneous footnote was removed from Table 10-4. Strong or 
moderate CYP3A4 inhibitors and inducers will not be determined by PK 
modelling but are identified based on published data and/or respective 
guidances.
In addition, minor editorial and formatting revisions have been made throughout the 
document.

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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........................................................................................................................... 11
1.3
Schedule of Activities (SoA) ......................................................................................... 11
1.3.1
Screening .................................................................................................................... 11
1.3.2
Treatment and follow-up ............................................................................................ 13
1.3.3
PK sampling schedule ................................................................................................ 14
2.
Introduction..................................................................................................................... 15
2.1
Study Rationale.............................................................................................................. 15
2.2
Background.................................................................................................................... 15
2.3
Benefit/Risk Assessment ............................................................................................... 16
2.3.1
Risk Assessment......................................................................................................... 16
2.3.2
Benefit Assessment .................................................................................................... 18
2.3.3
Overall Benefit: Risk Conclusion............................................................................... 19
3.
Objectives, Endpoints and Estimands........................................................................... 19
4.
Study Design .................................................................................................................... 21
4.1
Overall Design ............................................................................................................... 21
4.2
Scientific Rationale for Study Design ........................................................................... 22
4.2.1
Patients’ Input into Design ......................................................................................... 22
4.3
Justification for Dose..................................................................................................... 23
4.4
End of Study Definition................................................................................................. 23
5.
Study Population............................................................................................................. 23
5.1
Inclusion Criteria ........................................................................................................... 23
5.2
Exclusion Criteria .......................................................................................................... 25
5.3
Lifestyle Considerations ................................................................................................ 27
5.4
Screen Failures............................................................................................................... 27
5.5
Criteria for Temporarily Delaying Randomization ....................................................... 27
6.
Study Intervention(s) and Concomitant Therapy........................................................ 27
6.1
Study Intervention(s) Administered............................................................................... 28
6.2
Preparation/Handling/Storage/Accountability............................................................... 28
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 29
6.4
Study Intervention Compliance ..................................................................................... 30
6.5
Dose Modification ......................................................................................................... 30
6.6
Continued Access to Study Intervention after the End of the Study ............................. 30
6.7
Treatment of Overdose .................................................................................................. 30
6.8
Concomitant Therapy .................................................................................................... 31
6.8.1
Prohibited concomitant medications .......................................................................... 31

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6.8.2
Other Treatment Considerations................................................................................. 31
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 32
7.1
Discontinuation of Study Intervention........................................................................... 32
7.1.1
Liver Chemistry Stopping Criteria ............................................................................. 32
7.1.2
Platelet count Stopping Criteria.................................................................................. 33
7.1.3
Temporary Discontinuation........................................................................................ 33
7.1.4
Rechallenge ................................................................................................................ 33
7.1.4.1
Study Intervention Restart or Rechallenge After Liver Stopping Criteria Met ...... 33
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 33
7.3
Lost to Follow Up.......................................................................................................... 34
8.
Study Assessments and Procedures............................................................................... 34
8.1
Efficacy Assessments .................................................................................................... 35
8.1.1
Electronic Participant-Reported Outcomes (ePROs) ................................................. 35
8.1.1.1
Hot Flash Daily Diary (HFDD)............................................................................... 37
8.1.1.2
Patient-reported Outcomes Measurement Information System Sleep Disturbance 
Short Form 8b (PROMIS SF 8b)............................................................................. 38
8.1.1.3
Menopause Specific Quality of Life Scale (MENQOL)......................................... 38
8.1.1.4
Insomnia Severity Index (ISI)................................................................................. 38
8.2
Safety Assessments........................................................................................................ 39
8.2.1
Physical Examinations................................................................................................ 39
8.2.2
Vital Signs .................................................................................................................. 39
8.2.3
Electrocardiograms..................................................................................................... 40
8.2.4
Clinical Safety Laboratory Assessments .................................................................... 40
8.2.5
Pregnancy Testing ...................................................................................................... 41
8.2.6
Mammogram .............................................................................................................. 41
8.2.7
Transvaginal ultrasound (TVU).................................................................................. 41
8.2.8
Bone mineral density.................................................................................................. 42
8.2.9
Cervical cytology........................................................................................................ 43
8.2.10
Endometrial biopsy..................................................................................................... 43
8.2.11
Sleepiness Scale.......................................................................................................... 44
8.2.12
Suicidal ideation and behavior: Electronic Columbia-Suicide Severity Rating 
Scale (eC-SSRS)......................................................................................................... 44
8.3
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting.. 45
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 45
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 46
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 46
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 46
8.3.5
Pregnancy ................................................................................................................... 46
8.3.6
Adverse Events of Special Interest............................................................................. 47
8.4
Pharmacokinetics........................................................................................................... 48
8.5
Genetics ......................................................................................................................... 49
8.6
Biomarkers..................................................................................................................... 49
8.7
Immunogenicity Assessments........................................................................................ 50
8.8
Health Economics.......................................................................................................... 50
9.
Statistical Considerations ............................................................................................... 50
9.1
Statistical Hypotheses.................................................................................................... 50

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9.2
Sample Size Determination ........................................................................................... 50
9.3
Analysis Set ................................................................................................................... 51
9.4
Statistical Analyses........................................................................................................ 51
9.4.1
General Considerations............................................................................................... 51
9.4.2
Primary Endpoint........................................................................................................ 52
9.4.2.1
Calculations related to the frequency and severity of HF ....................................... 52
9.4.2.2
Primary analysis of the primary efficacy endpoints................................................ 53
9.4.3
Secondary Endpoints.................................................................................................. 54
9.4.4
Exploratory / Other Endpoints.................................................................................... 54
9.4.5
Other Safety Analysis................................................................................................. 54
9.4.6
Other Analysis............................................................................................................ 54
9.5
Interim Analysis............................................................................................................. 54
10. Supporting Documentation and Operational Considerations .................................... 55
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 55
10.1.1
Regulatory and Ethical Considerations ...................................................................... 55
10.1.2
Data Safety Monitoring Board ................................................................................... 55
10.1.3
Liver Safety Monitoring Board .................................................................................. 56
10.1.4
Financial Disclosure ................................................................................................... 56
10.1.5
Informed Consent Process.......................................................................................... 56
10.1.6
Data Protection ........................................................................................................... 56
10.1.7
Dissemination of Clinical Study Data ........................................................................ 57
10.1.8
Data Quality Assurance.............................................................................................. 57
10.1.9
Source Documents...................................................................................................... 58
10.1.10 Study and Site Start and Closure................................................................................ 58
10.1.11 Publication Policy....................................................................................................... 59
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 59
10.3
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 60
10.3.1
Definition of AE......................................................................................................... 60
10.3.2
Definition of SAE....................................................................................................... 62
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 63
10.3.4
Reporting of SAEs...................................................................................................... 65
10.4
Appendix 4: Collection of Pregnancy Information........................................................ 65
10.5
Appendix 5: Liver Safety Actions and Follow-up Assessments ................................... 66
10.5.1
Liver safety -related monitoring and discontinuation criteria .................................... 66
10.5.2
Close observation of participants with liver function test findings............................ 67
10.6
Appendix 6: Prohibited concomitant medications......................................................... 70
10.7
Appendix 7: Additional information on scoring and measurement properties of the 
HFDD, the PROMIS SD SF 8b and the MENQOL ...................................................... 72
10.7.1
HFDD ......................................................................................................................... 72
10.7.2
PROMIS SD SF 8b..................................................................................................... 72
10.7.3
MENQOL................................................................................................................... 72
10.8
Appendix 8: Abbreviations............................................................................................ 73
10.9
Appendix 9: Protocol amendment history ..................................................................... 75
10.9.1
Amendment 1 ............................................................................................................. 75
10.9.2
Amendment 2 ............................................................................................................. 80
11. References ........................................................................................................................ 80

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Table of Tables
Table 1–1: Schedule of Activities – Pre-Screening and Screening.......................................... 12
Table 1–2: Schedule of Activities - Treatment and follow-up................................................. 13
Table 1–3: PK sampling schedule............................................................................................ 14
Table 2–1: Risk assessment...................................................................................................... 16
Table 3–1: Objectives and endpoints ....................................................................................... 19
Table 3–2 : Primary Estimand: ICEs and Strategies to Address Them ................................... 21
Table 6–1: Study Interventions ................................................................................................ 28
Table 9–1: Sample size justification ........................................................................................ 51
Table 9–2: Definition of the analysis sets. ............................................................................... 51
Table 10–1: Clinical laboratory tests ....................................................................................... 59
Table 10–2: Liver Safety-Related Monitoring and Discontinuation Criteria .......................... 67
Table 10–3: Samples during close observation for liver safety ............................................... 68
Table 10–4: Prohibited concomitant medication and conditions for selected allowed 
medication potentially confounding efficacy........................................................ 70
Table 10–5: Prohibited concomitant medication potentially affecting PK.............................. 70
Table 10–6: Examples of clinical inhibitors for CYP3A4 ....................................................... 71
Table 10–7: Examples of clinical inducers for CYP3A4......................................................... 71
Table of Figures
Figure 1–1: Study Schema ....................................................................................................... 11

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1.
Protocol Summary
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 over 52 weeks in postmenopausal women 
Brief Title:
Overall Assessment of efficacy and Safety of elinzanetant In patients with 
vasomotor Symptoms (OASIS-3)
Rationale:
This is a phase 3 study to assess the efficacy and safety of elinzanetant for 
the treatment of VMS related to menopause.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the efficacy of 
elinzanetant for the treatment of 
VMS associated with the 
menopause
Primary endpoint 
Mean change in frequency of moderate to severe HF from baseline to
Week 12 (assessed by HFDD)
Exploratory endpoints 
Mean change in frequency of moderate to severe HF from baseline
over time (assessed by HFDD)
Mean change in severity of moderate to severe HF from baseline
over time (assessed by HFDD)
Secondary
To evaluate the efficacy of 
elinzanetant on:
o sleep quality 
o menopause related quality 
of life
o weight and body 
composition
in women being treated for relief 
of VMS associated with the 
menopause
Secondary endpoints:
Mean change in PROMIS SD SF 8b total score from baseline over 
time 
Mean change in MENQOL total score from baseline over time 
Exploratory endpoints:
Mean change in MENQOL VMS subscore from baseline over time 
Mean change in body weight from baseline over time 
Mean change in body composition from baseline over time 
To evaluate the safety of 
elinzanetant for the treatment of 
VMS associated with the 
menopause
Other endpoints:
Number of participants with non-benign endometrial biopsy results
Mean percentage change in BMD from baseline to Week 52
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 24, Week 36 and week 50 compared to baseline
The full list of exploratory endpoints will be presented in the SAP.
BMD = Bone mineral density, HF = Hot Flash, HFDD = Hot Flash Daily Diary, MENQOL=Menopause Specific 
Quality of Life Scale, PROMIS SD SF 8b=Patient-reported Outcomes Measurement Information System Sleep 
Disturbance Short Form 8b, TEAE = treatment emergent adverse event, VMS = vasomotor symptom(s)

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Overall Design:
This is a Phase 3 multi-center, multi-country, placebo-controlled, double blind, parallel group 
intervention study, in post-menopausal women with VMS.
Brief Summary:
The purpose of this study is to investigate efficacy and safety of elinzanetant for the treatment 
of VMS in postmenopausal women.
Study details include:

Total study duration for an individual participant: approximately 62 weeks (plus
potential wash-out period), including
o
Pre-screening / Wash-out period (if applicable)
o
Screening: approximately 6 weeks
o
Treatment: 52 weeks
o
Follow-up: 4 weeks

Visit Frequency: Every 4 weeks until Week 12, then approximately every 6 weeks
until week 42 and end of treatment visit at week 52, including 2 phone call visits.
Number of Participants:
Approximately 860 participants will be screened so that approximately 600 participants (300 
in the elinzanetant arm and 300 in the placebo arm) will be randomized and receive at least 
one dose of study intervention. 
Intervention Groups and Duration:
All participants will receive either 120 mg of elinzanetant or matching placebo orally once 
daily. There will be 2 arms in the study 

Elinzanetant for 52 weeks

Placebo for 52 weeks 
Data Monitoring/Other Committee:
Yes

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1.2
Schema
Figure 1–1: Study Schema
  
Approx. = Approximately, ICF = Signing of informed consent form, Rand. = randomization
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 (See Section 4.1
for further details). Some hormonal therapies may affect the laboratory test results of 
estradiol and follicle-stimulating hormone. For participants in whom these two 
parameters are needed to determine menopausal status, the currently used hormonal 
therapy needs to be evaluated, and if necessary, the washout needs to be completed by 
SCR-1 visit.

The duration between SCR-1 and baseline visit should typically not exceed 6 weeks
(see Section 5.5 for exceptions). The time required for central reading of endometrial 
biopsy samples needs to be considered for visit planning.

Participants who were screen failures from another OASIS study do not have to repeat 
the screening laboratory evaluations, ECG, vaginal ultrasound, mammogram, cervical 
smear, and endometrial biopsy provided that the criteria for inclusion in this study are 
met based on the screening evaluations that were conducted for the other OASIS study 
and are within an acceptable timeframe, i.e., within 6 weeks for laboratory parameters, 
ECG and vaginal ultrasound, within 3 months for endometrial biopsy, within 12 
months for the cervical smear and 6 months for the mammogram.

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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 educational level

()a
Reproductive history including numbers of pregnancy and 
birth


Medical history and concomitant medications, including 
history of menopause hormone therapy



eDiary and eCOA instruments 
Dispensation and training of participant’s hand-held device


HFDD (twice daily)
----------->
Sleepiness Scale (daily in the evening)


----------->
eC-SSRS


Screening and randomization
Inclusion/exclusion criteria



Safety
Complete physical examination (including height)

Vital signs, weight, hip and waist circumference

12-lead ECG

Mammogram (if applicable, see Section 8.2.6)

Transvaginal ultrasound
b
Bone mineral density (if applicable, see Section 8.2.8)

Cervical cytology (if applicable, see Section 8.2.9)


Endometrial biopsy (if applicable, see Section 8.2.10)
b
Laboratory (including safety)
Blood sampling (safety)



Urine pregnancy test 

b
b
Urinalysis


ECG = Electrocardiogram, eCOA = Electronic clinical outcome assessment, Pre-SCR = pre-screening Visit, SCR=screening 
Visit, 
Questionnaires: eC-SSRS = Electronic Columbia-Suicide Severity Rating Scale (patient rated), HFDD=Hot Flash Daily 
Diary, ISI=Insomnia Severity Index, 
a Only if Pre-screening visit is not performed
b Pregnancy test (only if participant has not been confirmed post-menopausal) and ultrasound has to be performed before 
an endometrial biopsy is taken. For participants who have been confirmed post-menopausal, no pregnancy test is needed at 
this visit.

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1.3.2
Treatment and follow-up
Table 1–2: Schedule of Activities - Treatment and follow-up
Visit name
BL
T1
T2
T3
T4
T5
T6
T7
T8
T9/
EoTa
FU
In person (IP) or phone visit
IP
IP
IP
IP
IP
IP
phone
IP
phone
IP
IP
Visit Week
1
4
8
12
18
24
30
36
42
52
56
Visit Day
1
22-
28
50-
56
85-
90
120-
126
162-
168
197-
210
246-
252
281-
294
351-
364
386-
399
Allowed window in days 
-7
-7
+6
-7
-7
-14
-7
-14
-14
±7
eDiary and eCOA instruments 
HFDD (twice daily, see Section 
8.1.1.1)
------------------------>
Three 2-week periodsb

Sleepiness scale (7 consecutive 
days, reported in the evening)
during Weeks 1, 4, 12, 24, 36 and 50

PROMIS SD SF 8b 
once weekly







ISI









MENQOL









eC-SSRS








Study drug intake documentation
---------------------------------------------------------------->

Check completeness of eDiary via 
web report
---------------------------------------------------------------->

Collection of hand-held device

Screening and randomization
Inclusion/exclusion criteria

Participant randomization

Safety/Laboratory
AEs / concomitant medications
------------------------------------------------------------------------------------->
Symptom-based physical exam









Complete physical exam









body composition 









Vital signs, weight, hip and waist 
circumference









Trans vaginal ultrasound

Mammogram
c
Bone mineral density (if applicable
see Section 8.2.8)

d
Endometrial biopsy (if applicable
see Section 8.2.10)

Blood sample (safety)









Blood samples (biomarkers)







Blood sample (PK)




Blood sample (pharmacogenetics, 
optional)

Urinalysis

Study intervention and study exit
Study drug dispensing/training





Study drug dispensing- IP option







Study drug dispensing- DtP option



Monthly
Supervised study drug intake at site








Study drug collection (if applicable)







Study drug compliance









Participant feedback survey










AEs = adverse events, BL = baseline, DtP = Direct to patient, eCOA = Electronic clinical outcome assessment, EoT = End of 
treatment Visit; FU = follow up, IP = In person; PK = pharmacokinetics, SCR = screening, T = treatment
Questionnaires: eC-SSRS = Electronic Columbia-Suicide Severity Rating Scale (participant rated), 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
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 

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followed after 4 weeks by the Follow-up 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 T9. The handheld device will be collected at the last scheduled IP visit.
b during Week 23 & 24, Week 35 & 36 and Week 49 & 50
c 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 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 T9
or EoT.
d T9 only
1.3.3
PK sampling schedule
Table 1–3: PK sampling schedule
Visit
BL
T4
T5
T9/EoT
Week
1
18
24
52
Study intervention 
intake on visit days
at site
at site and no dosing 
on the day before
at home the 
evening before 
at home the 
evening before 
Documentation of 
date and time of 
study intervention
on visit day
on visit day and the 
previous dosing day
on the previous 
dosing day
on the previous 
dosing day
PK sampling
post dose at:
0.5-3 hours
pre-dose, and two 
samples between 
0.5-4 hours post 
dose, at least 1 hour 
apart.
any time during 
the visit
any time during the 
visit
BL= baseline, EoT = End of treatment, T = treatment, PK = Pharmacokinetics
When PK samples must be taken pre-dose at Visit T4, the previous evening dose of study 
intervention will not be taken at home. On the day of BL visit and visit T4 with supervised 
study drug intake at the clinical site, the participant should not take any further study 
medication in the evening at home. 
If the participant has mistakenly taken the evening dose prior to Visit T4 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 samples, to 
be taken at least 1 hour apart (between each sampling), will be done at any time during Visit 
T4. 
For participants prematurely discontinuing study treatment, a PK sample is not required as 
part of the EoT activities.

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2.
Introduction
2.1
Study Rationale
This is a phase 3 study to assess the efficacy and safety of elinzanetant for the treatment of 
VMS related to menopause.
2.2
Background
VMS, commonly referred to as hot flashes (HF, also called “flushes”), are one of the most 
common, bothersome and distressing symptoms felt by women during the menopause 
transition, and the leading cause for seeking medical attention during this particular phase of a 
woman’s life (Pachman et al. 2010). Effective treatment options are mostly limited to 
hormone therapy, which despite being effective is associated with safety concerns such as 
increased risk of hormone-dependent cancers and cardiovascular adverse effects, including 
trombotic risk (BIJUVA® Prescribing Information 2018, PREMARIN® Prescribing 
information 2017). A low dose of the anti-depressant paroxetine is approved in US for 
treatment of VMS but has limited efficacy and a range of safety and tolerability concerns that 
prevent its widespread usage (BRISDELLE® Prescribing Information 2017). 
Since hormone treatment is not an option for many women suffering from moderate and 
severe VMS, either because of contraindications or personal preferences, there is a strong 
medical need for an effective non-hormonal treatment option with improved benefit / risk 
balance.
Elinzanetant (formerly NT-8141) is a dual neurokinin (NK)-1,3 receptor antagonist. Data
indicate that HF may be treated by targeting the neuroendocrine factors that trigger the VMS
(Rance et al. 2013).
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 and severity of HF. Furthermore, the SWITCH-1 study showed that 
the reduction in frequency and severity of HF was associated with marked improvements on 
participant reported outcomes of sleep, mood and quality of life.  
If these benefits are confirmed in further studies, it is anticipated that elinzanetant will be a
relevant improvement compared to currently available non-hormonal therapies. The efficacy 
is expected to be comparable to that seen with hormone therapy, but with a quicker onset of 
action and without the serious side effects associated with hormonal therapy. It is also 
anticipated to result in greater efficacy and a better tolerability profile than anti-depressants 
used for treating VMS.
A detailed description of the chemistry, pharmacology, efficacy, and safety of elinzanetant is 
provided in the IB.
                                                
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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2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of elinzanetant may be found in the IB.
2.3.1
Risk Assessment
Table 2–1: Risk assessment
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.
Concomitant use of strong 
CYP3A4 inhibitors
Concomitant use of CYP3A4 
substrates with narrow therapeutic 
range
Elinzanetant is moderate to sensitive 
substrate for the CYP3A4 enzyme 
and a weak inhibitor of CYP3A4.
Will be managed through 
exclusion of participants taking 
the interacting concomitant 
medications during clinical trials
Abnormal involuntary muscle 
contractions 
Observed in a repeat dose study in 
rats at all doses but not in 
subsequent longer-term studies in 
rat and cynomolgus monkeys. 
These findings are considered 
unlikely to be relevant safety 
findings but will continue to be 
monitored in clinical studies.
In the SWITCH-1 study, there were
2 non-serious cases of muscle 
spasm, both mild  in severity, at 
dosages of 120 and 160mg. Both
were assessed as related to the 
study intervention by the 
investigator.
Continuous AE monitoring 
Skeletal muscle toxicity
The reactions were observed in a 
repeat dose study in rats at high 
doses but not in subsequent longer-
term studies in rat and cynomolgus 
monkey. These findings are 
considered unlikely to be relevant 
safety findings but will continue to be 
monitored in clinical studies.
Continuous AE monitoring 
together with evaluation of 
related laboratory parameters 
(CK, AST, LDH) at specific time 
points will ensure proper 
evaluation of the risk during the 
study.

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Table 2–1: Risk assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
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 participating 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. 
Arrhythmias
A possible signal with respect to an 
increased incidence if 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 
who participated 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 eCRF.
Effects on reproductive function
There was no evidence of 
developmental or reproductive 
toxicity in embryo-fetal toxicity
studies at doses up to 100 
mg/kg/day in rats or up to 140 
mg/kg/day in rabbits representing
about 11- or 1-times 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 100 mg/kg/day, which 
exceeds human exposure at the 
anticipated therapeutic dose of 120 
mg/day by a factor of 11. The dose 
free of findings represents 3-times 
the human exposure.
Subjects are informed of these
effects on reproductive function. 
Subjects are also required to 
avoid pregnancy during the 
study.

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Table 2–1: Risk assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
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
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.
Participants are not expected to 
suffer undue medical 
consequences from absence of 
treatment. 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, CYP3A4 = Cytochrome 
P450 isoenzyme 3A4, ECG = Electrocardiogram, GGT = Gamma glutamyl transferase, LDH = Lactate 
dehydrogenase
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. These benefits may 
include 

reduction in frequency and severity of VMS,

sleep-related benefits,

improvement of mood and health-related quality of life.
It is expected that efficacy related to VMS will be comparable to that seen with hormone 
therapy, with the anticipation that the onset of effect will be more rapid. Furthermore, it is 
anticipated that treatment with elinzanetant will not be associated with some of the 
contraindications limiting the use of hormone treatment in the target population. 
Participants who are randomized to the placebo group are still expected to have some benefit 
from participation in the study as they will receive a thorough medical evaluation. 

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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.
3.
Objectives, Endpoints and Estimands
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 associated with the 
menopause
Primary endpoint 
Mean change in frequency of moderate to severe HF from baseline to 
Week 12 (assessed by HFDD)
Exploratory endpoints 
Mean change in frequency of moderate to severe HF from baseline
over time (assessed by HFDD)
Mean change in severity of moderate to severe HF from baseline
over time (assessed by HFDD)
Secondary
To evaluate the efficacy of 
elinzanetant on:
o sleep quality 
o menopause related quality 
of life
o weight and body 
composition
in women being treated for relief 
of VMS associated with the 
menopause
Secondary endpoints:
Mean change in PROMIS SD SF 8b total score from baseline over 
time 
Mean change in MENQOL total score from baseline over time 
Exploratory endpoints:
Mean change in MENQOL VMS subscore from baseline over time 
Mean change in body weight from baseline over time 
Mean change in body composition from baseline over time 
To evaluate the safety of 
elinzanetant for the treatment of 
VMS associated with the 
menopause
Other endpoints:

Number of participants with non-benign endometrial biopsy 
results

Mean percentage change in BMD from baseline to Week 52

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 24, Week 36, 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 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.

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BMD = bone mineral density, HFDD = Hot Flash Daily Diary, HF = Hot flashes, MENQOL=Menopause Specific 
Quality of Life Scale, PK = Pharmacokinetics, PROMIS SD SF 8b=Patient-reported Outcomes Measurement 
Information System Sleep Disturbance Short Form 8b, TEAEs = Treatment emergent adverse events, VMS = 
Vasomotor symptoms
Estimands
The attributes of the estimand for the primary endpoint, i.e. mean change in frequency of 
moderate to severe HF from baseline to Week 12 (assessed by HFDD), are as following:
A. Population: Post-menopausal women aged 40-65 with VMS as described by the 
inclusion/exclusion criteria detailed in the protocol.
B. Variable: Change in frequency of moderate to severe HF from baseline to Week 12
C. Treatment: 120 mg elinzanetant, Placebo 
D. Intercurrent events. See Table 3–2
E. Population level summary: Mean change in frequency of moderate to severe HF from 
baseline to Week 12. 

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Table 3–2 : Primary Estimand: ICEs and Strategies to Address Them
ICEsa
Reason for ICE
Strategy
Data handling method 
Temporary 
Treatment 
interruptionb
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. 
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.
b) Definition of temporary treatment interruption:Week 12= Treatment taken <80% during weeks 1-12 OR 
treatment taken on <5/7 days during either week 11 or 12.
4.
Study Design
4.1
Overall Design
This is a multi-center, multi-country, double-blind, randomized, parallel-group, placebo-
controlled, Phase 3 intervention study in post-menopausal women with VMS.
The study includes a wash-out period (if applicable), approximately 6-week screening, a 52-
week treatment and a 4-week follow-up period.

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Wash-out: After giving informed consent, participants will be withdrawn from prohibited 
concomitant medications (see Section 10.6) at Pre-SCR visit if needed.
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 in a stratified way 
into 2 arms, as depicted below. 

elinzanetant 

placebo
The randomization will be stratified by region: North America and rest of the world.
Treatment: Participants will receive either 120 mg of elinzanetant or matching placebo orally 
once daily. More details are provided in Section 6. Participant feedback 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. Participants will be required to 
consent prior to completing any study surveys. Results will be reported separately.
Follow-Up: The treatment phase will be followed by a 4-week safety follow-up period.
4.2
Scientific Rationale for Study Design
A double-blind placebo-controlled design 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.
Placebo is considered acceptable because post-menopausal VMS are uncomfortable and 
disruptive to affected individuals, but not life-threatening or life-limiting. The use of placebo 
is also considered adequate by both the US FDA and EU Committee for Medicinal Products 
for Human Use (CHMP) disease-specific guidelines (EMA 2005, FDA 2003).
The study includes multiple safety and efficacy endpoints in a population of patients with 
different degrees of moderate to severe VMS 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.
4.2.1
Patients’ Input into Design
Feedback was collected from patient population through a patient Advisory Board 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

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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 
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. 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 T3.
A participant is considered to have completed the study if she has completed all phases of the 
study including the last visit.
5.
Study Population
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 40 to 65 years, inclusive, at signing of informed consent.
Type of Participant and Disease Characteristics
2. Postmenopausal, defined as:
a. at least 12 months of spontaneous amenorrhea prior to signing of informed consent, 
or 
b. at least 6 months of spontaneous amenorrhea prior to signing of informed consent
with serum FSH levels > 40 mIU/mL and a serum oestradiol concentration of 
< 30 pg/mL, or 

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c. at least 6 months after hysterectomy at signing of informed consent with serum 
FSH levels > 40 mIU/mL2 and a serum estradiol concentration of < 30 pg/mL, or
d. surgical bilateral oophorectomy with or without hysterectomy at least 6 weeks prior 
to signing of informed consent.
3. Moderate to severe HF associated with the menopause and seeking treatment for this 
condition.
4. Negative urine pregnancy test at Screening.
5. In good general health, in the opinion of the investigator, based on the medical history, 
physical examination, 12-lead ECG, BMD, vital signs, gynecological ultrasound3, 
endometrial biopsy, mammogram, clinical laboratory tests, eC-SSRS, and other
assessments completed during screening.
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. HPV testing in participants with 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 “absence of endocervical/transformation zone 
component” 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 a screening mammogram performed, unless she is able to provide a 
written normal mammogram result obtained no more than 6 months prior to the start 
of screening.
9. Participant has completed HFDD for at least 11 days during the two weeks preceding 
baseline visit and is showing eligibility with respect to inclusion criterion 3 during this 
time period.
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
                                                
2 In women between 40 and 50 years of age, who are hysterectomized but who have intact ovaries, a second 
FSH test should be performed within around 1-3 weeks to confirm the postmenopausal status. (second value 
should also be >40mIU/mL)
3 Women with an ovarian cyst/cysts that need further diagnostic procedures to rule out the possibility of 
malignancy during screening should be excluded from participation.

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5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Any clinically significant prior or ongoing history of arrhythmias, heart block and QT 
prolongation either determined through clinical history or on ECG evaluation. 
2. Any clinically significant abnormal laboratory test result(s) measured during screening
(single re-test allowed, except for tests listed in inclusion criteria 2 and exclusion 
criteria 104).
3. Any active ongoing condition that could cause difficulty in interpreting VMS such as: 
infection that could cause pyrexia, pheochromocytoma, carcinoid syndrome.
4. Current or history (except complete remission for 5 years or more) of any malignancy 
(except basal and squamous cell skin tumours). Women receiving adjuvant endocrine 
therapy (e.g. tamoxifen, aromatase inhibitors, GnRH analogues) cannot be enrolled in 
this study.
5. Uncontrolled or treatment-resistant hypertension. Women with mild hypertension can 
be included in the study if they are medically cleared prior to study participation.5
6. 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.
7. Any unexplained post-menopausal uterine bleeding.
8. Clinically relevant abnormal findings on mammogram.6
9. Renal impairment greater than moderate (i.e. estimated glomerular filtration rate 
< 30 mL/min/1.73m2) at screening
10. Abnormal liver parameters (presence of at least one of the following criteria): 

AST > 2 x ULN 

ALT > 2 x ULN

AP > 2 x ULN 
                                                
4 Re-test of INR will be allowed once.
5 Hypertension is defined as systolic blood pressure >130 mmHg or diastolic blood pressure >80 mmHg over 
three readings on at least two different occasions. “Medically cleared” includes stable disease and compliance 
with treatment, if the blood pressure is SBP≤139mmHg and DBP≤89mmHg at screening period. 
6 Clinically relevant abnormal finding is defined as any finding requires further follow-up or diagnostic procedures 
per local guidelines.

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
TBL > ULN unless explained by Gilbert’s syndrome

INR > ULN unless explained by, e.g., intake of anticoagulants4

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.
11. Disordered proliferative endometrium, endometrial hyperplasia, polyp, or endometrial 
cancer diagnosed based on endometrial biopsy during screening (see Section 8.2.10).
12. Any other history, condition, therapy, or uncontrolled intercurrent illness which could 
in the opinion of the investigator affect compliance with study requirements.
Prior/Concomitant Therapy
13. Has used and is unwilling to wash-out use of any of the prohibited concomitant 
medications, as specified in Section 10.6.
14. Inability to comply with the use of prohibited medications as described in
Sections 6.8.1 and 10.6
Prior/Concurrent Clinical Study Experience
15. Concurrent (or within the 2 months prior to signing of ICF) participation in a clinical 
study with an investigational medicinal product (including medical devices).
Other Exclusions
16. At screening a suicidal ideation in the past 6 months (as indicated by “Yes” on item 4 
or item 5 of the suicidal ideation section of the eC-SSRS) or suicidal behavior in the 
past 6 months (indicated by “Yes” on any item of the suicidal behavior section of the 
eC-SSRS).
17. Clinically relevant drug or alcohol abuse within 12 months of signing of informed 
consent7.
18. 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).
19. Known hypersensitivity to elinzanetant or any of the excipients in the formulation.
20. 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.
                                                
7 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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5.3
Lifestyle Considerations
No restrictions to lifestyle are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
date of informed consent, date of last visit, screen failure details, history of menopause 
hormone therapy, and eligibility criteria based on completed procedures.
Re-screening is allowed once only. Re-screening can be performed in the following case:

If the inclusion/exclusion criteria, including related footnotes, preventing 
participant’s initial attempt to participate have been changed via a protocol 
amendment.
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. 
BMD, ECG, mammogram, endometrial biopsy) would constitute a reason for postponing 
randomization. 
Under these circumstances, the screening period may be extended until these conditions have 
resolved or the delayed assessment is available. 
6.
Study Intervention(s) and Concomitant Therapy
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
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6.1
Study Intervention(s) Administered
Table 6–1: Study Interventions
Arm name
Elinzanetant
Placebo
Intervention Name
BAY 3427080 / 
elinzanetant
Placebo
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
Current name
Former Name
BAY 3427080
NT-814
N/A
Alu = Aluminium; N/A = Not applicable
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 all 
treatment arms, with or without food. For requirements on drug intake for PK sampling, 
please refer to section 1.3.3.
If a participant forgets to take a dose in the evening, then the dose can be taken at any time up 
to 2 AM 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.
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.

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4. Further guidance and information for the final disposition of unused study 
interventions are provided in Investigator Site File.
5.
Interim pick-up appointments may be introduced to allow for monthly in person 
dispense in accordance with Sponsor, if needed. Where DtP distribution of study 
intervention occurs at selected sites and visits, the investigator delegates distribution 
responsibility to the sponsor. The investigator maintains responsibility and control for
dispensing via IxRS by confirming whether or not DtP distribution of study 
intervention can be triggered. The sponsor contracts a distribution provider to conduct 
DtP distribution of study intervention including the delegation of storage and 
handling as needed until handover to the participant.
Local destruction (if any) of the study drug must be properly documented consistent with the 
sponsor’s agreed and specified procedures. Written instructions on medication destruction 
will be made available to affected parties as applicable.
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. Investigators will remain blinded to each participant’s assigned study 
intervention throughout the course of the study. 
Unblinding
The IxRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the responsibility for determining if unblinding of a participant’s 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 
effort to contact the sponsor prior to unblinding a participant’s intervention assignment unless 
this could delay emergency treatment of the participant. 
If a participant’s intervention assignment is unblinded, the sponsor must be notified within 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 

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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 
participant’s intervention assignment, may be sent to investigators in accordance with local 
regulations and/or sponsor policy. 
An independent data analysis center will provide unblinded safety data to the independent 
Data Safety Monitoring Board.
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 the 
HFDD evening diary once daily at bedtime using the ‘Study drug intake documentation’ on 
the electronic 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.
6.6
Continued Access to Study Intervention after the End of the Study
No access to study intervention is planned after the end of the study.
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).

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In the event of an overdose, the investigator should:

Contact the Sponsor immediately.

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.
6.8.1
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.
Participants are permitted to continue to use antidepressant drugs and over the counter/herbal 
treatments 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) (see Section 10.6 for 
further information).
6.8.2
Other Treatment Considerations
Based on preclinical data, an increase in exposure of drugs that are sensitive substrates of 
OATP1B1/1B3, P-gp or 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 BCRP and OATP1B1/B3 substrate rosuvastatin showed no clinically 

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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. 
In the absence of clinical drug-drug interaction data with P-gp substrates including but not 
limited to fexofenadine, dabigatran, digoxin, the following precautionary measures have to be 
implemented: Participants receiving a combination of elinzanetant and P-gp substrates should 
be closely monitored for signs and symptoms of adverse events due to increased exposure of 
the co-administered P-gp substrate. Dose modification of sensitive P-gp substrates should be 
considered based on the prescriber information or such compounds should be avoided.
Vitamin D and calcium supplements
Postmenopausal women should take sufficient Vitamin D and Calcium (e.g. by food or 
supplement intake). 400 IU vitamin D, along with 500 mg to 1000 mg of calcium daily during 
the study period is considered sufficient. Investigators and study coordinators will be trained 
on the importance of vitamin D and calcium use. Participants will be counseled at every visit 
on the importance of taking vitamin D and calcium during the treatment period. If necessary, 
the dose of calcium or vitamin D supplementation may be modified or discontinued at the 
discretion of the investigator. The intake of vitamin D and calcium should be documented on 
the concomitant medication eCRF throughout the study.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant will be asked to remain in the study 
without receiving the study intervention until Visit T9 has been reached. 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.
For withdrawal from study see Section 7.2.
7.1.1
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.

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7.1.2
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.
7.1.3
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.
7.1.4
Rechallenge
Study intervention may be restarted after a temporary interruption if deemed clinically 
appropriate by the investigator in collaboration with the Sponsor’s Medical Monitor.
7.1.4.1
Study Intervention Restart or Rechallenge After Liver Stopping 
Criteria Met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study is not allowed.
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.
o
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 7.1.3) 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.

At the time of discontinuing from the study, if possible, an End of Treatment visit 
procedures should be conducted, followed by FU visit as shown in the SoA and in 
particular described in footnote a) in Table 1–2. 

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o
Participants who have been randomized but not yet started study intervention 
do not need to undergo further study procedures other than return of supplies, 
before their study participation terminates.
o
For withdrawal during the 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.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, she will be considered to have 
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

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
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. 

Procedures conducted as part of the participant’s routine clinical management (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.
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 participant’s 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. Additionally, data 
will be collected on tablet computers which will be used by the participants during the study 
visits at the study sites. Web-based back-up versions may be applied in addition.
ePROs collected on the participant’s 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

Evening HFDD

Sleepiness Scale (See Section 8.2.11)

Study drug intake documentation (See Section 6.4)

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After BL visit up to Visit T3 (inclusive) the PROMIS SD SF 8b and the MENQOL 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 T4 
onwards these ePROs will be completed by the participant during the study visits.
ePROs collected on a tablet computer at the study sites
The following PROs will be collected on a tablet computer:

eC-SSRS (See Section 8.2.12)
Time for completion
Time for completion of each item of the different PROs is conservatively estimated with 
approximately 30 seconds per individual item. The daily completion time, therefore, ranges 
from approximately 5 min during normal days to a maximum of 31 min on the days when 
all/most questionnaires are to be completed either at home or during study visits. 
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 participant’s 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.
Participants’ data entries from the hand-held device will be transmitted automatically by 
wireless connection to the electronic diary provider’s database, and later by the vendor to 
Sponsor’s 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 and tablet 
computer. 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 / data entry on the tablet 
computer is activated. Participants will be educated regarding the importance of their timely 
and accurate completion of the ePROs during all study visits. The participant 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.

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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 
the tablet computer at the site, 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 and the tablet computer 
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.
Measures to further prevent missing participants’ hand-held device entries
In case one entry on the HFDD, the Sleepiness Scale or the study intervention intake 
documentation was missed (for morning diaries in case this was not completed when getting 
up in the morning; for evening diaries, Sleepiness Scale or the study intervention intake 
documentation 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 11:00AM and 11:59PM. For 
the evening diary, the Sleepiness Scale and the study intervention intake documentation, the 
entry option will be available between midnight until 10:59AM 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 participant 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 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)
Participants’ assessments of 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 timepoints 
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 are defined as a “sensation of heat without sweating”, moderate HF are defined as a 
“sensation of heat with sweating, but able to continue activity”, and severe HF are defined as 
a “sensation of heat with sweating, causing cessation (stopping) of activity”. 

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8.1.1.2
Patient-reported Outcomes Measurement Information System Sleep 
Disturbance Short Form 8b (PROMIS 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.
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 
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'. 
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
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 
depending on the item (0=”none”, 4=”very severe” (Items 1-3); 0=”very satisfied”, 4=”very 
dissatisfied (Item 4)”; 0=”not at all noticeable”, 4=”very much noticeable” (Item 5); 0=”not at 
all worried”, and 4=”very much worried” (Item 6); 0=”not at all interfering”, 4=”very much 
interfering” (Item 7). The scores for each item are summed to produce the total score 
(maximum 28).
Total score categories:
0–7 = No clinically significant insomnia

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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 participants at 
baseline Visit to enable stratification of the study population by self-reported severity degree 
of insomnia.
8.2
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.
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.

Height will be measured at Screening Visit only.

Hip and waist circumference, weight and body composition will be recorded at visits 
indicated in the SoA. The same type of calibrated device must be used at all 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.

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
In case of abnormal results, repeat measurements should be performed to adequately 
document potential findings, e.g. hypertension.8
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.

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.
o
If clinically significant values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified,
and the sponsor notified.
o
All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
o
If laboratory values from non-protocol specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or 
                                                
8 Hypertension is defined as systolic blood pressure >130 mmHg or diastolic blood pressure >80 mmHg over 
three readings on at least two different occasions.

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dose interruption), then the results must be recorded according to the eCRF
completion guideline.
8.2.5
Pregnancy Testing
None of the participants of the study are women of childbearing potential. Nevertheless, a 
pregnancy test will be performed to confirm eligibility in all participants except those who 
have undergone total hysterectomy and/or bilateral oophorectomy.
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 
6 months prior to start of screening. Women with bilateral mastectomy do not have to 
provide a mammogram provided that all breast tissue has been removed.

At 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 
frequency of mammograms in the respective age group. 

In case a non-study mammogram was conducted during the time of study 
participation, the result should be documented.

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 for a certain period 
according to local guidance. In addition, it is recommended to schedule a COVID-19 
vaccination after the EoT mammogram (if a mammogram is required, see above).
8.2.7
Transvaginal ultrasound (TVU)

Ultrasound examination should be performed by a physician/examiner well 
experienced in gynecology 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.

The following safety parameters will be measured and recorded: 
o
Endometrial thickness (measured in the medio-sagittal section as double-layer 
in millimeters)
o
Overall safety 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 
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(left/right) for ovaries. If the printouts are on thermo-sensitive paper, they need to be 
copied as they will fade over time.
8.2.8
Bone mineral density
BMD measurements will be performed at designated study sites. The BMD assessment 
should be performed on all participants enrolled at these designated sites, as per the SoA. The 
aim is to have BMD assessments done for at least 50% of total study participants. DEXA scan 
of the lumbar spine and one hip will be performed for BMD assessment at time points
described in the SoA (section 1.3). BMD measurements do not have to be done on the same 
day as other assessments of that visit, but have to be performed within the time window of the 
respective visit. DEXA scans will be performed to assess the BMD of the total spine, total hip
and femoral neck (left hip/neck preferred; the right hip should be examined in case of known 
pathology at the left hip that may falsify DEXA assessment results, e.g., known severe 
arthrosis or hip prosthesis).
DEXA scans must be performed with either a GE Lunar (Madison, WI, U.S.A.) or a Hologic 
(Waltham, Massachusetts, U.S.A.) densitometer. The same DEXA instrument should be used
by the site for all measurements of a participant in this study. Preferably, the same technician 
should acquire all scans of a given participant throughout the course of the study. 
Study-specific training and a detailed imaging manual will be provided to the sites to 
standardize study procedures across sites. Study sites will be required to scan their quality 
assurance phantom (anthropomorphic lumbar spine or aluminum wedge phantoms) and 
submit those results to the imaging core laboratory as part of the instrument quality control 
procedure. These data will be used to monitor the stability of the DEXA device over the 
duration of the study. In addition, the image quality (e.g., correct positioning) and evaluability 
of each DEXA scan will be checked centrally and sites may be requested to re-scan 
participants, as appropriate. If received images are not evaluable due to quality issues, this 
will be queried to the site as part of the central image quality control and the DEXA scan 
should be repeated at the site within a maximum of 15 business days.
More details on the instrument quality control procedures and scan identification and 
submittal to the central imaging core lab for analysis will be provided in a separate DEXA 
imaging manual and DEXA image review charter.
Treatment decisions are made based on local DEXA assessment at the discretion of the 
investigator. Central DEXA assessment results will not be provided to the study sites.
All DEXA scans acquired for the study will be analyzed by an imaging technician at the 
central imaging laboratory. Central analysis of the DEXA scans will reduce the variability of 
the results. The DEXA analysis will provide BMD values, T-scores and Z-scores for each of 
the anatomic areas (lumbar spine, total hip and femoral neck) for all study DEXA visits. The 
BMD results from all DEXA visits will be used to calculate the % change in BMD over time
for each participant. The expected bone loss for untreated post-menopausal women is 
presumably 1-2% per year (Finkelstein et al. 2008). Further details of the central DEXA 
review and analysis are described in the corresponding DEXA image review charter. 

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8.2.9
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.
8.2.10
Endometrial biopsy
Timing and sampling of endometrial biopsy

Endometrial biopsy is to be performed only when applicable (i.e. women with intact 
uterus) at time points indicated in the SoA. All endometrial biopsies must be collected 
by qualified personnel.

Each participant should have an endometrial biopsy with a normal result (disordered 
proliferative endometrium, hyperplasia, polyp, and malignant findings will be 
considered as abnormal) documented at screening. 

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 experienced post-menopausal bleeding during the study.

The sterilized, disposable device Pipelle de Cornier will be used – a flexible and 
transparent polypropylene sheath with an internal plunger for aspiration. This device 
allows for gentle tissue sampling, without hysteroscopy, and generally requires no 
local anesthesia or cervical dilatation. 

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.

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Study sites will be informed about the individual diagnoses of the three pathologists to allow 
for clinical follow-up.
In case a sample is considered “not evaluable” by two or more of the pathologists, a repeat 
sample will be requested by the central laboratory.

At screening, an evaluable sample is required for inclusion. Women with a diagnosis 
of disordered proliferative endometrium, endometrial hyperplasia, polyp, or malignant 
neoplasm by any of the three pathologists will not be included.

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.
8.2.11
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, subsection “Measures to further prevent missing 
participants’ hand-held device entries”). 
Participants respond to the items using a 5-point verbal rating scale (“0”=not at all; “4”=very 
much). For the assessment of sleepiness 7-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. During the treatment period the assessment will be done on 7 consecutive 
evenings at timepoints indicated in the SoA.
8.2.12
Suicidal ideation and behavior: Electronic Columbia-
Suicide Severity Rating Scale (eC-SSRS)
Suicidal ideation and behavior will be monitored by eC-SSRS questionnaire. Use of the 
eC-SSRS is required by the US FDA in clinical trials of new compounds with a central mode 
of action.
The eC-SSRS is a fully structured participant rated questionnaire designed and developed for 
computer administration. Participants respond to standardized clinical questions presented in a 
uniform fashion and adhering to the original C-SSRS clinical conventions. The eC-SSRS 
assesses lifetime suicidality during an initial baseline evaluation, and then prospectively 
monitors ideations and behaviors at subsequent follow-up assessments. The eC-SSRS 
assesses the severity and frequency of suicidal ideation and behavior. The information 
collected in the eC-SSRS is classified into a set of 11 categories for suicidal ideation and 
suicidal behavior, and self-injurious behavior without suicidal intent.
See Exclusion Criteria 16 for information on when the participant should not be randomized 
based on suicidal behavior or ideation. 

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The investigator will receive an email notification if a participant has a “Yes” score on item 4 
or item 5 of the suicidal ideation section of the eC-SSRS or “Yes” on any item of the suicidal 
behavior section. If this happens after randomization, the participant can continue the study at 
the discretion of the investigator. The investigator has to report this as an adverse event. In 
addition, any suicidal ideation and/or behavior 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.
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 
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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 Investigator’s Brochure and 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
All the participants will be confirmed with postmenopausal status including hormonal level at 
baseline. 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 
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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 of the investigator’s awareness for 
expedited reporting to the health authorities:
o
ALT and/or AST >8x ULN OR
o
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 in the evening 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 indicated) 
according to the investigator’s clinical judgement and usual practice (unexplained 

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post-menopausal bleeding prior to randomization will exclude the participant from the 
study).
8.4
Pharmacokinetics
Blood samples for measurement of elinzanetant and its main metabolites in plasma for PK are
to be collected at the time points given in Table 1–3. The date and time of study drug intake 
on the previous dosing days prior to the PK sampling as indicated in Table 1–3, the time of 
the supervised drug intake, 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 drug intake 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 are determined using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS). 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.
Population pharmacokinetic 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 may 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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Population or nonlinear mixed effects PK models describe the relationship between dose, 
time, and the elinzanetant plasma drug concentration. A previously developed population PK 
model for elinzanetant based on Phase 1 and 2 data will be applied to all valid PK samples to 
evaluate the relationship between variability in PK and covariates, (ie, intrinsic [eg, body 
weight, race] and extrinsic factors [eg, concomitant medication]) that are of clinical relevance. 
If necessary, the population PK model will be adapted to adequately fit the data. Individual 
PK parameters of elinzanetant will be calculated.  
A separate Modeling and Simulation Analysis Plan, providing details of the model 
development and evaluation will be provided before the start of the population PK analysis. 
Evaluation of the data will be presented in a separate Modeling and Simulation Report.
Appropriate measures will be taken to maintain blinding of the study team (eg, data access 
will be restricted to specific people involved in the analysis and members of the study team 
will neither have access to the randomization list nor to individual data).  
8.5
Genetics
Genetic as well as non-genetic analyses may be part of the biomarker investigations in this 
study, if approved by local ECs / IRBs and competent authorities.
Pharmacogenetic investigations may be of any kind, except for whole genome sequencing. 
8.6
Biomarkers
In this study, genetic as well as non-genetic biomarkers (e.g., related to the mode of action or 
the safety of the study intervention and similar drugs) may be investigated. This applies to 
further biomarkers deemed relevant to VMS and associated health problems. These 
investigations may include e.g., diagnostic, safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers.
PD /safety biomarkers from blood 
The following table gives an overview on sample types collected:
Sample type
Description
Biomarker plasma
For PD / safety (optional assessment)
Biomarker serum
For PD / safety (optional assessment)
Biomarker whole blood
For pharmacogenetics testing

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
Not applicable
9.
Statistical Considerations 
9.1
Statistical Hypotheses
The hypothesis for the primary efficacy endpoint is defined as:
:  ≤	 versus 
:  > 	 where  and 	 stand for the mean change in frequency of 
moderate to severe HF from baseline in the placebo (P) and verum (V) group to Week 12.
The type I error rate will be controlled at a one-sided α=0.025 level.
All other endpoints will be summarized descriptively and therefore no multiplicity adjustment 
is needed.
9.2
Sample Size Determination 
Approximately 600 participants will be randomly assigned to study intervention. Of these, 
300 participants will be randomly assigned to elinzanetant and the other 300 participants will 
be randomly assigned to the placebo arm. Assuming an overall drop-out rate of 30% and 10% 
during the months 1-3 and 4-6 in the elinzanetant arm, approximately 210 participants will be 
available that were treated for 1 year and approximately 240 participants will be available that 
were treated for at least 6 months.
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 
1500 participants are required that were exposed to at least one dose of elinzanetant 120 mg. 
Of these 1500 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 upcoming phase 3 studies, the number of participants needed for the 
elinzanetant arm in this study is 300, also taking into account the assumed drop-out described 
above.
Screen failures are defined in Section 5.4. Assuming a screen failure rate of 30% 
approximately 860 participants need to be enrolled to achieve the required number of 600 
randomized participants. 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 endpoint using the 
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distribution. Drop-out rate during the first 3 months is assumed to be 10%. The power with 
treatment differences (ie. mean change in frequency of moderate to severe HF from baseline 
to Week 12), with N=270 per treatment group and assumed standard deviation are provided in
Table 9–1. The data from placebo arm in SWITCH-1 study (NCT03596762 2020) was used 
for assumption of standard deviation.
Table 9–1: Sample size justification
Standard 
deviation
Treatment difference
Elinzanetant vs. placebo
Power %
4.29
-1.00
-1.50
77.1 % 
98.2 %
-2.00
>99.9 %
PASS version 13.0.11 was used for sample size calculation.
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 sponsor’s applicable Standard Operating Procedures.
Details on additional subsets which may be of interest will be provided in the statistical 
analysis plan (SAP).
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 
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, 

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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 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.
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.
We considered a low impact of the COVID-19 pandemic on missing assessments of the 
frequency and severity of HF 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 
HF related endpoints.
COVID-19 is included as a reason for occurrence of the important ICEs in the study estimand 
strategy (Table 3–2).
9.4.2
Primary Endpoint
The primary efficacy endpoint for this study is mean change in frequency of moderate to 
severe HF from baseline to Week 12.
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 criteria 9, 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).

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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 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. 
Mean change in frequency of moderate to severe HF from baseline to Week 12/over 
time:
This will be calculated as the difference in the frequency of moderate to severe HF at Week 
12 or at various weeks, 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 HF for each week during the treatment period will be 
calculated using the available data during that particular week. 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 over time:
This will be calculated as the difference in the severity of HF at various weeks, 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 endpoint 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 and Week will be included as covariates in 
the model. The interaction terms baseline*Week and treatment*Week will also be included. 
The primary endpoint is the treatment difference between the elinzanetant and placebo at
Week 12. More details on model diagnostics, alternative modeling approaches, main and 

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sensitivity analysis, and details of the missing data handling/imputation will be given in the 
SAP.
9.4.3
Secondary Endpoints
The secondary efficacy endpoints in this study are:

Mean change in PROMIS SD SF 8b total score from baseline over time

Mean change in MENQOL total score from baseline over time
The calculation of the scores for PROMIS SD SF 8b, and for the MENQOL total score will be 
done according to the respective questionnaire guidelines. Details will be provided in the 
SAP.
The change from baseline for the secondary endpoints will be analyzed descriptively by 
treatment group using the number of non-missing observations, arithmetic mean and standard 
deviation, median, minimum and maximum using the FAS. In addition to the change from 
baseline over time, the values at various weeks will also be summarized accordingly.
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 data base lock of the Medical 
Dictionary for Regulatory Activities (MedDRA).
The percentage change from baseline in BMD in lumbar spine (total), total hip and femoral 
neck will be analyzed descriptively over time by treatment group in participants, who have
BMD data available.
Further details on safety analyses will be described in the SAP.
9.4.6
Other Analysis
Exploratory subgroup analyses using descriptive statistics will be provided for the primary 
and secondary endpoints by region. Further subgroup analyses including additional subgroups 
(e.g. by BMI) may be specified in the SAP.
9.5
Interim Analysis
No interim analysis is planned for this study. Blinded data may be used for evaluation of 
psychometric and other measurement properties of PRO instruments.

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10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (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

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) will be 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 will be described in the 
DSMB charter.

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10.1.3
Liver Safety Monitoring Board
An independent liver safety monitoring board (LSMB) will be 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 will be 
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

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.

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. 
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 his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 

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disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.7
Dissemination of Clinical Study Data
Result Summaries of Bayer's sponsored clinical trials in drug development phases 2, 3 and 4 
and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States (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 eCRF 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 eCRF. 

Guidance on completion of eCRFs will be provided in the eCRF 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).

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
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 
investigator’s site.

Data reported on the eCRF 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
First Act of Recruitment
The first participant’s signature of informed consent is considered the first act of recruitment
and will be the study start date.
Study/Site Termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:

Discontinuation of further study intervention development

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.
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, 
bicarbonate, magnesium, chloride, total protein, hemoglobin A1c, lactate 
dehydrogenase (LDH)

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Panel
Parameters (by category)
Coagulation: 
prothrombin time (Quick), INR, activated partial thromboplastin time (aPTT) 
Hormones:
follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), 
progesterone (P), prolactin, thyroid-stimulating hormone (TSH), triiodothyronine 
(T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), sex 
hormone-binding globulin (SHBG), total testosterone (tT) 
Bone markers 
bone-specific alkaline phosphatase (BALP), procollagen type 1 N-terminal pro-
peptide (P1NP), vitamin D (serum 25-hydroxyvitamin D), osteocalcin
Urine analysis
pH, urobilinogen, blood/hemoglobin, total protein, ketone, bilirubin, nitrite, 
glucose, leukocytes
Screening/Start of Intervention parameters
Urine pregnancy test
Beta human chorionic gonadotropin (β-hCG)
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 
Genetics (only consented participants)
Pharmacokinetics 
pre-and post-dose PK samples
Biomarkers 
For biomarkers, serum and plasma samples needed
ASCUS = atypical squamous cells of undetermined significance, BM = Biomarkers, DNA = Deoxyribonucleic acid, 
HCV = Hepatitis C virus, HPV-DNA = Human papilloma virus, INR = International normalized ratio; mRNA = 
Messenger ribonucleic acid; RNA = ribonucleic acid, WBC = White blood cell count, PG = 
Pharmacogenomics, PK = Pharmacokinetics 
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.
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 

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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.

“Lack of efficacy” or “failure of expected pharmacological action” per se will 
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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.

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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 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d.
Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse.

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10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to 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.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.

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Assessment of Causality

The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to 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.
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.

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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.
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 sponsor’s Pharmacovigilance department.

In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by
overnight mail or courier service.

Initial notification via telephone does 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
This study does not include Woman of Childbearing Potential (WOCBP). Therefore, cases of 
pregnancy are not expected. In the unlikely event that a pregnancy is detected during the
study, the following procedures should be adhered to.
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. 

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
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.
o
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.
o
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
o
In the case of increased liver values defined in Table 10–2, a retest may 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.

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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
Or 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.
o
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 
investigator’s awareness 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
o
The investigator may consider whether the observed increase in liver values 
would qualify as SAE (see Section 8.3.6).

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:
o Ensure participant safety
o Identify possible non-study-intervention-related causes of liver injury

A close observation has to be initiated during intervention or follow-up phase if liver 
function tests meet the criteria in Table 10–2. Close observation includes:

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o Sampling for the first batch of laboratory parameters (Table 10–3).
o 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.
o Obtaining a detailed history of the symptoms and prior or concurrent diseases  
o Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 
o Ruling out acute viral hepatitis, autoimmune or alcoholic hepatitis, nonalcoholic 
steatohepatitis, hypoxic/ischemic hepatology and biliary tract disease. 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.
o Obtaining a history of exposure to environmental chemical agents
o Obtaining additional tests to evaluate liver function as required (e.g. INR, direct 
bilirubin measurements)
o Considering gastroenterology or hepatology consultations 

Data for any findings are to be recorded in the corresponding eCRF pages

Stopping criteria for close observation:
o
2 consecutive normal/baseline results for liver enzymes in addition to 
availability of results from detailed close liver observation lab panel, related 
procedures, relevant medical and medication history and the reporting of signs 
and symptoms related to elevated liver enzymes, or
o
a confirmed clinical diagnosis explaining the elevated liver enzymes, or 
o
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.
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)
Complete blood count including WBC with differentials
Cholinesterase
Conjugated (direct) bilirubin
Creatine kinase (CK)
GGT
Hemoglobin
INR
Lactate dehydrogenase (LDH)
PT
Total bilirubin

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Table 10–3: Samples during close observation for liver safety
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
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 and conditions for selected allowed 
medication potentially confounding efficacy
Prohibited from the time shown until 1 week after the last dose of study drug
Hormonal therapies
From 4 weeks prior to 
Baseline Visit 
Vaginal hormonal products (rings, creams, gels and including DHEA or analogues 
thereof)
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
Selective estrogen receptor modulators
Intrauterine progestin therapy  
From 12 weeks prior to 
baseline Visit
Progestin implants and estrogen alone injectable drug therapy
Use of adjuvant endocrine therapy (e.g. tamoxifen, aromatase inhibitors, GnRH 
analogues)
From 24 weeks prior to 
Baseline Visit
Estrogen pellet therapy or progestin injectable drug therapy 
Non-hormonal therapies
From 4 weeks prior to 
Baseline Visit
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 (eg 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 menopausal symptoms.
Oxybutynin/ Oxybutynin hydrochloride
DHEA = Dehydroepiandrosteronacetat, ICF = Informed consent form
Table 10–5: Prohibited concomitant medication potentially affecting PK
Prohibited from the time shown until 1 week after the last dose of study medication
From 1 week prior to Baseline Visit:
CYP3A4 substrates with a narrow 
therapeutic range
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, 
terfenadine
From 2 weeks prior to Baseline Visit: 
Strong (or moderate) inhibitors of 
CYP3A4
See Table 10–6 for examples of most common moderate or potent 
CYP3A4 inhibitors
From 4 weeks prior to Baseline Visit:
Strong (or moderate) inducers of 
CYP3A4
See Table 10–7 for examples of most common moderate or potent 
CYP3A4 inducers
From 1 week prior to Baseline Visit:
P-glycoprotein inhibitors
azithromycin, conivaptan, cyclosporine, diltiazem, erythromycin, 
ketoconazole, quinidine, ranolazine, 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, propafenone, quinidine,  
From 1 week prior to Baseline Visit: 
P-glycoprotein substrates with a 
narrow therapeutic range
Digoxin
CYP3A4 = Cytochrome P450 isoenzyme 3A4, PK = Pharmacokinetics

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Table 10–6 and Table 10–7 list examples of the most common medication regarded as 
potent CYP3A4 inhibitors or inducers.
Table 10–6: Examples of clinical inhibitors for CYP3A4
Strong inhibitors
Moderate inhibitors
Weak inhibitors
▪
boceprevir
▪
aprepitant
▪
chlorzoxazone
▪
clarithromycin
▪
ciprofloxacin
▪
cilostazol
▪
cobicistat
▪
conivaptan
▪
cimetidine
▪
danoprevir and ritonavir
▪
crizotinib
▪
clotrimazole
▪
elvitegravir and ritonavir
▪
cyclosporine
▪
fosaprepitant
▪
grapefruit juice
▪
diltiazem
▪
istradefylline
▪
idelalisib
▪
dronedarone
▪
ivacaftor
▪
indinavir and ritonavir
▪
erythromycin
▪
lomitapide
▪
itraconazole
▪
fluconazole
▪
ranitidine
▪
ketoconazole
▪
fluvoxamine
▪
ranolazine
▪
lopinavir and ritonavir
▪
imatinib
▪
ticagrelor
▪
nefazodone
▪
tofisopam
▪
nelfinavir
▪
verapamil
▪
paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir)
▪
posaconazole
▪
ritonavir
▪
saquinavir and ritonavir
▪
telaprevir
▪
tipranavir and ritonavir
▪
telithromycin
▪
troleandomycin
▪
voriconazole
Source: (FDA 2020)
Table 10–7: Examples of clinical inducers for CYP3A4
Strong inducers
Moderate inducers
Weak inducers
▪
apalutamide
▪
bosentan
▪
armodafinil
▪
carbamazepine
▪
efavirenz
▪
modafinil
▪
enzalutamide
▪
etravirine
▪
rufinamide
▪
mitotane
▪
phenobarbital
▪
phenytoin
▪
primidone
▪
rifampin
▪
St. John’s wort
Source: (FDA 2020)

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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 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 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
The participant responded ‘NO’, she did not 
experience the problem
1
The participant experienced the problem and 
rated it as ‘0’ on the bothered scale;
2
The participant experienced the problem and 
rated it as ‘1’ on the bothered scale;
3
The participant experienced the problem and 
rated it as ‘2’ on the bothered scale;
4
The participant experienced the problem and 
rated it as ‘3’ on the bothered scale;
5
The participant experienced the problem and 
rated it as ‘4’ on the bothered scale;
6
The participant experienced the problem and 
rated it as ‘5’ on the bothered scale;
7
The participant experienced the problem and 
rated it as ‘6’ on the bothered scale;
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.

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10.8
Appendix 8: Abbreviations
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
ASCCP
American Society for Colposcopy and Cervical Pathology
ASCUS
Atypical squamous cells of undetermined significance
AST
Aspartate-aminotransferase
BCRP
Breast Cancer Resistance Protein
BL
Baseline
BM
Biomarker(s)
BMD
Bone mineral density
BMI
Body mass index
CHMP
Committee for Medicinal Products for Human Use
CK
Creatinine kinase
COVID-19
Coronavirus disease of 2019
CYP3A4
Cytochrome P450 isoenzyme 3A4
DBP
Diastolic blood pressure
DEXA scan
Dual energy x-ray absorptiometric scan
DHEA
Dehydroepiandrosteronacetat
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders
DSMB
Data safety monitoring board
DtP
Direct to patient
EC(s)
Ethics committee(s)
ECG
Electrocardiogram
eCOA(s)
Electronic clinical outcome assessments
eCRF(s)
Electronic case report form(s)
eC-SSRS
Electronic Columbia-Suicide Severity Rating Scale
EMA
European Medicines Agency
EoT
End of treatment
ePRO(s)
Electronic patient reported outcome(s)
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FU
Follow up
GCP
Good clinical practice
GGT
Gamma glutamyl transferase
GnRH
Gonadotropin-releasing hormone
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL 
High density lipoprotein
HDV
Hepatitis D virus
HEV
Hepatitis E virus
HF
Hot flash(es)
HFDD
Hot Flash Daily Diary
HPV
Human papilloma virus
HSV
Herpes simplex virus

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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
IU
international unit 
IxRS
Interactive voice – web response system
LC-MS/MS
Liquid chromatography and tandem mass spectrometry
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LH
Luteinizing hormone (once)
LSMB
Liver safety monitoring board
MedDRA
Medical dictionary for drug regulatory affairs
MENQOL
Menopause-specific quality of life questionnaire
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
PASS
Power Analysis & Sample Size
PCR
Polymerase chain reaction
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
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
SBP
Systolic blood pressure
SCR-1
Screening visit 1
SCR-2
Screening visit 2
SoA
Schedule of activities
SUSAR
Suspected unexpected serious adverse reaction(s)
TBL
Total bilirubin
TEAE(s)
Treatment-emergent adverse event(s)
TMF
Trial master file
TSH
Thyroid stimulating hormone
TVU
Transvaginal ultrasound
ULN
Upper limit of normal
US(A)
United States
VMS
Vasomotor symptoms

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WBC
White blood cell count
WOCBP
Women of childbearing potential
10.9
Appendix 9: Protocol amendment history
10.9.1
Amendment 1
Overall rationale for Amendment 1: 
Changes consist of three types, (i) they address comments from authorities (FDA and 
Portuguese Health Authority) during the initial CTA review process, (ii) will help to clarify 
certain aspects of the protocol or (iii) they are minor corrections. 
Key changes
Section # 
and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion criteria
Exclusion criterion 2 was modified as 
follows: Any clinically significant 
abnormal laboratory test result(s) 
measured during screening (single 
re-test allowed, except for tests listed 
in inclusion criteria 2 and exclusion 
criteria 10).
Retesting for FSH and serum 
estradiol concentration is not 
allowed.
Section 5.2 Exclusion criteria
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Exclusion criterion 4 was modified as 
follows: Women with current or 
previous history (except complete 
remission for 5 years or more) of any 
malignancy (except basal and 
squamous cell skin tumours) will be 
excluded. Women receiving adjuvant 
endocrine therapy (e.g. tamoxifen, 
aromatase inhibitors, GnRH 
analogues) cannot be enrolled in this 
study.
Women with a previous history of 
any malignancy (except basal 
and squamous cell skin tumors) 
that is longer than 5 years ago 
will be allowed to participate in 
the study. The most frequently 
reported adverse reaction of 
adjuvant endocrine therapy are 
hot flushes and these women will 
therefore be excluded from 
participation in this study. 
Section 5.2 Exclusion criteria
Section 10.2 Appendix 2 Clinical 
laboratory tests
Exclusion criteria 6 was modified to 
exclude current untreated hypo- or 
hyperthyroidism, instead of history of 
untreated hypo- or hyperthyroidism.
Definition for acceptable treated 
hyperthyroidism was added.
Triiodothyronine (T3), thyroxine (T4), 
free triiodothyronine (FT3) and free 
thyroxine (FT4) were added to the 
hormone laboratory tests.
The word current was added to 
clarify the precise exclusion 
criteria. 
A definition for treated 
hyperthyroidism was added for 
clarification
To correctly diagnose untreated 
hyperthyroidism and 
hypothyroidism, and to monitor 
thyroid function through the 
study.
Section 5.2 Exclusion criteria
Exclusion criteria 10 was modified to 
allow women with Gilbert’s syndrome 
to be enrolled.
This change was requested by 
FDA, since Gilbert’s syndrome 
affects up to 7% of the US 
population.

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Section # 
and Name
Description of Change
Brief Rationale
Section 6.8.2 Other treatment 
considerations
Instructions regarding drugs that are 
sensitive substrates of 
OATP1B1/1B3, P-gp or BCRP during 
co-administration of elinzanetant 
were updated to allow administration 
of BCRP and/or OATP1B1/1B3 
together with elinzanetant without 
restrictions.
New clinical data not present at 
the time of the initial CSP 
finalization was added. The new
clinical data are more relevant 
than the previously available 
preclinical data, allowing revision 
of the medication restrictions.
Section 7.1 Discontinuation of 
study intervention
In rare instances, it may be 
necessary for a participant to 
permanently discontinue study 
intervention.
This change was requested by 
the Portuguese Health Authority.
Section 7.2 Participant 
discontinuation/withdrawal from 
the study
A participant may withdraw from the 
study at any time at her own request, 
or may be withdrawn at any time at 
the discretion of the investigator for 
safety, behavioral, or compliance 
reasons. This is expected to be 
uncommon.
This change was requested by 
the Portuguese Health Authority.
Section 8.2.6 Mammogram
Mammogram should be done either 
prior to COVID-vaccinations, or it 
should be delayed for a certain 
period after a vaccination, according 
to local guidelines.
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 
Covid-19 vaccination or to delay 
the screening visit according to 
local guidelines.   
Section 8.3.6 Adverse events of 
special interest
Section 10.5.2 Close observation 
of participants with liver function 
test findings
Any  increase in liver enzymes 
meeting the following criteria needs 
to be reported to the sponsor within 
24 hours of the investigator’s 
awareness 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.
This change was requested by 
FDA as part of the 
comprehensive liver safety 
follow-up.
Section 9.4.2.2 Primary analysis 
of the primary efficacy endpoints
The primary endpoints will be 
analyzed using a mixed model with 
repeated measures (MMRM) on the 
change from baseline scores at 
different Weeks including also Week 
8.
Week 8 is used in the MMRM-
analysis to get equally spaced 
visits.
Section 10.5.1 Liver safety -
related monitoring and 
discontinuation criteria
Section 10.5.2 Close observation 
of participants with liver function 
test findings
Close liver observation was added in 
cases where AP>2xULN, 
Added as precautionary 
measure. as recommended by 
the Liver Safety Monitoring 
Board.

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Section # 
and Name
Description of Change
Brief Rationale
Section 10.5.2 Close observation 
of participants with liver function 
test finding
HCV-RNA was added to the 
parameters for samples during close 
liver observation that will be done 
immediately at the onset of the close 
liver observation and not only when 
antigen testing is positive.
Liver imaging has been indicated as 
a standard procedure in evaluation 
testing for competing causes of liver 
injury unless an obvious and firm 
non-drug induced liver injury 
diagnosis has already been made.
These changes were requested 
by FDA to exclude drug induced 
liver injury as soon as possible.
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Use of adjuvant endocrine therapy 
(e.g. tamoxifen, aromatase inhibitors, 
GnRH analogues) is not allowed 
during this study.
Women with a previous history of 
any malignancy (except basal 
and squamous cell skin tumors) 
that is longer than 5 years ago 
will be allowed to participate in 
the study. Vasomotor symptoms 
are a frequent side effect of 
adjuvant endocrine therapy and 
therefore women with a history of 
breast cancer who use adjuvant 
endocrine therapy cannot be 
included in the study.
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Vaginal hormonal products with 
systemic exposure are not allowed 
from 4 weeks prior to baseline. 
Vaginal hormonal products with 
local effect and no systemic 
exposure will not influence the 
efficacy analysis and should be 
allowed in the study considering 
the characters of the target 
population (prevalence of 
atrophic vagina).
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Oxybutynin / Oxybutynin 
hydrochloride are added to prohibited 
concomitant medications
Oxybutynin / Oxybutynin 
hydrochloride is used of label for 
the treatment of VMS and would 
therefore have an effect on the 
efficacy outcome.
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Progestin implants and estrogen 
alone injectable drug therapy are 
prohibited 12 weeks prior to baseline 
visit instead of screening visit.
The time point of counting the 
washout period should be 
consistent with other drugs that 
may affect the efficacy, so adjust 
that to baseline visit.
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Timepoints for prohibited 
concomitant medications potentially 
affecting PK were revised to allow for 
greater flexibility in using these 
drugs.
This change allows greater 
flexibility in using these drugs.
Clarifications to the protocol
Section # 
and Name
Description of Change

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Section # 
and Name
Description of Change
Section 1.1.Synopsis
Section 3 Objectives, endpoints 
and estimands
A footnote was added into the objectives and endpoints table stating that 
the full list of exploratory endpoints will be presented in the SAP.
Section 1.3.2 Treatment and 
follow-up
Weight is collected at the same visit frequency as Vitals not Physical 
Exam. Weight is also recorded on the Vitals eCRF. As such, the new 
wording is more accurate.
Hand-held device will not be returned at the EoT Visit. The participants 
need the hand-held device at the FU-visit to complete the questionnaires.
Section 1.3.2 Treatment and 
follow-up
Section 8.2.1 Physical 
Examinations
A clarification was made that weight, hip and waist circumference will be 
recorded at visits indicated in the SoA.
Section 1.3.3 PK sampling 
schedule
Clarification that all three PK samples at Visit T4 will be taken even if the 
participant has mistakenly taken the evening dose prior to Visit T4.
Section 4.1 Overall design
Wash-out: After giving informed consent, but before starting screening 
procedures. participants will be withdrawn from prohibited concomitant 
medications.
Section 5.1 Inclusion criteria
Footnote 2 in inclusion criterion 2c was revised for clarity, and it was 
precised that the value from the retest should also be >40mIU/mL.
Section 5.1 Inclusion criteria
A footnote was added to inclusion criterion 5 provide guidance to rule out 
possibility of malignancy during screening.
Section 5.2 Exclusion criteria
Exclusion criteria 7 was modified to clarify that women with any 
unexplained post-menopausal uterine bleeding should be excluded.
Section 6.3 Measures to Minimize 
Bias: Randomization and Blinding
A further explanation was added that an independent data analysis center 
will provide unblinded safety data to the independent Data Safety 
Monitoring Board.
Section 6.8 Concomitant Therapy
Dates of administration including start and end dates must be recorded.
Section 8.1.1 Electronic 
Participant-Reported Outcomes 
(ePROs)
Following clarifications were added:
Participants data entries will be transferred automatically to the eDiary 
provider’s database, and later by the vendor to Sponsor’s database.
Educational material will be available in the ePRO portal and the 
Investigator site file.
For the evening diary, the Sleepiness Scale and the Study Drug Intake 
documentation, the entry option will be available between midnight until 
10:59 AM on the day after the missed entry.
Section 9.4.2.2 Primary analysis 
of the primary efficacy endpoints
The primary endpoints will be analyzed using a mixed model with repeated 
measures (MMRM) on the change from baseline scores at different Weeks 
including also Week 8.
Section 10.5.2 Close observation 
of participants with liver function 
test finding
The Section heading was modified to include all liver test findings.

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Section # 
and Name
Description of Change
Section 10.6 Appendix 6: 
Prohibited concomitant 
medications
Further clarification was added that Vaginal hormonal products with 
systemic exposure are not allowed from 1 week prior to baseline. In 
addition, all timepoints were converted to weeks, and progestin implants 
and estrogen alone injectable drug therapy are prohibited 12 weeks prior to
baseline visit instead of screening visit.
Corrections of inconsistencies and minor corrections (editorial corrections not detailed):
Section # 
and Name
Description of Change
Section 1.1 Synopsis
Data monitoring committee info modified to Yes. The modification 
corrects the typo in the Synopsis and ensures that consistent 
information is provided throughout the protocol.
Section 1.1 Synopsis
Correction of Typo: other endpoints were corrected to reflect Section 3 
table.
Section 1.3.1 Screening
ECG, vaginal ultrasound, mammogram were added into the list of 
screening laboratory evaluations that do not need to be repeated for 
participants who were screen failures from other OASIS studies.
Section 1.3.3 PK sampling schedule
Correction of an inconsistency: PK sample is not required at EoT visit if 
the participant discontinues study intervention prematurely.
Section 2.3.1 Risk assessment
The number of non-serious muscle spasm cases in the SWITCH-1 
study was corrected to be 2.
Section 3 Objectives, endpoints and 
estimands
The following “other endpoint“ was corrected to align with the other 
endpoints: Mean percentage change in BMD from baseline to Week 52
Section 5.2 Exclusion criteria
Typo correction to the exclusion criteria 2: to refer to correct criterion 
about liver parameters.
Section 5.2 Exclusion criteria
In exclusion criteria 9 the eGFR unit of measurement was corrected to 
read mL/min/1.73m2.
Section 6.2 Preparation/Handling/
Storage/Accountability
Wording on DtP distribution was corrected.
Section  8.1.1 Electronic participant 
reported outcomes (ePROs)
The order of the ePROs that are collected in the study was corrected.
Section 8.2.9 Cervical Cytology
Correction of an inconsistency: Cervical smear performed during the 
last 12 months prior to signing of informed consent can be used for the 
screening assessment.
Section 9.4.2.2
Statistical model was changed to include baseline*week interaction, 
instead of baseline*treatment.

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Administrative changes
Section # 
and Name
Description of Change
Title page
Amendment number was added on the protocol title page.
In addition, minor editorial and formatting revisions have been made throughout the 
document.
10.9.2
Amendment 2
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). A separate file with tracked changes against the 
last integrated protocol version is available upon request.
11.
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