Conditions: Hot Flashes
Keywords: menopause fezolinetant ESN364 vasomotor symptoms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1831
Healthy volunteers: no

Brief summary:
This study was for women in menopause with hot flashes. Menopause, a normal part of aging, was the time of a woman's last period. Hot flashes can interrupt a woman's daily life.

The purpose of this study was to find out how safe it is for these women to take fezolinetant in long term (up to 52 weeks). To do that, the study looked at the number and severity of the "adverse events." Those were the side effects that study participants had while they were in the study.

The study treatments were fezolinetant 30 milligrams (mg) (1 tablet of fezolinetant and 1 placebo tablet) once a day, fezolinetant 45 mg (2 tablets of fezolinetant) once a day or placebo (2 tablets) once a day. (Placebo was a dummy treatment that looked like medicine but did not have any medicine in it.) Women in this study were picked for 1 of the 3 study treatments by chance alone. The study participants took study treatment for 52 weeks.

This study was "double-blinded." That means that the study participants and the study doctors did not know who took which of the study treatments (fezolinetant 30 mg, fezolinetant 45 mg or placebo).

At weeks 2 and 4 and then once a month, the study participants went to the hospital or clinic for a check-up. They were asked about medications, side effects and how they felt. Other checks included physical exam and vital signs (heart rate, temperature and blood pressure). Blood and urine were collected for laboratory tests. At some study visits, study participants completed questionnaires that were about their quality of life. At the first and last study visits, they had a dual-energy x-ray absorptiometry (DXA for short) test done. To measure bone loss in the hips and spine, DXA created pictures of the inside of these areas with low-dose x-rays. (The dose was approximately one-tenth of the amount of a normal chest x-ray.) Study participants who still had their uterus had 2 more tests done at the first and last study visits. One of the 2 tests was endometrial biopsy. This test involved removing a small amount of tissue from the inside lining of the uterus. The tissue was then checked under a microscope. The other test was transvaginal ultrasound. It used sound waves to create pictures of the organs in the pelvis. The sound waves were transmitted by a probe (transducer), which was placed inside the vagina. Study participants might have had a screening mammogram done at the first and/or last study visit. A mammogram is an x-ray picture of the breasts used to screen for breast cancer. Study participants who did not had this test done in the last 12 months had it done at the first study visit. They had done at the last study visit if they were due for their screening mammogram and their own doctor agreed.

The last check-up at the hospital or clinic was at 3 weeks after the last dose of study treatment.

Detailed description:
This study consisted of a screening period and a 52 week treatment period. Safety follow up occurred 3 weeks after the last dose of study drug.

Arms:
arm 1: Participants received fezolinetant 30 mg (one 30 mg fezolinetant tablet and one placebo tablet) orally, once daily (QD) for a period of 52 Weeks. arm 2: Participants received fezolinetant 45 mg (one 30 mg tablet and one 15 mg tablet) orally, QD for a period of 52 Weeks. arm 3: Participants received fezolinetant matching placebo (two fezolinetant matching placebo tablets) orally, QD for a of period of 52 Weeks.

Interventions: intervention 1: fezolinetant intervention 2: placebo
Intervention descriptions: intervention 1: administered orally intervention 2: administered orally

Protocol document:
Prot_000.pdf: 
Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
- CONFIDENTIAL -
19 Mar 2021 
Astellas 
Page 1 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
A Randomized, Placebo-Controlled, Double-Blind Phase 3  
Clinical Study to Investigate the Long-Term Safety of Fezolinetant 
in Women Suffering From Vasomotor Symptoms (Hot Flashes) 
Associated with Menopause 
Skylight 4 
ISN/Protocol 2693-CL-0304 
Version 3.2 
Incorporating Nonsubstantial Amendment 3 [See Section 13] 
19 March 2021 
IND 130277 
EudraCT 2019-000275-16 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
Protocol History: 
Version 1.0, Original [28 Jan 2019] 
Version 2.0 Incorporating Substantial Amendment 1 [17 May 2019] 
Version 2.1 Incorporating Nonsubstantial Amendment 1 [13 Dec 2019] 
Version 3.0 Incorporating Substantial Amendment 2 [15 Jun 2020] 
Version 3.1 [UA] Incorporating Country-specific Nonsubstantial Amendment 2 for Ukraine [23 Oct 
2020] 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence.  
NCT04003389


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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Table of Contents 
I. 
SIGNATURES ······················································································ 8 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 11 
IV. 
SYNOPSIS ·························································································· 15 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 24 
1 
INTRODUCTION ················································································· 29 
1.1 
Introduction to Fezolinetant ·································································· 29 
1.2 
Background ···················································································· 29 
1.2.1 
Vasomotor Symptoms (Hot Flashes): Epidemiology and Etiology ··············· 29 
1.3 
Fezolinetant Nonclinical and Clinical Data ················································ 30 
1.3.1 
Summary of Nonclinical Studies ······················································ 30 
1.3.2 
Summary of Clinical Studies ··························································· 31 
1.4 
Summary of Key Safety Information for Fezolinetant ···································· 34 
1.4.1 
Nonclinical studies ······································································ 34 
1.4.2 
Clinical Studies ·········································································· 35 
1.5 
Risk Benefit Assessment ····································································· 36 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 38 
2.1 
Study Objective(s) ············································································ 38 
2.1.1 
Primary Objective ······································································· 38 
2.1.2 
Secondary Objective ···································································· 38 
2.1.3 
Exploratory Objectives ································································· 38 
2.2 
Study Design and Dose Rationale ··························································· 38 
2.2.1 
Study Design ············································································· 38 
2.2.2 
Dose Rationale ··········································································· 41 
2.3 
Endpoints ······················································································· 43 
2.3.1 
Primary Endpoint ········································································ 43 
2.3.2 
Secondary Endpoints ···································································· 44 
2.3.3 
Exploratory Endpoints ·································································· 44 
3 
STUDY POPULATION ·········································································· 44 
3.1 
Selection of Study Population ······························································· 44 
3.2 
Inclusion Criteria ·············································································· 44 
3.3 
Exclusion Criteria ············································································· 45 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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4 
TREATMENT ····················································································· 47 
4.1 
Identification of Investigational Products ·················································· 47 
4.1.1 
Study Drug ··············································································· 47 
4.1.2 
Comparative Drug ······································································· 47 
4.2 
Packaging and Labeling ······································································ 47 
4.3 
Study Drug Handling ········································································· 48 
4.4 
Blinding ························································································ 48 
4.4.1 
Blinding Method ········································································· 48 
4.4.2 
Confirmation of the Indistinguishability of the Study Drugs ······················ 48 
4.4.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ·················································································· 49 
4.4.4 
Breaking the Treatment Code for Emergency ······································· 49 
4.4.5 
Breaking the Treatment Code by the Sponsor ······································· 49 
4.5 
Assignment and Allocation ·································································· 49 
5 
TREATMENTS AND EVALUATION ························································ 50 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 50 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 50 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) ································ 50 
5.1.3 
Previous and Concomitant Treatment (Medication and NonMedication 
Therapy) ·················································································· 50 
5.1.3.1 
Previous Medication (Drugs and Therapies) ··································· 50 
5.1.3.2 
Concomitant Medications (Drugs and Therapies) ····························· 51 
5.1.3.3 
Prohibited Concomitant Medications ··········································· 51 
5.1.4 
Treatment Compliance ·································································· 51 
5.1.5 
Criteria for Continuation of Treatment ··············································· 51 
5.1.6 
Restrictions During the Study ·························································· 51 
5.2 
Demographics and Baseline Characteristics ··············································· 51 
5.2.1 
Demographics ············································································ 51 
5.2.2 
Medical History ·········································································· 52 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 52 
5.3 
Order of Assessments ········································································· 52 
5.4 
Safety Assessments ··········································································· 53 
5.4.1 
Vital Signs ················································································ 53 
5.4.2 
Columbia Suicide Severity Rating Scale ············································· 53 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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5.4.3 
Laboratory Assessments ································································ 53 
5.4.4 
Papanicolaou Test ······································································· 55 
5.4.5 
Physical Examination ··································································· 55 
5.4.6 
Electrocardiogram ······································································· 55 
5.5 
Imaging ························································································· 55 
5.5.1 
Mammogram ············································································· 55 
5.5.2 
Dual-Energy X-Ray Absorptiometry (DXA) ········································ 55 
5.5.3 
Transvaginal Ultrasound ································································ 56 
5.6 
Biopsies ························································································ 56 
5.6.1 
Endometrial Biopsy ····································································· 56 
5.7 
Patient-Reported Outcome, Pharmacodynamic and Pharmacokinetic 
Assessments ··················································································· 57 
5.7.1 
Patient-Reported Outcome Assessments ············································· 57 
5.7.1.1 
Menopause-Specific Quality of Life (MENQoL) ······························ 58 
5.7.1.2 
EQ-5D-5L with Visual Analog Scale (VAS) ··································· 58 
5.7.2 
Pharmacodynamic Assessments ······················································· 59 
5.7.3 
Pharmacokinetic Assessments ························································· 59 
5.7.4 
Caffeinated Beverage Intake ··························································· 59 
5.8 
Adverse Events and Other Safety Aspects ················································· 60 
5.8.1 
Definition of Adverse Events ·························································· 60 
5.8.1.1 
Abnormal Laboratory Findings ·················································· 60 
5.8.1.2 
Potential Cases of Drug-Induced Liver Injury ································· 60 
5.8.1.3 
Disease Progression and Study Endpoints ······································ 60 
5.8.2 
Definition of Serious Adverse Events (SAEs) ······································· 61 
5.8.2.1 
Always Serious Adverse Events ················································· 61 
5.8.3 
Criteria for Causal Relationship to Study Drug ······································ 61 
5.8.4 
Criteria for Defining the Severity of an Adverse Event ···························· 63 
5.8.5 
Reporting of Serious Adverse Events (SAEs) ······································· 63 
5.8.6 
Follow-up of Adverse Events ·························································· 64 
5.8.7 
Adverse Events of Special Interest ···················································· 64 
5.8.8 
Special Situations ········································································ 65 
5.8.8.1 
Pregnancy ··········································································· 65 
5.8.8.2 
Lack of Efficacy ··································································· 66 
5.8.8.3 
Medication Error, Overdose and “Off-Label Use” ···························· 66 
5.8.8.4 
Misuse/Abuse ······································································ 66 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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5.8.8.5 
Suspected Drug-Drug Interaction ················································ 67 
5.8.9 
Supply of New Information Affecting the Conduct of the Study ·················· 67 
5.8.10 
Urgent Safety Measures ································································ 67 
5.8.11 
Reporting Urgent Safety Measures ···················································· 67 
5.9 
Test Drug Concentration ····································································· 67 
5.10 
Other Measurements, Assessments or Methods ··········································· 68 
5.11 
Total Amount of Blood ······································································· 68 
6 
DISCONTINUATION ············································································ 68 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment ······················· 68 
6.1.1 
Lost to Follow Up ······································································· 69 
6.2 
Discontinuation of the Site ··································································· 69 
6.3 
Discontinuation of the Study································································· 69 
7 
STATISTICAL METHODOLOGY ··························································· 69 
7.1 
Sample Size ···················································································· 69 
7.2 
Analysis Sets ··················································································· 70 
7.2.1 
Full Analysis Set (FAS) ································································ 70 
7.2.2 
Safety Analysis Set (SAF) ······························································ 70 
7.2.3 
Pharmacokinetic Analysis Set (PKAS) ··············································· 70 
7.2.4 
Pharmacodynamic Analysis Set (PDAS) ············································· 71 
7.3 
Demographics and Baseline Characteristics ··············································· 71 
7.3.1 
Subject Disposition ······································································ 71 
7.3.2 
Previous and Concomitant Medications ·············································· 71 
7.3.3 
Medical History ·········································································· 71 
7.4 
Analysis of Efficacy ·········································································· 71 
7.5 
Analysis of Exploratory Endpoints ························································· 71 
7.6 
Analysis of Safety ············································································· 72 
7.6.1 
Adverse Events ·········································································· 72 
7.6.2 
Laboratory Assessments ································································ 73 
7.6.3 
Vital Signs ················································································ 73 
7.6.4 
Physical Examination ··································································· 73 
7.6.5 
Routine 12-lead Electrocardiograms ·················································· 73 
7.6.6 
Endometrial Health Assessment ······················································· 74 
7.6.7 
Imaging ··················································································· 74 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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7.7 
Analysis of Pharmacokinetics ······························································· 74 
7.8 
Analysis of Pharmacodynamics ····························································· 74 
7.9 
Major Protocol Deviations ··································································· 74 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 75 
7.11 
Additional Conventions ······································································ 75 
8 
OPERATIONAL CONSIDERATIONS ······················································· 75 
8.1 
Data Collection ················································································ 75 
8.1.1 
Electronic Clinical Outcome Assessment/Electronic Patient-Reported 
Outcome ·················································································· 76 
8.2 
Screen Failures ················································································ 76 
8.3 
Major Protocol Deviations ··································································· 76 
9 
END OF TRIAL ··················································································· 77 
10 
STUDY ORGANIZATION ······································································ 77 
10.1 
Data Monitoring Committee ································································· 77 
10.2 
Other Study Organization ···································································· 77 
11 
REFERENCES ···················································································· 78 
12 
APPENDICES ····················································································· 80 
12.1 
Ethical, Regulatory, and Study Oversight Considerations ······························· 80 
12.1.1 
Ethical Conduct of the Study ··························································· 80 
12.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Competent Authorities (CA) ··························································· 80 
12.1.3 
Protocol Amendment and/or Revision ················································ 80 
12.1.4 
Financial Disclosure ···································································· 81 
12.1.5 
Informed Consent of Subjects ························································· 81 
12.1.5.1 
Subject Information and Consent ················································ 81 
12.1.6 
Source Documents ······································································ 82 
12.1.7 
Record Retention ········································································ 82 
12.1.8 
Subject Confidentiality and Privacy ··················································· 82 
12.1.9 
Arrangement for Use of Information and Publication of the Clinical Study ····· 83 
12.1.10 
Insurance of Subjects and Others ······················································ 83 
12.1.11 
Signatory Investigator for Clinical Study Report ···································· 83 
12.2 
Procedure for Clinical Study Quality Control ············································· 85 
12.2.1 
Clinical Study Monitoring ······························································ 85 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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12.2.2 
Direct Access to Source Data/Documents ············································ 85 
12.2.3 
Data Management ······································································· 85 
12.2.4 
Quality Assurance ······································································· 85 
12.3 
Contraception Requirements ································································· 86 
12.4 
List of Excluded Concomitant Medications················································ 88 
12.5 
Liver Safety Monitoring and Assessment ·················································· 92 
12.6 
Common Serious Adverse Events ··························································· 95 
12.7 
Clinical Study Continuity ···································································· 96 
13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 3 ·························· 101 
14 
SPONSOR SIGNATURES ···································································· 115 
 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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Version 3.2 Incorporating Nonsubstantial Amendment 3 
I. 
SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 14, 
Sponsor Signatures]. 
 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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19 Mar 2021 
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Version 3.2 Incorporating Nonsubstantial Amendment 3 
2.  INVESTIGATOR’S SIGNATURE 
A Randomized, Placebo-Controlled, Double-Blind Phase 3 Clinical Study to 
Investigate the Long-Term Safety of Fezolinetant in Women Suffering From 
Vasomotor Symptoms (Hot Flashes) Associated with Menopause 
ISN/Protocol 2693-CL-0304 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
19 Mar 2021  
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) guidelines and applicable local regulations. I will also ensure that subinvestigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH GCP 
guidelines to enable them to work in accordance with the provisions of these documents. 
Principal Investigator: 
 
Signature:   ------------------------------------------------------------------------------------------------------------ 
                                                                                                                           Date (DD Mmm YYYY) 
 
Printed Name:    ------------------------------------------------------------------------------------------------------ 
 <Insert name and qualification of the Investigator> 
 
Address:    ------------------------------------------------------------------------------------------------------------- 
 
                  ------------------------------------------------------------------------------------------------------------- 
  


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
19 Mar 2021 
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Page 10 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
24h-Contact for Serious 
Adverse Events (SAEs) 
 
See [Section 5.8.5 Reporting of 
Serious Adverse Events 
(SAEs)] for SAE Fax Number 
and Email 
Please fax or email the SAE Worksheet to: 
Astellas Pharma Global Development, Inc.  
Pharmacovigilance 
Fax number: +1 888-396-3750 
Alternate fax number: +1 847-317-1241 
Email: safety-US@astellas.com 
CRO Medical Monitor/Study 
Physician: 
 
 
ICON Clinical Research 
 
 
 
  
ICON Clinical Research  
 
 
 
 
Astellas Pharma Global Development, Inc. 
1 Astellas Way 
Northbrook, IL 60062 USA 
 
 
 
Clinical Research Contact: 
  
 
 
  
PPD
PPD
PPD
PPD
PPD
PPD


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
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Version 3.2 Incorporating Nonsubstantial Amendment 3 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AT 
serum aminotransferases 
AUC 
area under the concentration-time curve 
BC 
breast cancer 
bid 
twice daily 
BMD 
bone mass density 
CA 
Competent Authorities 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum concentration 
CRF 
case report form 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DBL 
direct bilirubin  
DILI 
drug-induced liver injury 
DILIsym 
drug-induced liver injury modeling software 
DMC 
Data Monitoring Committee 
DXA 
dual-energy X-ray absorptiometry  
E2 
estradiol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
early discontinuation 
EEA 
European Economic Area 
EH set 
endometrial health analysis set 
EOT 
end of treatment 
EU 
European Union 
EQ-5D-5L 
Euro-Qol 5D-5L 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
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Page 12 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
Abbreviations 
Description of abbreviations 
GMP 
Good Manufacturing Practice 
GnRH 
gonadotropin releasing hormone 
HFs 
hot flashes 
HRT 
hormone replacement therapy 
hNK 
human neurokinin 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
ISN 
international study number 
KNDy 
kisspeptin/neurokinin B/dynorphin 
LA-CRF 
liver abnormality case report form 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MENQoL 
Menopause-Specific Quality of Life 
MMRM 
mixed model for repeated measures 
MR-VMS 
menopause-related vasomotor symptoms 
NK3R 
neurokinin-3 receptor 
NKB 
neurokinin B 
NOAEL 
no adverse event level 
P4 
progesterone 
Pap 
Papanicolaou 
PDAS 
pharmacodynamic analysis set 
PKAS 
pharmacokinetic analysis set 
PRO 
patient-reported outcome 
QTLs 
quality tolerance limits 
RSI 
Reference Safety Information 
QA 
quality assurance 
QC 
quality control 
qd 
once daily 
SAE 
serious adverse event 
SAF 
Safety Analysis Set 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
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Page 13 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
Abbreviations 
Description of abbreviations 
SAP 
Statistical Analysis Plan 
SAR 
serious adverse reaction 
SHBG 
sex hormone-binding globulin 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
TBS 
trabecular bone score 
TEAE 
treatment-emergent adverse event 
TVU 
transvaginal ultrasound 
ULN 
upper limit of normal 
USM 
Urgent Safety Measure 
VAS 
visual analog scale 
VMS 
vasomotor symptoms 
 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
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Page 14 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
1. Observed values/findings, which are regarded as starting points for 
comparison. 
2. Time when ‘Baseline’ is observed. 
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
NOTE: Not all endpoints are themselves assessments since certain endpoints 
might apply to populations or emerge from analysis of results. That is, endpoints 
might be facts about assessments (e.g., prolongation of survival). 
Enroll 
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject. 
Intervention 
The investigational product under investigation to evaluate the effect on 
specified outcomes of interest (e.g., health-related quality of life, efficacy, 
safety and pharmacoeconomics).  
Investigational 
period 
This portion of the study refers to the time that a subject is receiving treatment 
(investigational product or placebo). This period of time is when major interests 
of protocol objectives are observed and continues until the last assessment is 
completed after final administration of the investigational product or placebo. 
Follow-up period 
Period of time after the last assessment of the protocol. Follow-up observations 
for sustained adverse events and/or survival are conducted during this period. 
Randomization 
The process of assigning subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.  
Rescreen  
Subject can rescreen up to 1 time with the approval of the medical monitor, 
which will result in a new 35-day screening window. The subject will be entered 
as a new subject in the interactive response technology.  
Retest 
Subject can retest up to 1 time with approval from the medical monitor within 
the current 35-day screening window. The subject will retain the same subject 
identification number.  
Screening 
A process of active consideration of potential subjects for randomization in a 
study. 
NOTE:  This is conducted after the subject signs the informed consent and 
agrees to be evaluated for study participation. 
Screen failure 
Potential subject who did not meet 1 or more inclusion criteria or met 1 or more 
exclusion criteria required for participation in a study and was not randomized. 
Screening period 
Period of time before entering the investigational period, usually from the time 
when a subject signs the consent until just before the test drug or comparative 
drug (sometimes without randomization) is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing the 
last study assessment. 
Variable 
Any entity that may change as a result of other factors; any attribute, 
phenomenon or event that can have different qualitative or quantitative values. 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
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Page 15 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
IV. 
SYNOPSIS 
Date and Version No. of Protocol Synopsis: 
19 Mar 2021, Version 3.2 
Sponsor:   
Astellas Pharma Global Development 
Protocol Number:  
2693-CL-0304 
Name of Study Drug:  
Fezolinetant 
Phase of Development: 
Phase 3 
Title of Study:   
A Randomized, Placebo-Controlled, Double-Blind Phase 3 Clinical Study to Investigate the 
Long-Term Safety of Fezolinetant in Women Suffering From Vasomotor Symptoms (Hot Flashes) 
Associated with Menopause 
Planned Study Period:  
From 2Q2019 to 3Q2022 
Objectives:  
Primary objective of the study: 
• 
To evaluate the long-term safety and tolerability of fezolinetant in women seeking treatment for 
relief of Vasomotor Symptoms (VMS) associated with menopause. 
• 
To evaluate the effect of fezolinetant on endometrial health after long-term treatment in women 
seeking treatment for relief of VMS associated with menopause. 
Secondary objective(s) of the study:  
• 
To evaluate the effect of fezolinetant on bone mineral density after long-term treatment in women 
seeking treatment for relief of VMS associated with menopause. 
Exploratory objectives of the study:  
• 
To evaluate the effect of fezolinetant on subject-reported quality of life measures. 
• 
To evaluate the pharmacokinetics of fezolinetant and its metabolite, ESN259564. 
Planned Total Number of Study Centers and Locations:   
Approximately 250 centers globally.  
Study Population:   
Women ≥ 40 years and ≤ 65 years of age seeking treatment for VMS associated with menopause. 
Number of Subjects to be Enrolled/Randomized:   
1740 total subjects are planned to be randomized at a 1:1:1 ratio of fezolinetant 45 mg once daily: 
fezolinetant 30 mg once daily: placebo with approximately 580 subjects randomized to each of the 
treatment groups.   
Study Design Overview:   
Eligible subjects will complete all screening requirements and randomize into the 52-week 
placebo-controlled, double-blind, parallel-group, multicenter clinical study to assess the safety and 
tolerability of fezolinetant and quality-of-life in women seeking treatment for VMS associated with 
menopause.  
This study will consist of a screening period (days -35 to -1, including the screening visit [visit 1] 
assessments), a 52-week treatment period (day 1 [visit 2] to week 52 [visit 15]) and a follow-up visit 
(week 55 [visit 16]) 3 weeks after the last dose of study drug. An extra 15 screening days are allowed 
for repeat biopsy, if necessary (days -50 to -1, including the screening visit [visit 1] assessments). 
NOTE: All study visits will be completed as outpatient visits.  


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
19 Mar 2021 
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Page 16 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
 
Study Design Overview (continued):   
The screening visit (visit 1) will occur up to 35 days prior to treatment initiation. Eligibility will be 
assessed via physical examination, clinical laboratory testing, urine pregnancy test, vital signs, 
electrocardiogram (ECG), Papanicolaou (Pap) test (or equivalent cervical cytology, mammography, 
transvaginal ultrasound (TVU) and endometrial biopsy. To participate in the study, subjects must be 
seeking medical treatment for relief of VMS.  
Subjects may be retested for assessments up to 1 time upon approval of the medical monitor within 
the current 35-day screening window and will retain the same subject screening identification number.  
Subjects may be rescreened in this study, which will result in a new 35-day screening window and a 
new subject screening identification number, up to 1 time upon approval of the medical monitor. The 
following assessments do not need to be repeated at the rescreen provided they fall within the 
acceptable procedure completed time frame and all results meet inclusion and no exclusion criteria:  
TVU (acceptable 3 months from date of procedure); dual-energy X-ray absorptiometry (DXA) 
(acceptable 3 months from date of procedure); endometrial biopsy (acceptable 3 months from date of 
procedure); subject has documentation of a normal/negative or no clinically significant mammogram 
findings (obtained at screening or within the prior 12 months of trial enrollment [appropriate 
documentation includes a written report or an electronic report indicating normal/negative or no 
clinically significant mammographic findings]), ECG (acceptable 3 months from procedure); and 
documentation of a normal or not clinically significant Pap test (or equivalent cervical cytology) in 
the opinion of the investigator within the previous 12 months. Subjects who screen failed due to 
COVID-19 pandemic study suspension and have a documented evaluable endometrial biopsy from 
the original screening period do not have to undergo a repeat biopsy should they decide to rescreen. 
Subjects who screened for the 2693-CL-0301 or the 2693-CL-0302 study who did not meet the 
minimum requirement for frequency and severity of VMS prior to randomization may be consented 
and screened for this study with a new 35-day screening window from the time of consent. For these 
subjects the following assessments that were completed and/or assessed do not need to be repeated 
provided they fall within the acceptable procedure completed time frame and all results meet 
inclusion and no exclusion criteria: TVU (acceptable 3 months from procedure); endometrial biopsy 
(acceptable 3 months from procedure); subject has documentation of a normal/negative or no 
clinically significant mammogram findings (obtained at screening or within the prior 12 months of 
trial enrollment [appropriate documentation includes a written report or an electronic report indicating 
normal/negative or no clinically significant mammographic findings]); ECG (acceptable 3 months 
from procedure); and documentation of a normal or not clinically significant Pap test (or equivalent 
cervical cytology) in the opinion of the investigator within the previous 12 months. These subjects 
will have to repeat screening labs and complete DXA procedure requirements.  
A suction endometrial biopsy will be performed any time during the study in the case of uterine 
bleeding, in addition to the protocol-required time points.  
 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
19 Mar 2021 
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Page 17 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
Study Design Overview (continued):   
At the end of treatment (EOT) (or the early discontinuation [ED] visit for subjects who withdraw from 
the study prior to completion), a TVU and a suction endometrial biopsy will be required. If a subject 
discontinues from the study, an endometrial biopsy is required at the discontinuation visit along with 
all other EOT procedures. During the treatment period, any woman with an abnormal endometrial 
biopsy reported as disordered proliferative endometrium, endometrial hyperplasia or endometrial 
cancer will be referred to standard of care clinical management and followed to resolution, and the 
report of any medical or surgical procedures and the resultant pathology will be obtained. The 
investigator should record any such biopsy, and the associated diagnostic and therapeutic measures, as 
an AE. A mammogram at week 52/EOT/ED will be conducted if it coincides with the regularly 
scheduled routine screening mammogram of the patient, in accordance with local medical practice 
guidelines and the patient’s primary care physician. During the treatment period, subjects will return 
to the study site as indicated in the Schedule of Assessments. Site-based patient-reported outcome 
(PRO) measures will be self-administered via an electronic device as indicated in the Schedule of 
Assessments. All assessments must be performed at the site and prior to all other required visit 
procedures. In the event a subject withdraws from the study prior to completion, all efforts to collect 
information on the site-based PRO measures should be made before or shortly after withdrawal. 
Following the completion of the treatment period (week 52 or ED), subjects will complete an EOT (or 
ED) visit and final safety follow-up visit 3 weeks after the last dose of study drug is administered 
(week 55 or 3 weeks following ED). 
A Data Monitoring Committee (DMC) will oversee the safety of fezolinetant for the duration of the 
study. 
COVID-19 Consideration:  
All attempts should be made to conduct the protocol-defined scheduled visits. In cases where a 
subject is unable to visit the clinic due to site closure related to the COVID-19 pandemic, the 
following alternative measures may be implemented to ensure subject safety and continuity of care 
while participating in the study: 
• 
Telemedicine Conferences (telephone visits) to evaluate changes in a subject’s medical condition 
or medications and completion of electronic patient-reported outcome questionnaires following 
the process defined in the COVID-19 Notification of Pause and Screening Enrollment memo 
released on 27 March 2020 provided to the site by the sponsor. 
• 
Safety laboratory tests collected at a local lab to include biochemistry, hematology, liver 
biochemistry and coagulation panel testing. 
• 
Home healthcare services may be available in cases where arrangements are made in advance by 
the site upon request from the subject(s) 
Due to the nature of the Screening (visit 1), Randomization, week 0 (visit 2) and EOT/ED week 52 
(visit 15) visits, which include important study procedures, these visits must be conducted in the 
clinic. All other visits during the COVID-19 pandemic may be conducted utilizing all or some of the 
following services: home healthcare, telemedicine conferences (telephone visits) or safety laboratory 
tests collected at a local laboratory.     
Subjects who screen failed due to COVID-19 pandemic study suspension and have a documented 
evaluable endometrial biopsy from the original screening period do not have to undergo a repeat 
biopsy should they decide to rescreen. 
 
 


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
19 Mar 2021 
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Page 18 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
Inclusion/Exclusion Criteria: 
Inclusion:  
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations must be obtained from the 
subject or legally authorized representative prior to any study-related procedures.  
2. Subject is born female, aged ≥ 40 years and ≤ 65 years of age at the screening visit. 
3. Subject has a body mass index ≥ 18 kg/m2 and ≤ 38 kg/m2. 
4. Subject must be seeking treatment or relief for VMS associated with menopause and confirmed as 
menopausal per 1 of the following criteria at the screening visit: 
● Spontaneous amenorrhea for  12 consecutive months 
● Spontaneous amenorrhea for  6 months with biochemical criteria of menopause (follicle 
stimulating hormone > 40 IU/L), or  
● Having had bilateral oophorectomy  6 weeks prior to the screening visit  
5. Subject is seeking treatment for relief for VMS associated with menopause. 
6. Subject is in good general health as determined on the basis of medical history and general 
physical examination, including a bimanual clinical pelvic examination and clinical breast 
examination devoid of relevant clinical findings, performed at the screening visit; hematology and 
biochemistry parameters; pulse rate and/or blood pressure; and ECG within the reference range 
for the population studied, or showing no clinically relevant deviations, as judged by the 
investigator. 
7. Subject has documentation of a normal/negative or no clinically significant mammogram findings 
(obtained at screening or within the prior 12 months of trial enrollment). Appropriate 
documentation includes a written report or an electronic report indicating normal/negative or no 
clinically significant mammographic findings. 
8. Subject is willing to undergo a TVU to evaluate the uterus and ovaries at screening and at 
week 52 (EOT). For subjects who are withdrawn from the study prior to completion, a TVU 
should be collected at the ED visit. 
9. Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT) or the ED 
visit for subjects who are withdrawn from the study prior to completion, and any time during the 
study in the case of uterine bleeding.  The endometrial biopsy obtained at screening must be 
considered evaluable. 
10. Subject has documentation of a normal or not clinically significant Pap test (or equivalent cervical 
cytology) in the opinion of the investigator within the previous 12 months or at screening.  
11. Subject has a negative urine pregnancy test at screening. 
12. Subject has a negative serology panel (i.e., negative hepatitis B surface antigen, negative hepatitis 
C virus antibody and negative human immunodeficiency virus antibody screens) at screening. 
13. Subject agrees not to participate in another interventional study while participating in the present 
study.  


Sponsor: APGD 
ISN/Protocol 2693-CL-0304 
EudraCT number 2019-000275-16 
 
- CONFIDENTIAL - 
19 Mar 2021 
Astellas 
Page 19 of 115 
Version 3.2 Incorporating Nonsubstantial Amendment 3 
Exclusion:  
Subject who meets any of the following criteria will be excluded from participation in the study: 
1. Subject uses a prohibited therapy (strong or moderate cytochrome P450 [CYP] 1A2 inhibitors, 
hormone replacement therapy [HRT], hormonal contraceptive, any treatment for VMS 
[prescription, over the counter or herbal]) or is not willing to wash out and discontinue such drugs 
for the full extent of the study. 
2. Subject has a known substance abuse or alcohol addiction within 6 months of screening, as 
assessed by investigator. 
3. Subject has previous or current history of a malignant tumor, except for basal cell carcinoma. 
4. Subject’s systolic blood pressure is ≥ 130 mmHg or diastolic blood pressure is ≥ 80 mmHg based 
on the average of 2 to 3 readings on at least 2 different occasions within the screening period.  
● 
Subjects who do not meet the criteria may, at the discretion of the investigator, be 
re-assessed after initiation or review of antihypertensive measures.  
● 
Subjects with a medical history of hypertension can be enrolled at the discretion of the 
investigator once they are medically cleared (stable and compliant).  
5. Subject has a history of severe allergy, hypersensitivity or intolerance to drugs in general, 
including the study drug and any of its excipients. 
6. Subject has an unacceptable result from the TVU assessment at screening, i.e., full length of 
endometrial cavity cannot be visualized or presence of a clinically significant finding. 
7. Subject has an endometrial biopsy confirming presence of disordered proliferative endometrium, 
endometrial hyperplasia, endometrial cancer, or other clinically significant findings in the opinion 
of the investigator at screening.  
8. Subject has a history within the last 6 months of undiagnosed uterine bleeding. 
9. Subject has a history of seizures or other convulsive disorders. 
10. Subject has a medical condition or chronic disease (including history of neurological [including 
cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], 
endocrine or gynecological disease) or malignancy that could confound interpretation of the study 
outcome in the opinion of the investigator. 
11. Subject has active liver disease, jaundice, elevated liver aminotransferases (ALT or AST), 
elevated or total bilirubin, elevated International Normalized Ratio (INR), or elevated, alkaline 
phosphatase (ALP). Patients with mildly elevated ALT or AST up to 1.5 times the upper limit of 
normal (ULN) can be enrolled if total and direct bilirubin (DBL) are normal. Patients with mildly 
elevated ALP (up to 1.5 × ULN) can be enrolled if cholestatic liver disease is excluded and no 
cause other than fatty liver is diagnosed. Patients with Gilbert’s syndrome with elevated total 
bilirubin (TBL) may be enrolled as long as DBL, hemoglobin, and reticulocytes are normal. 
12. Subject has creatinine > 1.5  ULN; or estimated glomerular filtration rate using the Modification 
of Diet in Renal Disease formula  59 mL/min per 1.73 m2 at the screening visit. 
13. Subject has a history of suicide attempt or suicidal behavior within the last 12 months or has 
suicidal ideation within the last 12 months (a response of “yes” to questions 4 or 5 on the suicidal 
ideation portion of the Columbia-Suicide Severity Rating Scale [C-SSRS]), or who is at 
significant risk to commit suicide, as assessed by the investigator at screening and at the time of 
visit 2 (randomization). 
14. Subject has previously been enrolled in a clinical trial with fezolinetant. 
 


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Exclusion continued: 
15. Subject is participating concurrently in another interventional study or participated in an 
interventional study within 28 days prior to screening, or received any investigational drug within 
28 days or within 5 half-lives prior to screening, whichever is longer. 
16. Subject is unable or unwilling to complete the study procedures. 
17. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation. 
18. This criterion has been removed. 
19. This criterion has been removed. 
20. Subject has had a partial or full hysterectomy.  
Waivers to the inclusion and exclusion criteria will NOT be allowed. 
Investigational Product(s): 
Fezolinetant 15 mg tablet 
Fezolinetant 30 mg tablet  
Dose(s):  
30 mg (One 30 mg tablet and one placebo tablet) once daily 
45 mg (One 15 mg tablet and one 30 mg tablet) once daily 
Mode of Administration: 
Oral 
Comparative Drug(s): 
Placebo, 2 tablets to match once daily 
Dose(s): 
Not applicable 
Mode of Administration: 
Oral 
Concomitant Medication Restrictions or Requirements:  
Medications for the treatment of VMS (including prescription medications, over the counter and 
herbal) taken during the 12 months prior to screening and other medication taken 90 days prior to the 
screening visit and up to the first dose of study medication (treatment period) will be documented in 
the appropriate electronic case report form (eCRF) as prior medication.  
Medications taken after the first dose of study medication and through the last study-related activity 
will be documented on the appropriate CRF as concomitant medication. Prior and concomitant 
medications to be documented include but are not limited to: vitamins, herbal remedies (e.g., St. 
John’s wort, valerian), over the counter and prescription medications. 
Subjects will be instructed not to take any concomitant medication without first consulting the 
investigator or study coordinator throughout the duration of the study.  
 


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Prohibited Concomitant Medications: 
The following medications and therapies are prohibited throughout the study (from signing of 
informed consent form [ICF] through the last study-related activity): 
● 
Use of hormonal medications such as hormone therapy, HRT or hormonal contraception or any 
treatment for menopausal symptoms (prescription, over the counter or herbal). 
● 
Investigational research products that have not been approved for any indication in the country 
where the subject is enrolled.  
● 
Strong or moderate CYP1A2 inhibitors are prohibited.  
Duration of Treatment:  
Subject will take study drug daily from day 1 (randomization) for a duration of 52 weeks. 
Formal Stopping Rules  
Subject Discontinuation:  
A subject must be withdrawn from the study treatment for any of the following reasons: 
● 
Withdrawal of informed consent. 
● 
Lost to follow-up. 
● 
If for safety reasons it is in the best interest of the subject that she be withdrawn, in the 
investigator’s opinion. 
● 
Development of a medical condition that requires concomitant treatment with a prohibited 
therapy. 
● 
Development of seizures or other convulsive disorders. 
● 
Breaking of the randomization code during administration of the study drug by the investigator 
or by a member of the site staff. If the code is broken by the sponsor for safety reporting 
purposes or early time point analysis, the subject may remain in the study. 
● 
Confirmed (within 72 hours from the notification of test result) decrease in platelets below 
75,000 mm3, which does not normalize after 7 days or immediate withdrawal in case of platelets 
below 50,000 mm3. 
● 
Development of severe hepatic abnormality defines as ALT or AST > 8  ULN. 
● 
Confirmed (within 72 hours from the notification of test result) severe hepatic abnormality 
defined as any of the following: 
○ ALT or AST > 5 × ULN for more than 2 weeks; 
○ ALT or AST > 3  ULN AND TBL > 2  ULN or INR > 1.5; or 
○ ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5% increase from 
baseline).  
● 
The subject becomes pregnant. 
● 
Category 2 results of secondary or tertiary screening endometrial biopsy diagnosis. 
Study Discontinuation: 
The sponsor may terminate this study prematurely, or treatment arm, either in its entirety or at any 
study site, for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If the 
sponsor terminates the study for safety reasons, the sponsor will immediately notify the investigator 
and subsequently provide written instructions for study termination. 
 


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Endpoints for Evaluation:  
Primary Endpoint: 
The primary variable will require the evaluation of the safety of fezolinetant on the following:  
● 
Frequency and severity of adverse events.  
● 
Percentage of subjects with endometrial hyperplasia.  
● 
Percentage of subjects with endometrial cancer. 
Secondary Endpoints: 
● 
Change from baseline in endometrial thickness at 12 months. 
● 
Percentage of subjects with disordered proliferative endometrium. 
● 
Change from baseline in bone mass density and trabecular bone score at hip and spine at 
12 months. 
● 
Vital signs: sitting systolic and diastolic blood pressure and pulse rate. 
● 
Laboratory tests: hematology, biochemistry and urinalysis 
● 
C-SSRS. 
● 
ECG parameters. 
Exploratory Endpoints: 
The exploratory variables include the effect of fezolinetant on the following: 
● Mean change on the Menopause-Specific Quality of Life (MENQOL) Total Score from baseline 
to specified time points (week 4, 12, 24 and 52). 
● Mean change on the MENQOL Domain Scores from baseline to specified time points (week 4, 
12, 24 and 52). 
● Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) Total Score from baseline to specified time 
points (week 4, 12, 24 and 52). 
● Change from baseline to specified time points in serum concentrations of sex hormones and sex 
hormone-binding globulin (SHBG) (week 4, 12, 24, 52 and 55). 
● Plasma concentrations of fezolinetant and the fezolinetant metabolite ESN259564 at specified 
time points (week 4, 12, 24 and 52). 
Statistical Methods:  
Sample Size Justification:  
The sample size is not calculated based on the statistical power for efficacy evaluation to detect 
treatment difference, as the primary objective of this study is to assess long-term safety.  
The total sample size will be 1740 subjects who will be randomly assigned 1:1:1 to fezolinetant 
45 mg once daily group (580); fezolinetant 30 mg once daily group (580 ) and placebo group (580). 
This sample size would provide high probability to observe events of special interest that has with a 
fairly low background event rate that is less than 1%. If an assumed background rate of 0.26% such as 
for endometrial hyperplasia, this sample size would be able to demonstrate that the point estimate is 
less than or equal to 1% and upper bound of one-sided 95% CI to be ≤ 4% with at least 95% 
probability, assuming up to 60% (including baseline, ED and subject refusal of endometrial biopsy at 
EOT) of subjects may not have evaluable biopsy data.  
 


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Safety:  
Safety analyses will be performed on the safety analysis set (SAF), which is defined as all subjects 
who received at least 1 dose of study medication.  
Endometrial health-related endpoints such as hyperplasia, cancer and proliferative endometrium will 
be analyzed on the endometrial health analysis set (EH set). The EH set is defined as subjects having 
1 year evaluable biopsy results.  
The number and percentage of treatment-emergent adverse events (TEAEs) reported during the study 
period will be summarized by system organ class, preferred term, seriousness, severity and 
relationship to treatment, overall and by treatment group. The rate of endometrial hyperplasia, cancer 
and disordered proliferative endometrium will be evaluated separately. 
Changes from baseline for vital signs, ECGs and laboratory assessments will be summarized in tables 
by treatment group and visit.  
Descriptive summary statistics and listing of events will be provided for the C-SSRS by timepoint and 
for the entire study. 
Efficacy: 
No efficacy data will be collected.  
Exploratory Endpoints:  
The exploratory endpoints include the MENQOL and EQ-5D-5L which will be assessed at baseline 
and weeks 4, 12, 24 and 52. The exploratory endpoints will be analyzed for the full analysis set 
(FAS). Summary statistics will be provided by treatment group. 
Pharmacokinetics:  
Descriptive statistics on the actual values will be summarized by visit and treatment arm. 
Pharmacokinetics may be evaluated by a population pharmacokinetic approach. All details of 
population analyses will be described in a separate analysis plan and a separate report will be written. 
When deemed necessary, data from this study may be combined with data from other studies. 
Pharmacodynamics:  
Individual plasma hormone concentration values and actual sampling times relative to study drug 
intake will be listed. Descriptive statistics on the actual values and changes from baseline values will 
be summarized by assessment timepoint and by treatment arm. Pharmacodynamic data and efficacy 
data may be evaluated by a population pharmacodynamics or population 
pharmacokinetic/pharmacodynamic approach. All details of population analyses will be described in a 
separate analysis plan and a separate report will be written. When deemed necessary, data from this 
study may be combined with data from other studies.  
Interim analyses:  
Not applicable.  




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Table 1 
Schedule of Assessments 
Assessments 
Screening 
Visita,x 
Randomi-
zationx 
Treatment Period 
Follow-
Up Visitb 
Study Visit 
Visit 1 
Visit 2 
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 12, 
13 and 14 
Visit 15/ 
EOT/EDy 
Visit 16 
Time of Visit 
Week -5 
to -1 
Week 0 
Week 2 
Week 4 
Week 8 Week 12 
Week 16 
Week 20 
Week 24 
Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days
Days -35 
to -1 
Day 1 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 169 
Day 197, 225, 253, 
281, 309 and 337 
Day 365 
Day 386 
Visit Window (days)c 
-35 to -1
- 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
-14 /+ 6
± 3 
Informed consentd 
X 
Inclusion/exclusion 
criteria 
X 
X 
Medical history/ 
concomitant diseases 
X 
Mammograme 
X 
X 
Demographic dataf 
X 
Physical examinationg 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
X 
Urine pregnancy test 
X 
Clinical laboratoryi and 
urinalysis 
X 
X 
X i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGk
X 
X 
Pap testl 
X 
Transvaginal ultrasound 
(TVU)m 
X 
X 
Endometrial biopsyn 
Xn 
Xo 
DXAp 
X 
X 
Serologyq 
X 
Table continued on next page 
Footnotes


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Assessments 
Screening 
Visita,x 
Randomi-
zationx 
Treatment Period 
Follow-
Up Visitb 
Study Visit 
Visit 1 
Visit 2 
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 12, 
13 and 14 
Visit 15/ 
EOT/EDy 
Visit 16 
Time of Visit 
Week -5 
to -1 
Week 0 
Week 2 
Week 4 
Week 8 Week 12 
Week 16 
Week 20 
Week 24 
Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days
Days -35 
to -1 
Day 1 
Day 15 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 169 
Day 197, 225, 253, 
281, 309 and 337 
Day 365 
Day 386 
Visit Window (days)c 
-35 to -1
- 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
-14 /+ 6
± 3 
Blood pharmacodynamic 
sampler 
X 
X 
X 
X 
X 
X 
Blood pharmacokinetic 
samples 
Xr 
X 
X 
X 
C-SSRSt
X 
X 
X 
X 
X 
X 
EQ-5D-5Lu 
X 
X 
X 
X 
X 
MENQoLu 
X 
X 
X 
X 
X 
ePRO training 
X 
Randomization 
X 
Dispense study drugv 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
and accountabilityw 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
and AEsx 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE: adverse event; anti-HBc: antibody to hepatitis B core antigen; anti-HBs: hepatitis B surface antibody; C-SSRS: Columbia Suicide Severity Rating Scale; E2: estradiol; ECG: electrocardiogram; 
eCRF: electronic Case Report Form; DXA: dual-energy X-ray absorptiometry; ED: early discontinuation; EOT: end of treatment; ePRO: electronic patient-reported outcome; EQ-5D-5L: Euro-Qol 5D-5L; 
FSH: follicle-stimulating hormone; HBsAG: hepatitis B virus surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; INR: International Normalized Ratio; LH: luteinizing 
hormone; MENQoL: Menopause-Specific Quality of Life; Pap test: Papanicolaou test; PD: pharmacodynamic; PK: pharmacokinetic; SHBG: sex hormone-binding globulin; TVU: transvaginal ultrasound; 
VMS: vasomotor symptoms. 
Footnotes continued on next page 


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a.
The screening visit is to occur on or within 35 days of randomization (day 1 [visit 2]). Subjects may be retested 1 time for assessments upon approval of the medical monitor. An extra 15 screening
days are allowed for repeat biopsy, if necessary (days -50 to -1, including the screening visit [visit 1] assessments). The following assessments do not need to be repeated at the rescreen provided
they still fall within the acceptable screening time window: TVU, DXA, endometrial biopsy, mammogram, ECG and Pap test (or equivalent cervical cytology). Subjects who screened for the
2693-CL-0301 or the 2693-CL-0302 study that did not meet the minimum requirement for frequency and severity of VMS prior to randomization may be re-screened for this study. The following
assessments do not need to be repeated at the rescreen provided they still fall within the acceptable screening time window: TVU, endometrial biopsy, mammogram, ECG and Pap test (or equivalent
cervical cytology). History of average caffeinated beverage intake will be collected at baseline. At each clinic visit, the caffeinated beverage intake within the past 24 hours will be recorded.
b. The follow-up visit (visit 16) will occur approximately 3 weeks following the last dose of study drug.
c.
Subjects will return to the study site for visits and procedures to occur within ±3 days of the scheduled day. Unscheduled visits can be planned outside the scheduled visits.
d. Signed informed consent will be collected for all subjects before any study-related procedures are conducted.
e.
At screening, in the event that the subject does not have a documented normal/negative or no clinically significant findings mammogram from the previous 12 months on record. A mammogram at
week 52/EOT/ED will be conducted if it coincides with the regularly scheduled routine screening mammogram of the patient, in accordance with local medical practice guidelines and the patient’s
primary care physician.
f.
Includes age, race, sex and smoking status (smoker/non-smoker), etc. Demographic information may vary based on country requirements.
g. Includes height (at the screening visit only), weight and waist circumference. A bimanual clinical pelvic and clinical breast examination will be performed at the screening visit. A bimanual clinical
pelvic examination can be performed at any time in the study where clinically indicated.
h. At day 1 (visit 2) thru week 48 (visit 14), excluding visit 2b, a symptom directed physical exam will be conducted which includes weight and waist circumference.
i.
Includes biochemistry, coagulation and hematology panel. Visit 2b will only include liver biochemistry and INR testing.
j.
Includes oral/tympanic temperature, sitting blood pressure and pulse rate (sitting).
k. The subject should rest in supine position for at least 10 minutes prior to the ECG.
l.
Only in the event the subject does not have a normal/negative or no clinically significant findings Pap test (or equivalent cervical cytology) from previous 12 months on record.
m. TVU will be performed at screening and at week 52/EOT and in case of uterine bleeding during treatment.
n. Endometrial biopsy will be performed at screening and in case of uterine bleeding during treatment. Subject may schedule the endometrial biopsy on a separate day, within the screening period.
Subjects that require a retest biopsy due to insufficient or unevaluable result, will have an extended screening period and will be allowed an additional 15 days of screening (i.e., days -50 to -1).
Screening biopsy results are valid for study entry up to 3 months from date of procedures for applicable subjects. Subjects who screen failed due to the COVID-19 pandemic study suspension and have
a documented evaluable endometrial biopsy from the original screening period do not have to undergo a repeat biopsy should they decide to rescreen.
o. Endometrial biopsy will be required at EOT or ED. For EOT/ED week 52 (visit 15) biopsies that are evaluated as insufficient material or unevaluable, a retest biopsy will be required. Any of the three
pathologists can determine if a EOT/ED biopsy is insufficient or unevaluable. However, if two pathologists read the EOT/ED endometrial biopsy as evaluable and issue the same diagnosis, and the 3rd
pathologist reads the biopsy as insufficient or unevaluable, the biopsy does not need to be repeated.
Footnotes continued on next page 


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p. For practical reasons, the timing of DXA may vary from the actual time of the visit, depending on the DXA availability (DXA appointment). The screening visit (days -35 to -1 [visit 1]) DXA can be
performed once the subject has been deemed eligible based on screening laboratory tests, or at visit 2 but must be performed before randomization. The week 52 (visit 15) DXA should be performed
between week 50 and week 52, inclusive. For subjects who are withdrawn from the study prior to completion, a DXA will be completed as soon as possible after study drug discontinuation (preferably
within 2 weeks).
q. For HBsAG, anti-HCV antibodies, anti-HBs antibodies, anti-HBc antibodies and anti-HIV antibodies.
r.
Pharmacodynamic samples will be taken predose (1 hour) at day 1 (visit 2), week 4 (visit 3), week 12 (visit 5), week 24 (visit 8), at week 52 (visit 15) and week 55 (visit 16). Markers include LH, FSH,
E2, SHBG, androstenedione, dehydroepiandrosterone, estrone and testosterone.
s.
Pharmacokinetic samples to be taken predose at week 4 (visit 3), week 12 (visit 5), week 24 (visit 8), and at EOT/ED week 52 (visit 15) and at 1 to 3 hour postdose at week 4 (visit 3). A predose
sample will be collected for any subject with a signal of elevated (> 3 × ULN) transaminases. For the week 52 (visit 15) PK/PD samples, the last dose of study drug should be administered the day
prior to the week 52 (visit 15) visit. Sites should collect week 52 (visit 15) PK/PD samples approximately at the same time when study drug would typically be given on site.
t.
A clinician will administer the C-SSRS measure electronically at the clinic visit, prior to any invasive procedures. This will be administered electronically via the site tablet at screening, (visit 1), week
0 (visit 2), week 12 (visit 5), week 24 (visit 8), EOT/ED week 52 (visit 15) and the follow-up visit (week 55 [visit 16]).
u. ePRO assessments are self-administered electronically via the site tablet at the study site at week 0 (visit 2), week 4 (visit 3), week 12 (visit 5), week 24 (visit 8) and week 52 (visit 15). The ePRO
assessments are administered before any other study assessments/procedures are performed; assessments at visit 2 must occur prior to randomization/first dosing; assessments at week 4 (visit 3), week
12 (visit 5), week 24 (visit 8) must occur prior to dosing; in the event a subject withdraws from the study, efforts to collect information on the site-based subject-reported outcome measures should be
made before or shortly after discontinuation.
v. Subjects will be assigned study drug as a kit containing either fezolinetant or placebo. Study drug intake will be done with a glass of room temperature tap water. The first intake of study drug will take
place at the study site on day 1 (visit 2) under the supervision of the study staff. On study visit days (except for EOT/ED week 52 [visit 15]), the daily dose of study drug will be taken at the study site,
under the supervision of the study staff, after collection of predose blood samples. On all other days throughout the treatment period, subjects will be instructed to take their study drug at home, in the
morning with water.
w. Subjects will be asked to return all unused study drug. Compliance of study drug intake will be assessed by counting returned study drug and recorded in the source documents and the IRT.
x. AEs and intake of concomitant medication(s) will be monitored continuously from informed consent until the last study-related activity.
y. Screening (visit 1), Randomization, week 0 (visit 2) and EOT/ED week 52 (visit 15) visits, must be conducted in the clinic and not home healthcare, telemedicine conferences or a local laboratory.


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1 
INTRODUCTION 
1.1 
Introduction to Fezolinetant 
Fezolinetant is a small-molecule, selective neurokinin-3 receptor (NK3R) antagonist currently 
being developed as an innovative non-hormonal treatment specifically targeting the cause of 
vasomotor symptoms (VMS) in postmenopausal women (menopause-related vasomotor 
symptoms [MR-VMS]).  
For more information, refer to the Investigator’s Brochure (IB) for fezolinetant. 
1.2 
Background 
1.2.1 
Vasomotor Symptoms (Hot Flashes): Epidemiology and Etiology 
VMS, commonly known as hot flashes (HFs), are the most common complaint among 
women entering menopause and for many women, may continue to occur for up to 5 years 
(although around 20% of women will continue to experience them for up to 15 years) 
[Stearns et al, 2003; Rossouw et al, 2002; Kronenberg, 1994]. The large prospective cohort 
Study of Women's Health Across the Nation found that overall prevalence of VMS was 
approximately 70% [Thurston & Joffe, 2011]. 
VMS can have a significant negative impact on quality of life and are therefore a major reason 
for menopausal women to seek medical attention. Despite the vast numbers of individuals 
affected, the physiology of VMS is not fully understood, although a disturbance in normal 
thermoregulatory function is thought to be the main underlying cause. The primary presentation 
of VMS is a subjective and transient sensation of heat, flushing and sweating that usually last 
4 to 10 min and may be followed by a feeling of being chilled. VMS may be accompanied by 
palpitations, feelings of anxiety and sleep disruption leading to fatigue or irritability; in rare 
occurrence, panic may occur [Kronenberg et al, 1994; Kronenberg et al, 1990].  
The most effective and commonly used treatment for VMS is hormone replacement therapy 
(HRT), but a Women’s Health Initiative study raised questions about the long-term safety of 
this treatment [Rossouw et al, 2002]. Thus, current guidelines recommend a limited duration 
of HRT due to associated risks of breast cancer (BC), coronary artery disease, stroke and 
thromboembolism [de Villiers et al, 2016; Rossouw et al, 2002]. Furthermore, the current 
safety data do not support the use of HRT in several groups of patients (e.g., those with 
BC/endometrial cancer, liver disease). The perceived limitations of HRT, coupled with the 
limited efficacy and adverse effects observed with nonhormonal therapies (e.g., selective 
serotonin reuptake inhibitors) have led clinicians to search for other treatment options for 
VMS. One selective serotonin reuptake inhibitor is approved in the US for the treatment of 
MR-VMS (Brisdelle®, low dose paroxetine). Studies of venlafaxine and fluoxetine in women 
with a prior history of BC have suggested that certain antidepressants with the ability to 
inhibit serotonin reuptake may significantly reduce MR-VMS [Loprinzi et al, 2002; Loprinzi 
et al, 2000; Stearns et al, 2000]. 
Over the past 20 years, a growing body of evidence has implicated neurokinin B (NKB) 
NK3R signaling in the etiology of menopausal VMS. Recent advances in the field have 


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demonstrated that the gonadotropin-releasing hormone (GnRH) pulse frequency is modulated 
by the kisspeptin/neurokinin B/dynorphin (KNDy) neurons (also known as ‘KiSS Neuron’) 
in the arcuate nucleus of the hypothalamus [Millar & Newton, 2013]. Neuroanatomical 
studies have shown that these neurons are sensitive to NKB/NK3R signaling [Hrabovszky, 
2014]. By studying brain specimens at post mortem, [Rance & Young, 1991] initially showed 
that in postmenopausal women, hypothalamic neurons are hypertrophied and have increased 
NKB gene expression and neuronal activity compared with premenopausal women. This was 
also found to be true in ovariectomized monkeys but moreover, this change could be reversed 
by treatment with sex steroid replacement thus suggesting this was a dynamic change in 
response to reduced circulating concentrations of estradiol (E2) as occurs in the menopause 
[Rance, 2009]. Subsequent work in rats highlighted the importance of the hypothalamic 
median pre-optic nucleus in the propagation of the NKB-mediated signal that results in VMS 
[Rance et al, 2013]. The median pre-optic nucleus is a neural area that receives input from, 
and projects to, the autonomic thermoregulatory pathway, expresses NK3R and hence results 
in activation of heat dissipation effectors that characterize VMS. Importantly, estrogen also 
acts directly on the estrogen receptor alpha expressed on KNDy neurons to decrease similarly 
KNDy neuron activity [Ruka et al, 2016; Lehman et al, 2010]. Additionally, Crandall et al. 
recently found that genetic variation in tachykinin receptor 3, which is the gene that encodes 
NK3R, may account for the variability in experience of VMS reported among women 
[Crandall et al, 2017]. 
1.3 
Fezolinetant Nonclinical and Clinical Data 
1.3.1 
Summary of Nonclinical Studies 
In vitro studies demonstrated that fezolinetant is a potent full inhibitor of human neurokinin 
3 (hNK3) receptor and is highly selective for hNK3 in comparison to the other members of 
tachykinin receptor family (hNK 1 and hNK) and other G-protein coupled receptors 
including the ones known to be implicated in modulation of GnRH axis. 
In vivo animal pharmacology studies have been focused on the effects of fezolinetant on 
reproductive hormones. These studies demonstrated that fezolinetant significantly reduces 
plasma luteinizing hormone (LH) levels in castrate male rats at a dose range of 3 to 20 mg/kg.  
In ovariectomized female rats, fezolinetant significantly reduced the mean plasma levels and 
pulsatile LH secretion frequency and amplitude at 10 mg/kg dosage. Fezolinetant 
significantly reduced circulating LH levels in castrate male monkeys following single and 
5-day repeated oral dosing at 5 mg/kg per day. After 5 consecutive days of dosing, 
fezolinetant had no effect on plasma follicle-stimulating hormone (FSH) levels, 
demonstrating that antagonism of the neurokinin 3 receptor is a means to selectively inhibit 
LH, but not FSH.  
More information including details on the toxicological studies can be found in the IB. 


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1.3.2 
Summary of Clinical Studies 
To date, 10 clinical studies have been completed with fezolinetant; 6 phase 1 studies 
(ESN364-CPK-101, ESN364-CPK-102, ESN364-CPK-103, 2693-CL-0020, 2693-CL-0006 
and 2693-CL-009) and 4 phase 2 studies (ESN364-HF-204, ESN364-UF-02, ESN364-PCO-
201 and ESN364_HF_205). Two of the 4 phase 2 studies were performed in women with 
MR-VMS (Studies ESN364_HF_204 and ESN364_HF_205). The 10 completed studies with 
fezolinetant are shown in Table 2.  
The pharmacokinetics of fezolinetant were characterized in studies in healthy subjects and in 
patients with VMS. After oral intake, fezolinetant showed generally dose proportional 
pharmacokinetics at doses between 20 and 60 mg once daily in female subjects. Maximum 
concentration (Cmax) was generally reached within 1 to 4 hours postdose with terminal half-life 
ranging between 4-6 hours in healthy subjects and patients. With a once daily dose regimen, 
steady state plasma concentrations were achieved by approximately day 2 with minimal 
accumulation. Low plasma protein binding of fezolinetant (50%) was observed with almost 
equal distribution of fezolinetant into red blood cells and plasma, with a blood-to-plasma ratio 
of 0.9.  
Fezolinetant undergoes extensive metabolism, primarily by cytochrome P450 (CYP) 1A2 
enzyme, to form the major metabolite ES259564. A strong CYP1A2 inhibitor (fluvoxamine) 
increased fezolinetant area under the concentration-time curve (AUC) and Cmax approximately 
9-fold and 1.8-fold, respectively, while smoking was shown to decrease AUC and Cmax to a 
geometric least squares mean ratio of 48.3% and 71.7%, respectively (2693-CL-0006).  
In a recently completed mass balance study (ESN364_CPK_103), the routes of excretion of 
fezolinetant were found to be via urine (76.9%) and feces (14.7%). In urine, a mean of 1.1% 
of the administered fezolinetant dose was excreted unchanged and 61.7% of the administered 
dose was excreted as metabolite ES259564. 
Fezolinetant did not show clinically significant food effects on its pharmacokinetic exposure 
parameters (ESN364_CPK_101). Based on population pharmacokinetic modeling analyses, 
body weight was not identified as an important predictor of AUC. However, male subjects 
are predicted to have 53.2% reduction AUC and 14.9% reduction in Cmax, compared to 
females. Asian population was predicted to have a 25% increase in steady-state Cmax and 
AUC, which is consistent with clinical observations (Study 2693-CL-0020) 
Based on a recently completed relative bioavailability study (2693-CL-0009), the tablet 
formulation showed slightly higher pharmacokinetic exposure (approximately 8% higher for 
AUC0-inf and 23% higher for Cmax) than capsule formulation.  


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Table 2 
Completed Studies with Fezolinetant 
Study Number 
Development 
Phase 
Description 
Location 
Number of 
Subjects/Patients 
Randomized 
ESN364-CPK-101 
1 
First-in-human study. 
Single and multiple 
ascending doses from 3 to 
180 mg tested in 
65 healthy males and 
females 
Belgium 
SAD: 
Fezolinetant = 12 
Placebo = 4 
MAD: 
Fezolinetant = 36 
Placebo = 12 
ESN364-CPK-102 
1 
180 to 900 mg single 
doses and up to 720 mg 
per day for 7 days in 
healthy males and 
females 
Belgium 
SAD: 
Fezolinetant = 18 
Placebo = 6 
MAD: 
Fezolinetant = 12 
Placebo = 4 
ESN364-CPK-103 
1 
14C-ESN-364 (270 µg) 
ADME study in healthy 
postmenopausal females 
Netherlands 
Fezolinetant = 5 
2693-CL-0020 
1 
Placebo-controlled, single 
and multiple oral dose 
study in healthy Japanese 
male and healthy 
Japanese pre- and 
postmenopausal female 
subjects 
Japan 
(Blinded) 
Fezolinetant = 33 
Placebo = 11 
2693-CL-0009 
1 
A randomized crossover 
study to assess the 
relative bioavailability of 
ESN364 following a 
single dose of tablet 
formulation compared to 
a single dose of capsule 
formulation in healthy 
postmenopausal female 
subjects 
US 
Fezolinetant = 16 
 
2693-CL-0006 
1 
“A Phase 1 Study to 
Assess the Effect of 
Multiple Doses of 
Fluvoxamine and 
Smoking on the Single 
Dose Pharmacokinetics of 
ESN364 in Healthy 
Postmenopausal Female 
Subjects” 
Germany 
(Open-label) 
Fezolinetant = 18 
ESN364_HF_204 
2a 
Proof of concept study in 
MR-VMS 
Belgium 
Fezolinetant 90 mg 
twice daily = 43 
Placebo = 44 
Table continued on next page 


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Study Number 
Development 
Phase 
Description 
Location 
Number of 
Subjects/Patients 
Randomized 
ESN364-UF-02 
2a 
Proof of concept study in 
heavy menstrual bleeding 
due to uterine fibroids 
EU 
Fezolinetant 60 mg 
once daily = 10 
Fezolinetant 180 mg 
once daily = 6 
Placebo = 7 
ESN364-PCO-201 
2a 
Proof of concept study in 
polycystic ovary 
syndrome 
EU 
Fezolinetant 60 mg 
once daily = 23 
Fezolinetant 180 mg 
once daily = 23 
Placebo = 27 
ESN364_HF_205 
2b 
Dose ranging study in 
menopausal VMS 
US 
Fezolinetant 15 mg 
twice daily = 45 
Fezolinetant 30 mg 
twice daily = 44 
Fezolinetant 60 mg 
twice daily = 45 
Fezolinetant 90 mg 
twice daily = 44 
Fezolinetant 30 mg 
once daily = 45 
Fezolinetant 60 mg 
once daily = 45 
Fezolinetant 120 mg 
once daily = 44 
Placebo = 44 
ADME: absorption, distribution, metabolism and excretion; MAD: multiple ascending dose; MR-VMS: 
Menopause-Related Vasomotor Symptoms; SAD: single ascending dose; VMS: vasomotor symptoms.  
Source: Fezolinetant (ESN-364) Investigator’s Brochure. 
Study ESN364_HF_204 was a 12-week double-blind, placebo-controlled, parallel-group, 
multicenter, proof of concept study to assess the effect of 12-week administration of 
fezolinetant in early postmenopausal women suffering from HFs. A total of 80 patients, 40 in 
each treatment group, completed the entire study. In this study, the mean HF frequency for 
the moderate and severe VMS at weeks 4 and 12 reduced by approximately 88% and 93% 
from baseline compared to a placebo decrease of 38% and 46%, respectively (P < 0.001). The 
mean HF score for the moderate and severe VMS at weeks 4 and 12 dropped approximately 
89% and 94% from baseline compared to a placebo decrease of 38% and 46%, respectively 
(P < 0.001). Most often a statistically significant difference between the fezolinetant and 
placebo group was observed after only 1 week of treatment, demonstrating a very rapid onset. 
Study ESN364_HF_205 was a 12-week double-blind, placebo-controlled, parallel-group, 
multicenter, dose-ranging study to assess the effect of 12-week administration of once daily 
and twice daily doses of fezolinetant in early postmenopausal women suffering from HFs 
(8 arm study). A total of 356 subjects were randomized into this study with 43 to 45 subjects 
in each treatment group. There was a clinically relevant treatment effect observed at multiple 
doses. All groups were significantly different from placebo with respect to mean change in 


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the frequency of moderate to severe VMS at both weeks 4 and 12. The improvement relative 
to placebo at weeks 4 and 12 was greater than 2 HFs per day, indicative of a clinically 
relevant improvement, for all dose groups except 15 mg twice daily. All groups were 
significantly different from placebo with respect to mean change in the severity of moderate 
to severe VMS from baseline to week 4, but only 60 mg twice daily, 90 mg twice daily and 
60 mg once daily demonstrated significance at week 12 in this study. 
These data provide clinical evidence that, via antagonism of increased KNDy neuronal 
activity, fezolinetant produces a marked clinically significant reduction in VMS related the 
menopause and is very likely to exhibit similar activity in other hypoestrogenic states such as 
occur in women undergoing hormonal treatment for BC. More information can be found in 
the IB.  
1.4 
Summary of Key Safety Information for Fezolinetant  
1.4.1 
Nonclinical studies 
In the nonclinical toxicology studies in rats and monkeys, fezolinetant was well tolerated and 
the no observed adverse event level (NOAEL) was considered to be 25 mg/kg per day in 
Cynomolgus monkeys as the most relevant species. Drug exposure (area under the curve) at 
this dose level in Cynomolgus monkey was similar to drug exposure levels measured in 
premenopausal women dosed at 540 mg/day. The main events that were observed in the 
nonclinical studies were considered to be related to the pharmacology of fezolinetant, 
including reduction of the ovarian activity in female monkeys. 
Liver hypertrophy without increases in alanine aminotransferase (ALT) and bilirubin seen in 
rats was related to enzyme induction since this finding coincided with thyroid follicular cell 
hypertrophy. The liver finding is generally regarded as not predictive for humans. The 
NOAEL was 10 mg/kg. In monkeys, no liver changes were seen. 
Adverse effects were observed at the high doses used in the nonclinical studies, at dose levels 
much higher than the clinical dosages. In monkeys, high doses of fezolinetant resulted in 
weight loss and a reduction in platelet counts, which resulted in observations of hemorrhage 
and regenerative anemia; these effects were recoverable with discontinuation of dosing. In 
rats, very high dose levels were associated with death and marked clinical signs and body 
weight loss during the first few days of treatment. 
Exposure to the main human metabolite ES259564 was evaluated in the long-term toxicity 
studies in rats and monkeys and the metabolite is considered to be toxicologically qualified 
up to the human dose of 180 mg/day. 
Fezolinetant did not show any genotoxic potential. 
Reproductive toxicology studies on both rats and rabbits demonstrated significant litter loss in 
both animal species; however, the surviving embryos did not show any adverse effect on 
development. The litter loss in this case is regarded as a pharmacologic effect on the hormonal 
and reproductive status. A fertility and early embryonic development study was also 


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completed in female rats without any reported adverse events (AEs; NOAEL = 100 mg/kg 
per day).  
1.4.2 
Clinical Studies 
The most frequently reported treatment-emergent adverse events (TEAEs) (i.e., in 
> 2 subjects [> 33.3%] per treatment group) following multiple ascending dosing for 21 days 
in healthy female subjects in the first in human study (ESN364-CPK-101) were: abdominal 
pain in 3 (50.0%) subjects each in placebo and in 180 mg fezolinetant treatment groups, 
nausea in 3 (50.0%) subjects in the 20 mg fezolinetant treatment group, headache in 
3 (50.0%) and 4 (66.7%) subjects in the 60 and 180 fezolinetant treatment groups, 
respectively, and dry skin in 3 (50.0%) subjects in the 180 mg fezolinetant treatment group. 
The events of nausea and headache were only reported in the 20, 60 and/or 180 mg 
fezolinetant treatment groups and not in the placebo group. Clinical observations related to 
sex hormones were due to the mode of action of the investigational medicinal product: 
fezolinetant resulted in prolongation of the menstrual cycle in females for the first cycle after 
dosing for the 60 mg and 180 mg dose levels, with a median change from baseline of 7.5 and 
9.5 days, respectively. Once withdrawn from the study drug, the normal menstrual cycle 
resumed immediately with cycle lengths comparable to the predose menstrual cycle. 
The most frequent TEAEs (in > 2 [12.5%] subjects in the fezolinetant total group 
[16 subjects]) in the single dose Part 1 of the subsequent dose ranging phase 1 study 
(ESN364-CPK-102), were headache, paresthesia and nausea. The highest incidence for 
headache was after 360 and 900 mg intake, for paresthesia after 540 and 900 mg intake and 
for nausea after 900 mg intake. A severe headache was reported after 900 mg fezolinetant 
intake. Based on the results from Part 1, the maximum tolerated dose was considered to be 
900 mg based on the occurrence of AEs (oral paraesthesia and severe headache). In the 
multiple dose administration (7 days) Part 2 in healthy female volunteers, the most frequent 
TEAEs (in > 2 [16.7%] subjects in the fezolinetant total group [540 and 720 mg combined]) 
were headache (4 [33.3%] subjects) and vaginal hemorrhage (3 [25.0%] subjects). In the 
single dose administration Part 3 in healthy male volunteers, the most frequent TEAE 
(in > 2 [28.6%] subjects in the fezolinetant total treatment groups [720 and 900 mg]) was oral 
paraesthesia (3 [42.9%] subjects). 
The most frequently reported TEAEs in the phase 2a study (ESN364_HF_204) reported in 
> 2 patients in the fezolinetant group [90 mg bid]) were headache, palpitations, diarrhea and 
influenza. All TEAEs were at most moderate in severity. Treatment-related TEAEs were 
reported in 13 (30.2%) patients in the fezolinetant group and in 11 (25.0%) patients in the 
placebo group. Most treatment-related TEAEs were gastrointestinal disorders (abdominal 
discomfort, diarrhea and oral paraesthesia) reported in 6 (14.0%) patients in the fezolinetant 
group and 0 patients in the placebo group. Two patients discontinued treatment in the 
fezolinetant group (for 1 patient due to the TEAE fibromyalgia, depression, dry mouth, 
headache, palpitations, diarrhea and vomiting: and for 1 patient due to the TEAE headache 
and vertigo). None of the subjects in the placebo group permanently stopped the study 
medication due to a TEAE. 


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In the phase 2b ESN364_HF_205 study, overall fezolinetant was well tolerated. During this 
study the rates of TEAEs were comparable across all groups and most events were mild or 
moderate in severity. No deaths or treatment-related serious adverse events (SAEs) were 
reported.  
The most common Medical Dictionary for Regulatory Activities (MedDRA) system organ 
classes (SOCs; ≥ 10% patients in any arm) in which TEAEs were reported were: 
gastrointestinal disorders, infections and infestations, general disorders and administration 
site conditions, investigations, nervous system disorders and skin and subcutaneous tissue 
disorders. 
The active dose groups had a higher proportion of TEAEs reported as drug-related, but only 
2 patients had severe drug-related TEAEs. TEAEs leading to discontinuations were reported 
in small numbers of patients across the treatment groups. A total of 5 patients discontinued 
due to changes in liver enzymes following ESN364; no discontinuations due to changes in 
liver enzymes occurred following placebo treatment. 
Of the TEAEs of special interest, there was 1 patient with oral paresthesia (in the 30 mg bid 
group) and a few isolated cases of uterine bleeding with no reports of endometrial 
hyperplasia. There were 9 patients with ALT or AST > 3 × upper limit of normal (ULN). Of 
these, 3 patients had ALT or AST > 8 × ULN (60 mg bid, 90 mg bid and 60 mg qd). There 
were no cases of total bilirubin (TBL) > 2 × ULN, and consequently no Hy’s law cases. 
There were no clinically meaningful changes in hematology, coagulation, vital signs, 
electrocardiograms (ECG), bone turnover markers, endometrial assessments, or suicide status. 
Overall in the clinical program to date, including indications other than MR-VMS, 
7 treatment-emergent SAEs have been reported. These SAEs were assessed as not related to 
the study medication, except for a case of superficial thrombophlebitis reported in the phase 
2a study in polycystic ovary syndrome (ESN364-PCO-201), which was assessed by the 
investigator as possibly related to the study medication; the study drug was interrupted and 
reinitiated after the event had resolved, with no recurrence of the event.  
Given the limited safety information with fezolinetant, there are no expected serious adverse 
reactions (SARs) at the start of the phase 3 program. For up to date information regarding 
expected SARs, refer to the Reference Safety Information (RSI). The RSI for fezolinetant is 
contained in the IB, Section 5.3.2 Expected Serious Adverse Drug Reactions. 
1.5 
Risk Benefit Assessment 
Fezolinetant is currently being developed for the treatment of VMS associated with the 
menopause (MR-VMS). 
Based on recent advances in science, as well as the clinical data derived from 2 phase 
2 clinical studies in women with VMS associated with the menopause, there are positive 
reasons to believe that fezolinetant can be an effective treatment for MR-VMS and 
treatment-resistant VMS. 


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When given to normally cycling healthy women, fezolinetant is capable of altering the 
menstrual cycle and decreasing the circulating levels of E2, LH, progesterone (P4) and 
testosterone. Since this study aims to include menopausal women, these effects will be of less 
importance because of the physiological changes that happen in the climacterium 
(anovulation with loss of P4 and E2 production and consequently increase of LH/FSH). 
In terms of hormonal changes, a mild to moderate decrease of the already elevated LH and 
FSH plasma levels is anticipated. There are no known risks associated with this decrease of 
the gonadotropins in menopausal women.  
Treatment with fezolinetant can cause adverse effects or other symptoms. Adverse effects 
that can be expected are those AEs that presented in fezolinetant clinical studies in healthy 
male and female volunteers, as well as in menopausal women.  
Details of the AE profile from the completed clinical studies are presented in [Section 1.3 
Fezolinetant Nonclinical and Clinical Data].  
Across the completed phase 1 and 2a studies, there have been a small number of mild, 
transitory transaminase elevations observed both in patients/subjects who received either 
fezolinetant or placebo. There were no incidences of raised TBL and none of the 
patients/subjects experienced associated symptoms. In the recently completed phase 2b study 
ESN364_HF_205, transitory increases in transaminase enzymes, ALT/aspartate 
aminotransferase (AST), have been reported in 7 subjects between 4 and 8 weeks after start 
of study treatment and in 2 unique subjects during study follow-up. Subjects were reported to 
be asymptomatic throughout and there was no evidence of functional liver impairment. 
Although there were cases with evidence of significant underlying hepatic conditions and 
other confounding factors, independent expert review of the cases that met a stopping rule 
concluded that the study drug was probably the cause of the increased transaminase levels. In 
all cases, transaminase enzyme levels rapidly decreased, in 2 cases during continuing 
treatment with study medication.  
Based on cases of increased AST and ALT > 5 × ULN in the phase 2b study 
ESN364_HF_205 that were assessed by external hepatic experts as related to the use of 
fezolinetant, liver injury has been categorized as an important potential risk. Monitoring of 
liver parameters is incorporated in the design of this protocol, including individual patient 
stopping rules and liver assessment per [Section 12.5]. Increased transaminases have not been 
observed at the dose selected for this study, i.e., 30 mg fezolinetant once daily [Section 2.2.2 
Dose Rationale]. 
Severe thrombocytopenia has been reported in non-clinical studies but not in clinical studies 
and has been categorized as an important potential risk. To date, 1 clinical case of mind, 
pre-existing, thrombocytopenia has been reported (in phase 2a Study ESN364_HF_204). 
Platelet counts are included in the hematological monitoring during the course of the study. 
Circumoral paresthesia has been reported by several subjects taking fezolinetant. Considering 
the reported cases in the phase 1 studies (ESN364-CPK-101 and ESN364-CPK-102) the 
occurrence of circumoral paresthesia is dose dependent for both intensity and duration, 


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usually starting within the first hour after drug intake, relatively short-lasting, with higher 
doses leading to a more intense and prolonged sensation. This type of paresthesia has been 
described as either plain paresthesia (oral, facial skin, tongue, scalp, lips), as a prickling 
sensation of the face, as a numbness of the tongue or as a tingling sensation (face, mouth, 
tongue).  
Circumoral paraesthesia has been recognized in the clinical studies and categorized as a 
non-important identified risk. No specific additional monitoring is recommended. 
Overall, the potential benefits of subjects receiving 30 mg or 45 mg once daily fezolinetant 
are considered to outweigh the potential risks. Although an important medical condition, 
VMS are not considered life-threatening and 52-week placebo treatment, which is also 
associated with improvement in VMS, is justifiable. 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objective(s) 
2.1.1 
Primary Objective 
● 
To evaluate the long-term safety and tolerability of fezolinetant in women seeking 
treatment for relief of VMS associated with menopause. 
● 
To evaluate the effect of fezolinetant on endometrial health after long-term treatment in 
women seeking treatment for relief of VMS associated with menopause. 
2.1.2 
Secondary Objective  
● 
To evaluate the effect of fezolinetant on bone mineral density after long-term treatment 
in women seeking treatment for relief of VMS associated with menopause. 
2.1.3 
Exploratory Objectives 
● 
To evaluate the effect of fezolinetant on subject-reported quality of life measures. 
● 
To evaluate the pharmacokinetics of fezolinetant and its metabolite, ESN259564. 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is a 52-week randomized, placebo-controlled, double-blind, parallel-group, multicenter 
clinical study to assess the safety and tolerability of fezolinetant in women seeking treatment 
for VMS associated with menopause. The study visits will be performed on an outpatient basis. 
This study will consist of a screening period (days -35 to -1, including the screening visit 
[visit 1] assessments), a 52 week treatment period (day 1 [visit 2] to week 52 [visit 15]) and a 
follow up visit (week 55 [visit 16]) 3 weeks after the last dose of study drug. An extra 
15 screening days are allowed for repeat biopsy, if necessary (days -50 to -1, including the 
screening visit [visit 1] assessments). 
The screening visit (visit 1) will occur up to 35 days prior to treatment initiation. Eligibility 
will be assessed via physical examination, clinical laboratory testing, urine pregnancy test, 
vital signs, ECG, Papanicolaou (Pap) test (or equivalent cervical cytology), mammography, 


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transvaginal ultrasound (TVU) and endometrial biopsy. To participate in the study, subjects 
must be seeking medical treatment for relief of VMS.  
Subjects may be retested for assessments up to 1 time upon approval of the medical monitor 
within the current 35-day screening window and will retain the same subject screening 
identification number.  
Subjects may be rescreened in this study, which will result in a new 35-day screening 
window and a new subject screening identification number, up to 1 time upon approval of the 
medical monitor. The following assessments do not need to be repeated at the rescreen 
provided they fall within the acceptable procedure completed time frame and all results meet 
inclusion and no exclusion criteria:  TVU (acceptable 3 months from date of procedure); 
dual-energy X-ray absorptiometry (DXA) (acceptable 3 months from date of procedure); 
endometrial biopsy (acceptable 3 months from date of procedure); subject has documentation 
of a normal/negative or no clinically significant mammogram findings (obtained at screening 
or within the prior 12 months of trial enrollment [appropriate documentation includes a 
written report or an electronic report indicating normal/negative or no clinically significant 
mammographic findings]), ECG (acceptable 3 months from procedure); and documentation 
of a normal or not clinically significant Pap test (or equivalent cervical cytology) in the 
opinion of the investigator within the previous 12 months. Subjects who screen failed due to 
COVID-19 pandemic study suspension and have a documented evaluable endometrial biopsy 
from the original screening period do not have to undergo a repeat biopsy should they decide 
to rescreen. 
Subjects who screened for the 2693-CL-0301 or the 2693-CL-0302 study who did not meet 
the minimum requirement for frequency and severity of VMS prior to randomization may be 
consented and screened for this study with a new 35-day screening window from the time of 
consent. For these subjects the following assessments that were completed and/or assessed do 
not need to be repeated provided they fall within the acceptable procedure completed time 
frame and all results meet inclusion and no exclusion criteria: TVU (acceptable 3 months from 
procedure); endometrial biopsy (acceptable 3 months from procedure); subject has 
documentation of a normal/negative or no clinically significant mammogram findings 
(obtained at screening or within the prior 12 months of trial enrollment [appropriate 
documentation includes a written report or an electronic report indicating normal/negative or 
no clinically significant mammographic findings]); ECG (acceptable 3 months from 
procedure); and documentation of a normal or not clinically significant Pap test (or equivalent 
cervical cytology) in the opinion of the investigator within the previous 12 months. These 
subjects will have to repeat screening labs and complete DXA procedure requirements. 
A suction endometrial biopsy will be performed any time during the study in the case of 
uterine bleeding, in addition to the protocol-required time points.  
At the end of treatment (EOT) (or the early discontinuation [ED] visit for subjects who 
withdraw from the study prior to completion), a TVU and a suction endometrial biopsy will 
be required. If a subject discontinues from the study, an endometrial biopsy is required at the 
discontinuation visit along with all other EOT procedures. During the treatment period, any 


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woman with an abnormal endometrial biopsy reported as disordered proliferative 
endometrium, endometrial hyperplasia or endometrial cancer will be referred to standard of 
care clinical management and followed to resolution, and the report of any medical or 
surgical procedures and the resultant pathology will be obtained. The investigator should 
record any such biopsy, and the associated diagnostic and therapeutic measures, as an AE. A 
mammogram at week 52/EOT/ED will be conducted if it coincides with the regularly 
scheduled routine screening mammogram of the patient, in accordance with local medical 
practice guidelines and the patient’s primary care physician. 
During the treatment period, subjects will return to the study site as indicated in the Schedule 
of Assessments [Table 1 Schedule of Assessments]. Site-based patient-related outcome 
(PRO) measures will be self-administered via an electronic device as indicated in the 
Schedule of Assessments. All assessments must be performed at the site and prior to all other 
required visit procedures. In the event a subject withdraws from the study prior to completion, 
all efforts to collect information on the site-based PRO measures should be made before or 
shortly after withdrawal. 
Following the completion of the treatment period (week 52 or ED), subjects will complete an 
EOT (or ED) visit and final safety follow-up visit 3 weeks after the last dose of study drug is 
administered (week 55 or 3 weeks following ED). 
A Data Monitoring Committee (DMC) will oversee the safety of fezolinetant for the duration 
of the study. 
The study drug will not be provided after study completion of the study without written 
approval from the sponsor. 
Approximately 1740 total subjects will be randomized into the study. Subjects will be 
randomized 1:1:1 into the following treatment groups:  
● Fezolinetant 30 mg once daily (approximately 580 subjects) 
● Fezolinetant 45 mg once daily (approximately 580 subjects) 
● Placebo once daily (approximately 580 subjects) 




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From the ESN364_HF_205 study, 352 subjects were randomized and received at least 1 dose 
of study drug, 287 (81%) completed the study (placebo: 84%; fezolinetant: 80%). 
Discontinuations occurred most commonly for withdrawal of consent (6.7%) and AEs (5.9%).  
The 4 co-primary efficacy endpoints for ESN364_HF_205 included the mean change in 
frequency and severity of moderate-to-severe VMS at weeks 4 and 12. VMS frequency and 
severity at weeks 4 and 12 were reduced in all fezolinetant groups. Differences from placebo 
in least squares mean changes from baseline in VMS daily frequency at week 4 
were -1.9, -3.0, -2.8 and -3.5 for 15, 30, 60 and 90 mg twice daily and -2.3, -3.0 and -2.4 for 
30, 60 and 120 mg once daily, respectively (common SE: 0.8; all P < 0.05, from a pairwise 
comparison against placebo without multiplicity adjustment). Differences at week 12 
were -1.8, -2.1, -2.3, -2.6 and -2.1, -2.6, -2.1, respectively (common SE: approximately 0.7; 
all P < 0.05 from a pairwise comparison against placebo without multiplicity adjustment). 
The improvement relative to placebo at weeks 4 and 12 was greater than 2, indicative of a 
clinically meaningful improvement, for all dose groups except 15 mg twice daily. For HF 
severity, all treatment groups were statistically significant compared to placebo at week 4, 
while only the 60 mg twice daily, 90 mg twice daily and 60 mg once daily were statistically 
different from placebo at week 12. Unlike frequency, a clinically meaningful improvement in 
HF severity has not been established.  
Fezolinetant was generally well-tolerated. No deaths or treatment-related serious adverse 
events (SAEs) were reported. The rates of TEAEs were comparable across groups and were 
mostly mild and moderate; however, overall the active dose groups had a higher proportion 
of AEs reported as treatment-related assessed by the site investigators. Nine subjects had 
ALT or AST elevations > 3 × ULN. There were no cases of TBL > 2 × ULN. Seven of the 
9 subjects with transaminase elevations received total daily doses of 120 mg or greater. 
A relationship between fezolinetant exposure (dose and concentration) and the incidence of 
liver parameter elevations appears to be present. Individual predicted exposures for subjects 
with transaminase elevations > 3 × ULN were compared to the broader distribution of 
fezolinetant exposure by treatment group. Subjects with ALT or AST elevations > 3 × ULN 
generally had steady-state Cmax and Cavg concentrations toward the higher end of the 
distribution for each dose group. Most cases of ALT or AST elevations > 3 × ULN occurred 
at fezolinetant exposures anticipated from 120 mg total daily doses or higher. Two subjects 
receiving a 60 mg total daily dose (1 in 30 mg bid and 1 in 60 mg qd) experienced ALT or 
AST elevations > 3 × ULN. The subject in the 60 mg once daily dose group had an average 
concentration consistent with the 75% percentile of exposure for the 120 mg total daily dose. 
The transaminase elevation for the subject in the 30 mg twice daily group occurred at the 
follow-up visit, 3 weeks after the last dose. The subject had normal liver parameters 
throughout the study and the elevation was considered to be unlikely related to study drug. 
Dose- and concentration-response models were developed to identify the minimum effective 
dose and the exposure-response relationship. Both the dose-response (Multiple Comparison 
Procedure – Modeling) and concentration-response (nonlinear mixed-effects models) 
analyses demonstrated increased improvements in HF frequency and HF severity with 


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increasing fezolinetant exposure. No clinically relevant difference was noted between 
predicted efficacy (frequency or severity) for the once daily and twice daily regimen given 
the same total daily dose. 
Modeling and simulation suggests that although baseline does not impact the percentage 
reduction in HF frequency, it does impact the placebo-corrected change from baseline. In 
Study ESN364_HF_205, subjects were eligible for enrolment if they experienced more than 
an average 7 HFs per day over a week during the screening period; however, during the 
specific baseline period used for the analysis purpose, the same criterions was not required. 
This resulted in a decreased mean baseline compared to historical studies. At week 12, the 
model predicts a mean placebo-corrected change from baseline reduction in HF frequency of 
-1.74 and -1.95 for the 30 mg once daily and 45 mg once daily doses, respectively, at a mean 
baseline of 9.5 HFs per day. At a mean baseline more consistent with historical studies, the 
mean predicted placebo-corrected change from baseline reduction in HF frequency for 30 mg 
and 45 mg once-daily doses is -2.11 and -2.37, respectively, at week 12. In summary, once 
daily doses of ≥ 30 mg are predicted to have clinically meaningful population mean 
reductions in HF frequency based on historical baseline values. For HF severity based on the 
moderate and severe HFs, the model predicted placebo-corrected change from baseline for 
30 mg and 45 mg once-daily doses was -0.34 and -0.41, respectively, at week 12. Based on 
these predicted reductions in HF severity and the increased sample size planned in the phase 
3 studies, these proposed doses are anticipated that a statistically significant reduction in HF 
severity can be achieved compared to placebo.  
In addition to the dose- and exposure-response analyses, drug-induced liver injury modeling 
software (DILIsym®) modeling was undertaken to better characterize and understand the 
increase in elevated transaminases noted for 9 subjects in Study ESN364-HF_205 and the 
potential for drug-induced liver injury (DILI). DILIsym predicted no cases of elevated 
transaminases greater than 3 × ULN for the 30 mg, 45 mg or 60 mg once-daily treatment 
regimens. 
Based on the efficacy results and modeling and simulation analyses, the 30 mg once-daily 
dosing regimen is considered the lowest effective dose. In addition, a 45 mg once-daily dose, 
while not previously studied, is predicted to increase the probability of achieving efficacy 
endpoints while limiting the risk of potential exposure related transaminase elevations and 
DILI.  
2.3 
Endpoints  
2.3.1 
Primary Endpoint 
The primary variable will required the evaluation of the safety of fezolinetant on the 
following: 
● 
Frequency and severity of AEs  
● 
Percentage of subjects with endometrial hyperplasia. 
● 
Percentage of subject with endometrial cancer. 


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2.3.2 
Secondary Endpoints  
● 
Change from baseline in endometrial thickness at 12 months. 
● 
Percentage of subjects with disordered proliferative endometrium. 
● 
Change from baseline in bone mass density (BMD) and trabecular bone score (TBS) at 
hip and spine at 12 months. 
● 
Vital signs: sitting systolic and diastolic blood pressure and pulse rate. 
● 
Laboratory tests: hematology, biochemistry and urinalysis. 
● 
C-SSRS. 
● 
ECG parameters. 
2.3.3 
Exploratory Endpoints 
● 
Mean change on the Menopause-Specific Quality of Life (MENQOL) Total Score from 
baseline to specified time points (week 4, 12, 24 and 52). 
● 
Mean change on the MENQOL Domain Scores from baseline to specified time points 
(week 4, 12, 24 and 52). 
● 
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) Total Score from baseline to specified 
time points (week 4, 12, 24 and 52). 
● 
Change from baseline to specified time points in serum concentrations of sex hormones 
and sex hormone-binding globulin (SHBG) (week 4, 12, 24, 52 and 55). 
● 
Plasma concentrations of fezolinetant and the fezolinetant metabolite ESN259564 at 
specified time points (week 4, 12, 24 and 52). 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
The study population will comprise women ≥ 40 and ≤ 65 years of age seeking treatment for 
VMS associated with menopause. 
3.2 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations must be obtained 
from the subject or legally authorized representative prior to any study-related 
procedures.  
2. Subject is born female, aged ≥ 40 years and ≤ 65 years of age at the screening visit. 
3. 
Subject has a body mass index  18 kg/m2 and  38 kg/m2  
4. Subject must be seeking treatment or relief for VMS associated with menopause and 
confirmed as menopausal per 1 of the following criteria at the screening visit. 
● 
Spontaneous amenorrhea for  12 consecutive months 
● 
Spontaneous amenorrhea for  6 months with biochemical criteria of menopause 
(FSH > 40 IU/L), or  


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● 
Having had bilateral oophorectomy  6 weeks prior to the screening visit. 
5. Subject is seeking treatment for relief for VMS associated with menopause. 
6. Subject is in good general health as determined on the basis of medical history and 
general physical examination, including a bimanual clinical pelvic examination and 
clinical breast examination devoid of relevant clinical findings, performed at the 
screening visit; hematology and biochemistry parameters; pulse rate and/or blood 
pressure; and ECG within the reference range for the population studied, or showing no 
clinically relevant deviations, as judged by the investigator. 
7. Subject has documentation of a normal/negative or no clinically significant mammogram 
findings (obtained at screening or within the prior 12 months of trial enrollment). 
Appropriate documentation includes a written report or an electronic report indicating 
normal/negative or no clinically significant mammographic findings. 
8. Subject is willing to undergo a TVU to evaluate the uterus and ovaries at screening and 
at week 52 (EOT). For subjects who are withdrawn from the study prior to completion, a 
TVU should be collected at the ED visit. 
9. Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT) 
or the ED visit for subjects who are withdrawn from the study prior to completion, and 
any time during the study in the case of uterine bleeding. The endometrial biopsy 
obtained at screening must be considered evaluable. 
10. Subject has documentation of a normal or not clinically significant Pap test (or 
equivalent cervical cytology) in the opinion of the investigator within the previous 
12 months or at screening.  
11. Subject has a negative urine pregnancy test at screening. 
12. Subject has a negative serology panel (i.e., negative hepatitis B surface antigen, negative 
hepatitis C virus antibody and negative human immunodeficiency virus antibody 
screens) at screening. 
13. Subject agrees not to participate in another interventional study while participating in the 
present study.  
Waivers to the inclusion criteria will NOT be allowed. 
3.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the 
study: 
1. Subject uses a prohibited therapy (strong or moderate CYP1A2 inhibitors, HRT, 
hormonal contraceptive, any treatment for VMS [prescription, over the counter or 
herbal]) or is not willing to wash out and discontinue such drugs for the full extent of the 
study. 


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2. Subject has a known substance abuse or alcohol addiction within 6 months of screening, 
as assessed by investigator. 
3. Subject has previous or current history of a malignant tumor, except for basal cell 
carcinoma. 
4. Subject’s systolic blood pressure is ≥ 130 mmHg or diastolic blood pressure is 
≥ 80 mmHg based on the average of 2 to 3 readings on at least 2 different occasions 
within the screening period.  
● 
Subjects who do not meet the criteria may, at the discretion of the investigator, 
be re-assessed after initiation or review of antihypertensive measures.  
● 
Subjects with a medical history of hypertension can be enrolled at the discretion 
of the investigator once they are medically cleared (stable and compliant).  
5. Subject has a history of severe allergy, hypersensitivity or intolerance to drugs in 
general, including the study drug and any of its excipients. 
6. Subject has an unacceptable result from the TVU assessment at screening, i.e., full length 
of endometrial cavity cannot be visualized or presence of a clinically significant finding. 
7.  Subject has an endometrial biopsy confirming presence of disordered proliferative 
endometrium, endometrial hyperplasia, endometrial cancer or other clinically significant 
findings in the opinion of the investigator at screening.  
8. Subject has a history within the last 6 months of undiagnosed uterine bleeding. 
9. Subject has a history of seizures or other convulsive disorders. 
10. Subject has a medical condition or chronic disease (including history of neurological 
[including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., 
moderate asthma], endocrine or gynecological disease) or malignancy that could 
confound interpretation of the study outcome in the opinion of the investigator. 
11. Subject has active liver disease, jaundice, elevated liver aminotransferases (ALT or 
AST), elevated total or direct bilirubin (DBL), elevated International Normalized Ratio 
(INR), or elevated alkaline phosphatase (ALP). Patients with mildly elevated ALT or 
AST up to 1.5 times the upper limit of normal (ULN) can be enrolled if total and DBL 
are normal. Patients with mildly elevated ALP (up to 1.5 × ULN) can be enrolled if 
cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. 
Patients with Gilbert’s syndrome with elevated TBL may be enrolled as long as DBL, 
hemoglobin, and reticulocytes are normal. 
12. Subject has creatinine > 1.5 × ULN; or estimated glomerular filtration rate using the 
Modification of Diet in Renal Disease formula ≤ 59 mL/min per 1.73 m2 at the screening 
visit. 
13. Subject has a history of suicide attempt or suicidal behavior within the last 12 months or 
has suicidal ideation within the last 12 months (a response of “yes” to questions 4 or 5 on 
the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale [C-SSRS]), 


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or who is at significant risk to commit suicide, as assessed by the investigator at 
screening and at the time of visit 2 (randomization). 
14. Subject has previously been enrolled in a clinical trial with fezolinetant. 
15. Subject is participating concurrently in another interventional study or participated in an 
interventional study within 28 days prior to screening, or received any investigational 
drug within 28 days or within 5 half-lives prior to screening, whichever is longer. 
16. Subject is unable or unwilling to complete the study procedures. 
17. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
18. This criterion has been removed. 
19. This criterion has been removed. 
20. Subject has had a partial or full hysterectomy. 
Waivers to the exclusion criteria will NOT be allowed. 
4 
TREATMENT 
4.1 
Identification of Investigational Products 
4.1.1 
Study Drug 
Fezolinetant study drug will be supplied in a blinded form by Astellas as fezolinetant 30 mg 
and 45 mg once daily tablets. 
4.1.2 
Comparative Drug  
Placebo for fezolinetant will be supplied by Astellas in a blinded form to match the active 
drug tablets. 
4.2 
Packaging and Labeling 
All study drug(s) used in this study will be prepared, packaged and labeled under the 
responsibility of qualified staff at APGD or sponsor’s designee in accordance with APGD or 
sponsor’s designee standard operating procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and 
applicable local laws/regulations. 
Each kit will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug. 
A qualified person of Astellas Pharma Europe B.V. or sponsor’s designee will perform the 
final release of the medication according to the requirements of the European Union (EU) 
Directive 2003/94/EC annex 13. 


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4.3 
Study Drug Handling  
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator or designee and that: 
● 
Such deliveries are recorded; 
● 
Study drug is handled and stored according to labeled storage conditions; 
● 
Study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol; and 
● 
Any unused study drug is returned to the sponsor.  
Study drug inventory and accountability records will be kept by the investigator, or designee. 
Study drug accountability throughout the study must be documented and reconciled. The 
following guidelines are therefore pertinent: 
● 
The investigator or designee agrees not to supply study drugs to any persons except the 
eligible subjects in this study in accordance with the protocol; 
● 
The investigator or designee (i.e., study drug manager) will keep the study drugs in a 
pharmacy or other locked and secure storage facility under controlled storage conditions, 
accessible only to those authorized by the investigator to dispense these study drugs; 
● 
A study drug inventory will be maintained by the investigator or designee (i.e., study 
drug manager). The inventory will include details of material received and a clear record 
of when they were dispensed and to which subject; 
● 
At the conclusion or discontinuation of this study, the investigator or designee (i.e., study 
drug manager) agrees to conduct a final drug supply inventory and to record the results 
of this inventory on the Drug Accountability Record. It must be possible to reconcile 
delivery records with those of used and/or returned study drug. Any discrepancies must 
be accounted for and documented. Appropriate forms of deliveries and returns must be 
signed by the site staff delegated this responsibility; 
● 
The site staff must return study drug to the sponsor or designee at the end of the study or 
upon expiration unless otherwise approved by the sponsor. 
4.4 
Blinding 
4.4.1 
Blinding Method  
This is a double blind study. Subjects will be randomized to receive fezolinetant 45 mg, 
fezolinetant 30 mg, or placebo in a blinded fashion such that the investigator, sponsor’s study 
management team, clinical staff, nor the subject will know which agent is being 
administered. The randomization number will be assigned based on information obtained 
from the Interactive Response Technology (IRT). 
4.4.2 
Confirmation of the Indistinguishability of the Study Drugs 
The appearance and the form of both the drug and packaging of fezolinetant 45 mg, 
fezolinetant 30 mg and placebo are identical.  


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4.4.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking  
The randomization list and study medication blind will be maintained by the IRT system. 
4.4.4 
Breaking the Treatment Code for Emergency  
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject. The IRT 
will be programmed with blind-breaking instructions that may only be requested by the 
investigator or subinvestigators designated to have access to perform blind-break. In case of a 
medical emergency, the investigator has the sole responsibility for determining if unblinding 
of subject’s treatment assignment is warranted. Subject safety must always be the first 
consideration in making such determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a subject’s treatment assignment unless this could delay emergency treatment for 
the subject.  
The investigator must have confirmed functionality to access code-break through the IRT 
system and must have a designated back up (e.g., redundant processes) to support emergency 
unblinding requirements.  
Prior to randomization, subjects should be provided with information that includes the site 
emergency contact number and back-up contact number in case of a medical emergency. Any 
unblinding by the investigational staff must be reported immediately to the sponsor and 
include an explanation of why the study drug was unblinded. If unblinding is associated with 
a SAE the investigator is to follow the instructions in [Section 5.8.5 Reporting of Serious 
Adverse Events (SAEs)].  
Care should be taken to limit knowledge of the randomization arm, in case this could affect 
the blinding of other subjects or future trial assessment for the subject.  
4.4.5 
Breaking the Treatment Code by the Sponsor  
The sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. Individual Emergency Codes will 
be provided to the limited staff who are responsible to break the codes for all SUSAR cases 
for reporting purposes. 
4.5 
Assignment and Allocation 
Subjects will be randomized in a 1:1:1 ratio of fezolinetant to placebo to a treatment arm 
according to the randomization schedules and stratified by smoking status (smoker or 
non-smoker) through IRT. The site personnel will dispense the treatment according to the 
IRT system’s assignment. Specific procedures for randomization through the IRT are 
contained in the study procedures manual. 


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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other 
Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
Subjects will be screening up to 35 days prior to randomization. Informed consent will be 
obtained prior to randomization and before any study-related procedures are performed. 
Subjects will be assigned study drug as a kit containing either fezolinetant or placebo at visits 
indicated in the schedule of assessments. Study drug intake will be done with a glass of room 
temperature tap water in the morning. The first intake of study drug will take place at the 
study site on day 1 (visit 2) under the supervision of the study staff.  
On study visit days (except for EOT/ED week 52 [visit 15]) study drug will be taken at the 
study site, under the supervision of the study staff, after collection of predose blood samples. 
On all other days throughout the treatment period, subjects will be instructed to take their 
dose of study drug at home with water, in the morning.  
In the event of a missed dose, the subject should skip the missed dose and continue with the 
next scheduled dose.  
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) 
Dose increases and decreases are not allowed. 
5.1.3 
Previous and Concomitant Treatment (Medication and NonMedication 
Therapy) 
Medications for the treatment of VMS (including prescription medications, over the counter 
and herbal) taken during the 12 months prior to screening and other medication taken 90 days 
prior to the screening visit and up to the first dose of study medication (treatment period) will 
be documented in the appropriate electronic case report form (eCRF) as prior medication.  
Medications taken after the first dose of study medication and through the last study-related 
activity will be documented on the appropriate CRF as concomitant medication. Prior and 
concomitant medications to be documented include but are not limited to: vitamins, herbal 
remedies (e.g., St. John’s wort, valerian), over the counter and prescription medications. 
Subjects will be instructed not to take any concomitant medication without first consulting 
the investigator or study coordinator throughout the duration of the study. 
5.1.3.1 Previous Medication (Drugs and Therapies) 
For women who recently discontinued hormone therapy, the therapy must have been 
discontinued for at least the following durations prior to the screening visit: 
● 
1 week or longer for prior vaginal hormonal products (rings, creams, gels, inserts); 
● 
4 weeks or longer for prior transdermal estrogen alone or estrogen/progestin products; 
● 
8 weeks or longer for prior oral estrogen and/or progestin therapy; 
● 
8 weeks or longer for prior intrauterine progestin therapy; 


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● 
3 months or longer for prior progestin implants and estrogen alone injectable drug 
therapy; or 
● 
6 months or longer for prior estrogen pellet therapy or progestin injectable drug therapy. 
5.1.3.2 Concomitant Medications (Drugs and Therapies) 
All concomitant medications and therapies (prescriptions, over the counter, and herbal), other 
than the study drug, administered from informed consent through 30 days post the last dose 
of study drug will be collected in the eCRF.  
5.1.3.3 Prohibited Concomitant Medications 
The following medications and therapies are prohibited throughout the study (from signing of 
informed consent through the last study-related activity): 
● Use of hormonal medications such as hormone therapy, HRT or hormonal contraception 
or any treatment for VMS (prescription, over the counter or herbal). 
● Investigational research products that have not been approved for any indication in the 
country where the subject is enrolled. 
● Strong or moderate CYP1A2 inhibitors. 
Refer to Appendix 12.4 List of Excluded Concomitant Medications for additional information. 
5.1.4 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with study drug. 
The investigator or designee should ensure that study subjects meet this goal throughout the 
study period. Compliance will be verified by the accounting of study drug at each monthly 
visit after baseline. When study drug is administered at the research facility, it will be 
administered under the supervision of study personnel. 
Compliance of the study drug will be monitored by the accounting of unused medication 
returned by the subject at visits. Compliance will be documented. 
If compliance is 80%, the investigator or designee is to counsel the subject and ensure steps are 
taken to improve compliance. Subjects who are less than 80% compliant with the dosage 
regimen for any 2 consecutive visit periods during the study should be withdrawn from the study. 
5.1.5 
Criteria for Continuation of Treatment  
Fezolinetant will not be made available after conclusion of the study.  
5.1.6 
Restrictions During the Study  
There are no restrictions during the study. 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic and baseline characteristics will be collected during screening for all subjects 
according to the Schedule of Assessments [Table 1 Schedule of Assessments] and will 
include age, sex, race, ethnicity (US only), smoking status and prior HT use.  


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5.2.2 
Medical History 
A detailed medical history for each subject, including date of last menstruation and/or date of 
surgical sterilization, will be obtained at the screening visit. All relevant past and present 
conditions will be recorded for the main body systems, as well as prior surgical procedures. 
Any untoward medical events that occur from the time of informed consent will be captured 
as AEs in the eCRF. A change in medical status or medical history from the time of signing 
informed consent is to be reported as an AE or SAE as appropriate. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
Subject must be seeking treatment or relief for VMS associated with menopause and 
confirmed as menopausal per 1 of the following criteria at the screening visit: 
● Spontaneous amenorrhea for ≥ 12 consecutive months;  
● Spontaneous amenorrhea for ≥ 6 months with biochemical criteria of menopause  
(FSH > 40 IU/L); 
● Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit 
5.3 
Order of Assessments  
All PRO measures are to be self-administered electrically via the site tablet, at the site first 
upon arrival of the subject and prior to performing all other procedures including the 
C-SSRS. The frequency and timing of these assessments are appropriate for the population 
under study, study design and objectives, and type of questions asked. The assessments will 
be administered electronically via the site tablet on week 0 (visit 2), week 4 (visit 3), week 12 
(visit 5), week 24 (visit 8) and week 52 (visit 15).  
Screening (days -35 to day -1): 
1. All screening procedures  
2. Endometrial biopsy* 
* An extra 15 screening days are allowed for repeat biopsy, if necessary (days -50 to -1, including the screening 
visit [visit 1] assessments). 
Visit 2 through Visit 16: 
The following sequence order will be in effect when more than 1 assessment is required at a 
time point:  
1. Order of PROs to be administered: 
● MENQOL (baseline, week 4, week 12, week 24, week 52); 
● EQ-5D-5L (baseline, week 4, week 12, week 24, week 52). 
2. The clinician administered C-SSRS. 
3. Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital 
signs and blood draws. 


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5.4 
Safety Assessments 
5.4.1 
Vital Signs 
Vital sign parameters will be assessed at each study visit. 
The vital sign parameters that will be assessed are body temperature (oral/tympanic), blood 
pressure (sitting) and pulse rate (sitting).  
Any change from baseline in vital sign values occurring during the study that is considered to 
be clinically relevant or that requires concomitant medication, as judged by the investigator, 
should be recorded in the source documents and the AE section of the eCRF. 
5.4.2 
Columbia Suicide Severity Rating Scale 
The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. A clinician 
will administer this measure electronically at the clinic visit. Administration should take 
place prior to any invasive procedures. 
The C-SSRS will be collected at screening days -35 to -1 (visit 1), day 1 (visit 2), week 12 (visit 
5), week 24 (visit 8), week 52 (visit 15/EOT) and the follow-up visit (week 55 [visit 16 ]).  
5.4.3 
Laboratory Assessments 
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
See [Table 1 Schedule of Assessments] for study visit collection dates.  
Urine Pregnancy Test 
β-HCG 
Hematology 
CBC: white blood cell count with differential (neutrophils, 
lymphocytes, eosinophils, monocytes, and basophils)  
hemoglobin  
hematocrit 
red blood cell count 
platelets  
reticulocytes 
Biochemistry 
Blood urea nitrogen 
Chloride 
Creatinine 
Inorganic phosphorus 
Sodium 
Bicarbonate 
Calcium 
Creatine kinase 
Estimated glomerular filtration rate 
Glucose 
Lactate dehydrogenase 
Potassium 
Uric acid 
Table continued on next page 


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Urine Pregnancy Test 
β-HCG 
Liver Biochemistry 
Alanine aminotransferase 
Alkaline phosphatase 
Aspartate aminotransferase 
Albumin 
Gamma-glutamyltransferase 
Total bilirubin 
Direct bilirubin  
Urinalysis  
Protein 
Glucose 
pH 
Blood 
Coagulation Panel 
International normalized ratio 
Activated partial thromboplastin time 
Prothrombin time 
Serology 
HBsAg 
HCV antibody 
HIV antibody 
Anti-HBs 
Anti-HBc 
Hormone Levels 
LH 
FSH 
Estradiol 
SHBG 
Testosterone Total/Free 
Androstenedione  
DHEA 
Estrone 
anti-HBc: antibody to hepatitis B core antigen; anti-HBs: antibody against hepatitis B antigen; β-HCG: beta 
human chorionic gonadotropin; BSAP: bone specific alkaline phosphatase; CBC: complete blood count; 
DHEA: dehydroepiandrosterone; FSH: follicle-stimulating hormone; HBsAG: hepatitis B virus surface antigen; 
HCV: hepatitis C virus; HIV: human immunodeficiency virus; LH: luteinizing hormone; SHBG: sex hormone-
binding globulin 
If the clinical laboratory results are outside the normal range, the investigator will document 
his/her assessment as clinically significant or not clinically significant.  
Unscheduled tests or a repeat of abnormal laboratory test(s) may be performed if clinically 
indicated and to follow-up on suspected AEs. 
Laboratory normal ranges will be outlined in the Laboratory manual and will be provided to 
all participating centers. 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/subinvestigator who is a qualified physician. 


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5.4.4 
Papanicolaou Test 
Pap tests will be performed at the screening visit (days -35 to -1 [visit 1]) only in the event 
that the subject does not have documentation of a normal/negative or no clinically significant 
findings Pap test (or equivalent cervical cytology) within the prior 12 months. Pap tests must 
show no clinically significant findings in order for subjects to be included in the study. 
Samples will be analyzed locally or at a central laboratory. For details on collection, handling 
and shipment instructions, refer to the laboratory manual.  
5.4.5 
Physical Examination  
A full physical examination will be performed at screening (visit 1), day 1 (visit 2), week 52 
(visit 15)/EOT and week 55 (visit 16)/follow-up which includes height (at the screening visit 
only), weight and waist circumference. A bimanual clinical pelvic and clinical breast 
examination will be performed at the screening visit. A bimanual clinical pelvic examination 
can be performed at any time in the study where clinically indicated. At week 2 (visit 3) thru 
week 48 (visit 14), a symptom directed physical exam will be conducted which includes 
weight and waist circumference. 
5.4.6 
Electrocardiogram  
The 12-lead ECG will be captured at the time points shown in [Table 1 Schedule of Assessments]. 
The subject should rest in supine position for at least 10 minutes prior to the ECG. 
5.5 
Imaging 
5.5.1 
Mammogram 
Mammograms will be performed at the screening visit (days -35 to -1 [visit 1]) only in the 
event that the subject does not have documentation of a normal/negative or no clinically 
significant findings mammogram within the prior 12 months of study enrollment. 
Mammograms must show no clinically significant findings in order for subjects to be 
included in the study. A mammogram at week 52/EOT/ED will be conducted if it coincides 
with the regularly scheduled routine screening mammogram of the patient, in accordance 
with local medical practice guidelines and the patient’s primary care physician. 
5.5.2 
Dual-Energy X-Ray Absorptiometry (DXA) 
Changes in BMD and TBS of hip and spine will be assessed by dual-energy X-ray 
absorptiometry (DXA) scan at screening (visit 1) and at week 52/EOT (visit 15). 
The central DXA reader vendor will provide instructions for performing the DXA scans. The 
results will be transferred to the central DXA reader vendor, who will ensure that all data will 
be analyzed in the same way and will be blinded to the treatment allocation. 
For practical reasons, the timing of DXA may vary from the actual time of the visit, 
depending on the DXA availability (DXA appointment). The screening visit (days -35 to -1 
[visit 1]) DXA can be performed once the subject has been deemed eligible based on 
screening laboratory tests, or at visit 2, but must be performed before randomization. The 
week 52 (visit 15) DXA should be performed between week 50 and week 52, inclusive. For 


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subjects who are withdrawn from the study prior to completion, a DXA will be completed as 
soon as possible after study drug discontinuation (preferably within 2 weeks). 
When DXA imaging is received, it goes through a quality control (QC) process to make sure 
the imaging parameters required for image review and assessment have been met. For TBS to 
be calculated, the DXA imaging is processed and analyzed as it would normally be and then 
evaluated using an automated algorithm to determine the TBS. TBS is a bone texture 
assessment that serves as a substitute for bone microarchitecture [Muschitz et al, 2015] and 
predicts fracture risk independent of BMD and clinical risk factors [McCloskey et al, 2016]. 
5.5.3 
Transvaginal Ultrasound 
Subjects will undergo a TVU to assess the uterus and ovaries at screening, at week 52 (EOT) 
and for subjects who withdraw from the study at the ED visit. The endometrium should be 
measured in the long axis or sagittal plane. The measurement is of the thickest echogenic area 
from 1 basal endometrial interface across the endometrial canal to the other basal surface. 
Care should be taken not to include the hypoechoic myometrium in this measurement. All 
TVUs will be centrally read.  
5.6 
Biopsies 
5.6.1 
Endometrial Biopsy 
Subjects will undergo a suction endometrial biopsy at the following time points:  
● Screening  
● At week 52/EOT  
● ED 
● All cases of uterine bleeding during treatment 
The screening endometrial biopsy must be evaluable. 
Subjects that require a retest biopsy, for insufficient material or unevaluable only, will have 
an extended screening period and will be allowed an additional 15 days of screening (i.e., 
days -50 to -1). A maximum of 1 retest biopsy during screening is allowed.   
Screening biopsy results are valid for study entry for up to 3 months from date of procedure 
for applicable subjects. 
An endometrial biopsy is required at EOT or ED. For EOT/ED week 52 (visit 15) biopsies 
that are evaluated as insufficient material or unevaluable, a retest biopsy will be required. 
Any of the three pathologists can determine if a an EOT/ED is insufficient or unevaluable. 
However, if two pathologists read the EOT/ED endometrial biopsy as evaluable and issue the 
same diagnosis, and the 3rd pathologist reads the biopsy as insufficient or unevaluable, the 
biopsy does not need to be repeated. 
During the treatment period, any woman with an abnormal endometrial biopsy reported as 
disordered proliferative endometrium, endometrial hyperplasia or endometrial cancer will be 
referred to standard of care clinical management and followed to resolution, and the report of 
any medical or surgical procedures and the resultant pathology will be obtained. The 


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investigator should record any such biopsy, and the associated diagnostic and therapeutic 
measures, as an AE. 
Subjects with endometrial fibroids may be included in the study provided the endometrial 
biopsy result at screening is satisfactory and the investigator is confident no treatment will be 
required during the study. 
Subjects will be allowed entry into the study on the primary endometrial result/diagnosis. A 
secondary and tertiary endometrial diagnosis will also be reported. A subject should 
discontinue the study if secondary or tertiary endometrial biopsy diagnosis is Category 2.  All 
3 pathology reports should be filed in the subject’s source document. Please reference the 
central laboratory manual for further details and timing of biopsy specimen results. 
All biopsies will be read concurrently by 3 independent expert pathologists from institutions 
with independent fiduciary and organizational reporting. Each pathologist should be blinded 
to the treatment group and to the readings of the other pathologists. For EOT/ED biopsies and 
all biopsies in cases of uterine bleeding during treatment the concurrence of 2 of the 
3 pathologists is accepted as the final diagnosis. If there is no agreement among the 
3 pathologists, the most severe pathologic diagnosis should be used as the final diagnosis.  
The 3 independent expert pathologists should use the same standardized criteria for the 
diagnosis of endometrial hyperplasia or endometrial cancer, and endometrial polyps should 
be fully characterized as to glandular proliferation and atypia. The standardized criteria for 
histologic evaluation can be viewed in the FDA Draft Guidance for Industry, Estrogen and 
Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal 
Atrophy Symptoms – Recommendations for Clinical Evaluation, 2003. 
5.7 
Patient-Reported Outcome, Pharmacodynamic and Pharmacokinetic 
Assessments 
5.7.1 
Patient-Reported Outcome Assessments 
The following patient-reported outcomes (PROs) will be self-administered electronically at 
the site visit: 
● MENQOL – assesses quality of life as it relates to menopausal symptoms 
● EQ-5D-5L – assesses general health-related quality of life 
All PRO measures will be administered in the local language. Only questionnaires provided 
by Astellas that have been linguistically validated and cognitively debriefed in the target 
language to which they have been translated will be used in this study. 
All PRO measures must be self-administered at the site and prior to performing any other 
procedures including the C-SSRS. The assessments will be administered electronically via 
the site tablet on day 1, week 4, week 12, week 24 and week 52.  
All sites and site personnel will undergo training to assist with any technology issues that 
arise due to electronic administration. Personnel will be trained on the acceptability of 


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defining terms for subjects if necessary; however, they will be instructed to not define a 
concept where the respondent’s subjective interpretation is required (e.g., “my sleep quality”).  
Site personnel will be instructed to have subjects complete the PRO measures in a quiet room, 
to complete all questions before leaving the room, and to read the instructions provided. After 
completion, subjects will be asked to confirm their responses. 
5.7.1.1 Menopause-Specific Quality of Life (MENQoL) 
The MENQOL is a 29-item PRO measure that assesses the impact of 4 domains of 
menopausal symptoms, as experienced over the last week: vasomotor (items 1 to 3), 
psychosocial (items 4 to 10), physical (items 11 to 26) and sexual (items 27 to 29). Items 
pertaining to a specific symptom are rated as present or not present, and if present, how 
bothersome on a zero (not bothersome) to 6 (extremely bothersome) scale [Lewis et al, 2005].  
Each item score ranges from 1 to 8, and each domain is scored separately; each domain mean 
ranges from 1 to 8 [Lewis et al, 2005; Hilditch et al, 1996]. The overall questionnaire score is 
the mean of the domain means. Higher scores represent more bothersome menopausal 
symptoms. 
The questionnaire should take, on average, 7 minutes to complete with a range of 5 to 
15 minutes based on the original English and French Canadian pretests [Lewis et al, 2005; 
Hilditch et al, 1996]. 
5.7.1.2 EQ-5D-5L with Visual Analog Scale (VAS) 
The EQ-5D-5L is a 5-item standardized measure of health status that provides a simple, 
generic measure of health for clinical and economic appraisal [van Reenen et al., 2015]. This 
PRO measure comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems and extreme problems. The subject is asked to indicate her health 
state by selecting the most appropriate statement in each of the 5 dimensions. This decision 
results in a 1-digit number that expresses the level selected for that dimension. The digits for 
the 5 dimensions can be combined into a 5-digit number that describes the patient’s health 
state. 
The EQ-5D-5L visual analog scale (VAS) is a subject-reported measure that records the 
respondent’s self-rated health on a vertical VAS where the endpoint is labeled “Best 
imaginable health state” and “Worst imaginable health state.” The scale ranges from 0 to 100, 
where 100 indicates the subject is in her best possible health state and 0 indicates the subject 
is in her worst possible health state. Subjects mark an ‘X’ on the scale to rate their health 
status that day. 
This measure should take approximately 2 minutes to complete. Due to the electronic 
administration of this PRO, risk for missing data is mitigated. 


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5.7.2 
Pharmacodynamic Assessments  
Venous blood samples will be collected predose (on dosing visits) for pharmacodynamic 
assessments at day 1 (visit 2), week 4 (visit 3), week 12 (visit 5), week 24 (visit 8) and 
week 52 (visit 15/EOT) and at the follow-up visit (week 55 [visit 16]) [see Table 1 Schedule 
of Assessments]. Markers include LH, FSH, E2, SHBG, androstenedione, 
dehydroepiandrosterone, estrone and testosterone.  
The exact date and time of blood sampling must be recorded in the source documents and on 
the eCRF. Serum will be collected and handled as specified in the central laboratory manual. 
After appropriate labeling, the serum samples will be stored below -20°C at the study site. 
Thereafter, the frozen serum samples will be transported/shipped on dry ice to the central 
laboratory for collection and storage below -20°C until analysis. 
Further procedures for sample collection, shipment, processing and storage are described in 
the laboratory manual. 
5.7.3 
Pharmacokinetic Assessments  
Venous blood samples will be collected for pharmacokinetic analysis of fezolinetant and 
metabolite ES259564 in plasma week 4 (visit 3) predose and 1 to 3 hours postdose, and 
predose at week 12 (visit 5), week 24 (visit 8) and week 52 (visit 15/EOT) [see Table 1 
Schedule of Assessments].  
A pharmacokinetic collection will be obtained for any subjects with signal of elevated 
transaminases (> 3 × ULN) during their visit for repeat blood draw. The sample will be held 
for potential analysis based on the patient’s clinical outcome. The exact date and time of the 
pharmacokinetic sampling must be recorded in the source documents and on the eCRF, as 
well as the exact time of last drug intake before the samples were taken. This means that for a 
predose blood sample, the time of the morning drug intake of the day before needs to be 
recorded, and for the postdose samples, the exact time of the morning dose on the very same 
day needs to be recorded. 
Further procedures for sample collection, shipment, processing, and storage are described in 
the laboratory manual.  
5.7.4 
Caffeinated Beverage Intake  
Subjects’ intake of caffeinated beverages (e.g., coffee) will be recorded to explore the 
interaction of fezolinetant with caffeine (a weak CYP1A2 inhibitor).  
History of average caffeinated beverage intake will be collected at baseline. At each clinic 
visit, the caffeinated beverage intake within the past 24 hours will be recorded. Details on 
data collection procedures will be provided in the eCRF completion guidelines.  


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5.8 
Adverse Events and Other Safety Aspects 
5.8.1 
Definition of Adverse Events  
An AE is any untoward medical occurrence in a subject administered a study drug, and which 
does not necessarily have to have a causal relationship with this treatment. 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 a medicinal 
product whether or not considered related to the medicinal product. 
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the informed consent 
and will be collected until 21 days after the last dose of study drug or the subject is 
determined to be a screen failure.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
5.8.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, clinical chemistry or urinalysis) or 
other safety assessment (e.g., ECGs, radiographic scans, vital signs measurements or physical 
examination), including those that worsen from baseline, that is considered to be clinically 
significant in the medical and scientific judgment of the investigator and not related to 
underlying disease, is to be reported as an (S)AE. 
Any clinically significant abnormal laboratory finding or other abnormal safety assessment 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE. 
5.8.1.2 Potential Cases of Drug-Induced Liver Injury 
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on DILI. Abnormal values in AST and/or ALT concurrent or with abnormal elevations in 
TBL that meet the criteria outlined in [Appendix 12.5 Liver Safety Monitoring and 
Assessment], in the absence of other causes of liver injury, are considered potential cases of 
DILI (potential Hy’s Law cases). Any subject discontinuations due to liver safety are always 
to be considered important medical events and reported per [Section 5.8.5 Reporting of 
Serious Adverse Events]. 
5.8.1.3 Disease Progression and Study Endpoints 
Under this protocol, the following event(s) will not be considered as an(S)AE: 


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● 
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic, or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical trial. These procedures are collected per the eCRFs Completion Guidelines. 
5.8.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
● 
Results in death; 
● 
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death); 
● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
● 
Results in congenital anomaly, or birth defect; 
● 
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE). Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious); 
● 
Discontinuation due to increases in liver enzymes [Section 6.1]; and 
● 
Other medically important events (defined in paragraph below). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
usually are considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.  
5.8.2.1 Always Serious Adverse Events 
The sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered by the sponsor to be an SAE per this classification as “always 
serious”, additional information on the event (e.g., investigator confirmation of seriousness, 
causality) will be requested.  
5.8.3 
Criteria for Causal Relationship to Study Drug 
A medically qualified investigator is obligated to assess the relationship between the study 
drug and each occurrence of each (S)AE. This medically qualified investigator will use 
medical judgment as well as the RSI (See Section 1.4 Summary of Key Safety Information 
for Fezolinetant) to determine the relationship. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 


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The medically qualified investigator is requested to provide an explanation for the causality 
assessment for each (S)AE and must document in the medical notes that he/she has reviewed 
the (S)AE and has provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the study drug and 
each (S)AE will be assessed by answering ‘yes’ or ‘no’ to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the study drug.” 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study drug (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship: 
● 
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug?  
● 
Plausibility; i.e., could the event been caused by the study drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and clinical study data, etc. 
● 
Dechallenge/Dose reduction/Rechallenge:  
o Did the (S)AE resolve or improve after stopping or reducing the dose of the 
suspect drug? Also consider the impact of treatment for the event when evaluating 
a dechallenge experience.  
o Did the (S)AE reoccur if the suspected drug was reintroduced after having been 
stopped?  
● 
Laboratory or other test results; a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the study drug (e.g., based on values pre-, during 
and post-treatment) 
● 
Available alternative explanations independent of study drug exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc. and strength of the alternative 
explanation 
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 medically qualified investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor. With limited or insufficient 
information about the event to make an informed medical judgment and in absence of any 
indication or evidence to establish a causal relationship, a causality assessment of ‘no’ is to 
be considered. In such instance, the investigator is expected to obtain additional information 
regarding the event as soon as possible and to re-evaluate the causality upon receipt of 
additional information. The medically qualified investigator may revise his/her assessment of 
causality in light of new information regarding the SAE and shall send an SAE follow-up 
report and update the eCRF with the new information and updated causality assessment.  


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5.8.4 
Criteria for Defining the Severity of an Adverse Event 
The investigator will use the following definitions to rate the severity of each AE 
● 
Mild:  
No disruption of normal daily activities 
● 
Moderate: Affect normal daily activities 
● 
Severe:  Inability to perform daily activities 
5.8.5 
Reporting of Serious Adverse Events (SAEs) 
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue until 21 days after last administration of study drug or the 
subject is determined to be a screen failure.  
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness). 
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by email or fax immediately 
(within 24 hours of awareness).  
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
Delegation of Authority Log). Signature confirms accuracy and completeness of the SAE 
data as well as the investigator causality assessment including the explanation for the 
causality assessment. 
If the SAE is associated with emergency unblinding as outlined in Section 4.4.4 Breaking the 
Treatment Code for Emergency this is to be recorded on the SAE worksheet. Within the SAE 
worksheet, the investigator is to include when unblinding took place in association with the 
SAE.  
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE/Special Situations Worksheet to: 
Astellas Pharma Global Development Inc. 
Pharmacovigilance 
Fax number: (+1) 888-396-3750 
Alternate fax number: (+1) 847-317-1241 
Email: safety-US@astellas.com 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's medical monitor/study physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel].  
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification). 
Full details of the SAE should be recorded on the medical records, SAE/Special Situation 
Worksheet and on the (e)CRF.  


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The following minimum information is required: 
● 
International Study Number (ISN)/Study number,  
● 
Subject number, sex and age, 
● 
The date of report, 
● 
A description of the SAE (event, seriousness criteria),  
● 
Causal relationship to the study drug (including reason), and 
● 
The drug provided (if any) <blinded regimen is also an option> 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 
regulatory requirements in participating countries. The sponsor or sponsor's designee will 
submit expedited safety reports (e.g., IND Safety Reports, SUSAR, CIOMS-I) to Competent 
Authorities (CA) and concerned Ethics Committee (cEC) per current local regulations, and 
will inform the investigators of such regulatory reports as required. Investigators must submit 
safety reports as required by their IRB/local IEC within timelines set by regional regulations 
(e.g., EMA, FDA) where required. Documentation of the submission to and receipt by the 
IRB/ local IEC of expedited safety reports should be retained by the site. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all SUSARs that require submission per local requirements IRB/local IEC/head 
of the study site. 
The investigator or designee should provide written documentation of IRB/IEC notification 
for each report to the sponsor. 
5.8.6 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.  
 If after the protocol defined AE collection period [see Section 5.8.1 Definition of Adverse 
Event], an AE progresses to a SAE, or the investigator learns of any (S)AE including death, 
where he/she considers there is reasonable possibility it is related to the study drug treatment 
or study participation, the investigator must promptly notify the sponsor. 
5.8.7 
Adverse Events of Special Interest  
AEs of special interest are AEs the sponsor may wish to carefully monitor. These AEs may 
be serious or non-serious and are not considered SAEs unless they meet the SAE definition in 
Section 5.8.1 Definition of Adverse Events. AEs of special interest should be reported on the 
eCRF as such.  


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If the AE of special interest meets the definition of an SAE, they are to be collected via the 
SAE/Special Situation worksheet and reported within 24 hours as described in Section 5.8.5 
Reporting of Serious Adverse Events (SAEs). Adverse events of special interest in this study 
will include: 
● 
AE of uterine bleeding 
● 
Endometrial hyperplasia/cancer or disordered proliferative endometrium 
● 
AE of thrombocytopenia 
● 
AE of liver test evalations 
● 
AE of bone fractures/bone loss ≥ 7% 
● 
AEs of abuse liability 
● 
AEs of depression 
● 
AEs of wakefulness  
● 
AEs of effect on memory  
5.8.8 
Special Situations  
Certain Special Situations observed in association with the study drug(s), such as incorrect 
administration (e.g., wrong dose of study drug, comparator, or background therapy) are 
collected, as Protocol Deviation per [Section 8.3 Major Protocol Deviations] or may require 
special reporting, as described in the subsections below.  
Special Situations are not considered AEs, but do require to be communicated to Astellas as 
per the timelines defined below. 
If a Special Situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the Special Situation and captured as an AE in the eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.8.5 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the SAE worksheet. 
Special Situations relevant to this protocol are: 
● 
Pregnancy  
● 
Lack of Efficacy [refer to Section 5.8.8.2 Lack of Efficacy] 
● 
Medication Error, Overdose and “Off label use” 
● 
Misuse/abuse 
● 
Suspected Drug-Drug interaction 
5.8.8.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 5.8.5 Reporting of Serious Adverse Events] using the 
Pregnancy Reporting Form and in the eCRF.  
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information. 


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While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per [Section 5.8.5 Reporting of Serious Adverse 
Events].  
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below: 
● 
"Spontaneous abortion" includes miscarriage, abortion and missed abortion; 
● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the study drug; 
● 
If an infant dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator; 
● 
Congenital anomaly (including anomaly in miscarried fetus). 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. 
5.8.8.2 Lack of Efficacy  
If lack of efficacy of the study drug is suspected, the investigator must forward the Special 
Situation worksheet to the sponsor by fax or email immediately (within 24 hours of 
awareness) and any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in [Section 5.8.5 Reporting 
of Serious Adverse Events] together with the details of the lack of efficacy. 
5.8.8.3 Medication Error, Overdose and “Off-Label Use” 
If a Medication Error, Overdose or “Off-Label Use” (i.e., use outside of what is stated in the 
protocol) is suspected, refer to Section 8.3 Major Protocol Deviations. Any associated 
(S)AEs are to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is 
also to be reported as described in [Section 5.8.5 Reporting of Serious Adverse Events] 
together with the details of the medication error, overdose and/or “Off-Label Use.” 
In the event of suspected fezolinetant overdose, the subject should receive supportive care 
and monitoring. The medical monitor/expert should be contacted as applicable. 
5.8.8.4 Misuse/Abuse 
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to the sponsor by fax or email immediately (within 24 hours of 
awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in [Section 5.8.5 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s). 


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5.8.8.5 Suspected Drug-Drug Interaction 
If a suspected drug-drug interaction associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to the sponsor by fax or email 
immediately (within 24 hours of awareness). Any associated (S)AEs are to be reported in the 
eCRF. If the AE meets the definition of a SAE, the SAE is also to be reported as described in 
[Section 5.8.5 Reporting of Serious Adverse Events] together with details of the suspected 
drug-drug interaction. 
5.8.9 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The investigator will also inform the subjects, who will be required to sign an updated 
informed consent form (ICF) in order to continue in the clinical study. 
5.8.10 Urgent Safety Measures  
An urgent safety measure (USM) is an intervention, which is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant CA, IRB/IEC, where applicable, in order to protect study participants from 
any immediate hazard to their health and/or safety. Either the investigator or the sponsor can 
initiate an USM. The cause of an USM can be safety, product or procedure related.  
5.8.11 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the Astellas Study Physician 
(within 24 hours of awareness). Full details of the potential USM are to be recorded in the 
subject’s medical records. The sponsor may request additional information related to the 
event to support their evaluation.  
If the event is confirmed to be an USM the sponsor will take appropriate action to ensure the 
safety and welfare of the patients. These actions may include but are not limited to a change 
in study procedures or study treatment, halting further enrollment in the trial, or stopping the 
study in its entirety. The sponsor or sponsor's designee will notify CA and cEC within the 
timelines required per current local regulations, and will inform the investigators as required. 
When required, investigators must notify their IRB/IEC within timelines set by regional 
regulations. 
5.9 
Test Drug Concentration 
Blood samples for pharmacokinetics of fezolinetant and metabolite ES259564 will be 
collected from every subject. Pharmacokinetic samples will be taken predose at week 4 
(visit 3), week 12 (visit 5), week 24 (visit 8), week 52 (visit 15), as well as any subject with a 
signal of elevated (> 3 × ULN) aminotransferases [Appendix 12.4 List of Excluded 


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Concomitant Medications]. Pharmacokinetic samples will be taken 1 to 3 hours postdose at 
week 4 (visit 3).  
Details on sampling, processing, storage and shipment procedures will be provided in a 
separate central laboratory manual.  
5.10 
Other Measurements, Assessments or Methods 
Not applicable 
5.11 
Total Amount of Blood 
Blood samples will be taken for the purposes of clinical laboratory tests, serology tests 
(screening only), pharmacokinetic samples, and pharmacodynamics samples. Repeat and 
additional blood samples may be taken if required. For each patient, the expect blood volume 
to be drawn will be approximately 175 mL over the course of the clinical study. 
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment  
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason. The reason for discontinuation from 
study treatment must be documented in the subject’s medical records. 
A subject must discontinue study treatment for any of the following reasons: 
● 
Withdrawal of informed consent 
● 
Lost to follow-up 
● 
If, for safety reasons, it is in the best interest of the subject that she be withdrawn, in the 
investigator’s opinion 
● 
Development of a medical condition that requires concomitant treatment with a 
prohibited therapy 
● 
Development of seizures or other convulsive disorders 
● 
Breaking of the randomization code during administration of the study drug by the 
investigator or by a member of the site staff. If the code is broken by the sponsor for safety 
reporting purposes or early time point analysis, the subject may remain in the study. 
● 
Confirmed (within 72 hours from the notification of test result) decrease in platelets 
below 75,000 mm3, which does not normalize after 7 days or immediate withdrawal in 
case of platelets below 50,000 mm3. 
● 
Development of severe hepatic abnormality defined as ALT or AST > 8  ULN 
● 
Confirmed (within 72 hours from the notification of test result) severe hepatic 
abnormality for any of the following: 
o ALT or AST > 5  ULN for more than 2 weeks; 
o ALT or AST > 3  ULN AND TBL > 2  ULN or INR > 1.5  ULN, and 
INR > 1.5; or 


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o ALT or AST > 3  ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5% increase 
from baseline). 
● The subject becomes pregnant. 
● Category 2 results of secondary or tertiary screening endometrial biopsy diagnosis. 
6.1.1 
Lost to Follow Up 
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data, and 
retrieve study drug.  
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor.  
6.3 
Discontinuation of the Study 
The sponsor may terminate this study or treatment arm, prematurely, either in its entirety or 
at any study site, for reasonable cause provided that written notice is submitted in advance of 
the intended termination. Advance notice is not required if the study is stopped due to safety 
concerns. If the sponsor terminates the study for safety reasons, the sponsor will immediately 
notify the investigator and subsequently provide written instructions for study termination.  
7 
STATISTICAL METHODOLOGY 
A Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database hard lock. Changes from the analyses planned in SAP that affect the statistical 
analysis will be documented in the Clinical Study Report (CSR). 
In general, continuous data will be summarized with descriptive statistics (number of subjects, 
mean, SD, minimum, median and maximum), and frequency and percentage for categorical 
data. 
7.1 
Sample Size 
The primary objective of this study is to assess long-term safety and tolerability. The sample 
size in this study is not calculated based on the statistical power for efficacy evaluation to 
detect treatment difference.  
The total sample size will be 1740, which will be randomly assigned 1:1:1 to a fezolinetant 
45 mg once daily group (580), fezolinetant 30 mg once daily group or placebo group (580) 
This sample size would provide high probability to observe events of special interest that has 
with a fairly low background event rate that is less than 1%. With the sample size, the 
following table illustrates the probability of observing 1 or more events, 2 or more events and 
3 or more events for different background event rate.  


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Fezolinetant 45 mg once daily/Fezolinetant 30 mg once daily/Placebo 
Sample Size (1:1:1) 
n = 580 
Background Event Rate 
Prob(#>=3) 
Prob(#>=2) 
Prob(#>=1) 
0.10% 
2.11% 
11.53% 
44.03% 
0.20% 
11.18% 
32.29% 
68.69% 
0.30% 
25.33% 
51.94% 
82.49% 
0.40% 
40.94% 
67.43% 
90.22% 
0.50% 
55.46% 
78.62% 
94.54% 
0.60% 
67.63% 
86.28% 
96.95% 
0.70% 
77.16% 
91.35% 
98.30% 
0.80% 
84.27% 
94.62% 
99.05% 
0.90% 
89.38% 
96.69% 
99.47% 
Prob(#>=1) means the probability of observing 1 or more events. 
Prob(#>=2) means the probability of observing 2 or more events. 
Prob(#>=3) means the probability of observing 3 or more events. 
In addition, if an assumed background rate of 0.26% such as for endometrial hyperplasia, this 
sample size would provide the final number of evaluable subjects to demonstrate that the 
point estimate is less than or equal to 1% and upper bound of 1-sided 95% CI to be ≤ 4% 
with at least 95% probability assuming up to 60% (including baseline, ED and subject refusal 
of endometrial biopsy at EOT) of subjects may not have evaluable biopsy data. 
7.2 
Analysis Sets 
7.2.1 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least 1 dose of study drug. This will be the primary analysis set for efficacy analyses. The 
randomized treatment for each subject will be used for summaries by treatment group based 
on the FAS, even if a subject erroneously received a different treatment. 
7.2.2 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) consists of all randomized subjects who took at least 1 dose of 
study drug, and will be used for safety analyses. A subject erroneously receiving a treatment 
different from their randomized treatment will be assigned to the treatment group that the 
patient received as first dose. 
7.2.3 
Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least 1 
pharmacokinetic parameter and for whom the time of dosing on the day of sampling is 
known. Additional subjects may be excluded from the PKAS at the discretion of the 
pharmacokineticist. Any formal definitions for exclusion of subjects or time-points from the 


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PKAS will be documented in the in the Classification Specifications and determined the 
Classification Meeting. 
7.2.4 
Pharmacodynamic Analysis Set (PDAS)  
The pharmacodynamic analysis set (PDAS) will include the subjects from the administered 
population for whom sufficient pharmacodynamic measurements were collected. The PDAS 
will be used for all analyses of pharmacodynamic data.  
7.3 
Demographics and Baseline Characteristics  
The demographic summary will include age, sex, race, ethnicity, smoking status and prior HT 
use. Baseline characteristics include caffeine used, weight, body mass index, diagnosis of the 
target disease, severity and duration of disease. Demographics and baseline characteristics 
will be summarized by treatment group as well as for all treatment groups combined.  
7.3.1 
Subject Disposition  
The number of subjects who are screened, randomized and treated will be summarized. The 
number and percentage of subjects who completed and discontinued treatment and reasons 
for treatment discontinuation will be presented for all randomized subjects and subjects in the 
SAF by treatment group and overall. All disposition details and dates of first and last 
evaluations for each subject will be listed. 
7.3.2 
Previous and Concomitant Medications  
All previous and concomitant medications will be summarized. 
7.3.3 
Medical History  
Medical history for each subject will be presented in a listing.  
7.4 
Analysis of Efficacy  
No efficacy data will be collected for this study.  
7.5 
Analysis of Exploratory Endpoints 
The exploratory endpoints include the MENQOL and the EQ-5D-5L which will be assessed 
at baseline and weeks 4, 12, 24 and 52. The exploratory endpoints will be analyzed for the 
FAS set. Summary statistics will be provided by treatment group.  
The exploratory variables include the effect of fezolinetant on the following: 
● 
Mean change on the MENQOL Total Score from baseline to specified time points. 
● 
Mean change on the MENQOL Domain Scores from baseline to specified time points. 
● 
Mean change on the EQ-5D-5L Total Score from baseline to specified time points. 
● 
Change from baseline to specified time points in serum concentrations of sex hormones 
and SHBG [see Section 7.2.4 Pharmacodynamic Analysis Set (PDAS)]. 
● 
Plasma concentrations of fezolinetant and the fezolinetant metabolite ESN259564 at 
specified time points [see Section 7.2.3 Pharmacokinetic Analysis Set (PKAS)]. 


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For the treatment comparison of continuous endpoints, a mixed model for repeated measures 
(MMRM) will be used. The model will include treatment, visit, and smoking status (current 
vs former/never) as factors, with baseline weight and baseline measurement as covariates, as 
well as an interaction of treatment by visit and an interaction of baseline measurement by 
visit., with an unstructured variance-covariance.  
7.6 
Analysis of Safety 
Overall long-term safety of fezolinetant will be the primary objective of this study. The safety 
assessments include adverse events, laboratory assessments, vital signs, C-SSRS, Pap test, 
physical examination, ECG, endometrial health assessment and imaging (mammogram, 
DXA, TVU). Safety analysis will be conducted on the SAF.  
Primary Safety Variables: 
The primary variable will require the evaluation of the safety of fezolinetant on the 
following:  
● 
Frequency and severity of AEs 
● 
Percentage of subjects with endometrial hyperplasia  
● 
Percentage of subjects with endometrial cancer 
Secondary Safety Variables: 
● 
Change from baseline in endometrial thickness at 12 months 
● 
Percentage of subjects with disordered proliferative endometrium 
● 
Change from baseline in BMD and TBS at hip and spine at 12 months 
● 
Vital signs: sitting systolic and diastolic blood pressure and pulse rate 
● 
Laboratory tests: hematology, biochemistry and urinalysis 
● 
C-SSRS 
● 
ECG parameters 
For each AE of special interests a summary statistics will be provided and the rate, odds ratio, 
and their corresponding 2-sided 95% confidence intervals will be presented. For the treatment 
comparison of bone density and endometrial thickness, an analysis of covariance model will 
be used. The model will include treatment and smoking status (current vs former/never) as 
factors, with baseline weight and baseline as covariates.  
7.6.1 
Adverse Events  
A TEAE is defined as an AE observed after starting administration of the study drug and 
21 days after the last dose of study drug. 
The number and percentage of subjects with treatment-emergent AEs, SAEs, AEs leading to 
withdrawal of treatment and AEs related to study drug will be summarized by SOC, preferred 
term and treatment group. The number and percentage of AEs by severity will also be 
summarized. All AEs will be listed. 
A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator. 


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AEs will be coded using MedDRA. An AE with onset at any time from first dosing until last 
scheduled procedure will be classified as treatment-emergent for inclusion in the summary 
tabulations. 
An overview and separate summaries by SOC and preferred term of the number and 
percentage of subjects with TEAEs, drug-related TEAEs, TEAEs leading to withdrawal of 
treatment and TEAEs excluding SAEs and drug-related TEAEs leading to withdrawal of 
treatment will be presented by treatment group. Also included in the overview are the number 
and percentage of subjects with serious TEAEs, drug-related serious TEAEs, TEAEs leading 
to death, and drug-related TEAEs leading to death.  
7.6.2 
Laboratory Assessments  
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF by treatment group and time point.  
Shifts relative to normal ranges from baseline to each time point during treatment period in 
lab tests will also be tabulated. Laboratory data will be displayed in listings. 
Number and percentage of subjects with platelets < 150x10^9/L will be separately 
summarized for each treatment group.  The liver safety assessments will be summarized by 
the categories below based on the measurements from ALP, ALT, TBL, AST and their 
combination. These parameters will be based on measurements from a central laboratory. 
The subject’s highest value during the treatment period will be used.  
● 
ALT > 3  ULN, > 5  ULN, > 10  ULN, > 20  ULN 
● 
AST > 3  ULN, > 5  ULN, > 10  ULN, > 20  ULN 
● 
ALT or AST > 3  ULN, > 5  ULN, > 10  ULN, > 20  ULN 
● 
ALP > 1.5  ULN 
● 
TBL > 2  ULN 
● 
(ALT or AST > 3  ULN) and TBL > 2  ULN 
● 
(ALT or AST > 3  ULN) and ALP < 2  ULN and TBL > 2  ULN 
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to 1 day apart. 
7.6.3 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF by treatment group and visit.  
7.6.4 
Physical Examination  
Physical examination will be listed by treatment group. 
7.6.5 
Routine 12-lead Electrocardiograms 
The 12-lead ECG results will be summarized by treatment group and time point. 
All ECG interpretations will be displayed in listings. 


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7.6.6 
Endometrial Health Assessment 
Data collected based on endometrial biopsy and endometrial thickness from transvaginal 
ultrasound images will be summarized by treatment group and time point. 
Endometrial hyperplasia, cancer and disordered proliferative endometrium endpoints will be 
analyzed for endometrial health analysis set (EH set) which is defined as SAF subjects who 
have 1 year evaluable biopsy. Further details for EH set including the analysis window for 
post-baseline evaluable biopsy will be defined in the SAP. Rates (percentage of subjects) and 
1-sided 95% confidence intervals with these abnormal findings will be calculated. 
For thickness, change from baseline to 52-week will be calculated and each fezolinetant 
group will be compared to placebo using an analysis of covariance (ANCOVA) model with 
treatment and smoking status as factors and baseline weight and baseline value as covariates. 
This analysis will be done on SAF set. 
7.6.7 
Imaging  
DXA (BMD, TBS) data will be summarized by treatment group. 
7.7 
Analysis of Pharmacokinetics 
Descriptive statistics (e.g., n, mean, SD, minimum, median, maximum, coefficient of 
variation [CV], geometric mean and geometric CV) on the actual values will be summarized 
for plasma concentrations of fezolinetant and the major metabolite ES259564 by visit and 
treatment arm. Pharmacokinetics may be evaluated by a population pharmacokinetic 
approach. All details of population analyses will be described in a separate analysis plan and 
a separate report will be written. When deemed necessary, data from this study may be 
combined with data from other studies. 
7.8 
Analysis of Pharmacodynamics 
Individual serum hormone concentration values and actual sampling times relative to study 
drug intake will be listed. Descriptive statistics (number of subjects, mean, SD, median, 
minimum and maximum) on the actual values and changes from baseline values will be 
summarized by assessment timepoint and by treatment arm. Pharmacodynamic data and 
efficacy data may be evaluated by a population pharmacodynamics or population 
pharmacokinetic/pharmacodynamic approach. All details of population analyses will be 
described in the SAP. When deemed necessary, data from this study may be combined with 
data from other studies. 
7.9 
Major Protocol Deviations  
Major protocol deviations as defined in [Section 8.3 Major Protocol Deviations] will be 
summarized for all randomized subjects by treatment group and total as well as by site. A 
data listing will be provided by site and subject. 
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. 


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7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
No formal interim analysis is planned for this study. 
7.11 
Additional Conventions 
The start and stop dates of AEs and concomitant medication will be imputed. The imputed 
dates will be used to allocate the concomitant medication and AEs to a treatment group, in 
addition to determining whether an AE is/is not treatment emergent. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be 
shown. See the SAP for details of the definition for analysis windows to be used for analyses 
by visit. 
8 
OPERATIONAL CONSIDERATIONS 
8.1 
Data Collection 
The investigator or site designee will enter data collected using an Electronic Data Capture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within 
5 days after the subject’s visit. 
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 
Laboratory tests are performed at a central laboratory. Central Laboratory data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The Central laboratory will provide the sponsor or designee with a complete and clean copy 
of the data.  
ECG results are performed at a central ECG reading. Central ECG read data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The central ECG laboratory will provide the sponsor or designee with a complete and clean 
copy of the data. 
TVU central results are performed by a central TVU reader. Central TVU read data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The central TVU imaging facility will provide the sponsor or designee with a complete and 
clean copy of the data. 
Endometrial biopsies will be analyzed by central pathologists. Central biopsy readings will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The central pathology facility will provide the sponsor or designee with a complete and clean 
copy of the data. 


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All procedures conducted under the protocol must be documented. For screen failures, the 
minimum demographic data (sex, birth date, race and informed consent date), outcome of 
eligibility assessment (inclusion and exclusion criteria), reason for screen failure and AEs 
details must be documented. 
The investigator or designee will be responsible for source data completion and that all data 
and queries are accurate, complete and are verifiable with the source. The source should be 
appropriately maintained by the clinical unit. 
Electronic data sources and any supporting documents should be available for review/retrieval 
by the sponsor/designee at any given time. 
8.1.1 
Electronic Clinical Outcome Assessment/Electronic Patient-Reported Outcome 
Subject questionnaires will be completed by the subject on an electronic device and the 
collected electronic source data will be hosted at the vendor. The investigator or site designee 
should review the questionnaire data while the subject is at the site.  
The questionnaire data will be transferred electronically to sponsor or designee at predefined 
intervals during the study. The vendor will provide the investigator with a complete and clean 
copy of their site’s data and will provide the sponsor or designee with a complete and clean 
copy of the study data. The ownership of this data is with the investigator and subsequently 
any changes requested to these subject reported data will be made using a Data Clarification 
Form to the vendor. The requested change must be supported by documented evidence at site.  
8.2 
Screen Failures 
For screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
8.3 
Major Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. Deviations from the protocol are to be 
recorded. A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol. Protocol waivers are strictly prohibited. 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and must protect the rights, safety and 
well-being of subjects. The investigator should not implement any deviation from, or changes 
of, the protocol, unless it is necessary to eliminate an immediate hazard to subjects.  
A major protocol deviation is 1 that may potentially impact the completeness, accuracy or 
reliability of data contributing to the primary endpoint or affect the rights, safety or well-being 
of a subject. Major protocol deviations will have additional reporting requirements. 
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 


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and/or efficacy or pharmacokinetic parameters of the subject to determine subject 
continuation in the study. 
The major protocol deviation criteria that will be summarized at the end of the study are as 
follows: 
PD1 - Entered into the study even though the subject did not satisfy entry criteria  
PD2 - Developed withdrawal criteria during the study and was not withdrawn 
PD3 - Received wrong treatment or incorrect dose 
PD4 - Received excluded concomitant treatment 
The investigator will also assure that deviations meeting IRB/IEC and appropriate regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and appropriate regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File.  
9 
END OF TRIAL  
The end of the study is defined as the last visit or scheduled procedure shown in the Schedule 
of Assessments for the last study participant in the study. 
10 
STUDY ORGANIZATION 
10.1 
Data Monitoring Committee  
A DMC will evaluate the safety data of subjects enrolled on a periodic basis during this 
study. DMC members will be clinicians with expertise in Women’s Health studies and are 
not investigators participating in the study or Astellas employees. A statistician will also be 
and DMC member. A separate charter will outline the activities of this committee. 
An independent data analysis center will provide analysis for the DMC. DMC members may 
include advice from other external advisors.  
10.2 
Other Study Organization 
A Liver Safety Monitoring Committee consisting of independent hepatologists experienced 
in the assessment of drug induced liver injury will be formed. This committee will conduct an 
independent review of individual subject cases that meet the individual withdrawal criteria 
pertaining to elevated transaminases or other liver health markers and advise the study 
sponsor whether the individual reviewed cases meet the criteria of a potential DILI. A 
separate charter will outline the activities of this committee.  


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11 
REFERENCES  
Crandall CJ, Manson JE, Hohensee C, Horvath S, Wactawski-Wende J, LeBlanc ES, et al. 
Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night 
sweats in the Women’s Health Initiative Study. Menopause. 2017;24(3):252-61. 
de Villiers TJ, Hall JE, Pinkerton JV, Cerdas Perez S, Rees M, Yang C, et al. Revised global 
consensus statement on menopausal hormone therapy. Climacteric. 2016;19:313-5. 
FDA Draft Guidance, Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms 
and Vulvar and Vaginal Atrophy Symptoms – Recommendations for Clinical Evaluation, 2003 
at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm071643.pdf 
Hilditch JR, Lewis J, Peter A, van Mark B, Ross A, Franssen E, et al. A menopause-specific quality 
of life questionnaire: development and psychometric properties. Maturitas. 1996;24:161-75. 
Hrabovszky E. Neuroanatomy of the human hypothalamic kisspeptin system. Neuroendocrinology. 
2014;99(1):33-48. 
Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci.1990;592:52-86. 
Kronenberg F. Hot flashes: phenomenology, quality of life, and search for treatment options. Exp 
Gerontol. 1994; 29:319-36. 
Lehman MN, Coolen LM, Goodman RL. Minireview: Kisspeptin/neurokinin B/dynorphin (KNDy) 
cells of the arcuate nucleus: A central node in the control of gonadotropin-releasing hormone 
secretion. Endocrinology. 2010;151(8):3479-89. 
Lewis JE, Hilditch JR, Wong CJ. Further psychometric property development of the 
Menopause-Specific Quality of Life questionnaire and development of a modified version, 
MENQOL-Intervention questionnaire. Maturitas. 2005;50:209-21. 
Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, La Vasseur BI, Barton DL, et al. Venlafaxine in 
management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 
2000;356:2059-63. 
Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of 
fluoxetine for treatment of hot flashes. J Clin Oncol. 2002;20:1578-83. 
McCloskey EV, Oden A, Harvey NC, Leslie WD, Hans D, Johansson H, et al. A meta-analysis of 
trabecular bone score in fracture risk prediction and its relationship to FRAX. J Bone Mineral 
Res. 2016;31(5):940-8. 
Millar RP, Newton CL. Current and future applications of GnRH, kisspeptin and neurokinin B 
analogues. Nat Rev Endocrinol. 2013;9:451-66. 
Muschitz C, Kocijana R, Haschka J, Pahr D, Kaider A, Pietschmann P, et al. TBS reflects trabecular 
microarchitecture in premenopausal women and men with idiopathic osteoporosis and 
low-traumatic fractures. Bone. 2015;79:259-66. 


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Rance NE, Young WS III. Hypertrophy and increased gene expression of neurons containing 
neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of 
postmenopausal women. Endocrinology. 1991;128:2239-47. 
Rance NE. Menopause and the human hypothalamus: Evidence for the role of kisspeptin/neurokinin 
B neurons in the regulation of estrogen negative feedback. Peptides. 2009;30:111-22. 
Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of 
body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and 
dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes. Front 
Neuroendocrinol. 2013;34(3):211-27. 
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick M L, et al. Risks and 
benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from 
the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33. 
Ruka KA, Burger LL, Moenter SM. Both estrogen and androgen modify the response to activation of 
neurokinin-3 and κ-opioid receptors in arcuate kisspeptin neurons from male mice. 
Endocrinology. 2016;157(2):752-63. 
Stearns V, Isaacs C, Rowland J, Crawford J, Ellis MJ, Kramer R, et al. A pilot trial assessing the 
efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer 
survivors. Ann Oncol. 2000;11:17-22. 
Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of 
menopausal hot flashes: A randomized controlled trial. JAMA. 2003;289(21):2827-34. 
Thurston RC and Joffe H. Vasomotor symptoms and menopause: Findings from the study of 
Women’s Health Across the Nation. Obstet Gynecol Clin North Am. 2011;38(3):489-501. 
van Reenen M and Jannssen B. EQ-5D-5L User Guide: basic information on how to use the EQ-5D-
5L instrument. Version 2.1. April 2015. Available at https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf. Accessed 11 October 2018. 
 


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12 
APPENDICES 
12.1 
Ethical, Regulatory, and Study Oversight Considerations 
12.1.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  
12.1.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Competent Authorities (CA) 
GCP requires that the clinical protocol, any protocol amendments, the IB, the informed 
consent and all other forms of subject information related to the study (e.g., advertisements 
used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. The 
IEC/IRB will review the ethical, scientific and medical appropriateness of the study before it 
is conducted. IEC/IRB approval of the protocol, informed consent and subject information 
and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to 
a study site. 
Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation, except for changes necessary to eliminate an immediate hazard to subjects. 
The investigator will be responsible for the following: 
● 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
● 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
● 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
12.1.3 Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or nonsubstantial amendments. 
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).  
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations. 


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If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor. An approved copy of the new informed consent must also be 
forwarded to the sponsor. 
12.1.4 Financial Disclosure 
Investigators and subinvestigators 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. 
12.1.5 Informed Consent of Subjects 
12.1.5.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject 
and answer all questions regarding this study. Prior to any study-related screening procedures 
being performed on the subject, the informed consent statement will be reviewed, signed and 
dated by the subject, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed ICF will be given to the 
subject and the original will be placed in the subject’s medical record. An entry must also be 
made in the subject’s dated source documents to confirm that informed consent was obtained 
prior to any study-related procedures and that the subject received a signed copy. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
1. Supply of New and Important Information Influencing the Subject’s Consent and 
Revision of the Written Information. The investigator or his/her representative will 
immediately inform the subject orally whenever new information becomes available that 
may be relevant to the subject’s consent or may influence the subject’s willingness to 
continue to participate in the study (e.g., report of serious drug adverse drug reaction). 
The communication must be documented in the subject’s medical records and whether 
the subject is willing to remain in the study or not must be confirmed and documented.  
2. The investigator must update the subject’s ICF and submit it for approval to the 
IRB/IEC. The investigator or his/her representative must obtain written informed consent 
from the subject on all updated ICFs throughout their participation in the study. The 
investigator or his/her designee must re-consent subjects with the updated ICF even if 
relevant information was provided orally. The investigator or his/her representative who 
obtained the written informed consent and the subject should sign and date the ICF. A 
copy of the signed ICF will be given to the subject and the original will be placed in the 
subject’s medical record. An entry must be made in the subject’s records documenting 
the re-consent process. 


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12.1.6 Source Documents 
Source data must be available at the site to document the existence of the study subjects and to 
substantiate the integrity of study data collected. Source data must include the original documents 
relating to the study, as well as the medical treatment and medical history of the subject.  
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are hand-written on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
achieved, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electric devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records, 
protocol related assessments, AE tracking, and/or drug accountability.  
Paper records from electronic systems used in place of electronic format must be certified 
copies. A certified copy must be an exact copy and must have all the same attributes and 
information as the original. Certified copies must include signature and date of the individual 
completing the certification. Certified copies must be a complete and chronological set of 
study records (including notes, attachments, and audit trail information (if applicable). All 
printed records must be kept in the subject file and available for archive.  
12.1.7 Record Retention 
The investigator will archive all study data (e.g., subject identification code list, source data, 
CRFs and investigator's file) and relevant correspondence. These documents are to be kept on 
file for the appropriate term determined by local regulation (for US sites, 2 years after 
approval of the NDA or discontinuation of the IND). The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued. The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving or transferring of any study-related records. The sponsor will archive and 
retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. 
12.1.8 Subject Confidentiality and Privacy 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless otherwise the subject provides 
written consent or approval. Additional medical information may be given only after 
approval of the subject to the investigator or to other appropriate medical personnel 
responsible for the subject's well-being. 
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 


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Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties.  
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number will identify subject data retrieved by the sponsor. However, 
the sponsor requires the investigator to permit the sponsor, sponsor's representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then the sponsor shall serve as the controller of 
such data, as defined by the European Union (EU) Data Protection Directive, and the 
investigator and/or third party shall act only under the instructions of the sponsor in regard to 
personal data. If the sponsor is not based in the EEA, the sponsor must appoint a third party 
to act as its local data protection representative or arrange for a co-controller established in 
the EU for data protection purposes in order to comply with the Directive. 
12.1.9 Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she 
has an obligation to provide the sponsor with all data obtained during the study. 
Publication of the study results is discussed in the clinical study agreement. 
12.1.10 Insurance of Subjects and Others  
The sponsor has covered this study by means of an insurance of the study according to national 
requirements. The name and address of the relevant insurance company, the certificate of 
insurance, the policy number and the sum insured are provided in the investigator's file.  
12.1.11 Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 


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it accurately describes the conduct and results of the study. The representative for 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock. 


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12.2 
Procedure for Clinical Study Quality Control 
12.2.1 Clinical Study Monitoring 
The sponsor or delegated contract research organization (CRO) is responsible for monitoring 
the clinical study to ensure that subject's human rights, safety, and well-being are protected, 
that the study is properly conducted in adherence to the current protocol and GCP, and study 
data reported by the investigator/subinvestigator are accurate and complete and that they are 
verifiable with study-related records such as source documents. The sponsor is responsible 
for assigning study monitor(s) to this study for proper monitoring. They will monitor the 
study in accordance with planned monitoring procedures.  
12.2.2 Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO, as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records including source documents 
when they are requested by the sponsor monitors and auditors, the IRB/IEC or regulatory 
authorities. The confidentiality of the subject's identities shall be well protected consistent 
with local and national regulations when the source documents are subject to direct access. 
12.2.3 Data Management 
Data Management will be coordinated by the Data Science of the sponsor in accordance with 
the SOPs for data management. All study-specific processes and definitions will be 
documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and World Health Organization Drug Dictionary, respectively. 
12.2.4 Quality Assurance 
The sponsor is implementing and maintaining quality assurance (QA) and QC systems with 
written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s). Where applicable, the QA and QC systems and written SOPs of the CRO will 
be applied. 
The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities. The audit may include on-site review of regulatory documents, CRFs and source 
documents. Direct access to these documents will be required by the auditors. 
To support quality around subject safety and reliability of study results, quality tolerance 
limits (QTLs) are defined and monitored. QTLs represent the acceptable variation of study 
data, taking into consideration the current state of medical and statistical knowledge about the 
variables to be analyzed as well as the statistical design of the study. It is a level, point, or 
value associated with a parameter that should trigger an evaluation if a deviation is detected 
to determine if there is a possible systematic issue (i.e., a trend has occurred). The QTLs 
defined for this study, information regarding the QTL limit and limit justification, as well as 
associated activities are documented in STL-3458 QTL monitoring plan. 


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12.3 
Contraception Requirements 
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Schedule of Assessments. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  
Women in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
● 
Post-menopausal 
Documentation of any of these categories can come from the site personnel’s review of the 
female subject’s medical records, medical examination, or medical history interview. 
A postmenopausal state is defined as at least 12 months after last regular menstrual bleeding 
without an alternative medical cause.  
● 
In case the last regular menstrual bleeding cannot be clearly determined, confirmation 
with repeated FSH measurements of at least > 40 IU/L (or higher per local institutional 
guidelines), is required.  
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status by repeated FSH measurements before study enrollment. 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING POTENTIAL 
One of the highly effective methods of contraception listed below is required at the time of 
informed consent and until the end of relevant systemic exposure, defined as 21days after the 
final study drug administration.a 
Highly Effective Contraceptive Methods (Failure rate of < 1% per year when used 
consistently and correctly)b 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
● 
oral 
● 
intravaginal 
● 
transdermal 


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Progestogen-only hormonal contraception associated with inhibition of ovulation 
● 
oral 
● 
injectable 
● 
implantable  
Hormonal methods of contraception containing a combination of estrogen and P4, vaginal 
ring, injectables, implants and intrauterine hormone-releasing systems 
● 
intrauterine device 
● 
bilateral tubal occlusion 
a Local laws and regulations may require use of alternative and/or additional contraception methods. 
b Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 


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12.4 
List of Excluded Concomitant Medications 
These lists are not inclusive of all possible prohibited medications. In case of doubt, the 
Investigator must contact the local medical monitor. 
● Use of hormonal medications such as hormone therapy, HRT or hormonal contraception 
or any treatment for menopausal symptoms (prescription, over the counter or herbal) is 
not allowed during the study.  
● Investigational research products that have not been approved for any indication in the 
country where the subject is enrolled. 








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12.5 
Liver Safety Monitoring and Assessment  
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN or bilirubin > 2 × ULN should undergo detailed 
testing for liver enzymes (including at least ALT, AST, ALP and TBL). Testing should be 
repeated within 72 hours of notification of the test results. For studies for which a central 
laboratory is used, alerts will be generated by the central laboratory regarding moderate and 
severe liver abnormality to inform the investigator and study team. Subjects should be asked 
if they have any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
 
ALT or AST 
 
TBL 
Moderate 
> 3 × ULN  
or 
> 2 × ULN 
Severe 
> 3 × ULN 
and 
> 2 × ULN 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 × ULN; 
● 
ALT or AST > 5 × ULN for more than 2 weeks;  
● 
ALT or AST > 3  ULN AND TBL > 2  ULN or INR > 1.5; or 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5% increase above baseline). 
The investigator may determine that abnormal liver test results, other than as described above, 
may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic tests should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site staff is to complete the liver abnormality 
case report form (LA-CRF). Subjects with confirmed liver aminotransferases (ALT or AST) 
should be followed as described below. 
Confirmed moderately abnormal liver tests should be repeated 2 to 3 times weekly then 
weekly or less if abnormalities stabilize or the study drug has been discontinued and the 
subject is asymptomatic.  
Severe liver test abnormalities as defined above, in the absence of another etiology, are 
considered an important medical event and should be reported as a SAE. The sponsor should 
be contacted and informed immediately of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed. 


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To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases is to be recorded as “AEs” within the eCRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic patients, and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.  
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, is to be entered in the eCRF. Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including:  
○ Acute viral hepatitis (A, B, C, D, E or other infectious agents),  
○ Ultrasound or other imaging to assess biliary tract disease, 
○ Other laboratory tests including INR and DBL. 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Treatment Discontinuation 
In the absence of an explanation for increased liver aminotransferases (ALT or AST) tests, 
such as viral hepatitis, preexisting or acute liver disease, or exposure to other agents 
associated with liver injury, the subject may be discontinued from study treatment. The 
investigator may determine that it is not in the subject’s best interest to continue study 
treatment. Study treatment must be discontinued and event reported as an SAE if: 
● 
ALT or AST > 8 × ULN; 
● 
ALT or AST > 5 × ULN for more than 2 weeks; 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 × ULN, and INR ; 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5% increase above 
baseline).  
Subjects who develop a signal for liver injury will be monitored every 2 to 4 weeks if the 
study drug is discontinued. If the subject remains on study drug, they will be closely 
monitored for liver biochemistry results.  
Subjects with a signal of elevated (> 3 × ULN) transaminases will have pharmacokinetic 
samples drawn in addition to repeat blood draws for liver biochemistry monitoring. These 
samples can be held for potential analysis based on the subject’s clinical outcome.   


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In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
*Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10 to 50% mortality 
(or transplant).  
The 2 “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in transaminase elevations higher 3 × ULN (2 × ULN elevations are too common in treated 
and untreated patients to be discriminating).  
2. Cases of increased bilirubin (at least 2 × ULN) in people with concurrent transaminase 
elevations to at least 3 × ULN (but it is almost invariably higher) and no evidence of intra- 
or extra-hepatic bilirubin obstruction (elevated ALP) or Gilbert’s syndrome [Temple, 
2006]. 
FDA Guidance for Industry titled “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009: 
FDA Guidance for Industry: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug 
or placebo. 
2. Among trial subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, one or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
References 
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3. 


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12.6 
Common Serious Adverse Events 
For this protocol, there is no list of common SAEs anticipated for the study population for the 
purposes of IND safety reporting.  
 


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12.7 
Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated Schedule of Assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the alternate 
measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed as described in [Section 5 
Treatments and Evaluation] due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent which explicitly informs them of the nature of, 
and rationale for these changes, and gain their agreement to continue participation in the 
study prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the principal investigator or designee will obtain oral 
agreement from the subject followed by written documentation as soon as is feasible. A 
separate addendum to the study informed consent will be provided to document the 
participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
• Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
• Site facilities have been closed for clinical study conduct  
• Site has been restricted to treating patients with conditions outside of the scope of the 
study 
• Site personnel have temporarily relocated the conduct of the study to a location that place 
a burden on the participant with respect to time and travel 


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• Participant(s) have temporarily relocated from the current study site to an alternate study 
site to avoid placing a burden on the participant with respect to travel 
• Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel 
• Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessment [Table 1] is 
expected, where plausible, in the case of a crisis. The alternate measures as noted in Table 3 
below are only permissible in the event of a crisis, and after discussing the need with the 
Astellas medical monitor to implement the alternate measures.  This is to allow for continuity 
of receiving investigational medicinal product (IMP) and maintaining critical safety and 
efficacy assessments for patients participating in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding time point(s). 


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Table 3 
Alternative Schedule of Assessments in Response to a Crisis 
Assessments 
Alternate Approaches 
Treatment Period 
Follow-up 
Visit 
Study Visit  
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 12, 
13 and 14 
Visit 15/ 
EOT/ED 
Visit 16 
Time of Visit  
Week 2 
Week 
4 
Week 
8 
Week 
12 
Week 16 
Week 
20 
Week 24 
Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days  
Day 15 
Day 
29 
Day 57 Day 85 
Day 113 
Day 
141 
Day 169 Day 197, 225, 253, 
281, 309 and 337 
Day 365 
Day 386 
Visit Window (days)  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
-14 /+ 6 
± 3 
Mammogram 
If imaging is delayed, should 
be completed as soon as 
possible. 
Please refer to protocol schedule of assessments. 
Demographic data 
Remote/Virtual/Telemedicine 
Visits allowed 
Please refer to protocol schedule of assessments. 
Urine pregnancy test 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site. To be 
completed at local laboratory. 
Please refer to protocol schedule of assessments. 
Clinical laboratory 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site. To be 
completed at local laboratory. 
Please refer to protocol schedule of assessments. 
Serology 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site. To be 
completed at local laboratory. 
Please refer to protocol schedule of assessments. 
Blood pharmacodynamic 
sample 
Delay the  measurements to 
subsequent visit. 
Please refer to protocol schedule of assessments. 
Blood pharmacokinetic 
sample 
Delay the measurements to 
subsequent visit. 
Please refer to protocol schedule of assessments. 
Table continued on next page 


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Assessments 
Alternate Approaches 
Treatment Period 
Follow-up 
Visit 
Study Visit  
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 12, 
13 and 14 
Visit 15/ 
EOT/ED 
Visit 16 
Time of Visit  
Week 2 
Week 
4 
Week 
8 
Week 
12 
Week 16 
Week 
20 
Week 24 
Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days  
Day 15 
Day 
29 
Day 57 Day 85 
Day 113 
Day 
141 
Day 169 Day 197, 225, 253, 
281, 309 and 337 
Day 365 
Day 386 
Visit Window (days)  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
-14 /+ 6 
± 3 
C-SSRS 
Remote/Virtual/Telemedicine 
Visits allowed 
Please refer to protocol schedule of assessments. 
EQ-5D-5L 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
MENQoL 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
ePRO training 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
Dispense study drug 
Patients can be brought into 
the clinic earlier to provide 
additional study drug. 
Courier service directly to 
patient allowed. 
Please refer to protocol schedule of assessments. 
Study drug compliance 
and accountability 
Patients can be brought into 
the clinic earlier to provide 
additional study drug. 
Courier service directly to 
patient allowed. 
Please refer to protocol schedule of assessments. 
Concomitant medications 
and AEs 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
AE: adverse event; C-SSRS: Columbia Suicide Severity Rating Scale; ED: early discontinuation; EOT: end of treatment; ePRO: electronic patient-reported outcome; EQ-5D-5L: Euro-Qol 5D-5L; 
MENQoL: Menopause-Specific Quality of Life.


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INVESTIGATIONAL MEDICINAL PRODUCT  SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are met, 
one or all of the following mitigating strategies will be employed, as needed, to ensure 
continuity of IMP supply to the participants: 
● 
Increase stock of IMP on site to reduce number of shipments required, if site space 
will allow. 
● 
Direct-to-Participant shipments of IMP from the site to the participant’s home. 
● 
Bringing the participant to the site earlier. 
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have 
been affected by a crisis and to accommodate data collection resulting from alternate 
measures implemented to manage the conduct of the study and participant safety.  
● 
Critical assessments for safety and efficacy based on study endpoints to be identified 
as missing or altered (performed virtually, at alternative locations, out of window, or 
other modifications) due to the crisis.  
 
 


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13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 3 
I.  The purpose of this amendment is: 
Nonsubstantial Changes 
1. Update End of Treatment (EOT) Visit Window 
DESCRIPTION OF CHANGE:  
The EOT visit window is expanded from 0/+6 to -14/+6 and a footnote is added to the 
endometrial biopsy at Visit 15/EOT/early discontinuation.  
 
RATIONALE: 
This is to provide more flexibility to investigators and subjects in scheduling the EOT/ED 
visit, to ensure that there is appropriate opportunity to collect all EOT/ED assessments. In 
case of an EOT/ED endometrial biopsy that is evaluated as ‘insufficient material’ or 
‘unevaluable’, the extended visit window will enable a retest biopsy to be conducted within 
the visit window. 
 
2. Clarification of Visit 15/EOT/ED Endometrial Biopsy Procedures 
DESCRIPTION OF CHANGE: 
Language is added to clarify that EOT/ED endometrial biopsies that are evaluated as 
‘insufficient material’ or ‘unevaluable’ a retest biopsy is required. In addition, language was 
also added to clarify when a repeat biopsy is required. 
 
RATIONALE: 
This change is made to further optimize the collection of EOT/ED endometrial biopsies for 
the primary objective/endpoint of the study and provide clarity on when a repeat biopsy is 
required. 
3. Add Clarification for Pharmacokinetic Sample at Week 52 
DESCRIPTION OF CHANGE:  
A statement added to the footnote for Blood Pharmacokinetic Sample in the schedule of 
assessments to clarify that the last dose of study drug should be administered the day prior to 
the week 52 (visit 15) visit. 
 
RATIONALE: 
This revision is made for clarification. 
 
4. Update Timing of Week 52 Dual-Energy X-Ray Absorptiometry (DXA)  
DESCRIPTION OF CHANGE:  
In Section 5.5.2 and the schedule of assessments, the timing of the week 52 DXA is changed 
to ‘between week 50 and 52.’ 
 


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RATIONALE: 
This revision is made to  align with the timing of the adjusted Visit 15/EOT/ED visit 
window. 
 
5. Clarification of Recording an Abnormal Endometrial Biopsy as an Advese Event 
(AE) 
DESCRIPTION OF CHANGE:  
Added that the investigator should record any abnormal biopsies and the associated 
diagnostic and therapeutic measures, as an AE. 
RATIONALE: 
Clarification provided to investigator so abnormal endometrial biopsies can be followed to 
resolution. 
 
6. Removed Platelet Reduction as AE of Special Interest 
DESCRIPTION OF CHANGE:  
Platelet reduction is removed as an AE of special interest 
 
RATIONALE: 
Not consistent with the statistical analysis plan. 
 
7. Removed Significance Testing 
DESCRIPTION OF CHANGE:  
Removed the significance testing for dichotomized endpoints. 
 
RATIONALE: 
The confidence intervals for odds ratio and rate is sufficient for interpretation. 
 
8. Add Appendix for Clinical Study Continuity 
DESCRIPTION OF CHANGE: 
A Clinical Study Continuity appendix is added to the protocol (Appendix 12.7). This 
appendix contains procedures for continuity of care during a crisis (e.g., natural disaster or a 
pandemic).  
 
RATIONALE: 
This appendix is added to provide acceptable alternate methods to assess safety and efficacy 
parameters in the event the clinical study is interrupted at the country, state, site or participant 
level during any crisis (e.g., natural disaster or pandemic). 
This is an appendix that is being standardized throughout Astellas. The procedures that are 
included in this appendix are aligned with what was already included in the previous version 
of the protocol. 


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9. Minor Administrative-type Changes 
DESCRIPTION OF CHANGE:  
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol) and updated list of abbreviations. 
 
RATIONALE: 
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures. 
 
II.  Amendment Summary of Changes: 
 
II Contact Details of Key Sponsor’s Personnel 
WAS: 
 
  
ICON Clinical Research  
 
 
IS AMENDED TO; 
 
 
  
ICON Clinical Research  
 
 
 
 
III List of Abbreviations and Definition of Key Terms 
List of Abbreviations 
ADDED: 
IMP 
investigational medicinal product 
PPD
PPD
PPD
PPD


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V Flow Chart and Schedule of Assessments 
Table 1 Schedule of Assessments 
WAS: 
Assessments 
Screening 
Visita,x 
Randomi-
zationx 
Treatment Period 
Follow-
Up Visitb 
Study Visit 
Visit 1 
Visit 2 
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 
12, 13 and 14 
Visit 15/ 
EOT/EDx 
Visit 16 
Time of Visit 
Week -5 to 
-1  
Week 0 
Week 2 
Week 4 
Week 
8 
Week 12 
Week 
16 
Week 20 
Week 
24 
Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days 
Days -35 to 
-1 
Day 1 
Day 15 
Day 29 
Day 
57 
Day 85 
Day 113 
Day 141 
Day 169 
Day 197, 225, 
253, 281, 309 and 
337 
Day 365 
Day 386 
Visit Window (days)c 
-35 to -1 
- 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
+ 6 
± 3 
Endometrial biopsyn 
X 
 
 
 
 
 
 
 
 
 
X 
 
DXAo 
X 
 
 
 
 
 
 
 
 
 
X 
 
Serologyp 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood pharmacodynamic 
sampleq 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Blood pharmacokinetic 
sampler 
 
 
 
Xr 
 
X 
 
 
X 
 
X 
 
C-SSRSs 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
EQ-5D-5Lt 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
MENQoLt 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Dispense study drugu 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug compliance 
and accountabilityv 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
and AEsw 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
n. 
Endometrial biopsy will be performed at screening and at week 52/EOT and in the case of uterine bleeding during treatment. Subject may schedule the endometrial biopsy on a separate day, within 
the screening period. Subjects that require a retest biopsy due to insufficient or unevaluable result, will have an extended screening period and will be allowed an additional 15 days of screening (i.e., 
days -50 to -1). Screening biopsy results are valid for study entry up to 3 months from date of procedures for applicable subjects. Subjects who screen failed due to the COVID-19 pandemic study 
suspension and have a documented evaluable endometrial biopsy from the original screening period do not have to undergo a repeat biopsy should they decide to rescreen. If a subject discontinues 
from the study, an endometrial biopsy will be performed at the discontinuation visit along with all other EOT procedures.  
p. 
For practical reasons, the timing of DXA may vary from the actual time of the visit, depending on the DXA availability (DXA appointment). The screening visit (days -35 to -1 [visit 1]) DXA can be 
performed once the subject has been deemed eligible based on screening laboratory tests, or at visit 2 but must be performed before randomization. The week 52 (visit 15) DXA should be performed 
between week 51 and week 52, inclusive. For subjects who are withdrawn from the study prior to completion, a DXA will be completed as soon as possible after study drug discontinuation 


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(preferably within 2 weeks). 
s. 
Pharmacokinetic samples to be taken predose at week 4 (visit 3), week 12 (visit 5), week 24 (visit 8), and at EOT/ED week 52 (visit 15) and at 1 to 3 hour postdose at week 4 (visit 3). A predose 
sample will be collected for any subject with a signal of elevated (> 3 × ULN) transaminases.  
v. 
Subjects will be assigned study drug as a kit containing either fezolinetant or placebo. Study drug intake will be done with a glass of room temperature tap water. The first intake of study drug will 
take place at the study site on day 1 (visit 2) under the supervision of the study staff. On study visit days, the daily dose of study drug will be taken at the study site, under the supervision of the study 
staff, after collection of predose blood samples. On all other days throughout the treatment period, subjects will be instructed to take their study drug at home, in the morning with water.  
 
IS AMENDED TO: 
Assessments 
Screening 
Visita,x 
Randomi-
zationx 
Treatment Period 
Follow-
Uup 
Visitb 
Study Visit 
Visit 1 
Visit 2 
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 
12, 13 and 14 
Visit 15/ 
EOT/EDxv 
Visit 16 
Time of Visit 
Week -5 to 
-1  
Week 0 
Week 2 
Week 4 
Week 
8 
Week 12 
Week 
16 
Week 20 
Week 
24 
Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days 
Days -35 to 
-1 
Day 1 
Day 15 
Day 29 
Day 
57 
Day 85 
Day 113 
Day 141 
Day 169 
Day 197, 225, 
253, 281, 309 and 
337 
Day 365 
Day 386 
Visit Window (days)c 
-35 to -1 
- 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
-14/+ 6 
± 3 
Endometrial biopsyn 
Xn 
 
 
 
 
 
 
 
 
 
Xo 
 
DXAop 
X 
 
 
 
 
 
 
 
 
 
X 
 
Serologypq 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood pharmacodynamic 
sampleqr 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Blood pharmacokinetic 
samplers 
 
 
 
Xr 
 
X 
 
 
X 
 
X 
 
C-SSRSst 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
EQ-5D-5Ltu 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
MENQoLtu 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Dispense study druguv 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug compliance 
and accountabilityvw 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
and AEswx 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
v. 
Endometrial biopsy will be performed at screening and at week 52/EOT and in the case of uterine bleeding during treatment. Subject may schedule the endometrial biopsy on a separate day, within 
the screening period. Subjects that require a retest biopsy due to insufficient or unevaluable result, will have an extended screening period and will be allowed an additional 15 days of screening (i.e., 


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days -50 to -1). Screening biopsy results are valid for study entry up to 3 months from date of procedures for applicable subjects. Subjects who screen failed due to the COVID-19 pandemic study 
suspension and have a documented evaluable endometrial biopsy from the original screening period do not have to undergo a repeat biopsy should they decide to rescreen. If a subject discontinues 
from the study, an endometrial biopsy will be performed at the discontinuation visit along with all other EOT procedures.  
o. 
Endometrial biopsy is required at EOT or ED. For EOT/ED week 52 (visit 15) biopsies that are evaluated as insufficient material or unevaluable , a retest biopsy will be required. Any of 
the three pathologists can determine if a EOT/ED biopsy is insufficient or unevaluable. However, if two pathologists read the EOT/ED endometrial biopsy as evaluable and issue the same 
diagnosis, and the 3rd pathologist reads the biopsy as insufficient or unevaluable, the biopsy does not need to be repeated. 
op  For practical reasons, the timing of DXA may vary from the actual time of the visit, depending on the DXA availability (DXA appointment). The screening visit (days -35 to -1 [visit 1]) DXA can be 
performed once the subject has been deemed eligible based on screening laboratory tests, or at visit 2 but must be performed before randomization. The week 52 (visit 15) DXA should be performed 
between week 5051 and week 52, inclusive. For subjects who are withdrawn from the study prior to completion, a DXA will be completed as soon as possible after study drug discontinuation 
(preferably within 2 weeks). 
rs   Pharmacokinetic samples to be taken predose at week 4 (visit 3), week 12 (visit 5), week 24 (visit 8), and at EOT/ED week 52 (visit 15) and at 1 to 3 hour postdose at week 4 (visit 3). A predose 
sample will be collected for any subject with a signal of elevated (> 3 × ULN) transaminases. For the week 52 (visit 15) PK/PD samples, the last dose of study drug should be administered the 
day prior to the week 52 (visit 15) visit. Sites should collect week 52 (visit 15) PK/PD samples approximately at the same time when study drug would typically be given on site. 
v. 
Subjects will be assigned study drug as a kit containing either fezolinetant or placebo. Study drug intake will be done with a glass of room temperature tap water. The first intake of study drug will 
take place at the study site on day 1 (visit 2) under the supervision of the study staff. On study visit days (except for EOT/ED week 52 [visit 15]), the daily dose of study drug will be taken at the 
study site, under the supervision of the study staff, after collection of predose blood samples. On all other days throughout the treatment period, subjects will be instructed to take their study drug at 
home, in the morning with water.  
 


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IV Synopsis, Study Design Overview and 2 Study Objectives, Design, and Endpoints 
2.2.1 Study Design 
WAS: 
At the end of treatment (EOT) (or the early discontinuation [ED] visit for subjects who 
withdraw from the study prior to completion), a TVU and a suction endometrial biopsy will 
be performed. If a subject discontinues from the study, an endometrial biopsy will be 
performed at the discontinuation visit along with all other EOT procedures.  
 
IS AMENDED TO: 
At the end of treatment (EOT) (or the early discontinuation [ED] visit for subjects who 
withdraw from the study prior to completion), a TVU and a suction endometrial biopsy will 
be performed. If a subject discontinues from the study, an endometrial biopsy will be is 
performed required at the discontinuation visit along with all other EOT procedures. 
 
IV Synopsis, Study Design Overview and 2 Study Objectives, Design, and Endpoints 
2.2.1 Study Design  
WAS: 
At the end of treatment (EOT) (or the early discontinuation [ED] visit for subjects who 
withdraw from the study prior to completion), a TVU and a suction endometrial biopsy will 
be performed. If a subject discontinues from the study, an endometrial biopsy will be 
performed at the discontinuation visit along with all other EOT procedures. During the 
treatment period, any woman with an abnormal endometrial biopsy reported as disordered 
proliferative endometrium, endometrial hyperplasia or endometrial cancer will be referred to 
standard of care clinical management and followed to resolution, and the report of any 
medical or surgical procedures and the resultant pathology will be obtained.  
IS AMENDED TO: 
At the end of treatment (EOT) (or the early discontinuation [ED] visit for subjects who 
withdraw from the study prior to completion), a TVU and a suction endometrial biopsy will 
be performed required. If a subject discontinues from the study, an endometrial biopsy will 
be performed is required at the discontinuation visit along with all other EOT procedures. 
During the treatment period, any woman with an abnormal endometrial biopsy reported as 
disordered proliferative endometrium, endometrial hyperplasia or endometrial cancer will be 
referred to standard of care clinical management and followed to resolution, and the report of 
any medical or surgical procedures and the resultant pathology will be obtained. The 
investigator should record any such biopsy, and the associated diagnostic and 
therapeutic measures, as an AE. 
 
5 Treatments and Evaluation 
5.1.1 Dose/Dose Regimen and Administration Period 
WAS: 


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On study visit days study drug will be taken at the study site, under the supervision of the 
study staff, after collection of predose blood samples. On all other days throughout the 
treatment period, subjects will be instructed to take their dose of study drug at home with 
water, in the morning.  
 
IS AMENDED TO: 
On study visit days (except for EOT/ED week 52 [visit 15]) study drug will be taken at the 
study site, under the supervision of the study staff, after collection of predose blood samples. 
On all other days throughout the treatment period, subjects will be instructed to take their 
dose of study drug at home with water, in the morning.  
 
5 Treatments and Evaluation 
5.5.2 Dual-Energy X-Ray Absorptiometry (DXA) 
WAS: 
The week 52 (visit 15) DXA should be performed between week 51 and week 52, inclusive. 
 
IS AMENDED TO: 
The week 52 (visit 15) DXA should be performed between week 5051 and week 52, 
inclusive. 
 
5 Treatments and Evaluation 
5.6.1 Endometrial Biopsy 
ADDED: 
An endometrial biopsy is required at EOT or ED. For EOT/ED week 52 (visit 15) 
biopsies that are evaluated as insufficient material or unevaluable, a retest biopsy will 
be required. Any of the three pathologists can determine if a an EOT/ED is insufficient 
or unevaluable. However, if two pathologists read the EOT/ED endometrial biopsy as 
evaluable and issue the same diagnosis, and the 3rd pathologist reads the biopsy as 
insufficient or unevaluable, the biopsy does not need to be repeated.…… 
The investigator should record any such biopsy, and the associated diagnostic and 
therapeutic measures, as an AE. 
 
 
5 Treatments and Evaluation 
5.8.7 Adverse Events of Special Interest 
WAS: 


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Version 3.2 Incorporating Nonsubstantial Amendment 3 
Adverse events of special interest in this study will include: 
● 
AE of uterine bleeding 
● 
Endometrial hyperplasia/cancer or disordered proliferative endometrium 
● 
AE of thrombocytopenia or platelets˂ 15000/uL 
● 
AE of liver test evalations 
● 
AE of bone fractures/bone loss ≥ 7% 
● 
AEs of abuse liability 
● 
AEs of depression 
● 
AEs of wakefulness  
● 
AEs of effect on memory  
 
IS AMENDED TO: 
Adverse events of special interest in this study will include: 
● 
AE of uterine bleeding 
● 
Endometrial hyperplasia/cancer or disordered proliferative endometrium 
● 
AE of thrombocytopenia or platelets˂ 15000/uL 
● 
AE of liver test evalations 
● 
AE of bone fractures/bone loss ≥ 7% 
● 
AEs of abuse liability 
● 
AEs of depression 
● 
AEs of wakefulness  
● 
AEs of effect on memory 
 
7 Statistical Methodology 
7.6.2 Laboratory Assessments 
WAS: 
The liver safety assessments will be summarized by the categories below based on the 
measurements from ALP, ALT, TBL, AST and their combination. These parameters will be 
based on measurements from a central laboratory. 
 
IS AMENDED TO: 
Number and percentage of subjects with platelets < 150x10^9/L will be separately 
summarized for each treatment group.  The liver safety assessments will be summarized 
by the categories below based on the measurements from ALP, ALT, TBL, AST and their 
combination. These parameters will be based on measurements from a central laboratory. 
 
12 Appendices 


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Version 3.2 Incorporating Nonsubstantial Amendment 3 
ADDED: 
12.7  Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety 
and efficacy parameters, as appropriate, in the event the clinical study is interrupted at 
the country, state, site or participant level during any crisis (e.g., natural disaster, 
pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in 
the clinical study setting is paramount during any crisis. The site is expected to follow 
the protocol and associated Schedule of Assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the 
alternate measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity 
and to provide acceptable alternate methods to complete the study required assessments 
and procedures if study activities are unable to be performed as described in [Section 5 
Treatments and Evaluation] due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this 
Appendix will be required to provide informed consent which explicitly informs them of 
the nature of, and rationale for these changes, and gain their agreement to continue 
participation in the study prior to the implementation of any of these changes. In the 
event the urgency of implementing the alternate measures does not allow for the 
participant to provide written consent prior to implementation, the principal 
investigator or designee will obtain oral agreement from the subject followed by written 
documentation as soon as is feasible. A separate addendum to the study informed 
consent will be provided to document the participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
• Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
• Site facilities have been closed for clinical study conduct  
• Site has been restricted to treating patients with conditions outside of the scope of 
the study 
• Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel 
• Participant(s) have temporarily relocated from the current study site to an alternate 
study site to avoid placing a burden on the participant with respect to travel 


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• Participant(s) have temporarily relocated from their home location and the new 
distances from the site would cause undue burden with respect to time and travel 
• Participant has risk factors for which traveling to the site poses an additional risk to 
the participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessment [Table 1] 
is expected, where plausible, in the case of a crisis. The alternate measures as noted in 
Table 3 below are only permissible in the event of a crisis, and after discussing the need 
with the Astellas medical monitor to implement the alternate measures.  This is to allow 
for continuity of receiving investigational medicinal product (IMP) and maintaining 
critical safety and efficacy assessments for patients participating in the study at a time 
of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, 
the site should document in the participant’s source document the justification for 
implementing the alternate measure and the actual alternate measures that were 
implemented, along with the corresponding time point(s). 


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Version 3.2 Incorporating Nonsubstantial Amendment 3 
12 Appendices 
ADDED: 
Table 3  Alternative Schedule of Assessments in Response to a Crisis 
Assessments 
Alternate Approaches 
Treatment Period 
Follow-
up Visit 
Study Visit 
 
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9, 10, 11, 12, 
13 and 14 
Visit 15/ 
EOT/ED 
Visit 16 
Time of Visit 
 
Week 2 
Week 4 
Week 
8 
Week 12 Week 16 Week 20 Week 24 Weeks 28, 32, 36, 
40, 44 and 48 
Week 52 
Week 55 
Visit days 
 
Day 15 
Day 
29 
Day 57 
Day 
85 
Day 113 Day 141 Day 169 Day 197, 225, 253, 
281, 309 and 337 
Day 365 
Day 386 
Visit Window (days) 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
-14 /+ 6 
± 3 
Mammogram 
If imaging is delayed, should be 
completed as soon as possible. 
Please refer to protocol schedule of assessments. 
Demographic data 
Remote/Virtual/Telemedicine 
Visits allowed 
Please refer to protocol schedule of assessments. 
Urine pregnancy test 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site. To be 
completed at local laboratory. 
Please refer to protocol schedule of assessments. 
Clinical laboratory 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site. To be 
completed at local laboratory. 
Please refer to protocol schedule of assessments. 
Serology 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site. To be 
completed at local laboratory. 
Please refer to protocol schedule of assessments. 
Blood 
pharmacodynamic 
sample 
Delay the measurements to 
subsequent visit. 
Please refer to protocol schedule of assessments. 


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Blood pharmacokinetic 
sample 
Delay the measurements to 
subsequent visit. 
Please refer to protocol schedule of assessments. 
C-SSRS 
Remote/Virtual/Telemedicine 
Visits allowed 
Please refer to protocol schedule of assessments. 
EQ-5D-5L 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
MENQoL 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
ePRO training 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
Dispense study drug 
Patients can be brought into 
the clinic earlier to provide 
additional study drug. 
Courier service directly to 
patient allowed. 
Please refer to protocol schedule of assessments. 
Study drug compliance 
and accountability 
Patients can be brought into 
the clinic earlier to provide 
additional study drug. 
Courier service directly to 
patient allowed. 
Please refer to protocol schedule of assessments. 
Concomitant 
medications and AEs 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits 
Please refer to protocol schedule of assessments. 
AE: adverse event; C-SSRS: Columbia Suicide Severity Rating Scale; ED: early discontinuation; EOT: end of treatment; ePRO: electronic patient-reported outcome; EQ-5D-5L: Euro-Qol 5D-
5L; MENQoL: Menopause-Specific Quality of Life. 


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Version 3.2 Incorporating Nonsubstantial Amendment 3 
12 Appendices 
ADDED: 
INVESTIGATIONAL MEDICINAL PRODUCT  SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are 
met, one or all of the following mitigating strategies will be employed, as needed, to 
ensure continuity of IMP supply to the participants: 
● 
Increase stock of IMP on site to reduce number of shipments required, if site 
space will allow. 
● 
Direct-to-Participant shipments of IMP from the site to the participant’s home. 
● 
Bringing the participant to the site earlier. 
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study 
may have been affected by a crisis and to accommodate data collection resulting from 
alternate measures implemented to manage the conduct of the study and participant 
safety.  
Critical assessments for safety and efficacy based on study endpoints to be identified as 
missing or altered (performed virtually, at alternative locations, out of window, or other 
modifications) due to the crisis. 
 
III.  Nonsubstantial Amendment Rationale: 
Rationale for Nonsubstantial Designation 
All revisions made to the protocol do not impact the safety or scientific value of the clinical 
study. 
 
 


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14 
SPONSOR SIGNATURES 
 
Attachment 1 
Electronic Sponsor Signatures 
 

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc 
SAP Version 2.0 
ISN/Protocol 2693-CL-0304 
08DEC2021 
Astellas 
Page 1 of 26 
STATISTICAL ANALYSIS PLAN 
Version 2.0, dated 08-Dec-2021 
A Randomized, Placebo-Controlled, Double-Blind Phase 3 
Clinical Study to Investigate the Long-Term Safety of 
Fezolinetant in Women Suffering From Vasomotor Symptoms 
(Hot Flashes) Associated with Menopause 
Skylight 4 
ISN/Protocol 2693-CL-0304 
IND number: 130277 
EudraCT 2019-000275-16 
Sponsor: Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
This document contains confidential information which is the intellectual property of Astellas. By accepting or reviewing 
this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where 
disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information 
is made to a member of the investigator’s team who agrees to hold this information in confidence. 
NCT04003389


Sponsor: Astellas Pharma Inc 
SAP Version 2.0 
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Page 2 of 26 
Table of Contents 
I.
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 4
1 
INTRODUCTION ································
································
··················
 5
2 
STUDY OBJECTIVE(S) AND DESIGN ································
·······················
 5
2.1 
Study Objective(s) ································
································
·············
 5 
Primary Objective ································
································
·····················
 5 
Secondary Objective································
································
···················
 5 
Exploratory Objectives ································
································
················
 5 
2.2 
Study Design ································
································
····················
 5 
2.3 
Randomization ································
································
··················
 6 
3 
SAMPLE SIZE································
································
······················
 6 
4 
ANALYSIS SETS ································
································
··················
 7 
4.1 
Full Analysis Set (FAS) ································
································
·······  7 
4.2 
Safety Analysis Set (SAF) ································
································
····  8 
4.3 
Endometrial Health Set (EH Set) ································
·····························
 8 
5 
ENDPOINTS ································
································
························
 8 
5.1 
Primary Safety Endpoint ································
································
······  8 
5.2 
Secondary Safety Endpoints ································
································
··  8 
5.3 
Exploratory Endpoints ································
································
·········  8 
5.3.1 
Menopause-Specific Quality of Life (MENQoL) ································
····  9 
5.3.2 
EQ-5D-5L with Visual Analog Scale (VAS) ································
·········  9 
6 
STATISTICAL METHODOLOGY ································
····························
 9 
6.1 
General Considerations ································
································
········  9 
6.2 
Study Population ································
································
··············
 10 
6.2.1 
Disposition of Subjects ································
································
· 10 
6.2.2 
Protocol Deviations ································
································
·····  10 
6.2.3 
Demographic and Other Baseline Characteristics ································
···  10 
6.2.4 
Previous and Concomitant Medications ································
··············
 11 
6.3 
Study Drug Exposure and Compliance ································
·····················
 11 
6.4 
Analysis of Efficacy ································
································
··········
 12 
6.4.1 
Analysis of Primary Efficacy Endpoint(s) ································
············
 12 
6.4.2 
Analysis of Secondary Efficacy Endpoints ································
···········
 12 


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6.4.3 
Analysis of Exploratory Endpoints ································
····················
 12 
6.5 
Analysis of Safety ································
································
·············
 13 
6.5.1 
Adverse Events ································
································
··········
 14 
6.5.2 
Clinical Laboratory Evaluation ································
························
 16 
6.5.3 
Vital Signs ································
································
················
 17 
6.5.4 
Electrocardiograms ································
································
······  17 
6.5.5 
Endometrial Health Assessment ································
·······················
 18 
6.5.6 
Bone Mass ································
································
················
 19 
6.5.7 
Other Safety-Related Assessments ································
····················
 19 
6.5.8 
Subgroups of Interest for safety ································
·······················
 19 
6.6 
Analysis of Pharmacokinetics ································
·······························
 20 
6.6.1 
Estimation of Pharmacokinetic Parameters ································
··········
 20 
6.7 
Analysis of Pharmacodynamics ································
·····························
 20 
6.8 
Other Analyses ································
································
················
 20 
6.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 20 
6.10 
Additional  Conventions ································
································
······  20 
6.10.1 
Analysis Windows ································
································
······  20 
6.10.2 
Imputation Rules for Incomplete Dates ································
···············
 22 
7 
REVISION AND RATIONALE ································
································
 23 
7.1 
List of Changes in SAP Version 2.0 ································
························
 23 
8 
REFERENCES ································
································
····················
 24 
9 
APPENDICES ································
································
·····················
 25 
9.1 
Appendix 1 Additional Statistical Analysis due to COVID-19 ··························
 25 
9.2 
Appendix 2 Author and Approver Signatures ································
·············
 26 
 


Sponsor: Astellas Pharma Inc 
SAP Version 2.0 
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Page 4 of 26 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
 
List of Abbreviations  
Refer to the protocol for the rest of abbreviations.  
Abbreviations 
Description of abbreviations 
AESI 
Adverse Events of Special Interest 
ANCOVA 
Analysis of Covariance 
BMI 
Body Mass Index  
CI 
Confidence Interval 
CMH 
Cochran Mantel Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
HLT 
High Level Term 
LSMP 
Liver Safety Monitoring Panel  
MMRM 
Mixed Model Repeated Measures 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NASH 
Non-Alcoholic SteatoHepatitis 
PD 
Protocol Deviation  
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
VMS 
Vasomotor Symptoms 
EH 
Endometrial Health 
 
List of Key Terms  
Refer to the protocol for the rest of key terms.  
Terms 
Definition of terms 
Follow-up Period 
Period of time after the last dose of study drug or last assessment of the 
protocol. Additional safety data and follow-up observations for sustained 
adverse events are conducted during this period. 
 


Sponsor: Astellas Pharma Inc 
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Page 5 of 26 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes procedures for 
executing the statistical analysis to fulfil the objectives of the study.  
The final version of this SAP will be approved prior to database lock and unblinding the 
subject treatment assignments.   
Changes from the planned analyses in the final SAP that impact the statistical analyses will 
be documented in the Clinical Study Report (CSR).  
2 
STUDY OBJECTIVE(S) AND DESIGN 
2.1 
Study Objective(s) 
Primary Objective 
● 
To evaluate the long-term safety and tolerability of fezolinetant in women seeking 
treatment for relief of Vasomotor Symptoms (VMS) associated with menopause.  
● 
To evaluate the effect of fezolinetant on endometrial health after long-term treatment in 
women seeking treatment for relief of VMS associated with menopause. 
Secondary Objective  
● 
To evaluate the effect of fezolinetant on bone mineral density after long-term treatment 
in women seeking treatment for relief of VMS associated with menopause. 
Exploratory Objectives 
● 
To evaluate the effect of fezolinetant on subject-reported quality of life measures. 
● 
To evaluate the pharmacokinetics of fezolinetant and its metabolite, ESN259564. 
2.2 
Study Design 
This is a 52-week randomized, placebo-controlled, double-blind, parallel-group, multicenter 
clinical study to assess the safety and tolerability of fezolinetant in women seeking treatment 
for VMS associated with menopause.  
The study visits will be performed on an outpatient basis. This study will consist of a 
screening period (days -35 to -1, including the screening visit [visit 1] assessments), a 
52 week treatment period (day 1 [visit 2] to week 52 [visit 15]) and a follow up visit 
(week 55 [visit 16]) 3 weeks after the last dose of study drug. An extra 15 screening days are 
allowed for repeat biopsy, if necessary (days -50 to -1, including the screening visit [visit 1] 
assessments). 
Approximately 1740 total subjects will be randomized into the study.  Subjects will be 
randomized 1:1:1 into the following treatment groups:  
● Fezolinetant 45 mg qd (approximately 580 subjects), 
● Fezolinetant 30 mg qd (approximately 580 subjects), 
● Placebo qd (approximately 580 subjects) 




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fairly low background event rate of less than 1%.  With the sample size, the following table 
illustrates the probability of observing 1 or more events, 2 or more events and 3 or more for 
different background event rates ranging from 0.10% to 0.90%.  
Per Treatment Arm 
Sample Size (1:1:1) 
n = 580 
Background Event Rate 
Prob(#>=3) 
Prob(#>=2) 
Prob(#>=1) 
0.10% 
2.11% 
11.53% 
44.03% 
0.20% 
11.18% 
32.29% 
68.69% 
0.30% 
25.33% 
51.94% 
82.49% 
0.40% 
40.94% 
67.43% 
90.22% 
0.50% 
55.46% 
78.62% 
94.54% 
0.60% 
67.63% 
86.28% 
96.95% 
0.70% 
77.16% 
91.35% 
98.30% 
0.80% 
84.27% 
94.62% 
99.05% 
0.90% 
89.38% 
96.69% 
99.47% 
Prob(#>=1) means the probability of observing 1 or more events. 
Prob(#>=2) means the probability of observing 2 or more events. 
Prob(#>=3) means the probability of observing 3 or more events. 
In addition, with an assumed background rate of 0.26% such as for endometrial hyperplasia, 
this sample size would provide the final number of evaluable subjectsto demonstrate that the 
point estimate for the rate of the event is less than or equal to 1% and the upper bound of the 
one-sided 95% confidence interval is less than or equal to 4% (as recommended in the FDA 
guidance on Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms) 
with greater than 95% probability assuming up to 60% (including baseline, ED and subject 
refusal of endometrial biopsy at EOT) of subjects may not have evaluable biopsy data.  
4 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
The determination of whether subjects are included or excluded from the safety analysis set 
and the full analysis set (for the PRO exploratory endpoints) will be made prior to database 
lock for the primary report and prior to unblinding.  
4.1 
Full Analysis Set (FAS)  
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least one dose of study drug. This will be the primary analysis set for the PRO exploratory 
endpoints.  The randomized treatment for each subject will be used for summaries by 
treatment group based on the FAS, even if a subject erroneously received a different 
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4.2 
Safety Analysis Set (SAF)  
The safety analysis set (SAF) consists of all randomized subjects who took at least 1 dose of 
study drug. A subject erroneously receiving a treatment that is different from the randomized 
treatment will be assigned to the treatment group that the patient received as first dose.  
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables. 
4.3 
Endometrial Health Set (EH Set) 
The endometrial health set (EH Set) will be defined as a subset of SAF who had evaluable 
biopsy at baseline and met the criteria specified in Section 6.5.5. This analysis set will be 
used to evaluate the incidence rate of endometrial hyperplasia and incidence rate of 
endometrial cancer and incidence rate of disordered proliferative endometrium.  
5 
ENDPOINTS  
5.1 
Primary Safety Endpoint 
The primary variable will require the evaluation of the effect of fezolinetant on the following: 
• Frequency and severity of AEs. 
• Percentage of subjects with endometrial hyperplasia. 
• Percentage of subjects with endometrial cancer. 
5.2 
Secondary Safety Endpoints 
The secondary endpoints are: 
● 
Change from baseline in endometrial thickness at 12 months. 
● 
Percentage of subjects with disordered proliferative endometrium. 
● 
Change from baseline in bone mass density (BMD) and trabecular bone score (TBS) at 
hip and spine at 12 months. 
● 
Vital signs: sitting systolic and diastolic blood pressure and pulse rate. 
● 
Laboratory tests: hematology, biochemistry and urinalysis. 
● 
C-SSRS. 
● 
ECG parameters. 
5.3 
Exploratory Endpoints 
The exploratory endpoints are: 
● 
Mean change on the Menopause-Specific Quality of Life (MENQOL) Total Score from 
baseline to specified time points (week 4, 12, 24 and 52). 
● 
Mean change on the MENQOL Domain Scores from baseline to specified time points 
(week 4, 12, 24 and 52).  
● 
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) Visual Analog Scale (VAS) from 
baseline to specified time points (week 4, 12, 24 and 52).   


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● 
Euro-Qol 5D-5L (EQ-5D-5L) domain scores at specified time points (week 4, 12, 24 and 
52).   
● 
Change from baseline to specified time points in serum concentrations of sex hormones 
and sex hormone-binding globulin (SHBG) (week 4, 12, 24, 52 and 55). 
● 
Plasma concentration of fezolinetant and the fezolinetant metabolite ESN259564 at 
specified timepoints (week 4, 12, 24 and 52). 
5.3.1 
Menopause-Specific Quality of Life (MENQoL)  
The MENQOL is a 29-item PRO measure that assesses the impact of 4 domains of 
menopausal symptoms, as experienced over the last week: vasomotor (items 1 to 3), 
psychosocial (items 4 to 10), physical (items 11 to 26) and sexual (items 27 to 29). Items 
pertaining to a specific symptom are rated as present or not present, and if present, how 
bothersome on a zero (not bothersome) to 6 (extremely bothersome) scale [Lewis et al, 
2005].  
Each item score ranges from 1 to 8, and each domain is scored separately; each domain mean 
ranges from 1 to 8 [Lewis et al, 2005; Hilditch et al, 1996]. The overall questionnaire score is 
the mean of the domain means. Higher scores represent more bothersome menopausal 
symptoms. 
5.3.2 
EQ-5D-5L with Visual Analog Scale (VAS)   
The EQ-5D-5L is a 5-item standardized measure of health status that provides a simple, 
generic measure of health for clinical and economic appraisal [EuroQol Research 
Foundation, 2018; van Reenen & Janssen, 2015]. This PRO measure comprises 5 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
Each dimension has 5 levels: no problems, slight problems, moderate problems, severe 
problems and extreme problems. The subject is asked to indicate her health state by selecting 
the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit 
number that expresses the level selected for that dimension. The digits for the 5 dimensions 
can be combined into a 5-digit number that describes the patient’s health state. 
The EQ-5D-5L VAS is a subject-reported measure that records the respondent’s self-rated 
health on a vertical VAS where the endpoint is labeled ‘Best imaginable health state’ and 
‘Worst imaginable health state.’ The scale ranges from 0 to 100, where 100 indicates the 
subject is in her best possible health state and 0 indicates the subject is in her worst possible 
health state. Subjects mark an ‘X’ on the scale to rate their health status that day. 
6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
Continuous data will be summarized descriptively including the number of subjects (n), 
mean, standard deviation (SD), median, minimum and maximum.  Categorical data will be 
summarized by frequencies and percentages. Percentages by categories will be based on the 
number of subjects with no missing data, i.e. the percentages for the non-missing categories 
will add up to 100%. 


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All statistical comparisons, if applicable, will be conducted using 2-sided tests at the 5% 
significance level.  
All data summarization and analyses will be performed using SAS® on Unix. Specifications 
for table, figures, and data listing formats can be found in the Tables Listings and Figures 
(TLF) specifications. 
6.2 
Study Population 
In general, data such as patient disposition, demographics and baseline characteristics will be 
summarized for SAF population.  
6.2.1 
Disposition of Subjects  
Disposition of subjects will be summarized for the SAF by treatment group and overall. 
Number of subjects who complete or prematurely discontinue from the treatment or study (ie, 
follow up period) will be summarized by treatment group and overall. For the 
discontinuation, the primary reason reported by the investigator will be summarized. 
Number and percentage of subjects for each analysis set will be summarized by treatment 
group and overall.  
6.2.2 
Protocol Deviations  
The number and percentage of subjects with the following protocol deviation criteria will be 
summarized for SAF for each criterion and overall, by treatment group  and  total as well as 
by investigative site. Subjects deviating from a criterion more than once will be counted once 
for the corresponding criterion. 
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
The number of subjects who were impacted by COVID-19 will be summarized by impact 
item and treatment group and overall for SAF population. The impact items include treatment 
discontinuation, dosing change/interruption, death from COVID-19, healthcare encounter due 
to COVID-19, protocol deviation due to COVID-19.  
An overview listing of subjects who were affected by COVID-19 will be generated by the 
impact items.   
Detailed information on how these assessments are impacted by COVID-19 can be found in 
relevant data listings with a flag for COVID-19.   
6.2.3 
Demographic and Other Baseline Characteristics 
The Demographics, tobacco history (smoking status), substance use (e-cigarette, alcohol, 
cannabis), caffeine beverage intake, height and weight, and targeted medical history  will be 


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summarized descriptively by treatment group and total group for SAF. Age group categories 
include <40 years, ≥40 years to <46 years, ≥46 years to <51 years, ≥51 years to <56 years, 
≥56 years to <61 years, ≥61 years to <66 years, and ≥66 years. Hormone replacement therapy 
history will be summarized descriptively by treatment groupand total group for SAF.  
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT), by treatment group and total group for the SAF. 
6.2.4 
Previous and Concomitant Medications 
Previous and concomitant medications will be summarized by therapeutic subgroup (ATC 
2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name by treatment 
group for the SAF. Subjects taking the same medication multiple times will be counted once 
per medication and investigational period.  
Previous medications are defined as medications that patients started prior to first 
administration of study medication. Concomitant medications are defined as any medications 
that patients took after the first dose of study medication and through 30 days from last dose 
of study drug. Medications that started prior to first administration of study drug  and  
continued while study drug was given will be counted in both previous and concomitant 
medications. 
6.3 
Study Drug Exposure and Compliance  
Duration and compliance  of study drug will be summarized for SAF by treatment group, 
fezolinetant total and overall.  
Number and percentages of subjects with the following categories of study drug duration will 
be summarized:  
• > 0 to ≤ 1 days; 
• > 1 to ≤ 7 days; 
• > 7 to ≤ 14 days; 
• > 14 to ≤ 21 days; 
• > 21 to ≤ 28 days; 
• > 28 to ≤ 42 days; 
• > 42 to ≤ 56 days; 
• > 56 to ≤ 84 days; 
• > 84 to ≤ 168 days; 
• > 168 to ≤ 252 days; 
• > 252 to ≤ 365 days; 
• > 365 days.  
Number and percentages of subjects with the following cumulative categories of study drug 
duration will be summarized:  
• ≥ 1 day; 
• ≥ 7 days; 
• ≥ 14 days;  


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• ≥ 21 days;  
• ≥ 28 days;  
• ≥ 42 days;  
• ≥ 56 days; 
• ≥ 84 days;  
• ≥ 168 days;  
• ≥ 252 days;    
• ≥ 365 days.   
Overall treatment compliance with the dosing schedule will be examined for subjects in the 
SAF whose total study drug count and first and last days of treatment are known. Compliance 
will be calculated compared to the actual treatment period of dosing (first to last day of the 
treatment period), not to the planned treatment period. 
Percent overall compliance will be summarized in two ways for the SAF by treatment group, 
fezolinetant total and overall: 
● 
Descriptive statistics. 
● 
Percent compliance will be categorized according to the following categories: 
○ Less than 50%, 
○ at least 50%, less than 85%, 
○ at least 85%, less than 120%, 
○ Over or equal to 120%, and 
○ Unknown. 
To evaluate impact of the COVID-19 to study drug intake, additional analyses will be 
performed by excluding the days of missing study drug/drug interruption due to COVID-19 
in the duration and compliance calculation, according to the study drug interruption CRF 
page.  
6.4 
Analysis of Efficacy  
6.4.1 
Analysis of Primary Efficacy Endpoint(s) 
Not applicable.  
6.4.1.1 Primary Analysis for Primary Efficacy Endpoint(s) 
Not applicable.  
6.4.2 
Analysis of Secondary Efficacy Endpoints 
Not applicable.  
6.4.3 
Analysis of Exploratory Endpoints  
The exploratory endpoints include the MENQOL and the EQ-5D-5L which will be assessed 
at baseline and weeks 4, 12, 24 and 52.  The exploratory PRO endpoints will be analyzed for 
the FAS set if not specified.  Summary statistics will be provided by treatment group. For 
analyses by visit, the visit windows from Section 6.10.1 will be applied.  


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The exploratory PRO variables include the effect of fezolinetant on the following:  
● 
Mean change on the Menopause-Specific Quality of Life (MENQOL) Total Score from 
baseline to specified time points. 
● 
Mean change on the MENQOL Domain Scores from baseline to specified time points. 
● 
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L)  Visual Analog Scale (VAS) from 
baseline to specified time points. 
● 
Euro-Qol 5D-5L (EQ-5D-5L) domain scores 
For the treatment comparison of continuous endpoints, a mixed model for repeated measures 
(MMRM) will be used.  The model will include treatment, visit, and strata smoking status 
(current vs former/never) as factors, with baseline weight and baseline measurement as 
covariates, as well as an interaction of treatment by visit and an interaction of baseline 
measurement by visit. An unstructured covariance structure shared across treatment groups 
will be used to model the within-patient errors (and then Toeplitz if model does not 
converge).  The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom and adjust standard errors. EQ-5D domain scores will be summarized and 
analyzed using Cochran Mantel Haenszel (CMH) test with modified ridit scores. EQ-5D will 
also be adjusted for the baseline score.  
6.5 
Analysis of Safety 
Overall long-term safety of fezolinetant and the effect of fezolinetant on endometrial health 
will be the primary objective of this study.  The safety assessments include adverse events, 
laboratory assessments, vital signs, C-SSRS, ECG, endometrial health assessment and 
imaging (mammogram, DXA, TVU).  In all analysis of safety,  the treatment group includes 
placebo, fezolinetant 30mg, fezolinetant 45mg and fezolinetant total will be presented by 
treatment group for SAF, unless specified otherwise. For analyses by visit, the analysis 
windows from Section 6.10.1 will be applied. Except for adverse events and follow-up visit 
data, only data up to one day after the last dose date will be considered for the analyses.  
The baseline value for safety endpoint will be the last non-missing value taken on or prior to 
first dose of study drug unless otherwise noted. 
Primary Safety Variables  
● 
Frequency and severity of AEs.  
● 
Percentage of subjects with endometrial hyperplasia. 
● 
Percentage of subjects with endometrial cancer. 
Secondary Safety Variables 
● 
Change from baseline in endometrial thickness at 12 months. 
● 
Percentage of subjects with disordered proliferative endometrium. 
● 
Change from baseline in bone mass density (BMD) and trabecular bone score (TBS) at 
hip and spine at 12 months. 
● 
Change from baseline to each timepoint in vital signs: sitting systolic and diastolic blood 
pressure and pulse rate. 


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● 
Change from baseline to each timepoint in laboratory tests: hematology, biochemistry 
and urinalysis. 
● 
C-SSRS at each timepoint. 
● 
Change from baseline to each timepoint in ECG parameters  
Exploratory Safety Variables 
● 
Change from baseline to specified time points in serum concentrations of sex hormones 
and sex hormone-binding globulin (SHBG) (week 4, 12, 24, 52 and 55). 
● 
Plasma concentration of fezolinetant and the fezolinetant metabolite ESN259564 at 
specified timepoints (week 4, 12, 24 and 52). 
In general, summary statistics will be provided for all the safety parameters. Treatment 
comparisons will be performed for endometrial and bone density related endpoints. For 
AESI, the rate, odds ratio and their corresponding 95% exact confidence intervals will be 
presented, which will be constructed based on Santner-Snell approach. An ANCOVA model, 
with treatment and strata smoking status (current vs former/never) as factors, with baseline 
weight and baseline as covariates, will be used for single assessment continuous endpoints. 
Each following section will specify the analysis method appropriately.  
The change and percentage reduction in serum concentrations of sex hormones and sex 
hormone-binding globulin (SHBG) from baseline to each analysis visit will be summarized. 
For hormone related parameters, if the value is below the low limit of quantification, the 
value will be imputed as half of the LLOQ. In addition, the percentage of subjects who have 
BLOQ values at baseline who then have measurable post-baseline values will be 
summarized.  
6.5.1 
Adverse Events 
Per protocol, a treatment emergent adverse event (TEAE) is defined as the AEs that occurred 
on or after first dose of study drug and 21 days after the last dose of study drug (when AE 
collection closes).  
A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator. 
The sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered by the sponsor to be an SAE per this classification as “always 
serious”, the AE will be treated as an SAE in tables and listings, and flagged as ‘always 
serious’ in AE listings. 
An overview table will include the following 
● 
Number of TEAEs, 
● 
Number and percentage of subjects with TEAEs, 
● 
Number of drug related TEAEs, 
● 
Number and percentage of subjects with causally drug related TEAEs, 
● 
Number of serious TEAEs, 


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● 
Number and percentage of subjects with serious TEAEs, 
● 
Number of serious drug related TEAEs, 
● 
Number and percentage of subjects with serious drug related TEAEs, 
● 
Number of TEAEs leading to permanent discontinuation of study drug, 
● 
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, and 
● 
Number of deaths.  
In order to adjust for differences in subjects’ durations and the potential differential dropout 
rates between the treatment groups, an overview table to report exposure adjusted incidence 
rate (per 100 subject-years) for the above AE categories will be summarized. The total 
subject-years of exposure is calculated as the sum over subjects of the total duration of 
exposure divided by 365.25: 

+
−
i
i
i
fd
ld
25
.
365
1
, 
where fdi  and ldi  denote the first dose date of study drug and the last dose date of study drug 
for subject i. 
The number and percentage of subjects with TEAEs in the following AE categories will be 
summarized for each treatment group by system organ class (SOC), high level term (HLT) 
and preferred term (PT):  
● 
TEAEs 
● 
drug related TEAEs.  
The number and percentage of subjects with TEAEs in the following AE categories will be 
summarized by SOC and PT:  
● 
serious TEAEs,  
● 
drug related serious TEAEs,  
● 
TEAEs leading to permanent discontinuation of study drug,  
● 
drug related TEAEs leading to permanent discontinuation of study drug,  
● 
TEAEs that equal to or exceed a threshold of 5.0% in any treatment group (threshold is 
based on PT). 
● 
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5.0% in 
any treatment group.  
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized for each treatment group. 
The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will be summarized by severity and by relationship to study drug. In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the subject will be counted once with the worst severity and 
highest degree of relationship. If severity or relationship is missing for all episodes of the 
event, the subject will be counted under missing severity or relationship. In the adverse event 


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count, the adverse events will be presented in each category they were classified to. Drug 
related TEAEs will be presented in a similar way by severity only.  
Among TEAEs, following adverse events of special interest (AESI) are defined: 
● Adverse event of endometrial hyperplasia/cancer or disordered proliferative endometrium 
● Adverse event of liver test elevations  
● Adverse event of uterine bleeding 
● Adverse event of thrombocytopenia 
● Adverse event of bone fractures 
● Adverse event of abuse liability 
● Adverse event of depression 
● Adverse event of wakefulness 
● Adverse event of effect on memory  
Search terms defining the AESIs will be pre-specified and documented. The number and 
percentage of subjects with AESIs as classified by PT will be separately summarized for each 
treatment group.  
The number and percentage of subjects with TEAEs associated with COVID-19, as classified 
by PT, will be summarized for each treatment group, fezolinetant total and overall.  
6.5.2 
Clinical Laboratory Evaluation 
Quantitative values evaluated by the central laboratory including hematology, biochemistry, 
and urinalysis will be summarized using mean, standard deviation, minimum, maximum and 
median by treatment group at each analysis visit. Additionally, a within-subject change will 
be calculated as the post-baseline measurement minus the baseline measurement and 
summarized in the same way. Each laboratory result will be classified as low (L), normal (N), 
or high (H) at each visit according to the laboratory supplied reference ranges. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit. 
Number and percentage of subjects with platelets < 150x10^9/L will be separarely 
summarized for each treatment group. 
For hematology and biochemistry shift tables will be presented for each treatment group: 
Summary shifts of reference range changes from baseline to worst finding during the 
treatment period (shift from normal or high to low, shift from normal or low to high, 
categorized increase [shift from low to normal or from normal to high], categorized no 
change [value stays in the same reference range], categorized decrease [shift from high to 
normal or from normal to low]). 
6.5.2.1 Liver Safety Assessment 
The liver safety assessments will be summarized by the categories below based on the 
measurements from  Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total 


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bilirubin, Aspartate Transaminase (AST) and their combination. These parameters will be 
based on measurements from a central laboratory. 
The subject’s highest value during the investigational period (from day of first dose of study 
drug until last dose of treatment period + 1 day) will be used.  
● 
ALT > 3xULN, > 5xULN, > 8xULN, > 10xULN, >20xULN 
● 
AST > 3xULN, > 5xULN, > 8xULN, > 10xULN, >20xULN 
● 
ALT or AST > 3xULN, > 5xULN, > 8xULN, > 10xULN, >20xULN 
● 
ALP > 1.5xULN 
● 
Total Bilirubin >2xULN 
● 
(ALT or AST > 3xULN) and Total Bilirubin > 2xULN 
● 
(ALT or AST > 3×ULN) and Total Bilirubin > 1.5×ULN 
● 
(ALT or AST > 3xULN) and ALP< 2xULN and Total Bilirubin > 2xULN 
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to 1 day apart. The denominator for each criterion will be the number 
of subjects who have at least one value during the double-blind investigational period. The 
number and percentage of subjects meeting the criteria during the double-blind 
investigational period  will be summarized by treatment group. 
Due to COVID-19, patients might not be able to visit the clinical site and have clinical 
laboratory tests taken at the clinical site and evaluated by the central laboratory, in this case 
clinical laboratory tests can be taken by a local laboratory. The liver biochemistry safety 
assessments will be summarized including central and locally collected laboratory data due to 
COVID-19. This analysis is considered the primary analysis for the liver safety assessments.   
The secondary analysis for liver biochemistry will be repeated by the data evaluated by the 
central laboratory but excluding the data that are impacted by COVID-19, which include the 
data recorded after the subjects were diagnosed of COVID-19, after study drug 
discontinuation due to COVID-19, during dose interruption due to COVID-19, and visits that 
are out of protocol window or data collected via home visits due to COVID-19 recorded in 
the eCRF.  
6.5.3 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure and pulse rate) and BMI and 
weight will be summarized using mean, standard deviation, minimum, maximum and median 
by treatment group and visit. Additionally, a within-subject change will be calculated per 
visit as the post-baseline measurement minus the baseline measurement and summarized by 
treatment group and visit.  
6.5.4 
Electrocardiograms 
ECG variables will be summarized using mean, standard deviation, minimum, maximum and 
median for each treatment group at each treatment visit, including changes from baseline. If 
multiple ECG variable values are available in one visit, use the mean value.  


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Number and percent of subjects with normal and abnormal results as assessed by central 
reader for the 12 lead ECG will be tabulated by treatment group at each treatment visit. 
The QTc interval will be summarized using frequency tables for each treatment visit for 
values of clinical importance using the range criteria below. 
 
QTc Interval Criteria Value (msec)  
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450  
> 480  
> 500 
Number and percent of subjects with 12 lead ECG abnormalities as well as number and 
percent of subjects whose 12 lead ECG reading changed from normal at baseline to abnormal 
will be tabulated by treatment group at each treatment visit. 
6.5.5 
Endometrial Health Assessment 
Ultrasound results (endometrial thickness) will be summarized using mean, standard 
deviation, minimum, maximum and median by treatment group and visit. The within-subject 
change will be calculated per visit as the post-baseline measurement minus the baseline 
measurement and summarized by treatment group and visit. For change from baseline in 
endometrial thickness, an ANCOVA model, with treatment and strata smoking status (current 
vs former/never) as factors, with baseline weight and baseline value as covariates, will be 
used for treatment comparisons. 
The descriptive reasons for not evaluable biopsy will be summarized. It includes reasons of 
not done from eCRF page, reasons of not done from lab and pathologiest readings. 
For all postbaseline biopsies, the concordance of 2 of the 3 pathologists reviews will be 
accepted as the final diagnosis. If there is no agreement among the three pathologists, the 
most severe diagnosis will then be used as the final diagnosis. 
The satisfactory endometrial biopsy results will be summarized for the endometrial health set 
(EH set). EH set consists of all subjects who are randomized and receive at least one dose of 
study drug, had the postbaseline biopsy done within 30 days after the last dose of study drug, 
and  
● 
had an acceptable biopsy at Baseline (at least one endometrial biopsy with satisfactory 
tissue and no read of hyperplasia, disordered proliferative pattern or malignant); and 
● 
had an satisfactory endometrial biopsy result after or on Day 326 or had a postbaseline 
final diagnosis of hyperplasia, disordered proliferative or malignant prior to Day 326. 
Baseline biopsy is the last non-missing value on or prior to first dose of study drug. When 
more than one biopsy results are present at postbaseline, if no final diagnosis of hyperplasia, 
disordered proliferative pattern or malignant, the last non-missing satisfactory result within 
the window will be counted; otherwise, the more severe result will be counted. 


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For percentage of subjects with final diagnosis of endometrial hyperplasia, percentage of 
subjects with endometrial cancer, and percentage of subjects with disordered proliferative 
endometrium, the exact (Clopper-Pearson) upper one sided 95% confidence interval will be 
provided. 
6.5.6 
Bone Mass   
Dual-energy X-ray absorptiometry (BMD, TBS) data will be summarized using mean, standard 
deviation, minimum, maximum and median by treatment group and visit. The within-subject 
change will be calculated per visit as the post-baseline measurement minus the baseline 
measurement. The records marked as poor image quality will be excluded from the analysis.  
Change from baseline in bone mass density (BMD) and trabecular bone score (TBS) at hip 
and spine at 12 months will be derived for separate locations. An ANCOVA model, with 
treatment and smoking status (current vs former/never) as factors, with baseline weight and 
baseline value as covariates, will be used for treatment comparisons.  
A sensitivity analysis will be performed by including patients with baseline but missing any 
post-baseline value, assuming no changes (the change score to be 0).  
6.5.7 
Other Safety-Related Assessments   
C-SSRS 
C-SSRS (including suicidal ideation and suicidal hehavior) results at each visit including 
baseline will be summarized by treatment group.  
Imaging  
A mammogram at week 52/EOT/ED will be conducted if it coincides with the regularly 
scheduled routine screening mammogram of the patient, in accordance with local medical 
practice guidelines and the patient’s primary care physician. Mammogram results will only 
be listed, if applicable.  
6.5.8 
Subgroups of Interest for safety   
The following factors are medically important subgroups for safety analysis: Race, smoking 
status, BMI category, NAFLD, and NASH. The data are being analyzed by subgroup are as 
follows:  
o Age (< 55 years, ≥ 55 years): Treatment emergent AE (TEAE) table by SOC and PT, 
and Categorical Liver function table 
o Race 1 (White, Non-White): Treatment emergent AE (TEAE) table by SOC and PT, 
and Categorical Liver function table 
o Race 2 (White, Black, Asian, Other): Treatment emergent AE (TEAE) table by SOC 
and PT, and Categorical Liver function table  
o Race 3 (Black, Non-Black): Treatment emergent AE (TEAE) table by SOC and PT, 
and Categorical Liver function table 
o Geographical region (Europe, North American): Treatment emergent AE (TEAE) 
table by SOC and PT, and Categorical Liver function table 


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o Smoking Status(current, former/never, per substance use – tabacco history CRF 
page): Treatment emergent AE (TEAE) table by SOC and PT, and Categorical Liver 
function table  
o BMI category (>=18.5 kg/m2 to <25 kg/m2, >=25 kg/m2 to <30 kg/m2, >=30 kg/m2) :  
Treatment emergent AE (TEAE) table by SOC and PT, and Categorical Liver 
function table  
o Isolated non-alcoholic fatty liver disease (NAFLD) (Yes, No, per targeted medical 
history CRF page): Categorical liver function table  
o Non-alcoholic steatohepatitis (NASH) (Yes, No, per targeted medical history CRF 
page): Categorical liver function table 
o Diabetic Status (Yes, No): Categorical liver function table 
6.6 
Analysis of Pharmacokinetics  
The statistical methods for PK data will be described in a separate analysis plan. Results of 
the population PK analysis will not be reported in the Clinical Study Report but in a separate 
population PK report. 
Plasma concentration of fezolinetant and ES259564 will be listed. 
6.6.1 
Estimation of Pharmacokinetic Parameters 
All details of the population PK analysis will be described in a separate analysis plan. 
6.7 
Analysis of Pharmacodynamics  
Serum concentrations of sex hormones [luteinizing hormone (LH), follicle-stimulating 
hormone (FSH), estradiol (E2), Testosterone Total/Free, Androstenedione, 
dehydroepiandrosterone (DHEA), Estrone] and sex hormone-binding globulin (SHBG) will 
be summarized using descriptive statistics (number of subjects, mean, SD, median, minimum 
and maximum) for each visit and time point and for change from the baseline to each 
postdose visit, if the data is available.  
6.8 
Other Analyses  
Not applicable.  
6.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
There will be no interim analysis. 
6.10 
Additional  Conventions  
6.10.1 Analysis Windows 
Study Day for analysis windows will be calculated as date of visit/assessment – first dose 
date +1.   
Study Day for the follow-up (FUD) phase will be calculated as date of visit/assessment – last 
dose date of study treatment (Date of EOT). 




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6.10.2 Imputation Rules for Incomplete Dates  
In case of missing partial start and stop dates for concomitant medications or targeted 
medical history, the following rules will be used: 
If the start date is missing or partial: 
● 
if the month is missing, use January 
● 
if the day is missing, use the first day of the month under consideration 
● 
if the year is missing, use year of the informed consent date 
● 
if the entire date is missing, use informed consent date 
If the stop date is missing or partial: 
● 
if the month is missing, use December 
● 
if the day is missing, use the last day of the month under consideration 
● 
if the year or the entire date is missing, set the stop date to December 31st, 2099 
If the imputed start date is after the stop date, then the imputed start date will be 1 day prior 
to the stop date. 
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing, the imputed onset date will be the date of first dose of study drug.  
If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates: 
● 
Date of first dose of study drug  
● 
January 1 of the year of AE onset date  
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
● 
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date. 
● 
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates: 
○ Date of first dose of study drug 
○ Surrogate onset date 
If the imputed onset date is after the adverse event end date, the imputed onset date will be 
the same as the adverse event end date. 


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7 
REVISION AND RATIONALE  
7.1 
List of Changes in SAP Version 2.0 
SAP Sections 
Description 
Rationale 
Relevant Sections 
Added additional statistical 
analysis due to COVID-19 
To evaluate potential impact of COVID-
19  
2.1, 5.1, 5.2, 5.3 
Modified the primary objective 
and secondary objective  
To be consistent with the protocol 
amendments (version 2.1) 
2.2 
Modified the sample size  
To be consistent with the protocol 
amendments (version 2.1) 
3 
Modified the sample size and its 
rational 
To be consistent with the protocol 
amendments (version 2.1) 
5.3, 6.4.3 
Added two exploratory endpoints 
(change of baseline in serum 
concentrations and plasma 
concentration) and its statistical 
analysis. 
These two endpoints were missed in the 
previous version. 
6.3 
Modified the categories of drug 
duration and cumulative duration 
To make it one year 
6.4.3 
Added analysis method for EQ-
5D domain scores 
EQ-5D domain scores are categorical 
endpoint. Statistical analysis method for 
continuous endpoints is not applicable. 
6.5 
Removed the significance testing 
for dichotomized endpoints 
To be consistent with the protocol 
amendments (version 3.0) 
6.5.1 
Added exposure adjusted TEAE 
tables 
To take the differences in subjects’ 
duration and potential differential 
dropout rates between treatment groups 
into consideration 
6.5.1 
Modified list of AESIs 
To be consistent with the protocol 
amendments (version 2.1) 
6.5.2.1 
Added one category 
To reflect CIOMS and FDA guidance 
6.5.4 
Removed the summary of QTc 
change from baseline outliers 
The summary of QTc change from 
baseline outliers provides limited 
additional medical relevant information     
6.5.5 
Updated the biopsy analysis 
window  
To make the window longer. 
6.5.6 
Modified the analysis to exclude 
the records marked as poor image 
quality. 
To reflect the true BMD changes but 
rather artificial ones. 
6.5.8 
Added subgroup on Age (<55, 
≥55), BMI cut-off 30 kg/m2, 
Geographical region (Europe, 
North American) and Diabetic 
Status (Yes, No) 
To add medically meaningful subgroups    
 


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8 
REFERENCES 
● 
EuroQol Research Foundation. EQ-5D-5L: About. Version 18 Apr 2017. Available at 
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/. Accessed 11 Oct 2018. 
● 
FDA Draft Guidance, Estrogen and Estrogen/Progestin Drug Products to Treat 
Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms – Recommendations 
for Clinical Evaluation. January 2003. Available at: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm071643.pdf. Accessed 14 Jan 2019. 
● 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study 
Reports, November 1995. (www.ich.org; Guidelines) 
● 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, 
February 1998. (www.ich.org; Guidelines) 
● 
Lewis JE, Hilditch JR, Wong CJ. Further psychometric property development of the 
Menopause-Specific Quality of Life questionnaire and development of a modified 
version, MENQOL-Intervention questionnaire. Maturitas. 2005;50:209-21. 
● 
van Reenen M, Janssen B. EQ-5D-5L User Guide: basic information on how to use the 
EQ-5D-5L instrument. Version 2.1. April 2015. Available at https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf. Accessed 11 Oct 2018. 


Sponsor: Astellas Pharma Inc 
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9 
APPENDICES 
9.1 
Appendix 1 
Additional Statistical Analysis due to COVID-19 
The novel coronavirus (SARS-CoV-2) is a new strain of coronavirus that had not previously 
been identified in humans. On January 30, 2020, the World Health Organization (WHO) 
declared the outbreak a public health emergency of international concern. On March 11, 
2020, WHO characterised COVID-19 as a pandemic. Regulatory agencies have rapidly 
published guidance for clinical trial sponsors to address COVID-19 issues (FDA 2020, EMA 
2020a, 2020b).  
The COVID-19 pandemic has a global impact on the conduct of clinical trials of medical 
products. Challenges may arise, for example, from quarantines, site closures, travel 
limitations, interruptions to the supply chain for the investigational product, or other 
considerations if site personnel or subjects become infected with COVID-19. While the top 
priority is to protect the safety of the subjects, the other two objectives are to maintain the 
scientific integrity of the study and to ensure compliance with good clinical practice (GCP).  
For this study, subjects were randomized into the study before Astellas paused recruitment in 
all the clinical studies on March 30, 2020. After Astellas lifted recruitment pause, the rest of 
the planned subjects were randomized into the study.  
In order to capture the relevant impact of COVID-19, dedicated CRF pages, the risk benefit 
plans, and alternative measures were implemented in the study. Since the study data may be 
impacted by COVID-19, additional statistical analyses are planned for this study.   
The additional statistical analysis due to COVID-19 is planned in the following sections.  
Section 
Topic  
6.2.2  
Study population  
6.3 
Study Drug Exposure and Compliance 
6.5.1 
Adverse Events 
6.5.2.1 
Clinical Laboratory Evaluation  
 
 
 
 
 
 
 
 
 


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9.2 
Appendix 2 
Author and Approver Signatures  
E-signatures are attached at the end of document.  
Appendix 2: Signatures 
 
Prepared by: 
E-signatures are attached at end of document 
Date: 
 
 
 PhD 
 
 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
E-signatures are attached at end of document 
Date: 
 
 
 PhD 
 
 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
E-signatures are attached at end of document 
Date: 
 
 
 MD, PhD  
 
 
 
Date (DD Mmm YYYY) 
 
PPD
PPD
PPD
PPD
PPD
PPD