A Randomized, Parallel-group Treatment, Phase 2, Double-blind Pilot Study to Investigate the Efficacy and Safety of Elinzanetant Compared With Placebo for Treatment of Sleep Disturbances Associated With Menopause.
Phase: PHASE2
Conditions: Sleep Disturbances Associated With Menopause
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
A randomized, parallel-group treatment, Phase 2, double-blind, 
pilot study to investigate the efficacy and safety of elinzanetant 
compared with placebo for treatment of sleep disturbances 
associated with menopause 
NCT Number: 
NCT06112756 
Document Date: 
21 SEP 2023 
 

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Title Page 
Protocol Title: 
A randomized, parallel-group treatment, Phase 2, double-blind pilot study to investigate the 
efficacy and safety of elinzanetant compared with placebo for treatment of sleep disturbances 
associated with menopause. 
Protocol Number: 
22423 
Protocol Version:  
2.0 
Amendment Number: 
Amendment 1 
Compound Number: 
BAY 3427080 / elinzanetant 
Short Title:  
A pilot study to assess the effects of elinzanetant on sleep 
disturbances associated with menopause 
Study Phase: 
2 
Acronym: 
NIRVANA 
Sponsor Name and 
Legal Registered Address: 
Bayer Consumer Care AG, Peter-Merian-Strasse 84, 4052 Basel, Switzerland 
Regulatory Agency Identifier Number(s):  
EU-CT number: 
 
 
2023-504955-28-00 
Protocol Date: 
21 SEP 2023 
Name: 
Role: 
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request. 
Medical Monitor name and contact information will be provided separately. 
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 1 
2.0 
21 SEP 2023 
Version addressing FDA 
comments dated 
17 AUG 2023. 
Clinical Study Protocol 
1.0 
13 JUN 2023 
Initial version. 
 
Protocol Amendment Summary of Changes Table 
Amendment 1 (21 SEP 2023) 
This amendment/modification is considered to be substantial based on the relevant criteria of 
the European Union clinical trial legislation. 
Overall Rationale for the Amendment: 
The changes address comments from FDA.  

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Key changes 
Section #  
and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
Criteria 
Inclusion criterion 2 was changed to only 
include women who are in post-menopausal 
period AND hysterectomized. 
To address comments 
from FDA. 
Section 5.1 Inclusion 
Criteria 
Criterion 12 was added:  
Normal breast cancer screening result 
available prior to start of treatment in line with 
the method and frequency recommended in 
the respective country. The time elapsed 
since the last screening examination should 
be sufficiently short that no further routine 
screening examination needs to be 
scheduled during the course of the study. 
To address a comment 
from FDA. 
Section 5.1 Inclusion 
Criteria 
Criterion 13 was added: 
In individuals with a cervix: normal cervical 
cancer screening result available prior to start 
of treatment in line with the method and 
frequency recommended in the respective 
country. The time elapsed since the last 
screening examination should be sufficiently 
short that no further routine screening 
examination needs to be scheduled during 
the course of the study. 
To address a comment 
from FDA. 
Section 5.2 Exclusion 
Criteria 
Criterion 21 was added: 
Current diagnosis of the following pre-
malignant conditions: cervical dysplasia; 
breast atypia including atypical ductal 
hyperplasia, atypical lobular hyperplasia, 
lobular carcinoma in situ; cirrhosis of the 
liver; and nodular hepatic lesions. 
To address a comment 
from FDA. 
Section 8 Study 
Assessments and 
Procedures 
A bullet was added: 
If cervical cancer screening or breast cancer 
screening results are not available at the time 
of signing of ICF, they can be performed 
locally. 
Changed to match the 
updated inclusion 
criteria. 
Section 8.3.4 
Pregnancy Testing 
Pregnancy testing is not performed in 
participants who have undergone 
hysterectomy AND bilateral oophorectomy. 
Changed to match the 
updated inclusion 
criteria. 
Section 8.4.6 Adverse 
Events of Special 
Interest 
Wording related to post-menopausal bleeding 
was adjusted. 
Changed to match the 
updated inclusion 
criteria. 
Section 10.5.3 Follow-
up assessments 
Wording related to pregnancy as a reason for 
elevated AP levels was removed. 
Changed to match the 
updated inclusion 
criteria. 
Section 10.7 Washout 
periods for hormonal 
therapies and 
prohibited concomitant 
medications 
Intrauterine progestin therapy was removed 
from the washout period table. 
Changed to match the 
updated inclusion 
criteria. 

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Administrative changes 
Section #  
and Name 
Description of Change 
Title page  
Amendment details have been added to the title page 
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 
List of Abbreviations and Definitions of Terms ................................................................ 9 
1. 
Protocol Summary ...................................................................................................... 11 
1.1 
Synopsis ..................................................................................................................... 11 
1.2 
Schema ....................................................................................................................... 13 
1.3 
Schedule of Activities (SoA) ..................................................................................... 14 
2. 
Introduction ................................................................................................................. 16 
2.1 
Study Rationale .......................................................................................................... 16 
2.2 
Background ................................................................................................................ 16 
2.3 
Benefit/Risk Assessment ........................................................................................... 17 
2.3.1 
Risk Assessment ..................................................................................................... 17 
2.3.2 
Benefit Assessment ................................................................................................ 20 
2.3.3 
Overall Benefit: Risk Conclusion ........................................................................... 20 
3. 
Objectives, Endpoints, and Estimands ...................................................................... 20 
4. 
Study Design ................................................................................................................ 22 
4.1 
Overall Design ........................................................................................................... 22 
4.2 
Scientific Rationale for Study Design ....................................................................... 23 
4.3 
Justification for Dose ................................................................................................. 24 
4.4 
End-of-Study Definition ............................................................................................ 24 
5. 
Study Population ......................................................................................................... 24 
5.1 
Inclusion Criteria ....................................................................................................... 24 
5.2 
Exclusion Criteria ...................................................................................................... 26 
5.3 
Lifestyle Considerations ............................................................................................ 27 
5.3.1 
Meals and Dietary Restrictions .............................................................................. 27 
5.4 
Screen Failures ........................................................................................................... 27 
5.5 
Criteria for Temporarily Delaying Randomization ................................................... 28 
6. 
Study Intervention(s) and Concomitant Therapy .................................................... 28 
6.1 
Study Intervention(s) Administered ........................................................................... 29 
6.1.1 
Medical Devices ..................................................................................................... 29 
6.2 
Preparation, Handling, Storage, and Accountability ................................................. 29 
6.3 
Assignment to Study Intervention ............................................................................. 30 
6.4 
Blinding ..................................................................................................................... 30 
6.5 
Study Intervention Compliance ................................................................................. 31 
6.6 
Dose Modification ..................................................................................................... 31 
6.7 
Continued Access to Study Intervention after the End of the Study ......................... 31 
6.8 
Treatment of Overdose .............................................................................................. 32 
6.9 
Prior and Concomitant Therapy ................................................................................. 32 

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6.9.1 
Prohibited concomitant medications ...................................................................... 32 
6.9.2 
Other Treatment Considerations ............................................................................. 33 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...................................................................................... 33 
7.1 
Discontinuation of Study Intervention ....................................................................... 33 
7.1.1 
Liver Chemistry Stopping Criteria ......................................................................... 33 
7.1.2 
Platelet count Stopping Criteria .............................................................................. 34 
7.1.3 
Temporary Discontinuation .................................................................................... 34 
7.1.4 
Rechallenge ............................................................................................................ 34 
7.1.4.1 
Study Intervention Restart After Liver Stopping Criteria Are Met .................... 34 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 34 
7.3 
Lost to Follow Up ...................................................................................................... 35 
8. 
Study Assessments and Procedures ........................................................................... 35 
8.1 
Administrative and Baseline Procedures ................................................................... 36 
8.2 
Efficacy Assessments ................................................................................................ 36 
8.2.1 
Measures to Evaluate Sleep Quality Using a Device ............................................. 36 
8.2.1.1 
Polysomnography (PSG) ..................................................................................... 36 
8.2.1.2 
Sleepiz One+ ....................................................................................................... 37 
8.2.2 
Electronic Patient-Reported Outcomes (ePROs) .................................................... 37 
8.2.2.1 
Sleep Diary (SD) ................................................................................................. 39 
8.2.2.2 
Hot Flash Daily Diary (HFDD) ........................................................................... 40 
8.2.2.3 
Patient-reported Outcomes Measurement Information System Sleep Disturbance 
Short Form 8b (PROMIS SF 8b)......................................................................... 40 
8.2.2.4 
Insomnia Severity Index (ISI) ............................................................................. 40 
8.2.2.5 
Patient Global Impression of Severity (PGI-S) and Change (PGI-C) ................. 41 
8.2.2.6 
Generalized Anxiety Disorder-7 (GAD-7) .......................................................... 41 
8.3 
Safety Assessments .................................................................................................... 41 
8.3.1 
Physical Examinations ............................................................................................ 41 
8.3.2 
Vital Signs .............................................................................................................. 42 
8.3.3 
Clinical Safety Laboratory Tests ............................................................................ 42 
8.3.4 
Pregnancy Testing .................................................................................................. 42 
8.3.5 
Suicidal Ideation and Behavior: Electronic Columbia-Suicide Severity Rating 
Scale (eC-SSRS) ..................................................................................................... 43 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting
 ................................................................................................................................... 43 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information................... 43 
8.4.2 
Method of Detecting AEs and SAEs ...................................................................... 44 
8.4.3 
Follow-up of AEs and SAEs .................................................................................. 44 
8.4.4 
Regulatory Reporting Requirements for SAEs ...................................................... 44 
8.4.5 
Pregnancy ............................................................................................................... 44 
8.4.6 
Adverse Events of Special Interest ......................................................................... 45 
8.4.7 
Medical Device Deficiencies .................................................................................. 45 
8.5 
Pharmacokinetics ....................................................................................................... 46 
8.6 
Pharmacodynamics .................................................................................................... 47 
8.7 
Genetics ..................................................................................................................... 47 
8.8 
Biomarkers ................................................................................................................. 47 
8.9 
Immunogenicity Assessments .................................................................................... 47 
8.10 Medical Resource Utilization and Health Economics ............................................... 47 

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9. 
Statistical Considerations ........................................................................................... 47 
9.1 
Statistical Hypothesis ................................................................................................. 48 
9.2 
Analysis Sets .............................................................................................................. 48 
9.3 
Statistical Analyses .................................................................................................... 48 
9.3.1 
General Considerations........................................................................................... 48 
9.3.2 
Primary Endpoint/Estimand Analysis .................................................................... 49 
9.3.2.1 
Definition of Endpoint ........................................................................................ 49 
9.3.2.2 
Main Analytical Approach .................................................................................. 49 
9.3.2.3 
Sensitivity Analyses ............................................................................................ 49 
9.3.2.4 
Supplementary Analyses ..................................................................................... 49 
9.3.3 
Secondary Endpoints/Estimands Analysis ............................................................. 50 
9.3.4 
Exploratory Endpoint(s) Analysis .......................................................................... 51 
9.3.5 
Safety Analysis ....................................................................................................... 51 
9.3.6 
Other Analysis ........................................................................................................ 51 
9.4 
Interim Analysis ......................................................................................................... 51 
9.5 
Sample Size Determination ....................................................................................... 51 
10. Supporting Documentation and Operational Considerations ................................ 51 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 51 
10.1.1 Regulatory and Ethical Considerations .................................................................. 51 
10.1.2 Financial Disclosure ............................................................................................... 52 
10.1.3 Informed Consent Process ...................................................................................... 52 
10.1.4 Recruitment Strategy .............................................................................................. 53 
10.1.5 Data Protection ....................................................................................................... 53 
10.1.6 Dissemination of Clinical Study Data .................................................................... 53 
10.1.7 Data Quality Assurance .......................................................................................... 54 
10.1.8 Source Documents .................................................................................................. 54 
10.1.9 Study and Site Start and Closure ............................................................................ 55 
10.1.10 Publication Policy ................................................................................................... 55 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 56 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 57 
10.3.1 Definition of AE ..................................................................................................... 57 
10.3.2 Definition of SAE ................................................................................................... 58 
10.3.3 Recording and Follow-Up of AE and/or SAE ........................................................ 59 
10.3.4 Reporting of SAEs .................................................................................................. 61 
10.4 Appendix 4: Collection of Pregnancy Information .................................................... 62 
10.5 Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ............. 62 
10.5.1 Thresholds for liver chemistry ................................................................................ 62 
10.5.2 Immediate actions ................................................................................................... 63 
10.5.3 Follow-up assessments ........................................................................................... 66 
10.6 Appendix 6: Medical Device AE, SAE, and Device Deficiencies: Definitions ........ 66 
10.6.1 Definition of Medical Device AE ........................................................................... 67 
10.6.2 Definition of Medical Device SAE ........................................................................ 67 
10.6.3 Definition of Device Deficiency............................................................................. 67 
10.7 Appendix 7: Washout periods for hormonal therapies and prohibited concomitant 
medications ................................................................................................................ 67 
10.8 Appendix 8: Country/region-specific Requirements ................................................. 71 
10.9 Appendix 9: Protocol Amendment History ............................................................... 72 

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10.9.1 Amendment 1 (21 SEP 2023) ................................................................................. 72 
11. References .................................................................................................................... 72 
 
 
Table of Tables 
Table 1-1: Primary Estimand: ICEs and Strategies to Address Them ..................................... 12 
Table 1-2: Schedule of Activities ............................................................................................. 14 
Table 2-1: Risk assessment ...................................................................................................... 17 
Table 3-1: Objectives and endpoints ........................................................................................ 21 
Table 3-2: Primary Estimand: ICEs and Strategies to Address Them ..................................... 22 
Table 6-1: Study Interventions ................................................................................................. 29 
Table 10-1: Clinical laboratory tests ........................................................................................ 57 
Table 10-2: Laboratory tests for close liver observation .......................................................... 65 
Table 10-3: Washout periods for hormonal therapies. ............................................................. 68 
Table 10-4: Prohibited concomitant medication potentially confounding efficacy. ................ 69 
Table 10-5: Medication with limited use during the study ...................................................... 70 
Table 10-6: Prohibited concomitant medication potentially affecting PK. .............................. 70 
Table 10-7: Examples of clinical inhibitors for CYP3A4 ........................................................ 71 
Table 10-8: Examples of clinical inducers for CYP3A4 .......................................................... 71 
 
 
Table of Figures 
Figure 1–1: Study Schema ....................................................................................................... 13 
 
 
 

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List of Abbreviations and Definitions of Terms 
Abbreviations: 
AE(s) 
Adverse event(s) 
AESI 
Adverse event of special interest 
AHI 
Apnea hypopnea index / Respiratory Irregularity Index (for Sleepiz One+) 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BCRP 
Breast Cancer Resistance Protein 
BL 
Baseline 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CIOMS 
The Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case report form 
CT 
Computed tomography 
CTIS 
EU Clinical Trials Information System 
CYP3A4 
Cytochrome P450 isoenzyme 3A4 
ECG 
Electrocardiogram 
eCOA(s) 
Electronic clinical outcome assessments 
eCRF(s) 
Electronic case report form(s) 
eC-SSRS 
Electronic Columbia-Suicide Severity Rating Scale 
eDiary 
Electonic diary 
EMA 
European Medicines Agency 
EoT 
End of treatment 
ePRO(s) 
Electronic patient-reported outcome(s) 
ERCP 
Endoscopic retrograde cholangiopancreatography 
EU 
European Union 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GAD-7 
General Anxiety Disorder-7 
GCP 
Good clinical practice 
GGT 
Gamma glutamyl transferase 
Hbs-antigen 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus 
HF(s) 
Hot flash(es) 
HFDD 
Hot Flash Daily Diary 
HT 
Hormone therapy 
IB 
Investigator brochure 
ICE(s) 
Intercurrent event(s) 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
(I)EC 
(Independent) ethics committee 
IMM 
IRT and Medication Manager 
INR 
International normalized ratio 
IP 
In person 
IRB 
Institutional review board 
IRT 
Interactive Response Technology 
ISI 
Insomnia Severity Index 
ISO 
International Organization for Standardization 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LPS 
Latency to persistent Sleep – the number of minutes from lights off to the first 
10 consecutive minutes of non-wakefulness) 

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MDR 
Medical Device Regulation 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mmHg 
Millimeter of mercury 
MMRM 
Mixed model with repeated measures 
MRI 
Magnetic resonance imaging 
MRCP 
Magnetic resonance cholangiopancreatography 
N/A 
Not applicable 
NK / NK-1 / NK-3 
Neurokinin / neurokinin 1 / neurokinin 3 
NOAC 
New oral anticoagulants 
OATP 
Organic-anion-transporting polypeptide 
PD 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PLMAI 
Periodic Limb Movement disorders with Arousal Index 
PopPK 
Population pharmacokinetics 
PROMIS SD SF 
8b 
Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short 
Form 8b 
PSG 
Polysomnography 
PT 
Prothrombin time 
QTL(s) 
Quality tolerance limit(s) 
RNA 
Ribonucleic acid 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus -2 
SAS 
Statistical analysis software 
SCR-1/ SCR-2,  
Screening Visit 1 / screening Visit 2 
SD 
Sleep Diary 
SDLL 
Source Data Location List 
SE 
Sleep Efficiency – ratio between the total time a participant is asleep (TST) to the total 
time spent in bed. Presented as a percentage 
SoA 
Schedule of activities 
SUSAR 
Suspected unexpected serious adverse reaction(s) 
T1/T2/T3 
Treatment Visit 1/ Treatment Visit 2/ Treatment Visit 3 
TBL 
Total bilirubin 
TEAE(s) 
Treatment-emergent adverse event(s) 
TMF 
Trial master file 
TST 
Total Sleep Time – total number of minutes the participant is asleep 
ULN 
Upper limit of normal 
US 
United States 
VMS 
Vasomotor symptoms 
WASO 
Wakefulness after sleep onset – total number of minutes that a participant is awake after 
having initially fallen asleep 
WOCBP 
Woman of childbearing potential 
Definition of terms: 
Throughout this document, terms “study intervention”, “study medication” and “study 
treatment” are used interchangeably. 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
A randomized, parallel-group treatment, Phase 2, double-blind pilot 
study to investigate the efficacy and safety of elinzanetant compared 
with placebo for treatment of sleep disturbances associated with 
menopause.  
Short Title: 
A pilot study to assess the effects of elinzanetant on sleep disturbances 
associated with menopause. 
 
Regulatory Agency Identifier Number(s): 
EU-CT number: 
 
2023-504955-28-00 
 
Envisaged indication: Sleep disturbances associated with menopause 
 
Rationale: 
This is a Phase 2 study to assess the efficacy and safety of elinzanetant 
for the treatment of sleep disturbances related to menopause. 
 
Objectives, Endpoints and Estimands: 
Objectives 
Endpoints  
Primary 
• 
To explore the efficacy of elinzanetant 
on sleep disturbances associated with 
menopause as determined by PSG 
Primary endpoint 
• 
Change from baseline in WASO at 
Week 4 as measured by PSG 
Secondary endpoints 
• 
Change from baseline in WASO at 
Week 12 as measured by PSG 
• 
Change from baseline in SE at Week 4 
as measured by PSG 
• 
Change from baseline in SE at 
Week 12 as measured by PSG 
Secondary 
• 
To explore the efficacy of elinzanetant 
on sleep disturbance associated with 
menopause as determined by patient-
reported outcomes 
 
• 
Change from baseline in PROMIS SD 
SF 8b total score at Week 4 
• 
Change from baseline in PROMIS SD 
SF 8b total score at Week 12 
• 
Change from baseline in ISI total score 
at Week 4 
• 
Change from baseline in ISI total score 
at Week 12 
• 
To evaluate the safety of elinzanetant 
for the treatment of sleep disturbances 
associated with menopause 
• 
TEAEs 
• 
Abnormal laboratory parameters 
The full list of exploratory endpoints will be presented in the SAP. 
ISI = Insomnia Severity Index, PROMIS SD SF 8b = Patient-Reported Outcomes Measurement  
Information System Sleep Disturbance Short Form 8b, PSG = Polysomnography, SAP = statistical  
analysis plan, SE = Sleep Efficiency, TEAE = Treatment-emergent adverse event,  
WASO = Wakefulness after sleep onset. 

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Estimands 
The primary clinical question of interest for the primary objective is: 
What is the difference in mean change from baseline in WASO as measured by PSG at 
Week 4 comparing elinzanetant to placebo in women with sleep disturbances associated with 
menopause assuming no study treatment interruption and discontinuation and no use of 
prohibited concomitant medications impacting sleep?  
The attributes of the main estimand for the primary endpoint are as follows: 
• Population: Women aged 40–65 with sleep disturbance associated with the 
menopause, further defined by the key inclusion/exclusion criteria. 
• Variable: Change from baseline in WASO measured by PSG at Week 4. 
• Treatment: Elinzanetant 120 mg or placebo. 
• ICEs and strategies: Important ICEs to consider are listed in Table 1–1. 
 
Table 1–1: Primary Estimand: ICEs and Strategies to Address Them 
ICEs 
Proposed 
Strategy 
Data Handling Method 
Interpretation 
Temporary study 
treatment interruption 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants complied with 
treatment 
Premature 
discontinuation of study 
treatment 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants did not 
discontinue the randomized 
treatment 
Intake of prohibited 
concomitant medication 
having impact on 
efficacy 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants did not take 
prohibited concomitant 
medications impacting sleep 
ICE = Intercurrent event. 
• Population level summary: Mean change from baseline in WASO measured by PSG at 
Week 4 
 
Overall Design Synopsis: 
This is a multi-center, multi-country, double-blind, randomized, parallel-group, placebo-
controlled, pilot intervention study in women with sleep disturbances associated with 
menopause. 
Short Summary: 
The purpose of this study is to assess efficacy and safety of elinzanetant on sleep disturbances 
associated with menopause. Study details include: 
The study duration will be about 23 weeks (plus potential washout period). 
The treatment duration will be approximately 12 weeks.  

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The visit frequency will be once every 1–2 weeks during the screening period (depending 
on the scheduling of PSG) and once every 4–5 weeks during the intervention and 
follow-up periods. 
 
Number of Participants: 
Approximately 223 participants will be screened to achieve 78 participants to be randomized 
in a 1:1 ratio to investigational intervention. This will result in an estimated 70 participants 
(35 per study intervention) evaluable for the primary efficacy analysis. 
 
Study Arms and Duration: 
All participants will receive either 120 mg of elinzanetant or matching placebo orally once 
daily prior to going to sleep: 
• Elinzanetant 120 mg for 12 weeks 
• Placebo for 12 weeks 
Treatment may be prolonged by up to 1 week to allow for scheduling of the sleep laboratory 
assessment at EoT. 
 
Data Monitoring/Other Committee: 
No 
 
1.2 
Schema 
Figure 1–1: Study Schema 
 
ICF = signing of informed consent form. 
 

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1.3 
Schedule of Activities (SoA) 
SoA is presented in Table 1–2. 
Table 1–2: Schedule of Activities 
Period 
Screening period a 
Intervention period 
FU 
period 
Visit name 
SCR-1 
SCR-2 
BL 
T1 
T2 
T3/ 
EoT b,c 
FU 
In person (IP) or 
phone visit 
IP 
IP 
IP 
IP 
 
IP 
 
Visit week 
Please see footnote a 
4 
8 
12 
16 
Visit day 
-42 to 
 -24 a 
-10 a 
1 a 
29 
57 
85 
113 
Allowed window in 
days 
Please see footnote a 
+7 
+7 
+7 
+7 
Baseline characteristics 
Informed consent 
⚫ 
 
 
 
 
 
 
Demography 
⚫ 
 
 
 
 
 
 
Medical history 
(includes substance 
usage) 
⚫ 
 
 
 
 
 
 
Check for prohibited 
medication washout 
(Section 10.7) 
⚫ 
⚫ 
⚫ 
 
 
 
 
Screening and randomization 
Inclusion and 
exclusion criteria 
⚫ 
⚫ d 
⚫ 
 
 
 
 
IRT Screening  
⚫ 
 
 
 
 
 
 
IRT Screen fail (if 
applicable) 
⚫ 
⚫ 
⚫ e 
 
 
 
 
IRT Randomization 
 
 
⚫ 
 
 
 
 
Study medication and study exit 
Study medication 
dispensing/training 
 
 
⚫ 
 
 
 
 
Study medication 
 
 
Starts on Visit Day 1 evening 
-----------------------------------------------------> 
 
Study medication 
collection (if 
applicable) 
 
 
 
 
 
⚫ 
 
Study intervention 
compliance 
 
 
Starts after the first dose of study medication 
-----------------------------------------------------> 
 
IRT for EoT  
 
 
 
 
 
⚫ 
 
Participant feedback 
survey (optional) 
 
 
 
 
 
⚫ 
 
Safety / laboratory 
Complete physical 
examination including 
height and weight 
⚫ 
 
 
 
 
 
 
Vital signs 
⚫ 
 
 
⚫ 
 
⚫ 
 
Blood samples 
(safety)  
⚫ 
 
 
⚫ 
 
⚫ 
 
Urine pregnancy test 
(if applicable, 
Section 8.3.4) 
⚫ 
 
 
 
 
 
 
Urinalysis 
⚫ 
 
 
 
 
⚫ 
 
Blood sample (PK) 
 
 
 
⚫ f 
 
⚫ f 
 

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Table 1–2: Schedule of Activities 
Period 
Screening period a 
Intervention period 
FU 
period 
Visit name 
SCR-1 
SCR-2 
BL 
T1 
T2 
T3/ 
EoT b,c 
FU 
In person (IP) or 
phone visit 
IP 
IP 
IP 
IP 
 
IP 
 
Visit week 
Please see footnote a 
4 
8 
12 
16 
Visit day 
-42 to 
 -24 a 
-10 a 
1 a 
29 
57 
85 
113 
Allowed window in 
days 
Please see footnote a 
+7 
+7 
+7 
+7 
Symptom-based 
physical examination 
 
 
 
⚫ 
 
⚫ 
 
AE (Section 8.4.1) 
Procedure-related 
AEs only 
Starts after the first dose of study medication 
-----------------------------------------------------------------> 
Prior and concomitant 
medication 
-------------------------------------------------------------------------------------> 
Digital health technology tools 
PSG g + Sleepiz 
One+ (2 consecutive 
nights) 
 
⚫ 
 
⚫ 
 
⚫ 
 
Sleepiz One+ device 
dispensation and 
training 
 
⚫ 
 
 
 
 
 
Sleepiz One+ (at 
home) 
 
-------------------------------------------------------------> 
 
Sleepiz One+ device 
collection 
 
 
 
 
 
⚫ 
 
eDiary and eCOA instruments 
Dispensation and 
training of 
participant’s handheld 
device 
⚫ 
 
 
 
 
 
 
eC-SSRS 
⚫ 
 
 
⚫ 
 
⚫ 
 
SD (daily) 
---------------------------------------------------------> 
 
HFDD (twice daily) 
---------------------------------------------------------> 
 
PROMIS SD SF 8b h  
⚫ 
 
------------------------------------------> 
 
ISI 
⚫ 
 
⚫ 
⚫ 
 
⚫ 
 
GAD-7 
 
 
⚫ 
⚫ 
 
⚫ 
 
PGI-S i 
 
---------------------------------------------------------------> 
 
PGI-C j 
 
 
Starts 1 weeks after BL 
---------------------------------------------------> 
 
Study medication 
intake documentation 
 
 
Starts after the first dose of study medication 
-----------------------------------------> 
 
Collection of 
handheld device 
 
 
 
 
 
⚫ 
 
AE = adverse event, BL = baseline, eCOA = Electronic clinical outcome assessments, EoT = End of  
Treatment, ePRO = Electronic patient-reported outcome, FU = follow-up, IP = In person,  
IRT = Interactive response technology, PK = pharmacokinetics, PSG = polysomnography,  
SCR = screening, SoA = Schedule of activities, T = treatment. 
Questionnaires: eC-SSRS = Electronic Columbia-Suicide Severity Rating Scale, GAD-7 =  
Generalized Anxiety Disorder Scale -7, HFDD = Hot Flash Daily Diary, ISI = Insomnia Severity Index,  
PGI-C = Patient Global Impression of Change, PGI-S = Patient Global Impression of Severity, 
PROMIS SD SF 8b = Patient-reported Outcomes Measurement Information System Sleep  
Disturbance Short Form 8b, SD = Sleep Diary.  

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a All screening evaluations should typically be completed within 4–6 weeks with at least 14 days 
between SCR-1 and SCR-2 and at least 7 days at home after SCR-2 and before BL. The time 
required for scheduling for PSG and central reading of PSG needs to be considered for visit planning. 
b All EoT assessments (except for the safety and PK sample) are performed in the morning after the 
second night in the PSG lab. 
c If a participant discontinues prematurely from treatment, an EoT visit will be performed as soon as 
possible; it will comprise all assessments scheduled for the EoT visit. The EoT visit will be followed 
after 4 weeks by the FU visit. The handheld device will be collected at the last scheduled IP visit. 
d Eligibility check on inclusion criterion 3 (HFDD) should be assessed prior to PSG. 
e Including consultation about results obtained from screening procedures. 
f PK sample is collected on the second day in the PSG lab together with the safety lab sample. 
g All PSGs scheduled for T1 and T3 need to be performed under treatment, i.e., the second PSG 
night at EoT needs to be performed at the latest during the night after the last capsule has been taken. 
h The PROMIS SD SF 8b will be collected at SCR-1 and weekly from BL until EoT. 
i The PGI-S will be collected weekly from SCR-2 until EoT. 
j The PGI-C will be collected weekly following the PGI-S from 1 week after BL until EoT. 
 
2. 
Introduction 
2.1 
Study Rationale 
This is a Phase 2 study to assess the efficacy and safety of elinzanetant for the treatment of 
sleep disturbances related to menopause. 
2.2 
Background 
Menopause is a stage of natural aging that marks the end of a woman’s reproductive period 
and is characterized by various physiological changes. Among menopausal symptoms, sleep 
disturbances are one of the most debilitating symptoms that occur during menopause. 
Nighttime awakenings due to vasomotor symptoms (also known as night-sweats or hot 
flashes) are one instigator of sleep disturbances, however sleep disturbances associated with 
menopause are not completely explained by nocturnal vasomotor symptoms and likely has a 
multifactorial basis (Baker et al. 2018a, Woods et al. 2016). The effect of hormone treatment 
on sleep disturbances in this group of women is small (Guthrie et al. 2018) indicating that 
additional biological mechanisms beyond reduced estrogen receptor signaling and nighttime 
awakening due to VMS may contribute to sleep disturbances during the menopausal period.  
Clinical studies using objective measurement methods have identified increases in night time 
awakenings and WASO as key aspects of sleep disturbance in peri-/postmenopausal women, 
but have not found differences in total sleep time or hyperarousal compared with younger 
women (Baker et al. 2018b, Coborn et al. 2022, Pengo et al. 2018).  
A small double-blind, randomized cross-over study in healthy male volunteers confirmed the 
involvement of Substance P in sleep disturbances. After intravenous infusion of Substance P 
both polysomnography and subjective rating scales indicated a significant decrease of sleep 
quantity and quality (Lieb et al. 2002). Antagonizing Substance P activity with a NK-1 
receptor antagonist is therefore expected to show an improvement in sleep. A much larger 
study has shown that vestipitant, a NK-1 receptor antagonist improves WASO in 161 male 
and female patients with primary insomnia (Ratti et al. 2013).  
There are currently no approved treatments that are specifically targeted towards sleep 
disturbances associated with menopause. The current clinical practice guidelines recommend 
cognitive behavioral therapy for insomnia (CBT-I), HT, antidepressants, or sleep medications 
(Riemann et al. 2017, Sateia et al. 2017, Silvestri et al. 2019).  

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Elinzanetant (formerly NT-8141) is a dual neurokinin (NK)-1,3 receptor antagonist and is in 
development for the treatment of moderate to severe vasomotor symptoms. SWITCH-1 (814-
PM-02), a Phase 2b study, showed statistically significant and clinically meaningful 
improvements on elinzanetant 120 mg and 160 mg once daily compared to placebo in global 
Pittsburgh Sleep Quality Index (PSQI) and total ISI (Simon et al. 2023).  
If benefits of elinzanetant on sleep are confirmed in further studies, it is anticipated that 
elinzanetant will be a relevant improvement for women with sleep disturbances associated 
with menopause.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of elinzanetant is 
provided in the IB.   
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 
contraction 
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 160 mg. 
Both were assessed as related 
to the study intervention by the 
investigator. Clinical data 
Continuous AE monitoring 
                                                 
1 The compound was initially developed by GSK, then NeRRe Therapeutics Ltd. on behalf of KaNDy 
Therapeutics Ltd. On 08 SEP 2020 Bayer AG acquired KaNDy Therapeutics Ltd. and continues development of 
elinzanetant. 

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Table 2–1: Risk assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
originated from ongoing 
(blinded) Phase 3 studies did 
not reveal any new or relevant 
safety concern. 
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. 
Clinical data originated from 
Phase 2 and ongoing (blinded) 
Phase 3 studies did not reveal 
any new or relevant safety 
concern. 
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. 
Phototoxicity 
Preclinical safety finding. The 
in vitro 3T3 Neutral Red Uptake 
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. Clinical data 
originated from ongoing 
(blinded) Phase 3 studies did 
not reveal any new or relevant 
safety concern. 
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 Phase 1 
study (814-1- 05) who was 
found to have increased 
transaminases. The participant 
had abnormal GGT at 
screening and fatty liver. 
Defined exclusion criteria. 
Regular monitoring of liver 
parameters during the study.  
Defined strategy for close 
observation and defined 
stopping criteria for participants 
with increased liver parameters 
during the study. 

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Table 2–1: Risk assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Clinical data originated from 
ongoing (blinded) Phase 3 
studies did not reveal any new 
or relevant safety concern. 
Arrhythmias 
A possible signal with respect 
to an increased incidence of 
arrhythmias was identified in 
Phase 1 studies in healthy 
male volunteers but has not 
been substantiated in 
subsequent studies. Clinical 
data originated from ongoing 
(blinded) Phase 3 studies did 
not reveal any new or relevant 
safety concern. 
Continuous AE monitoring. 
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. 
Elinzanetant reduced plasma 
estradiol, progesterone and 
luteinizing hormone in 
premenopausal females. These 
effects were correlated in one 
of the studies with delayed or 
irregular menses. 
Defined inclusion criterion 
negative urine pregnancy test 
at screening. Women going 
through the menopausal period 
have a low chance of getting 
pregnant, therefore participants 
are informed of the effects on 
reproductive function. 

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Table 2–1: Risk assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Procedures 
No relevant risks are expected 
related to the study procedures 
All study procedures are 
routine medical procedures in 
this participant population. 
All study procedures will be 
conducted by appropriately 
trained staff. 
Other 
Non-effective treatment for 
participants who are 
randomized to placebo. 
Participants who are 
randomized to placebo will not 
receive active treatment for the 
total duration of the study. 
Participants are not expected 
to suffer undue medical 
consequences from absence of 
treatment. 
AE = Adverse event, AST = Aspartate aminotransferase, CK = Creatine kinase, CYP3A4 = Cytochrome 
P450 isoenzyme 3A4, GGT = Gamma glutamyl transferase, LDH = Lactate dehydrogenase. 
 
2.3.2 
Benefit Assessment 
There are currently no approved treatments that are specifically targeted towards sleep 
disturbances associated with menopause although sleep disturbances are one of the most 
common and debilitating symptoms experienced by women in the menopausal period. The 
dual mechanism of elinzanetant acting congruently on the 2 main symptoms of menopause, 
VMS and sleep disturbances can be a significant addition to the treatment options available to 
healthcare professionals and patients. 
Based on the mode of action, preclinical, and clinical data it is expected that treatment with 
elinzanetant will provide relevant clinical benefits to menopausal women with sleep 
disturbances. These benefits may include, but are not limited to:  
Reduction of wakefulness after sleep onset  
Improvements in sleep efficiency  
Improvements in sleep quality 
Participants who are randomized to placebo are still expected to have some benefit from 
participation in the study as they will receive a thorough medical evaluation.  
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 sleep disturbances associated with 
menopause. 
3. 
Objectives, Endpoints, and Estimands 
Objectives and endpoints are listed in Table 3–1. 

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Table 3–1: Objectives and endpoints 
Objectives 
Endpoints  
Primary 
• 
To explore the efficacy of elinzanetant 
on sleep disturbances associated with 
menopause as determined by PSG 
Primary endpoint 
• 
Change from baseline in WASO at 
Week 4 as measured by PSG 
Secondary endpoints 
• 
Change from baseline in WASO at 
Week 12 as measured by PSG 
• 
Change from baseline in SE at Week 4 
as measured by PSG 
• 
Change from baseline in SE at 
Week 12 as measured by PSG 
Secondary 
• 
To explore the efficacy of elinzanetant 
on sleep disturbance associated with 
menopause as determined by patient-
reported outcomes 
 
• 
Change from baseline in PROMIS SD 
SF 8b total score at Week 4 
• 
Change from baseline in PROMIS SD 
SF 8b total score at Week 12 
• 
Change from baseline in ISI total score 
at Week 4 
• 
Change from baseline in ISI total score 
at Week 12 
• 
To evaluate the safety of elinzanetant 
for the treatment of sleep disturbances 
associated with menopause 
• 
TEAEs 
• 
Abnormal laboratory parameters 
Exploratory 
• 
To explore the relationship between HF 
and sleep disturbances as determined 
by PSG 
• 
Frequency of HFs over time  
• 
WASO as measured by PSG over time 
• 
To explore the efficacy of elinzanetant 
on the frequency of anxiety symptoms 
• 
Change from baseline in GAD-7 total 
score over time 
• 
To evaluate the efficacy of 
elinzanetant on the PGI-S and PGI-C  
• 
Actual values of the PGI-C individual 
item scores over time 
• 
Change from baseline in PGI-S 
individual item scores over time 
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 the study 
intervention and similar compounds 
(e.g., mode-of-action-related effects, 
safety) and to further investigate 
pathomechanisms deemed relevant to 
sleep disturbances associated with 
menopause. 
• 
Various biomarkers (e.g., diagnostic, 
safety, pharmacodynamic, monitoring, 
or potentially predictive biomarkers) 
 
• 
To investigate the efficacy of 
elinzanetant on sleep disturbance 
associated with menopause 
determined by Sleepiz One+ 
• 
Parameters captured remotely and 
continuously at home by Sleepiz One+ 
including e.g. WASO, TST, SE 
The full list of exploratory endpoints will be presented in the SAP. 
GAD-7 = General Anxiety Disorder-7, HF = Hot Flash, ISI = Insomnia Severity Index, PGI-C = Patient  
Global Impression of Change, PGI-S = Patient Global Impression of Severity, PK = Pharmacokinetics,  
PROMIS SD SF 8b = Patient-Reported Outcomes Measurement Information System Sleep  
Disturbance Short Form 8b, PSG = Polysomnography, SAP = Statistical analysis plan, SE = Sleep  
Efficiency, TEAE = Treatment-emergent adverse event, TST = Total Sleep Time,  

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WASO = Wakefulness after sleep onset.  
 
Estimands 
The primary clinical question of interest for the primary objective is: 
What is the difference in mean change from baseline in WASO as measured by PSG at 
Week 4 comparing elinzanetant to placebo in women with sleep disturbances associated with 
menopause assuming no study treatment interruption and discontinuation and no use of 
prohibited concomitant medications impacting sleep?  
The attributes of the main estimand for the primary endpoint are as follows: 
• Population: Women aged 40–65 with sleep disturbance associated with the 
menopause, further defined by the key inclusion/exclusion criteria. 
• Variable: Change from baseline in WASO measured by PSG at Week 4. 
• Treatment: Elinzanetant 120 mg or placebo. 
• ICEs and strategies: Important ICEs to consider are listed in Table 3–2. 
 
Table 3–2: Primary Estimand: ICEs and Strategies to Address Them 
ICEs 
Proposed 
Strategy 
Data Handling Method 
Interpretation 
Temporary study 
treatment interruption 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants complied with 
treatment 
Premature 
discontinuation of study 
treatment 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants did not 
discontinue the randomized 
treatment 
Intake of prohibited 
concomitant medication 
having impact on 
efficacy 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants did not take 
prohibited concomitant 
medications impacting sleep 
ICE = Intercurrent event. 
• Population level summary: Mean change from baseline in WASO measured by PSG at 
Week 4. 
 
4. 
Study Design 
4.1 
Overall Design 
This is a multi-center, multi-country, double-blind, randomized, parallel-group, placebo-
controlled, pilot intervention study in women with sleep disturbances associated with the 
menopause. 

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Screening: After giving informed consent, participants will be withdrawn from prohibited 
concomitant medications (see Section 10.7) at SCR-1 visit if needed. Screening period 
consists of 3 visits. 
Randomization: At the end of the screening period (BL visit), the participants will be 
randomized into elinzanetant and placebo arms in a 1:1 ratio. Randomization will be stratified 
by the average weekly frequency of moderate to severe HFs (including night-time HFs) over 
the 14 days prior to the respective eligibility check (<35 moderate to severe HFs per week, 
≥35–<50 moderate to severe HFs per week, ≥50 moderate to severe HFs per week). 
Intervention period: Intervention period will last about 12 weeks: 
• 120 mg (2x 60 mg soft gel capsules) of elinzanetant or matching placebo orally once 
daily for 12 weeks 
Follow-up: The intervention period will be followed by a 4-week safety follow-up period. 
The study includes 3 stationary visits in a sleep laboratory. Each of these visits encompasses 
2 consecutive nights. This results in a total of 6 nights in the sleep laboratory. 
 
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. A meta-analysis on the effect of placebo on PSG parameters in participants with 
primary insomnia showed that a placebo response of up to 63% can be expected (Winkler and 
Rief 2015). Therefore, comparison to placebo is relevant to describe the true treatment effect 
of elinzanetant.  
Placebo is considered acceptable because sleep disturbances associated with menopause 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). 
A treatment duration of 12 weeks is considered adequate to describe the difference regarding 
the primary variable between active treatment and placebo (see Section 9 for details) and to 
obtain information on the maintenance of treatment and placebo effect. 
PSG is considered the current standard method to obtain objectively measured sleep related 
parameters. Therefore this method is used to assess the primary and several secondary 
endpoints. Use of the Sleepiz One+ home sleep monitor will be used to obtain continuous 
sleep related parameters throughout the entire observational period of the elinzanetant Phase 2 
study at home. For more information regarding Sleepiz One+ device please see Section 6.1.1 
and Section 8.2.1.2. 

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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 on VMS, sleep disturbances, safety and receptor 
pharmacology.  
The 120 mg once daily dose was effective on a range of measures in the SWITCH-1 study 
that included post-menopausal women and was more effective in improving sleep quality than 
the 2 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 NK-1 receptors throughout a dose interval at steady state as demonstrated in a 
human PET study. Although it is not possible to assess NK-3 receptor occupancy directly, as 
a suitable NK-3 PET ligand does not exist, the achieved concentrations are also very likely to 
fully occupy central NK-3 receptors during the dose interval.  
This is the first study in the clinical development program that focuses primarily on sleep 
disturbances associated with menopause. The same product, same dose and dosing regimen 
that was assessed to be effective for the VMS indication in Phase 2 studies and is currently 
being tested in Phase 3 studies for the VMS indication will be used to assess safety and 
efficacy of elinzanetant for the treatment of sleep disturbances associated with menopause. 
The rationale for assessing the same dose for this second indication is based on the intention 
to achieve complete occupancy on both receptors and the observed effects on sleep 
parameters in SWITCH-1 which follow as similar dose response pattern as the effects on 
VMS.  
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 visit of the last participant in the study 
globally. 
The primary completion date is the date when the last participant completes Week 4 visit of 
the intervention period. 
A participant is considered to have completed the study if the participant has completed all 
periods 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. 

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Type of Participant and Disease Characteristics 
2. Being in the post-menopausal period, defined as: serum FSH levels >40 mIU/mL and 
a serum estradiol concentration of <30 pg/mL at screening,  
AND 
Hysterectomy performed at least 6 weeks prior to screening.  
3. Experiencing VMS associated with menopause, defined as:  
Participant has completed HFDD for at least 11 days during the 2 weeks prior to the 
respective eligibility check, and during this period participant has recorded a 
weekly average of at least 20 moderate or severe HF (including night-time HF). 
4. The participant’s self-reported sleep history includes ongoing sleep disturbances 
associated with menopause characterized by waking up at night and/or poor quality of 
sleep. 
5. The participant’s self-reported ongoing sleep disturbances cause distress or 
impairment in social, occupational, or other important areas of functioning.  
6. WASO of 30 minutes or more (mean of 2 screening PSGs with neither of the 2 nights 
<20 min). 
7. The participant’s self-reported time in bed between 6 and 9 hours. 
8. The participant’s self-reported bedtime is usually between 21.00 and 24.00 hours and 
it does not vary by more than ±2 hours. 
9. Negative urine pregnancy test at screening. 
10. BMI between 18 and 38 kg/m2 at screening. 
Informed Consent 
11. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
Additional criteria 
12. Normal breast cancer screening result available prior to start of treatment in line with 
the method and frequency recommended in the respective country. The time elapsed 
since the last screening examination should be sufficiently short that no further routine 
screening examination needs to be scheduled during the course of the study. 2 
13. In individuals with a cervix: normal cervical cancer screening result available prior to 
start of treatment in line with the method and frequency recommended in the 
respective country. The time elapsed since the last screening examination should be 
sufficiently short that no further routine screening examination needs to be scheduled 
during the course of the study.  
                                                 
2 E.g., for US: Normal breast cancer screening result must be documented no more than 9 months prior to start of 
treatment. 

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5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Medical history, or baseline PSG assessment, includes a diagnosis of a sleep disorder 
other than sleep disturbances associated with the menopause (e.g., sleep apnea, restless 
leg syndrome, circadian rhythm sleep disorder).3 
2. Clinically significant abnormalities that interfere with the study goals, in the opinion 
of the investigator, based on the medical history, physical examination, vital signs, 
clinical laboratory tests4, eC-SSRS, and other assessments completed during 
screening. 
3. Current or history (except complete remission for 5 years or more) of any malignancy 
(except basal and squamous cell skin tumors). 
4. Renal impairment greater than moderate (i.e. estimated glomerular filtration rate 
<30 mL/min/1.73 m2) at screening. 
5. Abnormal liver parameters (presence of at least one of the following criteria):  
• AST >2 x ULN 
• ALT >2 x ULN 
• AP >2 x ULN 
• TBL >ULN unless explained by Gilbert’s syndrome 
• INR >ULN unless explained by, e.g., intake of anticoagulants5 
• 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. 
Prior/Concomitant Therapy 
6. Has used and is unwilling to wash-out use of any of the prohibited concomitant 
medications, as specified in Sections 6.9 and 10.7. 
7. Inability to comply with the use of prohibited medications as described in 
Sections 6.9.1 and 10.7.  
8. Current cognitive behavioral therapy for sleep disorders. 
Prior/Concurrent Clinical Study Experience 
9. Concurrent (or within 2 months prior to signing of ICF) participation in a clinical 
study with an investigational medicinal product (including medical devices) with the 
exception for participants who completed another elinzanetant study. 
                                                 
3 Details are provided in the PSG manual. 
4 Single re-test allowed. 
5 Re-test of INR will be allowed once. 

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Other Exclusion Criteria 
10. Shift work within 2 weeks prior to the SCR-2 visit, or planned shift work during the 
study. 
11. AHI >15 on the first PSG screening night.  
12. PLMAI >15 on the first PSG screening night. 
13. Travel across ≥3 time zones within 2 weeks prior to the SCR-2 visit, or planned travel 
across ≥3 time zones during study. 
14. Regular napping i.e. >3 naps per week each with duration of >30 minutes. 
15. 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). 
16. Clinically relevant drug or alcohol abuse within 12 months of signing of informed 
consent. 
17. Use of substances that in the opinion of the investigator contribute to the participant’s 
sleep disturbances (e.g. caffeine, alcohol, cannabis and its derivatives).  
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 or ePRO completion. 
Additional criteria 
21. Current diagnosis of the following pre-malignant conditions: cervical dysplasia; breast 
atypia including atypical ductal hyperplasia, atypical lobular hyperplasia, lobular 
carcinoma in situ; cirrhosis of the liver; and nodular hepatic lesions.  
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
During their stay in the study center for the PSGs, participants may consume food and 
beverages provided or allowed by the study center. 
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 medication. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, date of informed consent, date of last visit, screen 
failure details, and eligibility criteria based on completed procedures. Screening PROs 
(PROMIS, ISI, HFDD and SD) and screening lab PSG data (if available) will also be 

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collected on screen failures to identify sleep PROs that predict sleep disturbances associated 
with the menopause. 
Re-screening is allowed only once. Re-screening can be performed in the following cases, 
whichever occurs first: 
• If the inclusion/exclusion criteria, including related footnotes, preventing 
participant’s initial attempt to participate have been changed via a protocol 
amendment, OR 
• In case of abnormal or implausible results, which may be caused by 
intercurrent diseases, short-term treatable conditions, other temporary health 
disorders (e.g. acute infection, laboratory changes), or circumstances affecting 
safety and/or efficacy evaluation (e.g. technical issues affecting central/local 
laboratory analyses or the assessment at the sleep laboratory) the investigator 
may decide to repeat the respective screening parameter(s). 
The investigator should ensure that the repeated screening procedures do not expose the 
participant to an unjustifiable health risk.  
For re-screening, the participant must sign a new ICF and 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 medication in a 
participant to a time when the condition has resolved.  
A delayed assessment or report of procedures required for assessment of eligibility 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. In case the screening period is extended to 
more than 8 weeks, a new blood sample has to be taken and urinalysis as well as a urine 
pregnancy test need to be performed for assessment of eligibility. 
6. 
Study Intervention(s) and Concomitant Therapy 
Study interventions are all pre-specified, investigational and non-investigational medicinal 
products, medical devices and other interventions (e.g., surgical and behavioral) intended to 
be administered to the study participants during the study conduct. 

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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 and the first 
dose should be taken at home in the evening on the same day. In general, study treatment will 
be taken once daily before going to sleep with or without food. 
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. 
6.1.1 
Medical Devices 
During the conduct of this study, the following medical devices will be provided. 
• No Sponsor-manufactured medical devices (or devices manufactured for the 
Sponsor by a third party) will be used in this study. 
• Medical devices supplied by the eCOA vendor, on behalf of the Sponsor, for use 
in this study are: 
a. Sleepiz One+ sleep monitor (also see Section 8.2.1.2) 
Sleepiz One+ is an FDA-listed class II medical device under 510k exempt and was EU MDR 
certified as a class IIa product. Instructions for medical device use and study-specific 
Handling Instruction are provided in the respective handling instructions and manuals 
provided separately.  
6.2 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate conditions (e.g. temperature) 
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, prepare or administer study intervention.  
3. 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. 

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4. 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, reconciliation and 
destruction return information will be captured in IRT. 
5. Further guidance and information for the final disposition of unused study 
interventions are provided in Investigator Site File. 
Local destruction (if any) of the study intervention 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 
Assignment to Study Intervention 
Participants who meet all eligibility criteria will be centrally assigned to randomized study 
intervention using IRT. Before the study is initiated, the log in information and directions for 
the IRT 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 in a 1:1 ratio to receive study intervention. The 
randomization will be stratified by the average weekly frequency of moderate to severe HFs 
(including night-time HFs) over the 14 days prior to the respective eligibility check (<35 
moderate to severe HFs per week, ≥35–<50 moderate to severe HFs per week, ≥50 moderate 
to severe HFs per week), to ensure a balanced distribution of baseline HF frequency across 
the treatment groups. There will not be any limitations to the size of the different groups.  
6.4 
Blinding 
This is a double-blind study in which participants and investigators are blinded to study 
intervention. Investigators will remain blinded to each participant’s assigned study 
intervention throughout the course of the study. In addition, the centralized reading of PSG-
data will also be blinded to study intervention. 
Unblinding 
The IRT 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. 

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In case of unblinding, only those individuals who are required to know treatment allocation 
may be given this information. All others must remain blinded to treatment, including the 
participant.  
Pharmacometrics staff may be unblinded according to Bayer standard operating procedures. 
Pharmacokinetic and exposure-response analysis might be performed using population 
approaches (popPK and popPK/PD, e.g., by non-linear mixed effect modeling). Analysis and 
report will be done under a separate cover. This evaluation might be started prior to database 
lock. If this is applicable, appropriate measures will be taken to maintain blinding of the study 
team, e.g., data will be stored separately, and members of the study team will neither have 
access to the randomization list nor to individual data. 
Sponsor global pharmacovigilance staff may unblind the intervention assignment for any 
participant with an SAE/SUSAR. If the SAE/SUSAR requires that an expedited regulatory 
report be sent to one or more regulatory agencies, a copy of the report, identifying the 
participant’s intervention assignment, may be sent to investigators in accordance with local 
regulations and/or Sponsor policy.  
6.5 
Study Intervention Compliance 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed by site/study personnel/staff at each visit. Compliance will be 
assessed by review of daily diary entries and confirmatory capsule counts during the site visits 
and documented in the source documents and relevant form by site. Deviation(s) from the 
prescribed dosage regimen should be recorded. 
A record of the number of capsules dispensed to and administered by each participant must be 
maintained and reconciled with study intervention and compliance records. An adequate 
record of receipt, distribution, and return/destruction of all study intervention must be 
captured on the dispensing log and/or in the IRT. If the participant is unable to continue 
taking the study intervention as required, she should contact the study site. 
Study intervention capsules not returned will be considered to have been taken unless 
otherwise specified. At the end of the study, any remaining capsules will be collected and 
returned to the Sponsor, destruction depot or destroyed at the site. Any discrepancies between 
the returned and expected returned study interventions should be explained. 
Study medication 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 medication intake 
documentation’ on the electronic handheld device during the treatment period as indicated in 
the SoA. 
6.6 
Dose Modification 
Not applicable, all participants receiving active treatment will stay on the same dose. 
6.7 
Continued Access to Study Intervention after the End of the Study 
No access to study intervention is planned after the end of the study. 

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6.8 
Treatment of Overdose 
For this study, any dose of elinzanetant greater than 240 mg within a 24-hour time period will 
be considered an overdose. 
There is no known specific treatment (no antidote) for an overdose with elinzanetant. An 
overdose should be treated as clinically indicated based on signs and symptoms.  
Overdose per se will not be reported as an AE and/or SAE unless it is associated with 
clinically relevant signs and/or symptoms, or an intentional overdose taken with possible 
suicidal and/or self-harming intent (see Sections 10.3.1 and 10.3.2). 
In the event of an overdose, the investigator should: 
• Contact the Sponsor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, 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. 
6.9 
Prior and Concomitant Therapy 
Any medications (including over-the-counter or prescription medicines, contrast media, 
vaccines), vitamins and/or herbal supplements that the participant receives during the study 
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. 
6.9.1 
Prohibited concomitant medications 
Section 10.7 presents a comprehensive (but not exhaustive) list of prohibited concomitant 
medications and washout periods (recently approved drugs may not be included in the list as 
well as the drugs used off-label for treatment of sleep disturbances and should be checked on 
a case-by-case basis). 
Prior use of sleep therapies within 3 months before SCR-2 visit should be recorded in the 
CRFs. The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 

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6.9.2 
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 the BCRP and OATP1B1/B3 substrate rosuvastatin showed no 
clinically relevant effect on the pharmacokinetics of rosuvastatin when administered together 
with elinzanetant. Therefore, medications that are substrates of BCRP and/or OATP1B1/1B3 
can be administered together with elinzanetant without restrictions. Results from a clinical 
drug-drug interaction study with the sensitive P-gp substrate dabigatran etexilate 
(Study 22081: Open-label, fixed sequence crossover study to determine the effects of a single 
dose of elinzanetant (BAY 3427080) on the pharmacokinetics of dabigatran etexilate in 
healthy participants) showed no clinically relevant interaction. Therefore, medications that are 
substrates of P-gp can be administered together with elinzanetant without restrictions. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1. 
7.1 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue study intervention. As a 
general rule, all procedures scheduled for the EoT 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. The EoT visit should be followed by FU visit as shown in the SoA. 
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 below 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. 
Based on potentially safety-relevant deviations of liver laboratory values, the action described 
below need to be taken. Monitoring and follow-up assessments are provided in Section 10.5. 
Discontinuation of study intervention 
Permanent discontinuation  
Permanent discontinuation of treatment should be considered if any of the following occurs: 

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• ALT or AST ≥3 x ULN  
and any of the following: 
− Total bilirubin (TBL) ≥2 x ULN 
− INR ≥1.5 
(Relevant only if the participant is not on vitamin K antagonists, new oral 
anticoagulants [NOACs] or heparin) 
− Appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain or 
tenderness, fever, rash and/or eosinophilia (>5%) 
• ALT or AST ≥5 x ULN for ≥2 weeks 
• ALT or AST ≥8 x ULN 
Participants permanently withdrawn from study intervention should be considered for 
withdrawal from study participation (see Section 7.2). 
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 intervention 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 2 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 After Liver Stopping Criteria Are Met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study are not allowed. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at the participant’s own 
request, for any reason (or without providing any reason).  

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• A participant 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. 
• A participant may be withdrawn from the study at the specific request of the Sponsor 
in liaison with the investigator (e.g., obvious non-compliance, safety concern). 
• At the time of discontinuing from the study, if possible, EoT visit procedures should 
be conducted, followed by FU visit as shown in the SoA and in particular described in 
footnote c) in Table 1–2. 
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 from the study intervention and 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 the participant 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, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether 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, the participant will be 
considered to have withdrawn from the study. 
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 

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• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within 
the timeframe defined in the SoA.  
• If cervical cancer screening or breast cancer screening results are not available at the 
time of signing of ICF, they can be performed locally. 
• In the event of a significant study-continuity issue (eg, 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.  
• 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. 
8.1 
Administrative and Baseline Procedures 
Baseline assessments are listed in the SoA (Section 1.3). 
8.2 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
Refer to Section 8.8 for biomarkers supporting assessment of efficacy. 
8.2.1 
Measures to Evaluate Sleep Quality Using a Device 
8.2.1.1 
Polysomnography (PSG) 
On-site PSG assessments (each including 2 consecutive nights) will be performed in qualified 
sleep laboratories by qualified staff at timepoints described in the SoA. 
Parameters derived from PSG will include but are not limited to: 
• WASO 
• Number of arousals and awakenings 
• LPS 
• TST 
• SE 
• Number of minutes and percentage of time in each hypnogram stage (W, R, N1, N2, 
N3) 
Additional details are provided in the PSG manual. 
PSG recordings will be sent for interpretation and scoring to a vendor, where an experienced 
team will perform blinded, centralized reading and scoring of PSG data. The Sponsor will be 

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provided with a relevant subset of the data. Centralized PSG interpretation will be governed 
by a vendor’s standard operating procedures (SOPs) charter established prior to study start. 
Participant eligibility will be based primarily on the PSG reading as assessed by centralized 
reading. In case PSG is not evaluable due to technical reasons it may be repeated after 
discussion with the Sponsor. Participant may fail screening after the first PSG night based on 
the local PSG assessment only, if AHI and/or PLMAI exclusion criteria is/are met. The PSG 
manual will be maintained at the site and instructions will be provided to sites in the Study 
Procedure Manual. 
8.2.1.2 
Sleepiz One+ 
At study sites in countries where the Sleepiz One+ system is approved for commercial use 
and at sites where the Sleepiz One+ system has been IRB/EC approved specifically for use in 
this clinical study, all participants will be invited to take part in continuous nighttime sleep 
monitoring. The sleep monitor uses radar principle based on radiofrequency scanning and 
reflection (in the mm-wavelength range) to collect physiologic data during sleep in a 
contactless manner. Participants who decline to use the sleep monitor may still be enrolled in 
the study. Data collected with the sleep monitor will not be available to sites or participants. 
Sites will receive information regarding test quality and participant adherence. 
Parameters derived from Sleepiz One+ will include but are not limited to: 
WASO 
LPS 
TST 
SE 
Total time in bed 
Wake up latency 
Wake up count 
Out of bed count 
AHI 
Pulse Rate (Mean, Max, Min, Upper Percentile, Lower Percentile) 
Breathing rate (Mean, Max, Min, Upper Percentile, Lower Percentile) 
The sleep monitor will be provided to the participants at SCR-2 visit. The sleep monitor will 
be used by the participant to continuously collect sleep data at home in addition to the nights 
of PSG assessment. A vendor will host and transmit data of the sleep monitoring device via 
their system. 
Participants will receive an instruction document to ensure correct setup and use of the sleep 
monitor at home. The sleep monitor user manual will be maintained at the site and 
instructions will be provided to sites in a Study Procedure Manual. 
8.2.2 
Electronic Patient-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 handheld 
device during the entire study duration both for entries at home (including days of the study 

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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. Participant data 
obtained via handheld or tablet devices will be managed by a vendor. 
ePROs collected on the participant’s handheld device 
The following ePROs will be collected on a handheld device in the following sequence in 
accordance with the assessment schedule: 
• SD 
• HFDD (morning diary) 
• PROMIS SD SF 8b 
• ISI 
• GAD-7 
• PGI-S 
• PGI-C 
• HFDD (evening diary) 
• Study medication intake documentation (See Section 6.5) 
ePROs collected on a tablet computer at the study sites 
The following PROs will be collected on a tablet computer: 
• eC-SSRS (See Section 8.3.5) 
Time for completion 
Time for completion of each item of the different PROs is conservatively estimated to be 
30 seconds per individual item. The daily completion time therefore ranges from 6 min when 
only the SD and the HFDD will be completed to a maximum of 30 min on the days of the 
study visits when most questionnaires are to be completed.  
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 handheld 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 handheld 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 handheld device will be transmitted automatically by 
wireless connection to the electronic diary provider’s database and 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. 

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Training of participants 
During screening, participants will be trained on the use of the handheld 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 handheld 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. 
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 handheld 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 
Investigator Site File. The study site staff will provide a standardized technical training on the 
handling of the participant handheld device and the tablet computer to the participants during 
SCR-1, 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’ handheld device entries 
In case one entry on the HFDD, the SD or the study medication intake documentation was 
missed (for HFDD morning diaries and SD in case this was not completed when getting up in 
the morning; for HFDD evening diaries, and the study medication intake documentation in 
case this was not completed in the evening when going to bed), retrospective data entry is 
possible for a pre-defined period of time (provided separately). 
When the study site becomes aware of missing participant handheld 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 handheld 
device entries, at all the study visits following SCR-2, the participant handheld device entries 
will be checked, and the checks documented by the study site personnel for completeness. 
8.2.2.1 
Sleep Diary (SD) 
Participants’ assessments of sleep disturbances will be recorded electronically daily using the 
Sponsor developed SD. The SD will be completed in the morning after waking up (morning 

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diary) on the handheld device from visit SCR-1 until EoT as reflected in the SoA. The SD 
items assess the total sleep time duration by asking for time going to bed, falling asleep and 
waking up, as well as time spend in bed, number and the duration of awakenings during the 
night. 
8.2.2.2 
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 handheld device from visit SCR-1 
until EoT as reflected in the SoA. The HFDD items assess the number of mild, moderate, and 
severe HF experienced during the day and during the night and the severity of sleep 
disturbances due to HFs experienced during the night.  
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”.  
8.2.2.3 
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. 
8.2.2.4 
Insomnia Severity Index (ISI) 
The ISI is a 7 item instrument that quantifies the participant perception of insomnia severity, 
along with the impact of insomnia on daytime functioning in adults in the last 2 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 5 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 
8–14 = Subthreshold insomnia 
15–21 = Clinical insomnia (moderate severity) 
22–28 = Clinical insomnia (severe) 

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In this study the ISI will be applied electronically and should be completed as indicated in the 
SoA. 
8.2.2.5 
Patient Global Impression of Severity (PGI-S) and Change (PGI-C) 
The PGI-S includes 2 items assessing sleep problems using a 5-point response scale (No sleep 
problems to Very severe for the PGI-S item 1 (severity of sleep problems) and None of the 
time to nearly all of the time for the PGI-S item 2 (time spent awake after first falling asleep)). 
The recall period for PGI-S items is “the past week”. Each item is scored independently. 
The PGI-C includes 2 items assessing change in sleep problems since the participant started 
taking the study medication. A 5-point response scale is used ranging from e.g. ‘much better’ 
to ‘much worse’ for the PGI-C item 1 (change in severity of sleep problems) and ‘much less’ 
to ‘much more’ for the for the PGI-C item 2 (change in time spent awake). Each item is 
scored independently. 
Both instruments, the PGI-S and the PGI-C are self-invented by the sponsor with the 
objective to serve as reference measures for a planned psychometric analysis. 
In this study the PGI-S and PGI-C will be applied electronically using the handheld device 
and responded to by the participants at home at timepoints indicated in the SoA. 
8.2.2.6 
Generalized Anxiety Disorder-7 (GAD-7) 
The GAD-7 is a 7 item patient-reported instrument that quantifies the symptom severity in 
generalized anxiety disorder in the last 2 weeks (Spitzer et al. 2006). Concepts assessed are in 
particular the frequency of being anxious, worried, having troubles relaxing, being restless, 
annoyed or irritated and feeling afraid. The items are scored on a 4-point Likert scale from 0 
to 3 (0 = “not at all”; 1 = “several days”; 2 = “more than half the days”; 3 = “nearly every 
day”). The scores for each item are summed to produce the total score (maximum of 21), with 
higher scores indicating a higher frequency of anxiety symptoms. 
Participants with a GAD-7 score ≥10 during the study should be further evaluated by the 
investigator and referral to a specialist considered. 
The investigator will receive an email notification if a GAD-7 of ≥10 is reported. 
In this study the GAD-7 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. 
8.3 
Safety Assessments  
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1 
Physical Examinations 
• A complete physical examination will be performed at visits indicated in the SoA. It 
will include, at a minimum, height, weight, and assessments of the Cardiovascular, 
Respiratory, Gastrointestinal and Neurological systems.  
• A symptom-based physical examination will be performed as indicated in the SoA, in 
a response to new symptoms, or changes in symptoms. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 

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• Abnormal physical examination findings, including overweight/obesity when 
BMI >30 kg/m2, are to be recorded either as medical history or as adverse events. 
8.3.2 
Vital Signs 
• Pulse rate, and systolic and diastolic blood pressure will be assessed. 
• Vital signs measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).  
• Vital signs should be taken before blood collection for laboratory tests. 
• Blood pressure and pulse rate measurements will be assessed once in a sitting position 
with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
• In case of abnormal results, repeat measurements should be performed to adequately 
document potential findings, e.g. hypertension.6  
8.3.3 
Clinical Safety Laboratory Tests 
• See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
for the timing and frequency.  
• The investigator must review the laboratory results, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
results must be retained with 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. 
• If clinically significant values do not return to normal/baseline within a 
period of time judged reasonable by the investigator, the etiology should be 
identified, and the Sponsor notified. 
• All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the Laboratory manual and the SoA.  
• If laboratory values from non-protocol specified laboratory tests 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 dose modification), then the results must be recorded. 
8.3.4 
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 hysterectomy and bilateral oophorectomy.  
                                                 
6 Hypertension is defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg over 
3 readings on at least 2 different occasions. 

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8.3.5 
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 15 for information on when the participant should not be randomized 
based on suicidal behavior or ideation.  
• 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. 
8.4 
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. 
The definitions of device-related safety events including medical device adverse events (AE), 
serious adverse events (SAE), and device deficiency can be found in Section 10.6. Device 
deficiencies are covered in Section 8.4.7. 
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). This includes events reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative). 
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. 
8.4.1 
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 timepoints specified in the SoA (Section 1.3). (S)AEs which are related to protocol-
required study procedures (e.g., (S)AE related to invasive study procedures) will be recorded 
as (S)AEs from the signing of the ICF. 

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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 as medical history/current medical conditions, not as (S)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 the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.  
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 
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 8.4.6), 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.  
8.4.4 
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 
(IRBs)/independent ethics committees (IECs), 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 IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary. 
8.4.5 
Pregnancy 
In case of a suspected pregnancy, a pregnancy test should be performed. In the unlikely event 
of a pregnancy the following applies: 
• Details of all pregnancies in participants will be collected after the start of study 
intervention and until end of Follow-up. 

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• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• 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 8.4.1 and Section 8.4.4. 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 
permanently discontinue study intervention. 
See Section 10.4 for details on collection of pregnancy information. 
8.4.6 
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. 
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: 
o ALT and/or AST >8x ULN OR 
o 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. 
• Post-menopausal bleeding: Any participant experiencing unexplained post-
menopausal bleeding after randomization should be referred to a gynecologist and 
undergo a transvaginal ultrasound with subsequent investigation and management 
according to the gynecologist’s clinical judgment and usual practice. 
8.4.7 
Medical Device Deficiencies 
Medical devices are being provided by or on behalf of the Sponsor for use in this study. To 
fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that occur 
during the study with such devices.  
The definition of a medical device deficiency can be found in Section 10.6.3.   

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Device deficiencies associated with a medical device AE/SAE (as defined in Section 10.6) 
will follow the processes outlined in Section 8.4 of the protocol and shall be documented and 
reported as a complaint to Bayer and eCOA vendor by the investigator. 
Device deficiencies not associated with a medical device AE/SAE will be communicated 
directly to the eCOA vendor by the study site. 
All device deficiencies have to be reported to the device manufacturer by the eCOA vendor 
according to their manual.  
8.5 
Pharmacokinetics 
Blood samples for measurement of elinzanetant and its principal metabolites in plasma for PK 
are to be collected at the time points given in the SoA (Section 1.3). PK sample is collected 
before the second PSG night (together with the safety lab sample) in the PSG lab shortly 
before intake of the study medication to obtain trough levels. The date and time of the last 
study medication intake prior to the PK sampling as indicated in the SoA (Section 1.3) 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 must be recorded. These time deviations are not to be 
considered as important deviations. 
If a participant discontinues study medication 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 intervention 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 LC-MS/MS. Quality 
control and calibration samples are analyzed concurrently with study samples. The results of 
calibration samples, quality control 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. 
Intervention 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 efficacy and safety. 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 endpoints or parameters 

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obtained in this study to investigate the relationship between elinzanetant exposure and 
response.  
Population or nonlinear mixed effects PK models describe the relationship between dose, 
time, and the elinzanetant plasma intervention 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, bodyweight, 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 (M&S) 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 M&S 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).   
8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
In this study biomarkers e.g. related to mode-of-action-related effects or safety and 
biomarkers deemed relevant to investigate pathomechanims of sleep disturbances associated 
with menopause may be investigated. These investigations may include e.g., diagnostic, 
safety, pharmacodynamic, monitoring, or potentially predictive biomarkers. 
PK samples (Section 8.5), safety lab samples (Section 10.2 and Section 10.5) and sleep 
laboratory data (Section 8.2.1) might be used for biomarker studies. For timing see SoA 
(Section 1.3). 
The results of biomarker investigations may be reported separately (e.g. in a biomarker 
evaluation report). 
8.9 
Immunogenicity Assessments 
Not applicable. 
8.10 
Medical Resource Utilization and Health Economics  
Medical resource utilization and health economics parameters are not evaluated in this study. 
9. 
Statistical Considerations  
The analysis and reporting will be done on all data from all participants at the time the study 
ends. 
The SAP will be finalized prior to database lock and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 

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summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.1 
Statistical Hypothesis 
The primary objective for the study is to estimate the treatment effect of elinzanetant 
compared to placebo in the change from baseline in WASO at Week 4 as measured by PSG. 
No hypotheses are planned to be tested.  
9.2 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set 
• All participants randomly assigned to study treatment.  
Safety analysis set 
• All participants randomly assigned to study treatment who 
were exposed to study treatment at least once. 
The full analysis set is used to analyze endpoints related to the efficacy objectives and 
participants will be analyzed according to their randomized study treatment. The Safety 
Analysis Set is used to analyze the endpoints and assessments related to safety and 
participants will be analyzed according to the study treatment received. 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
The statistical analyses will be performed in SAS and/or ValidR. The versions used will be 
specified in the SAP. 
All variables will be summarized using descriptive statistics as appropriate by study 
treatment. Continuous variables will be summarized using at least the following descriptive 
statistics: number of non-missing observations, arithmetic mean, standard deviation, median, 
minimum and maximum. Categorical data will be summarized with frequency tables with the 
number of observations and percentages. Confidence intervals will be 2 sided with a 
confidence level of 90%.  
Unless otherwise specified, baseline is defined as the latest available valid measurement at or 
before the start of study treatment. If the last observation available prior to randomization is 
the measurement from the screening visit, this would be used as the baseline value.  
Important ICEs for this study are defined as: 
• Temporary study treatment interruption, defined as: 
a. Week 4 = Treatment taken <80% during weeks 1–4 OR treatment taken on 
<5/7 days during either Week 3 or 4. 
b. Week 12 = Treatment taken <80% during weeks 1–12 OR treatment taken on 
<5/7 days during either Week 11 or 12. 
• Permanent discontinuation of randomized study treatment 
• Intake of prohibited concomitant medications having impact on efficacy 

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The number of observed ICEs will be summarized by study treatment and overall for each 
intercurrent event. 
9.3.2 
Primary Endpoint/Estimand Analysis 
9.3.2.1 
Definition of Endpoint 
The primary endpoint is the change from baseline in WASO at Week 4 as measured by PSG.  
Polysomnography assessments will be performed on 2 consecutive nights during screening 
and at Week 4. The baseline WASO value will be the mean value of the 2 consecutive nights 
at screening. Similarly, the Week 4 value will be the mean value of the 2 consecutive nights at 
Week 4.  
The change from baseline in WASO to Week 4 will be calculated as below: 
Change from baseline = WASO mean value at Week 4 – WASO mean value at baseline 
9.3.2.2 
Main Analytical Approach 
The primary endpoint will be analyzed using a MMRM on the change from baseline values at 
Week 4 and 12. Baseline value, study treatment, average weekly frequency of moderate-to-
severe HFs (stratification factor) and week will be included as covariates in the model as well 
as the interaction terms baseline-by-week and study treatment-by-week. An unstructured 
covariance structure will be used. If convergence cannot be attained, alternative structures 
will be attempted. Additional details will be provided in the SAP. The least square means for 
each study treatment and the least square means differences comparing elinzanetant with 
placebo will be estimated with corresponding 90% confidence intervals.  
Implementation of Strategies for Intercurrent Event Handling and Data Point Selection 
Prior to performing the MMRM model, missing data will be handled in alignment with the 
estimand strategy for ICEs (described in Section 3). 
The hypothetical strategy will be used to handle all of the ICEs in the primary estimand. This 
strategy will estimate the full efficacy potential of elinzanetant in the ideal situation if 
participants adhered to randomized study treatment up to Week 4 without taking prohibited 
concomitant medications impacting sleep. Data collected after the occurrence of any ICE will 
be discarded, and missing and unobserved data will be modeled using participants from the 
same study treatment who adhered to study treatment without taking prohibited concomitant 
medications impacting sleep to Week 4 and have observed data at Week 4. 
Details of the imputation model will be provided in the SAP. 
9.3.2.3 
Sensitivity Analyses 
A tipping point analysis will be applied to assess the sensitivity of the main analysis results to 
modeling of the missing data that occur in presence of all ICEs. This will be done by applying 
an unfavorable additive shift (referred to as delta adjustment) to the values imputed by the 
imputation model. Additional details on the tipping point analysis will be provided in the 
SAP. 
9.3.2.4 
Supplementary Analyses 
A supplementary estimand for the primary endpoint will be estimated. The attributes are the 
same as the primary estimand (Section 3) except for the handling of the ICEs which will be 
addressed using the below strategies: 

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ICEs 
Proposed 
Strategy 
Data Handling Method 
Interpretation 
Temporary study 
treatment interruption 
Treatment 
Policy 
Utilize the available data 
regardless of the occurrence of 
ICE 
The treatment effect includes 
the effect of treatment 
interruptions 
Premature 
discontinuation of study 
treatment 
Hypothetical 
Discard data collected after the 
ICE 
 
The treatment effect that would 
be if participants who 
discontinue the randomized 
treatment remain untreated on 
randomized treatment 
Intake of prohibited 
concomitant medication 
having impact on 
efficacy 
Treatment 
Policy 
Utilize the available data 
regardless of the occurrence of 
ICE 
The treatment effect includes 
the effect of prohibited 
concomitant medications 
impacting sleep 
ICE = Intercurrent event. 
A treatment policy will be applied to handle the ICE temporary study treatment interruption 
and intake of prohibited concomitant medication having impact on efficacy. A treatment 
policy approach for these ICEs are appropriate as this likely reflects the behavior of the target 
population. According to this strategy, all collected data should be utilized in the analysis 
irrespective of occurrence of the ICEs. Although all participants are expected to be followed 
after these ICEs, some missing data may occur which will be handled in line with the 
estimand strategy. 
A hypothetical strategy will be applied to handle the ICE premature discontinuation of study 
treatment to estimate the treatment effect that would be if participants who prematurely 
discontinue study treatment remain untreated (do not receive the experimental study treatment 
until the planned assessment timepoint). This approach reflects what would happen if 
participants remain in the study after premature discontinuation of study treatment. Missing 
and unobserved data will be modeled using placebo participants who remain on study 
treatment to Week 4 and have observed data at Week 4. 
Full details of the analysis will be provided in the SAP.  
9.3.3 
Secondary Endpoints/Estimands Analysis  
The secondary endpoints in this study are: 
• Change from baseline in WASO at Week 12 as measured by PSG 
• Change from baseline in sleep efficiency at Week 4 as measured by PSG 
• Change from baseline in sleep efficiency at Week 12 as measured by PSG 
• Change from baseline in PROMIS SD SF 8b total score at Week 4 
• Change from baseline in PROMIS SD SF 8b total score at Week 12 
• Change from baseline in ISI total score at Week 4 
• Change from baseline in ISI total score at Week 12  
The secondary endpoint change from baseline in WASO at Week 12 as measured by PSG will 
be derived similarly to the primary endpoint and analyzed using the same model as proposed 
for the primary efficacy analysis (see Section 9.3.2). 
The secondary endpoints on sleep efficiency, PROMIS SD SF 8b and ISI will be analyzed 
descriptively by study treatment. In addition, the individual items in each patient-reported 

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outcome will be summarized descriptively. All data will be utilized in the analysis regardless 
of the occurrence of ICEs. The calculation of the total scores for PROMIS SD SF 8b and ISI 
will be done according to the respective questionnaire guidelines.   
9.3.4 
Exploratory Endpoint(s) Analysis 
Details for the analysis of the exploratory endpoints will be provided in the SAP. 
9.3.5 
Safety Analysis 
Analysis on safety data will be performed on the Safety Analysis Set.   
TEAEs will be analyzed by descriptive statistics, such as frequency tables. All TEAEs will be 
tabulated by system organ class and preferred term, as coded by the current version of the 
MedDRA. Further tables will be provided for serious and/or drug-related TEAEs. 
Additional details for the safety analyses will be provided in the SAP. 
9.3.6 
Other Analysis 
Subgroup analyses of the primary endpoint and secondary endpoint change from baseline in 
WASO at Week 12 as measured by PSG will be provided by the average weekly frequency of 
moderate to severe HF over the 14 days prior to the respective eligibility check (<35 moderate 
to severe HFs per week, ≥35–<50 moderate to severe HFs per week, ≥50 moderate to severe 
HFs per week). Descriptive statistics will be provided and additional subgroups (e.g. region, 
BMI) will be specified in the SAP. 
9.4 
Interim Analysis 
No interim analysis is planned. 
9.5 
Sample Size Determination 
The primary objective for the study is to estimate the treatment effect of elinzanetant 
compared to placebo in the change from baseline in WASO to Week 4. Therefore, the sample 
size is based on precision (i.e. the half width of the confidence interval).  
There are no data available on the primary endpoint WASO measured by PSG in women with 
sleep disturbance associated with the menopause. Therefore, the standard deviation used in 
the sample size calculation is obtained from a study in patients with insomnia disorder 
(Mignot et al. 2022). Assuming the pooled standard deviation is 33.2 for the change from 
baseline in WASO at Week 4, a total sample size of 70 participants (35 per arm) would give a 
90% probability that the 2-sided 90% confidence interval will have a half width of 14.7 
minutes or less. To account for missing data and possible inflation in variability due to 
missing data imputation, a total of approximately 78 participants (39 per arm) will be 
randomized in a 1:1 ratio to both treatments. Approximately 223 participants will be screened 
to achieve 78 randomized participants. 
10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
 

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• 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 CIOMS international ethical 
guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (e.g., advertisements) must be submitted reviewed and approved in 
accordance with national legislation and undergo scientific and ethical assessment 
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 GCP 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, as applicable: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
• The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the potential participants and answer all 
questions regarding the study.  
• Potential participants must be informed that their participation is voluntary. They will 
be required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, privacy and data protection 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 

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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. 
10.1.4 
Recruitment Strategy 
Detailed description of the recruitment strategy will be provided in country-specific 
documentation as required. 
10.1.5 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant 
records, datasets or biological samples that are transferred to the Sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
• Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data 
to be used as described in the informed consent.  
• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The contract between Sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
10.1.6 
Dissemination of Clinical Study Data 
Bayer fulfills its commitment to publicly disclose study results through posting the result of 
the studies on public registries in accordance with applicable law and regulations. 
Result Summaries of Bayer's sponsored clinical studies in drug development Phases 2, 3 and 
4 and Phase 1 studies in patients are provided in the Bayer Clinical Trials Explorer application 
after marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition results of clinical drug 
trials will be provided on the publicly funded website ClinicalTrials.gov and EU Clinical 
Trials Information System (CTIS) in line with the applicable regulations. 
In accordance with the current EU regulation, result summaries will be submitted within one 
year from the end of the studies in adult populations or within 6 months for studies in 
pediatric population, in all participating countries. No preliminary data analysis (eg, on EU 
data only) will be performed, as this might compromise data integrity and the scientific 
validity of the study. Bayer commits to sharing upon request from qualified scientific and 

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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. 
10.1.7 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the Sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in the CRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents.  
• Quality tolerance limits (QTLs) will be predefined 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, including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification 
to the Sponsor.  
10.1.8 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in the Source 
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• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Sponsor or designee will perform monitoring to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• For ePRO and Sleepiz One+ data, the service provider database is the source. 
10.1.9 
Study and Site Start and Closure 
Study Start 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The start of a clinical study in EU is defined as the date on which the first site is declared by 
the Sponsor to be ready to enroll in a country and clinical study will be open for recruitment 
of participants.  
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but 
are not limited to: 
For study termination: 
Discontinuation of further study intervention development 
For site termination: 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.10 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
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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. 

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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 (MCV), mean corpuscular hemoglobin (MCH), 
%reticulocytes, platelet count and WBC differentials (absolute and relative 
values) 
Clinical chemistry:  
 
Sodium, potassium, glucose, urea (blood urea nitrogen), creatinine (including 
eGFR*), creatine kinase (CK), albumin, calcium, phosphate, bilirubin (total and 
direct), alkaline phosphatase** (AP), aspartate transaminase (AST), alanine 
transaminase (ALT), gamma glutamyl transferase (GGT), total cholesterol, high 
density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, 
triglycerides, magnesium, chloride, total protein, hemoglobin A1c, lactate 
dehydrogenase (LDH) 
* The laboratory parameter eGFR will be calculated by the central laboratory 
based on the CKD-EPI formula. The formula used for calculating eGFR (in 
mL/min/1.73 m2) will be the 2009 CKD-EPI equation based on creatinine and 
including age, sex and race (Levey et al. 2009) 
** If alkaline phosphatase is elevated, consider fractionating 
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)  
Urine analysis 
pH, urobilinogen, blood/hemoglobin, total protein, ketone, bilirubin, nitrite, 
glucose, leukocytes 
Screening/Start of Intervention parameters 
Urine pregnancy 
test 
Highly sensitive 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) 
PK 
Pharmacokinetics  
Pre-dose PK samples 
CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration, eGFR = estimated glomerular filtration rate,  
HCV = Hepatitis C virus; INR = International normalized ratio; mRNA = Messenger ribonucleic acid;  
PK = Pharmacokinetics, RNA = ribonucleic acid; WBC = White blood cell count. 
Additional laboratory tests to be assessed for close liver observation are described in 
Table 10–2.  
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. 

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Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Sign, symptoms, or the clinical sequelae of suspected medication errors, misuse and abuse 
of either study intervention or a concomitant medication. Medication errors, misuse 
and abuse per se will not be reported as an AE/SAE, unless it is resulting in AE/SAE. 
Such medication errors, misuse and abuse should be reported regardless of sequelae. 
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 abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
10.3.2 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets the one or 
more of the criteria listed: 
a. Results in death 
b. Is life threatening 

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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) that 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 that may not be immediately life-threatening or result in death or 
hospitalization but 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. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, convulsions, or development of intervention dependency or 
intervention abuse. 
10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The investigator will then record all relevant AE/SAE information. 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to 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 

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participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
For device deficiencies, it is required that the investigator describes any corrective or 
remedial actions taken to prevent recurrence of the deficiency.  
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence.  
Assessment of Intensity  
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 
Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research participant. 
Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
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. 
Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
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. 
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. 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes There may be situations in which an SAE has 
occurred and the investigator has minimal information to include in the initial report to 
the Sponsor. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
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The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other healthcare professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor with a copy of any postmortem 
findings including histopathology. 
New or updated information will be recorded in the originally submitted documents. 
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 
Reporting of SAEs 
SAE Reporting to Sponsor via an Electronic Data Collection Tool 
The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next 
section) or to the local pharmacovigilance contact person by telephone. 
Contacts for SAE reporting can be found in the Investigator Site File. 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
Email transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s Pharmacovigilance department. 
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 timeframes. 
Contacts for SAE reporting can be found in the Investigator Site File. 

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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 pregnancy information 
will be recorded on the appropriate form and submitted to the Sponsor within 24 hours 
of learning of a participant's pregnancy.  
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(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 8.4.1 and Section 8.4.4. 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 permanently 
discontinue study intervention. 
10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments  
10.5.1 
Thresholds for liver chemistry 
Actions, monitoring and follow-up assessments as outlined in Section 10.5.2 and 10.5.3 are 
required if any of the following abnormal laboratory results at local or central laboratory are 
noticed by the investigator: 

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1. Any of the following (for confirmation, re-test within 48–72 hours is required): 
− Confirmed elevation of ALT or AST ≥3 x ULN after start of study intervention 
and normal values at baseline  
− Confirmed ALT or AST 2-fold increases above baseline values and elevated liver 
enzymes before drug exposure  
− Confirmed AP (alkaline phosphatase) value increases to ≥2 x ULN in the absence 
of bone pathology driving the rise in AP level and irrespective of the level of 
transaminase (ALT or AST) values 
2. ALT or AST ≥3 x ULN and any of the following 
− Total bilirubin (TBL) ≥2 x ULN 
− INR ≥1.5 
(Relevant only if the participant is not on Vitamin K antagonist, new oral 
anticoagulants (NOACs) or heparin) 
− Appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain or 
tenderness, fever, rash and/or eosinophilia (> 5%) 
3. ALT or AST ≥5 x ULN for ≥2 weeks 
4. ALT or AST ≥8 x ULN 
10.5.2 
Immediate actions 
If any of the criteria specified in Section 10.5.1 is met, the following immediate actions 
should be initiated: 
Discontinuation decision  
Criterion 1: 
Discontinuation of study intervention should be considered, also 
in case the participants does not adhere to procedures required for 
close observation7 
Criteria 2 to 4: 
Discontinuation of study intervention should be decided 
Expedited reporting 
The investigator has to report the event to the Sponsor on AE/SAE eCRF pages within 
24 hours of the investigator`s awareness if the event meets any of the following criteria: 
1. Qualifies for an SAE (Section 10.3.2) 
The investigator should consider whether the observed increase in liver values 
would qualify as SAE 
2. Qualifies for an AESI requiring expedited reporting (Section 8.4.6)  
                                                 
7 In case visits for close observation could not be arranged with a frequency deemed adequate by the 
investigator, despite of reasonable efforts. 

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Close observation  
The participant needs to be closely observed as described below until the abnormalities of the 
liver chemistry resolve, stabilize, or return to baseline. The objective is to ensure participant 
safety and to rule out acute viral or autoimmune hepatitis and other not previously diagnosed 
liver or biliary tract diseases. 
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. 
Close observation includes: 
1. Repeat liver chemistry tests (ALT, AST, AP and total bilirubin) 2 to 3 times weekly 
until recovery.  
2. Frequency of retesting can decrease to once a week or less if abnormalities stabilize and 
the participant is asymptomatic. 
3. Complete general chemistry forms in liver eCRF (in case local lab is used). 
4. Obtain additional tests such as gamma glutamyl transferase (GGT), creatine kinase 
(CK), lactate dehydrogenase (LDH), prothrombin time (PT), INR, albumin, blood cell 
count with differentials as appropriate. 
5. Take blood for viral- and autoimmune serology, as well as liver-specific tests. Details 
are provided in Table 10–2. 
6. Serum bilirubin fractionation should be performed if total bilirubin is increased. 
Specific laboratory tests for close liver observation are specified in Table 10–2. Samples 
should be analyzed preferably by a central laboratory; if medically indicated to allow 
immediate clinical actions, an additional local laboratory should be considered. All results, 
including locally obtained, must be entered into the study database.  
If the investigator learns about an AE diagnosed by another treating physician, every effort 
should be made to obtain all relevant information. 

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Table 10–2: Laboratory tests for close liver observation 
As soon as possible (may be combined with first follow-up sampling) 
To be repeated in case of abnormalities or if medically indicated 
General chemistry 
• Bilirubin total, bilirubin direct, bilirubin indirect, alkaline 
phosphatase, GGT, AST, ALT, creatine kinase (CK, CPK), LDH, 
cholesterol total, triglycerides, glucose, hemoglobin A1c, 
albumin 
Coagulation 
• Prothrombin time, PT-INR  
Hematology 
• Hematocrit, hemoglobin, RBC, WBC, Platelets, MCV, 
neutrophils absolute count; lymphocyte absolute count, 
monocytes absolute count, eosinophils absolute count, 
basophils absolute count, neutrophils total (%), lymphocyte (%), 
monocytes (%), eosinophils (%), basophils (%) 
Once only upon start of close liver observation 
Liver-specific chemistry  
• Ferritin, total iron, saturation transferrin, ceruloplasmin, alpha-1 
antitrypsin, IgG level in blood (Immunoglobulin G) 
Virus serology 
in serum unless otherwise 
indicated 
• Anti-Hepatitis-A-virus antibody IgM  
• Hepatitis B virus surface antigen (HbsAg) in serum, anti-
hepatitis B core antibody (anti-HBc), hepatitis B virus DNA (if 
HbsAg positive), anti-hepatitis B surface antibody (Anti-Hbs), 
anti-hepatitis D antibodies (if HbsAg positive) 
• Anti-hepatitis-C-virus antibody, hepatitis C virus RNA 
• Anti-hepatitis-E-virus IgG antibody, anti-hepatitis-E-virus IgM 
antibody, hepatitis E virus RNA (detection per PCR) 
• Anti-cytomegalovirus (CMV) IgM antibodies  
• Anti-Epstein-Barr-virus (EBV) IgM antibodies  
• Herpes simplex IgM (anti-HSV IgM)  
• HIV1/HIV2 antibody screen 
Autoimmune serology  
in serum unless otherwise 
indicated 
• Antinuclear antibodies (ANA)  
• Anti-smooth-muscle antibodies (ASMA or smooth muscle 
antibody) 
• Anti-mitochondrial autoantibodies (AMA) – only in case of 
cholestatic pattern 
• If medically indicated, the following test should be considered: 
− Anti-LKM-1 antibodies,  
− Anti-P-ANCA antibodies or  
perinuclear anti-neutrophil cytoplasmic antibodies,  
− Anti-C-ANCA antibodies or  
anti-neutrophil cytoplasmic antibodies,  
− Anti-F-actin antibody,  
− Anti-LC1 antibodies or anti-SLA/LP antibodies might be 
considered in subsequent tests. 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, C-ANCA= neutrophil cytoplasmic, 
CK = creatine kinase, CPK = creatine phosphokinase, DNA = desoxyribonucleic acid, GGT = gamma glutamyl 
transferase, HIV = human immunodeficiency virus, IgG = immunoglobulin G, IgM = immunoglobulin M, INR = 
international normalized ratio, LC1 = liver cytosol type 1, LDH = lactate dehydrogenase, LKM-1 = liver kidney 
microsomal type 1, MCV = Mean corpuscular volume, SLA/LP = soluble liver antigen/liver pancreas, P-ANCA= 
anti-neutrophil perinuclear antibodies, PCR = polymerase chain reaction, PT = prothrombin time, RBC= red blood 
cell count, RNA = ribonucleic acid, WBC = white blood cell count.  

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10.5.3 
Follow-up assessments 
If any of the criteria specified in Section 10.5.1 is met, the following follow-up assessments 
should be initiated: 
1. Rule out relevant acute intercurrent diseases (e.g. alcoholic hepatitis; fatty liver; 
hypoxic/ischemic hepatopathy; biliary tract disease or viral hepatitis types A, B, C, D, 
and E; or autoimmune hepatitis). Details for virus and autoimmune serology are provided 
in Table 10–2. 
→ Report corresponding lab values on the 'Virus serology' and 'Autoimmune serology' 
eCRF forms 
2. Obtain clinical signs and symptoms and a detailed history of prior or concurrent diseases. 
Special attention is to be paid to new or worsening symptoms believed to be related to 
liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
→ Complete 'Clinical Sings and Symptoms' and 'Pre-existing medical Conditions' eCRF 
forms 
3. Obtain a history of liver-specific risk factors (e.g. specific concomitant drugs including 
non-prescription medications and herbal and dietary supplement preparations, 
recreational drug use, exposure to environmental chemical agents, and special diets)  
Fill in 3 different 'Risk Factors' eCRF forms 
4. Capture alcohol consumption and recent changes of consumption.  
→ Report on 'Substance Use - Alcohol' eCRF form 
5. In case of confirmed AP ≥ 2 x ULN in the absence of bone pathologies, liver images (e.g. 
ultrasound, MRCP, ERCP) are indicated. In all other liver events consider liver imaging 
(e.g. ultrasound, MRI, CT, MRCP, ERCP, magnetic resonance spectroscopy and/or liver 
biopsy) – if applicable, report on corresponding 'Hepatic Imaging / Liver Biopsy' eCRF 
forms 
6. Consider gastroenterology or hepatology consultations 
 
10.6 
Appendix 6: Medical Device AE, SAE, and Device Deficiencies: 
Definitions  
The definitions and procedures detailed in this appendix are in accordance with ISO 
14155 and the European Medical Device Regulation (MDR) 2017/745 for clinical 
device research (if applicable).  
Both the investigator and the Sponsor will comply with all local reporting requirements 
for medical devices. 
The detection and documentation procedures described in this protocol apply to the 
medical devices supplied by or on behalf of the Sponsor for use in the study. See 
Section 6.1.1 for the list of medical devices supplied by or on behalf of the Sponsor. 

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10.6.1 
Definition of Medical Device AE  
Medical Device AE  
A medical device AE is any untoward medical occurrence in a clinical study participant, 
users, or other persons, temporally associated with the use of study intervention, 
whether or not considered related to the investigational medical device. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of an investigational medical device. This definition includes events related to the 
investigational medical device or comparator and events related to the procedures 
involved except for events in users or other persons, which only include events related 
to investigational devices. 
10.6.2 
Definition of Medical Device SAE 
A Medical Device SAE is any SAE that: 
a. Led to death 
b. Led to serious deterioration in the health of the participant, that either resulted in: 
A life-threatening illness or injury. 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. 
A permanent impairment of a body structure or a body function. 
Inpatient or prolonged hospitalization, planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
Chronic disease (MDR 2017/745). 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product  
10.6.3 
Definition of Device Deficiency 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use 
errors, and inadequacy of the information supplied by the manufacturer. 
10.7 
Appendix 7: Washout periods for hormonal therapies and prohibited 
concomitant medications 
Tables below present a comprehensive (but not exhaustive) list of prohibited concomitant 
medications and respective washout periods, as well as a list of medications with limited use 
during the study. Washout periods are shown in Table 10–3 for hormonal therapies, Table 10–
4 for therapies affecting sleep and Table 10–6 for concomitant medications affecting PK. 
Table 10–5 lists medications that are allowed provided their use is limited during the study. 
Table 10–7 and Table 10–8 list examples of the most common medication regarded as potent 
CYP3A4 inhibitors or inducers, or P-gp inhibitors.  

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Table 10–3: Washout periods for hormonal therapies. 
Prohibited from the time shown until after last PSG in the study and last dose of study 
medication. 
Washout period 
Hormonal therapies 
From 4 weeks prior 
to SCR-2 visit  
 
Vaginal hormonal products (rings, creams, gels and including DHEA or 
analogues thereof) 
From 4 weeks prior 
to SCR-2 visit 
Transdermal estrogen alone or estrogen/progestin products 
From 8 weeks prior 
to SCR-2 visit 
 
• 
Oral estrogen and/or progestin therapy 
• 
Selective estrogen receptor modulators 
From 12 weeks prior 
to SCR-2 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 SCR-2 visit 
Estrogen pellet therapy or progestin injectable drug therapy   
DHEA = Dehydroepiandrosterone, GnRH = Gonadotropin-releasing hormone,  
PSG = polysomnography, SCR = Screening. 
 

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Table 10–4: Prohibited concomitant medication potentially confounding efficacy.  
Prohibited from the time shown until after last PSG in the study and last dose of study 
medication. 
Washout period 
Therapies that may affect sleep/wake function 
At least 4 weeks or 5 half-
lives (whichever is longer) 
prior to SCR-2 visit 
Chronic use of anxiolytics/hypnotics (defined as a use for ≥4 times 
per week over a longer period of time than recommended per 
respective product monograph or treatment guidelines) 
At least 2 weeks or 5 half-
lives (whichever is longer) 
prior to SCR-2 visit 
• 
Antidepressant drugs  
• 
Anticonvulsants 
• 
Antipsychotics (for depot neuroleptics consider long half-lives) 
• 
Anxiolytics (benzodiazepines, non-benzodiazepines)  
• 
Hypnotics  
• 
Centrally acting anticholinergics  
• 
Mood stabilizers  
• 
Muscle relaxants (centrally acting with psychotropic effects)  
• 
Central Alpha-2 Receptor Agonists 
• 
Sodium oxybate 
• 
Sedating antihistamines  
• 
Melatonin and melatonin receptor agonists 
• 
Stimulants 
• 
Adenosine Receptor Antagonist  
• 
Systemic corticosteroids (inhaled corticosteroids are allowed) 
• 
Diet pills that contain active substance and/or ingredients that 
can affect sleep 
• 
Isotretinoin 
• 
Any recreational drugs, even if used for medicinal reasons 
• 
Opioids/narcotics  
• 
Over-the-counter (OTC) /herbal treatments including: 
• Supplements with possible psychotropic effect  
• Extended-release pseudoephedrine 
• Traditional Chinese medicine used for sleep 
improvement/disturbances 
PSG = polysomnography, SCR = Screening. 
 

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Table 10–5: Medication with limited use during the study 
During the study 
Therapies 
Allowed up to twice per week 
• 
Non-sedating antihistamines. See Table 10–6 for non-
sedating antihistamines which are prohibited during the study 
as CYP3A4 substrates.  
• 
Pseudoephedrine 
CYP3A4 = Cytochrome P450 isoenzyme 3A4. 
 
Table 10–6: Prohibited concomitant medication potentially affecting PK.  
Prohibited from the time shown until 1 week after the last dose of study medication 
Washout period before SCR-2 
Therapies 
At least 2 weeks or 5 half-lives 
(whichever is longer) prior to 
SCR-2 visit: CYP3A4 substrates 
with a narrow therapeutic range 
Alfentanil, astemizole, fentanyl, pimozide, terfenadine 
 
At least 2 weeks or 5 half-lives 
(whichever is longer) prior to 
SCR-2 visit: Strong or moderate 
inhibitors of CYP3A4 
Nefazodone, fluvoxamine, tofisopam 
 
At least 2 weeks or 5 half-lives 
(whichever is longer) prior to 
SCR-2 visit: Strong or moderate 
inducers of CYP3A4 
Carbamazepine, phenytoin, St. John’s wort, phenobarbital, 
primidone 
 
Washout period before BL 
Therapies 
From 1 week prior to BL visit:  
CYP3A4 substrates with a narrow 
therapeutic range 
Cisapride, cyclosporine, dihydroergotamine, ergotamine, 
quinidine, sirolimus, tacrolimus 
From 2 weeks prior to BL visit:  
Strong or moderate inhibitors of 
CYP3A4 
See Table 10–7 for examples of most common moderate and 
strong CYP3A4 inhibitors 
From 4 weeks prior to BL visit: 
Strong or moderate inducers of 
CYP3A4 
See Table 10–8 for examples of most common moderate and 
strong CYP3A4 inducers  
From 1 week prior to BL visit:  
P-glycoprotein inhibitors 
Azithromycin, conivaptan, cyclosporine, diltiazem, 
erythromycin, ketoconazole, ranolazine,  
amiodarone, carvedilol, clarithromycin, dronedarone, 
itraconazole, lapatinib, propafenone, quinidine   
BL = Baseline, CYP3A4 = Cytochrome P450 isoenzyme 3A4, PK = Pharmacokinetics,  
SCR = Screening. 
 

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Table 10–7: Examples of clinical inhibitors for CYP3A4 
Strong inhibitors 
Moderate inhibitors 
boceprevir 
aprepitant 
clarithromycin 
ciprofloxacin 
cobicistat 
conivaptan 
danoprevir and ritonavir 
crizotinib 
elvitegravir and ritonavir 
cyclosporine 
grapefruit juice 
diltiazem 
idelalisib 
dronedarone 
indinavir and ritonavir 
erythromycin 
itraconazole 
fluconazole 
ketoconazole 
fluvoxamine 
lopinavir and ritonavir 
imatinib 
nefazodone 
tofisopam 
nelfinavir 
verapamil 
paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir) 
 
posaconazole 
 
ritonavir 
 
saquinavir and ritonavir 
 
telaprevir 
 
tipranavir and ritonavir 
 
telithromycin 
 
troleandomycin 
 
voriconazole 
 
CYP3A4 = Cytochrome P450 isoenzyme 3A4. 
Source: (FDA 2020) 
 
Table 10–8: Examples of clinical inducers for CYP3A4 
Strong inducers 
Moderate inducers 
apalutamide 
bosentan 
carbamazepine 
efavirenz 
enzalutamide 
etravirine 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
 
St. John’s wort 
 
CYP3A4 = Cytochrome P450 isoenzyme 3A4. 
Source: (FDA 2020) 
 
10.8 
Appendix 8: Country/region-specific Requirements 
Not applicable. 
 

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10.9 
Appendix 9: Protocol Amendment History 
10.9.1 
Amendment 1 (21 SEP 2023) 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
 
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