Clinical trial NCT04003142
Conditions: Hot Flashes
Keywords: ESN364 menopause fezolinetant vasomotor symptoms
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2019-07-10; Completion date: 2021-04-23
Enrollment: 501 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

The study treatments are fezolinetant 30 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 is a dummy treatment that looks like medicine but does not have any medicine in it.) The study compared fezolinetant and placebo after 4 and 12 weeks of dosing. The study evaluated if fezolinetant reduces the number of hot flashes and the study evaluated if fezolinetant reduces the severity of the hot flashes.

Women in the study received an electronic handheld device at the first study visit. (It is similar to a smart phone.) Each day of the study, study participants used this to record their hot flashes. Their record for the 10 days before the start of study treatment was checked. They remained in the study if their record shows 7 or 8 moderate to severe hot flashes per day (50 or more per week). Next, they were picked for 1 of the 2 study treatments (fezolinetant or placebo) by chance alone. It is like flipping a coin.

The study participants took study treatment for 52 weeks. The first 12 weeks of study treatment 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) during that time. The last 40 weeks of study treatment was "noncontrolled." That means that each study participant and the study doctors knew which study treatment that study participant took during that time. Women who took fezolinetant during the first 12 weeks continued to take the same dose. Women who took placebo during the first 12 weeks took fezolinetant. Their dose was either 30 mg or 45 mg fezolinetant.

At weeks 2, 4, 8, 12, 14, 16 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 was collected for laboratory tests. Study participants completed questionnaires that were about how hot flashes affect their daily life. Study participants who had their uterus had the following 2 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. This test used sound waves to create pictures of the organs in the pelvis. The sound waves are transmitted by a probe (transducer), which was placed inside the vagina. Study participants might have 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 have 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 agrees.

The last check-up at the hospital or clinic was 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, QD up to week 12 during double-blind treatment period followed by fezolinetant 30 mg orally, QD from week 13 up to Week 52 during extension treatment period. arm 2: Participants received fezolinetant 45 mg (one 30 mg tablet and one 15 mg tablet) orally, QD up to week 12 during double-blind treatment period followed by fezolinetant 45 mg orally, QD from week 13 up to Week 52 during extension treatment period. arm 3: Participants received fezolinetant matching placebo (two fezolinetant matching placebo tablets) orally, once daily (QD) up to week 12 during double-blind treatment period. arm 4: Participants who received placebo during double-blind treatment period were re-randomized to receive fezolinetant 30 mg orally, QD from week 13 up to week 52 during extension treatment period. arm 5: Participants who received placebo during double-blind treatment period were re-randomized to receive fezolinetant 45 mg orally, QD from week 13 up to week 52 during extension treatment period.
Interventions: intervention 1: Fezolinetant intervention 2: placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral Tablet

Protocol documents:
Prot_000.pdf: 
Sponsor: APGD
ISN/Protocol 2693-CL-0302
EudraCT 2018-003529-27
- CONFIDENTIAL -
01 Jul 2020
Astellas
Page 1 of 118
Version 3.0 Incorporating Substantial Amendment 2
A Phase 3, Randomized, Placebo-controlled, 12-week Double-blind
Study, followed by a Non-Controlled Extension Treatment Period,
to Assess the Efficacy and Safety of Fezolinetant in Women 
Suffering from Moderate to Severe Vasomotor Symptoms 
(Hot Flashes) Associated with Menopause
Skylight 2
ISN/Protocol 2693-CL-0302
Version 3.0
Incorporating Substantial Amendment 2 [See Section 13]
01 July 2020
IND 130277
EudraCT 2018-003529-27
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 Original [28 January 2019]
Version 2.0 Incorporating Substantial Amendment 1 [17 May 2019]
Version 2.1 Incorporating Nonsubstantial Amendment 1 [05 Dec 2019]
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. 
NCT04003142


Sponsor: APGD
ISN/Protocol 2693-CL-0302
EudraCT 2018-003529-27
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01 Jul 2020
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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··························································································16
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································27
1
INTRODUCTION·················································································32
1.1
Introduction to Fezolinetant··································································32
1.2
Background ····················································································32
1.2.1
Vasomotor Symptoms (Hot Flashes): Epidemiology and Etiology·················32
1.3
Fezolinetant Nonclinical and Clinical Data ················································33
1.3.1
Summary of Nonclinical Studies························································33
1.3.2
Summary of Clinical Studies ····························································34
1.4
Summary of Key Safety Information for Study Drugs ···································37
1.4.1
Nonclinical Studies ·······································································37
1.4.2
Clinical Studies············································································38
1.5
Risk Benefit Assessment ·····································································39
2
STUDY OBJECTIVES, DESIGN AND ENDPOINTS·····································41
2.1
Study Objectives ··············································································41
2.1.1
Primary Objective·········································································41
2.1.2
Key Secondary Objective ································································41
2.1.3
Secondary Objectives·····································································41
2.1.4
Exploratory Objectives···································································41
2.2
Study Design and Dose Rationale···························································42
2.2.1
Study Design ··············································································42
2.2.2
Dose Rationale ············································································44
2.3
Endpoints·······················································································46
2.3.1
Co-primary Endpoints····································································46
2.3.2
Key Secondary Endpoints································································46
2.3.3
Secondary Endpoints ·····································································47
2.3.4
Exploratory Endpoints····································································47
2.3.5
Safety Endpoints ··········································································48
3
STUDY POPULATION··········································································48


Sponsor: APGD
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3.1
Selection of Study Population ·······························································48
3.2
Inclusion Criteria··············································································49
3.3
Exclusion Criteria ·············································································50
4
TREATMENT(S)··················································································51
4.1
Identification of Investigational Product(s) ················································51
4.1.1
Study Drug(s)··············································································51
4.1.2
Comparative Drug(s) ·····································································51
4.2
Packaging and Labeling ······································································51
4.3
Study Drug Handling ·········································································52
4.4
Blinding ························································································52
4.4.1
Blinding Method ··········································································52
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ························52
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking····················································································53
4.4.4
Breaking the Treatment Code for Emergency ·········································53
4.4.5
Breaking the Treatment Code by the Sponsor·········································53
4.5
Assignment and Allocation ··································································53
5
TREATMENTS AND EVALUATION························································54
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················54
5.1.1
Dose/Dose Regimen and Administration Period······································54
5.1.2
Increase or Reduction in Dose of the Study Drug(s)··································54
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication Therapy)54
5.1.3.1
Previous Medication (Drugs and Therapies) ···································54
5.1.3.2
Concomitant Medications (Drugs and Therapies) ·····························55
5.1.3.3
Prohibited Concomitant Medications ···········································55
5.1.4
Treatment Compliance ···································································55
5.1.5
Criteria for Continuation of Treatment ·················································55
5.1.6
Restrictions During the Study ···························································55
5.2
Demographics and Baseline Characteristics ···············································56
5.2.1
Demographics ·············································································56
5.2.2
Medical History ···········································································56
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease ················56
5.3
Efficacy | Pharmacodynamics | Pharmacokinetics | Assessments ·······················56
5.3.1
Efficacy Assessment······································································56


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ISN/Protocol 2693-CL-0302
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5.3.1.1
Vasomotor Symptom Diary ······················································56
5.3.2
Key Secondary Efficacy Assessment···················································57
5.3.3
Patient-reported Outcome Assessments ················································57
5.3.3.1
Patient Global Impression Scale ·················································58
5.3.3.2
PROMIS SRI SF 8a ·······························································58
5.3.3.3
MENQOL···········································································59
5.3.3.4
EQ-5D-5L with Visual Analog Scale ···········································59
5.3.3.5
WPAI-VMS ········································································59
5.3.4
Pharmacodynamic Assessments·························································60
5.3.5
Pharmacokinetic Assessments···························································60
5.3.6
Pharmacogenomic sample ·······························································61
5.4
Safety Assessment ············································································61
5.4.1
Vital Signs ·················································································61
5.4.2
Columbia Suicide Severity Rating Scale···············································61
5.4.3
Laboratory Assessments ·································································61
5.4.4
Physical Examination·····································································63
5.4.5
Electrocardiogram ········································································63
5.4.6
Imaging·····················································································63
5.4.6.1
Mammogram ·······································································63
5.4.6.2
Transvaginal Ultrasound··························································64
5.4.7
Endometrial Biopsy·······································································64
5.4.8
Papanicolaou Test·········································································65
5.4.9
Order of Assessments·····································································65
5.5
Adverse Events and Other Safety Aspects ·················································66
5.5.1
Definition of Adverse Events····························································66
5.5.1.1
Abnormal Laboratory Findings ··················································66
5.5.1.2
Potential Cases of Drug-induced Liver Injury··································66
5.5.1.3
Disease Progression and Study Endpoints······································67
5.5.2
Definition of Serious Adverse Events ··················································67
5.5.2.1
Always Serious Adverse Events ·················································67
5.5.3
Criteria for Causal Relationship to Study Drug ·······································68
5.5.4
Criteria for Defining the Severity of an Adverse Event ······························69
5.5.5
Reporting of Serious Adverse Events ··················································69
5.5.6
Follow-up of Adverse Events····························································70
5.5.7
Adverse Events of Special Interest······················································71


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5.5.8
Special Situations ·········································································71
5.5.8.1
Pregnancy···········································································71
5.5.8.2
Medication Error, Overdose and “Off-Label Use” ····························72
5.5.8.3
Misuse/Abuse ······································································72
5.5.8.4
Suspected Drug-Drug Interaction················································72
5.5.9
Supply of New Information Affecting the Conduct of the Study ···················73
5.5.10
Urgent Safety Measures··································································73
5.5.11
Reporting Urgent Safety Measures ·····················································73
5.6
Test Drug Concentration ·····································································73
5.7
Other Measurements, Assessments or Methods ···········································74
5.7.1
Blood Sample for Future Pharmacogenetic Analysis (Retrospective 
Pharmacogenetic Analysis) ······························································74
5.7.2
Caffeinated Beverage Intake·····························································74
5.8
Total Amount of Blood·······································································74
6
DISCONTINUATION············································································75
6.1
Discontinuation of Individual Subject(s) from Study Treatment························75
6.1.1
Lost to Follow-up ·········································································75
6.2
Discontinuation of the Site···································································75
6.3
Discontinuation of the Study·································································76
7
STATISTICAL METHODOLOGY ···························································76
7.1
Sample Size····················································································76
7.2
Analysis Sets···················································································77
7.2.1
Full Analysis Set ··········································································77
7.2.2
Per Protocol Set ···········································································78
7.2.3
Safety Analysis Set ·······································································78
7.2.4
Pharmacokinetic Analysis Set ···························································78
7.3
Demographics and Baseline Characteristics ···············································78
7.3.1
Subject Disposition ·······································································78
7.3.2
Previous and Concomitant Medications················································78
7.3.3
Medical History ···········································································78
7.4
Analysis of Efficacy ··········································································79
7.4.1
Analysis of Co-primary Endpoint·······················································79
7.4.1.1
Co-primary Analysis ······························································79
7.4.1.2
Sensitivity Analysis of Co-primary Endpoints·································80


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7.4.1.3
Subgroup Analysis·································································80
7.4.2
Analysis of Secondary Endpoints·······················································80
7.4.2.1
Key Secondary Endpoint ·························································80
7.4.2.2
Secondary Endpoints······························································81
7.4.3
Analysis of Exploratory Endpoints ·····················································81
7.5
Analysis of Safety·············································································81
7.5.1
Adverse Events············································································81
7.5.2
Laboratory Assessments ·································································82
7.5.3
Vital Signs ·················································································82
7.5.4
Physical Examination·····································································82
7.5.5
Routine 12-lead Electrocardiograms····················································82
7.5.6
Endometrial Health Assessment·························································82
7.6
Analysis of Pharmacokinetics ·······························································82
7.7
Analysis of Pharmacodynamics ·····························································83
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················83
7.9
Additional Conventions ······································································83
8
OPERATIONAL CONSIDERATIONS·······················································83
8.1
Data Collection················································································83
8.1.1
Electronic Clinical Outcome Assessment/Electronic Patient-reported Outcome··84
8.2
Screen Failures ················································································85
8.3
Major Protocol Deviations ···································································85
9
END OF STUDY ··················································································85
10
STUDY ORGANIZATION······································································86
10.1
Data Monitoring Committee·································································86
10.2
Other Study Organization ····································································86
11
REFERENCES ····················································································87
12
APPENDICES ·····················································································90
12.1
Ethical, Regulatory and Study Oversight Considerations ································90
12.1.1
Ethical Conduct of the Study ····························································90
12.1.2
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities ·················································································90
12.1.3
Protocol Amendment and/or Revision··················································90
12.1.4
Financial Disclosure ······································································91


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12.1.5
Informed Consent of Subjects ···························································91
12.1.5.1
Subject Information and Consent················································91
12.1.5.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························91
12.1.6
Source Documents ········································································92
12.1.7
Record Retention··········································································92
12.1.8
Subject Confidentiality and Privacy ····················································92
12.1.9
Arrangement for Use of Information and Publication of the Clinical Study·······93
12.1.10
Signatory Investigator for Clinical Study Report ·····································94
12.2
Procedure for Clinical Study Quality Control ·············································95
12.2.1
Clinical Study Monitoring ·······························································95
12.2.2
Direct Access to Source Data/Documents ·············································95
12.2.3
Data Management·········································································95
12.2.4
Quality Assurance·········································································95
12.3
List of Excluded Concomitant Medications················································96
12.4
Liver Safety Monitoring and Assessment ··················································99
12.5
Common Serious Adverse Events························································· 102
12.6
Pharmacogenomic Analysis with Banked Sample ······································ 103
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2 ································ 105
14
SPONSOR SIGNATURES ···································································· 118


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I.
SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 14
Sponsor Signatures].


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2.  INVESTIGATOR’S SIGNATURE
A Phase 3, Randomized, Placebo-controlled, 12-week Double-blind Study, 
followed by a Non-Controlled Extension Treatment Period, to Assess the Efficacy 
and Safety of Fezolinetant in Women Suffering from Moderate to Severe 
Vasomotor Symptoms (Hot Flashes) Associated with Menopause
ISN/Protocol 2693-CL-0302
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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:


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II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL
24-hour Contact for Serious 
Adverse Events (SAEs)
See [Section 5.5.5 Reporting of 
Serious Adverse Events] 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
PPD


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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
14C
carbon-14
ADME
absorption, disposition, metabolism and excretion
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APGD
Astellas Pharma Global Development, Inc.
AST
aspartate aminotransferase
AT
serum aminotransferases
BC
breast cancer 
bid
bis in die; twice daily
BSAP
bone specific alkaline phosphatase
CA
Competent Authorities
CAT
computerized adaptive test
cEC
concerned Ethics Committee
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
CTX
carboxy-terminal telopeptide of type I collagen
CYP1A2
cytochrome P450 1A2
DBL
direct bilirubin
DCF
Data Clarification Form
DHEA
dehydroepiandrosterone
DILI
drug-induced liver injury
DMC
data monitoring committee
E2
estradiol
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EOT
end of treatment
ePRO
electronic patient-reported outcome
EQ-5D-5L
Euro-Qol 5D-5L


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Abbreviations
Description of abbreviations
EMA
European Medicines Agency
ED
early discontinuation
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
good clinical practice
GCS
Greene Climacteric Scale
GLP
good laboratory practice
GMP
good manufacturing practice
GnRH
gonadotropin-releasing hormone
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HF
hot flash
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
hNK3
human neurokinin 3 receptor
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
KNDy
kisspeptin/neurokinin B/dynorphin
LA-CRF
liver abnormality case report form
LH
luteinizing hormone
LLOQ
lower limit of quantification
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 observed adverse effect level
P1NP
procollagen type 1 amino-terminal propeptide
P4
progesterone
Pap
Papanicolaou


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Abbreviations
Description of abbreviations
PGI-C
Patient Global Impression of Change
PGI-C SD
Patient Global Impression of Change in Sleep Disturbance
PGI-C VMS
Patient Global Impression of Change in Vasomotor Symptoms
PGI-S
Patient Global Impression of Severity
PGI-S SD
Patient Global Impression of Severity in Sleep Disturbance
PGx
pharmacogenomic
PRO
Patient-reported outcome
PROMIS SD SF 8b
Patient-reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8b
PROMIS SRI SF 
8a
Patient-reported Outcomes Measurement Information System Sleep-Related
Impairment – Short Form 8a
PPS
per protocol set
QA
quality assurance
QC
quality control
RSI
reference safety information
(S)AE
adverse event or serious adverse event
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SHBG
sex hormone-binding globulin 
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TVU
transvaginal ultrasound
ULN
upper limit of normal
USM
urgent safety measure
VMS
vasomotor symptoms
WPAI-VMS
Work Productivity and Activity Impairment questionnaire specific to VMS


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Definition of Key Study Terms
Terms
Definition of terms
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).
Enrollment/ 
Randomization
After a subject has successfully completed the screening period and deemed 
eligible to move forward in the study, this subject will then be enrolled into 
the treatment period of the study. At that time, randomization will occur. 
Randomization is the process of assigning study subjects to 1 of 2 treatment 
arms using an element of chance to reduce bias. The randomization 
assignments in this study will be blinded.
NOTE: The visit in which the subject is enrolled and administered the first 
dose of treatment (investigational product or placebo) is the baseline visit 
(day 1). 
NOTE: Unequal randomization is used to allocate subjects into groups at a 
differential rate (e.g., 3 subjects may be assigned to a treatment group for 
every 1 assigned to the control group). 
Follow-up Period
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events are conducted during this period.
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.
Rescreen
Subject can rescreen up to 1 time with approval from 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. Subjects may 
not rescreen if the vasomotor symptoms eligibility report has been run. 
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. 
Screening
A process of active consideration of potential subjects for enrollment in a 
study.
NOTE: This is conducted after the subject signs the informed consent form 
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.
Screening period
Period of time before entering the investigational period, usually from the 
time when a subject signs the informed consent form until just before the test 
drug or comparative drug (sometimes without randomization) is given to a 
subject. 


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Terms
Definition of terms
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.


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IV.
SYNOPSIS
Date and Version No of Protocol Synopsis:
01 Jul 2020, Version 3.0
Sponsor:  
Astellas Pharma Global Development
Protocol Number: 
2693-CL-0302
Name of Study Drug: 
Fezolinetant
Phase of Development:  
Phase 3
Title of Study:  
A Phase 3, Randomized, Placebo-controlled, 12-week Double-blind Study, followed by a Non-
Controlled Extension Treatment Period, to Assess the Efficacy and Safety of Fezolinetant in Women 
Suffering from Moderate to Severe Vasomotor Symptoms (Hot Flashes) Associated with Menopause
Planned Study Period:
From Q3 2019 to Q4 2021
Study Objective(s): 
Primary objective:
●
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of moderate 
to severe vasomotor symptoms (VMS). 
o
The estimand of the primary objective will use a hypothetical strategy and compare 
patients as though they had continued on the assigned treatment. 
Key secondary objective:
●
To evaluate the efficacy of fezolinetant versus placebo on patient-reported sleep disturbance.
Secondary objectives: 
●
To evaluate the effect of fezolinetant versus placebo on the frequency and severity of moderate to 
severe VMS at weekly time points. 
●
To evaluate the safety and tolerability of fezolinetant.
Exploratory objectives: 
●
To evaluate pharmacokinetics of fezolinetant and metabolite ES259564.
●
To evaluate the effect of fezolinetant on pharmacodynamic markers.
●
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of mild, 
moderate and severe VMS. 
●
To evaluate the short-term and sustained effects of fezolinetant versus placebo on patient-reported 
sleep disturbance.
●
To evaluate the effect of fezolinetant versus placebo on the following patient-reported outcomes 
(PROs): global assessments of VMS and sleep disturbance, overall sleep-wake function, quality 
of life and work productivity.
Planned Total Number of Study Centers and Location(s):  
Approximately 200 centers globally
Study Population:  
Women ≥ 40 years and ≤ 65 years of age with moderate to severe VMS (≥ 50/week) associated with 
menopause.


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Number of Subjects to be Enrolled/Randomized:  
Approximately 450 subjects will be enrolled into this study. One hundred and fifty subjects will be 
randomized per treatment arm. 
Study Design Overview:  
This is a randomized, 12- week double-blind, placebo-controlled, parallel group, multicenter clinical 
study to assess the efficacy and safety of fezolinetant in women suffering from moderate to severe 
VMS associated with menopause. Approximately 450 subjects will be enrolled into this study, 
150 subjects per treatment arm. Duration of treatment is 52 weeks. After completing 12 weeks of 
treatment, subjects on placebo will be reassigned to 30 mg or 45 mg of active treatment in a non-
controlled extension treatment period through end of study. Subjects who were already randomized on 
an active arm will continue on their assigned dose for the remaining 40 weeks of treatment. Following 
the completion (or early discontinuation [ED]) of the treatment period (week 52), subjects will 
complete an end of treatment (EOT; or ED) visit and final safety follow-up visit 3 weeks after the last 
dose of study drug is administered (week 55). 
This study will consist of a screening period (days -35 to -1, including the screening visit [visit 1] and 
collection of VMS frequency and severity assessments), and a 52-week treatment period (day 1 
[visit 2] to week 52 [visit 15]). The study will be performed on an outpatient basis. The screening visit 
(visit 1) will occur up to 35 days prior to randomization (visit 2). Eligibility will be assessed via 
physical examination; clinical laboratory testing; vital signs; electrocardiogram (ECG); Papanicolaou 
(Pap) test (or equivalent cervical cytology); mammography; transvaginal ultrasound (TVU); and 
endometrial biopsy. Endometrial biopsy will be performed at screening, at week 52/EOT, for subjects 
with uterine bleeding, and for subjects who are withdrawn from the study prior to completion. If a 
subject discontinues from the study, an endometrial biopsy will be performed at the discontinuation 
visit along with all other EOT procedures. During treatment, 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. 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.
Subjects may be retested up to 1 time, retaining the same screening number, upon approval of the 
medical monitor within the current 35-day screening window. Subjects may be rescreened up to 1 
time, with a new screening number, upon the approval of the medical monitor, which will result in a 
new 35-day screening window. Subjects may not rescreen if the VMS eligibility report has been run. 
The following assessments do not need to be repeated at the rescreen provided they fall within the 
acceptable procedure competed timeframe 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 findings 
mammogram obtained within the prior 12 months of study 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.
Within the 10 days prior to randomization, subjects must have a minimum average of 7 to 
8 moderate to severe hot flashes (HFs; VMS) per day, or 50 to 60 per week. Subjects are to 
record HFs for the entirety of the screening period. The electronic diary will be reviewed by 
study site staff at visit 2 to confirm study eligibility. 


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During the 52-week treatment period, subjects will return to the study site from visit 2 through 15 for 
assessments as indicated in the Schedule of Assessments. Subjects will record their VMS via their 
electronic dairy on a daily basis throughout their study participation.
Site-based PRO measures will be self-administered via an electronic device as indicated in the 
Schedule of Assessments. Assessments at visit 2 must occur prior to randomization/first dosing; 
assessments at weeks 4, 12, 24 and 52 must occur prior to dosing. All self-administered assessments 
will be performed first upon arrival at the site and prior to all other procedures. In the event a subject 
withdraws from the study, efforts to collect information on the site-based PRO measures should be 
made before or shortly after discontinuation.
A Data Monitoring Committee (DMC) and a Liver Safety Monitoring Panel 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 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.

Subjects should be instructed to continue entering their hot flashes in the daily handheld diary as 
instructed regardless of site closure.

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) and 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.
Inclusion/Exclusion Criteria:
Inclusion:  
Subject who meets 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:


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
Spontaneous amenorrhea for 12 consecutive months

Spontaneous amenorrhea for 6 months with biochemical criteria of menopause 
(follicle-stimulating hormone [FSH] > 40 IU/L); or 

Having had bilateral oophorectomy 6 weeks prior to the screening visit.
5.
Within the 10 days prior to randomization, subject must have a minimum average of 7 to 
8 moderate to severe HFs (VMS) per day, or 50 to 60 per week.
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 findings mammogram 
(obtained at screening or within the prior 12 months of study 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), and for subjects who are withdrawn from the study prior to completion, a TVU at the 
ED visit. 
9.
Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), for 
subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to 
completion. 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.
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 1A2 [CYP1A2] 
inhibitors, hormone replacement therapy [HRT], hormonal contraceptive or any treatment for 
VMS [prescription, over the counter or herbal]) or is not willing to wash out and discontinue use 
of such drugs for the full duration of study conduct.
2.
Subject has known substance abuse or alcohol addiction within 6 months of screening, as assessed 
by the 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 these 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 clear (stable and compliant).


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5.
Subject has 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 or elevated liver aminotransferases (ALT or AST), 
elevated total or direct bilirubin, elevated 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 are normal. Patients with mildly elevated ALP (up to 1.5 x 
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 may be enrolled as long 
as direct bilirubin, hemoglobin and reticulocytes are normal. 
12. Subject has creatinine > 1.5 × ULN; or estimated glomerular filtration rate (eGFR) using the 
Modification of Diet in Renal Disease formula 59 mL/min per 1.73 m2 at screening.
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 question 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 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. This criterion has been removed.
18. This criterion has been removed.
19. Subject has any condition, which in the investigator’s opinion, makes the subject unsuitable for 
study participation.
20. Subject has had a partial or full hysterectomy.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
Fezolinetant 15 mg tablet
Fezolinetant 30 mg tablet


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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, two tablets to match once daily
Dose(s):
Not applicable
Mode of Administration:
Oral
Concomitant Medication Restrictions or Requirements:   
Medication for VMS 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 through the last study-related activity will 
be documented on the appropriate eCRF 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) and over the counter and prescription medication. 
Subjects will be instructed not to take any concomitant medication without first consulting the 
investigator or study coordinator throughout the duration of the study.
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.
Duration of Treatment:  
Subject will take study drug daily from day 1 (randomization) for a duration of 52 weeks.


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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 defined 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 International Normalized Ratio (INR) 
> 1.5 
○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 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:
Co-primary:
●
Mean change in the frequency of moderate to severe VMS from baseline to week 4
●
Mean change in the frequency of moderate to severe VMS from baseline to week 12 
●
Mean change in the severity of moderate to severe VMS from baseline to week 4 
●
Mean change in the severity of moderate to severe VMS from baseline to week 12 
Key Secondary:
●
Mean change in the Patient-reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8b (PROMIS SD SF 8b) Total Score from baseline to week 12
Secondary:
●
Mean change in the frequency of moderate and severe VMS from baseline to each week up to 
week 12
●
Mean change in the severity of moderate and severe VMS from baseline to each week up to 
week 12
●
Mean percent reduction in the frequency of moderate and severe VMS from baseline to each 
week up to week 12
●
Percent reduction ≥ 50% and at 100% in the frequency of moderate and severe VMS from 
baseline to each week up to week 12
●
Mean change in the frequency of moderate to severe VMS from baseline to week 24
(descriptive) 
●
Mean change in the severity of moderate to severe VMS from baseline to week 24 (descriptive)
●
Mean score on the Patient Global Impression of Change (PGI-C) in VMS from baseline to each 
visit


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Exploratory:
●
Mean change in the frequency of mild, moderate and severe VMS from baseline to each week up 
to week 12
●
Mean change in the severity of mild, moderate and severe VMS from baseline to each week up to 
week 12
●
Mean percent reduction in the frequency of mild, moderate and severe VMS from baseline to 
each week up to week 12
●
Percent reduction ≥ 50% and at 100% in the frequency of mild, moderate and severe VMS from 
baseline to each week up to week 12
●
Mean change in the frequency and severity of moderate and severe VMS from baseline to each 
visit in the non-controlled extension period and the follow-up visit
●
Change in serum concentrations of sex hormones and sex hormone-binding globulin (SHBG) 
from baseline to each visit
●
Mean change in serum concentrations of bone specific alkaline phosphatase (BSAP), procollagen 
type 1 amino-terminal propeptide (P1NP) and carboxy-terminal telopeptide of type I collagen 
(CTX) from baseline to each visit
●
Plasma concentrations of fezolinetant and metabolite ES259564 at pre-specified time points
●
Mean change on the PROMIS SD SF 8b total score from baseline to each visit
●
Mean change on the Patient-reported Outcomes Measurement Information System Sleep-Related 
Impairment – Short Form 8a (PROMIS SRI SF 8a) total score from baseline to each visit
●
Mean change on the Patient Global Impression of Severity in Sleep Disturbance (PGI-S SD) 
from baseline to each visit
●
Mean score on the Patient Global Impression of Change in Sleep Disturbance (PGI-C SD) from 
baseline to each visit
●
Mean change on the Menopause-Specific Quality of Life (MENQOL) total score from baseline 
to each visit
●
Mean change on the MENQOL domain scores from baseline to each visit
●
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) total score and Visual Analog Scale (VAS) 
from baseline to each visit
●
Mean change on the Work Productivity and Activity Impairment questionnaire specific to VMS 
(WPAI-VMS) domain scores from baseline to each visit
NOTE: Assessments after the 12 week placebo-controlled period are descriptive only, because there is 
no placebo control.
Safety:
Safety evaluations will include the following endpoints, but are not limited to:
●
Frequency and severity of AEs
●
TVUs and endometrial biopsy findings
●
Change from baseline to each time point in vital signs: sitting systolic and diastolic blood pressure 
and pulse rate
●
Change from baseline to each time point in ECG parameters
●
Change from baseline to each time point in laboratory tests: hematology, biochemistry and 
urinalysis


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Statistical Methods:
Sample size justification: 
A total of 450 subjects are planned to be randomized; 150 subjects in each treatment arm.
For a pairwise comparison of the primary endpoint of mean daily frequency using a 2-sample t-test at 
a 2-sided 2.5% alpha (adjusting for 2 active doses), 120 subjects would provide at least 79% power to 
detect differences from placebo of -2.0 or larger, assuming a SD of 5.
For a pairwise comparison of the primary endpoint of mean severity using a 2-sample t-test at a 
2-sided 2.5% alpha (adjusting for 2 active doses), 120 subjects would provide at least 79% power to 
detect differences from placebo of -0.40 or larger, assuming a SD of 1.
Assuming approximately 20% of subjects discontinue prematurely, the number of subjects will be 
increased from 120 to 150 subjects per arm.
This sample size would also provide over 95% power to detect a difference of 4.3 from placebo on the 
key secondary endpoint of the PROMIS sleep disturbance questionnaire, using a 2-sample t-test at a 
2-sided 2.5% alpha (adjusting for 2 active doses) assuming a SD of 7 [Avis et al, 2016].
Efficacy:  
For each of the 4 co-primary efficacy endpoints, a mixed models repeated measures analysis of 
covariance (MMRM) will be used with treatment group, week, 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 week and an interaction of baseline measurement by week, consistent with 
the hypothetical strategy used for the estimand, which is to compare patients as though they had 
continued on the assigned treatment. 
Comparisons between fezolinetant and placebo will be calculated based on least-squares mean 
contrasts using a 2-tailed 95% confidence interval (CI). The family-wise type 1 error rate for the 
2 active dose groups compared to placebo will be controlled using a Hochberg approach.
The PROMIS SD scale will be analyzed using MMRM, similar to the analysis of the co-primary 
endpoints.
If all the co-primary endpoints are statistically significant between fezolinetant and placebo at both 
doses, the statistical test will be performed on the key secondary efficacy endpoint between 
fezolinetant and placebo, using Hochberg with alpha = 0.05, as part of the family-wise error rate.
Pharmacokinetics:  
Plasma concentrations of fezolinetant and metabolite ES259564 will be listed and summarized using 
descriptive statistics by scheduled time point. Mean fezolinetant plasma concentration and mean 
metabolite ES259564 plasma concentration will be plotted against scheduled time-point. 
Pharmacokinetics may be evaluated by a population pharmacokinetics 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:  
Serum hormone concentration and changes from baseline will be listed and summarized using 
descriptive statistics by scheduled time point. Mean serum hormone concentration and changes from 
baseline will be plotted against scheduled time-point. Pharmacodynamic data and efficacy data may 
be evaluated by a population pharmacodynamic 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.


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Safety:  
Safety will be assessed by examining the incidence of adverse events, physical examinations findings, 
the clinician-administered C-SSRS, TVU’s, endometrial biopsies, vital signs, ECGs, clinical 
laboratory tests, and bone marker concentrations over time.
Interim Analysis:  
No interim analysis is planned for this study.
12-week Analysis and 52-week Analysis: 
Given the design, a 12-week treatment analysis will occur to assess efficacy and safety during the 
double-blind treatment phase. This will occur after all subjects have completed 12 weeks of treatment. 
Efficacy and safety data will be analyzed, excluding the endpoints measured after 12 weeks. Since all 
primary and secondary analyses only based on data through week 12, no alpha adjustment is required 
as the information fraction at the 12-week analysis is 100%. 
Once the entire 52-week study is completed and locked, additional efficacy and safety will be 
summarized without statistical comparison to placebo.  




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Table 1
Schedule of Assessments
Assessments
Screening 
Visit y
Randomization 
Visit y
Treatment Period
Follow-up 
Visit
Study Visit
Visit 1
Visit 2
Visit 
2b
Visit 3
Visit 4
Visit 5
Visit 5b
Visits 6, 7, 8, 9, 10, 
11, 12, 13 and 14
Visit 15/
EOT/ED y
Visit 16
Visit weeks
-5 to -1
Week 
2
Week 4
Week 
8
Week 
12
Week 14
Weeks 16, 20, 24, 
28, 32, 36, 40, 44
and 48
Week 52
Week 55b
Visit days
Days
-35 to -1a
Day 1
(Randomization)
Day 
15
Day 29
Day 57
Day 85
Day 99
Day 113, 141, 169, 
197, 225, 253, 281, 
309 and 337
Day 365
Day 386
Visit Windowc
-
-
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Informed consentd
X
Informed consent PGxd
X
Inclusion/exclusion criteria
X
X
Medical history/concomitant diseases
X
ePRO’s Assessmente
   PGI-C VMSe
X
X
Xe
X
   PROMIS SD SF 8be
X
X
X
Xe
X
   PGI-S SDe
X
X
X
Xe
X
   PGI-C SDe
X
X
Xe
X
   PROMIS SRI SF 8ae
X
X
X
Xe
X
   MENQOLe
X
X
X
Xe
X
   EQ-5D-5Le
X
X
X
Xe
X
   WPAI-VMSe
X
X
X
Xe
X
Study Procedures:
C-SSRS (clinician-administered)f
X
X
X
Xf
X
X
Mammogramg
X
Xg
Demographic datah
X
Physical examinationi
X
Xj
Xj
Xj
X
Xj
X
X
Table continued on next page


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Assessments
Screening 
Visit y
Randomization 
Visit y
Treatment Period
Follow-up 
Visit
Study Visit
Visit 1
Visit 2
Visit 
2b
Visit 3
Visit 4
Visit 5
Visit 5b
Visits 6, 7, 8, 9, 10, 
11, 12, 13 and 14
Visit 15/
EOT/ED y
Visit 16
Visit weeks
-5 to -1
Week 
2
Week 4
Week 
8
Week 
12
Week 14
Weeks 16, 20, 24, 
28, 32, 36, 40, 44
and 48
Week 52
Week 55b
Visit days
Days
-35 to -1a
Day 1
(Randomization)
Day 
15
Day 29
Day 57
Day 85
Day 99
Day 113, 141, 169, 
197, 225, 253, 281, 
309 and 337
Day 365
Day 386
Visit Windowc
-
-
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Urine pregnancy test
X
Clinical laboratoryk and urinalysis
X
X
Xk
X
X
X
Xk
X
X
X
Vital signsl
X
X
X
X
X
X
X
X
12-lead ECGm
X
X
X
X
Pap test (or equivalent cervical 
cytology)n
X
TVUo
X
X
Endometrial biopsyo
X
X
Serologyp
X
Blood pharmacodynamic sampleq
X
X
X
Xq
Xq
X
Blood pharmacokinetic sampler
X
X
Xr
Xr
Blood PGx samples
X
VMS diaryt
X
X
X
X
X
X
X
X
X
X
ePRO training
X
Randomization
X
Bone markeru
X
X
X
Dispense study drugv
X
X
X
X
X
Study drug compliance and 
accountabilityw
X
X
X
X
X
X
Concomitant medications and AEsx
X
X
X
X
X
X
X
X
X
X
Footnotes appear on next page


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AE: adverse event; anti-HBc: antibody to hepatitis B core antigen; anti-HBs: antibody against hepatitis B antigen; BSAP: bone specific alkaline phosphatase; C-SSRS: Columbia 
Suicide Severity Rating Scale; CTX: C-telopeptides of type 1 collagen; E2: estradiol; ECG: electrocardiogram; ED: early discontinuation; ePRO: electronic patient-reported outcomes; 
EQ-5D-5L: EuroQol group 5 Dimensions questionnaire; EOT: end of treatment; FSH: follicle-stimulating hormone; HBsAG: hepatitis B virus surface antigen; HCV: hepatitis C virus; 
HIV: human immunodeficiency virus; LH: luteinizing hormone; MENQOL: Menopause-Specific Quality of Life; P1NP: N terminal pro-peptides of type 1 collagen; Pap test: 
Papanicolaou test; PGI-C SD: Patient Global Impression of Change in Sleep Disturbance; PGI-C VMS: Patient Global Impression of Change in vasomotor symptoms; PGI-S SD: 
Patient Global Impression of Severity in Sleep Distrubance; PGx: pharmacogenomic; PROMIS SD SF 8b: Patient-reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8b; PROMIS SRI SF 8b: Patient-reported Outcomes Measurement Information System Sleep-Related Impairment – Short Form 8b; SHBG: sex hormone-
binding globulin; TVU: transvaginal ultrasound; VMS: vasomotor symptom; WPAI-VMS: Work Productivity and Activity Impairment questionnaire specific to vasomotor symptoms
a.
The screening visit is to occur within 35 days of randomization (day 1 [visit 2]). Subjects will record daily VMS during the screening period in an electronic diary. To qualify for 
the study, within 10 days prior to randomization, subject must have a minimum average of 7 to 8 moderate to severe hot flashes (VMS) recorded per day, or 50 to 60 per week.
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. Subjects 
may be retested 1 time for assessments upon approval of the medical monitor. Subjects may be rescreened up to 1 time, upon the approval of the medical monitor. Subjects may 
not rescreen if the VMS eligibility report has been run. The following assessments do not need to be repeated at the rescreen provided they still fall within the acceptable procedure 
completed time frame window: TVU, endometrial biopsy, mammogram, ECG and Pap test (or equivalent cervical cytology).
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 done. Subjects who do not consent to PGx sampling are not excluded from 
participating in the study. 
e.
ePRO assessments will be self-administered at the study site first upon arrival and before any other study assessments/procedures are performed; assessments at visit 2 must occur 
prior to randomization/first dosing; assessments at all other visits must occur prior to dosing. In the event a subject withdraws from the study, efforts to collect information on the 
site-based ePRO measures should be made before or shortly after discontinuation. The assessments will be administered electronically via the site tablet on day 1, week 4, week 
12, week 24 and week 52.
f.
A clinician will administer the C-SSRS measure electronically at the clinic visit, prior to any invasive procedures. This will be administered at screening (visit 1), day 1 (visit 2), 
week 12 (visit 5), week 24 (visit 8), week 52 (visit 15) and the follow-up visit (week 55 [visit 16]).
g.
At screening, in the event that the subject does not have a normal/negative or no clinically significant findings mammogram from previous 12 months on record a mammogram 
will be required. 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.
h.
Includes age, race, sex and smoking status.
i.
Height, weight and waist circumference will be measured. A bimanual clinical pelvic examination and clinical breast examination will be performed at screening and can be 
performed at any time in the study where clinically indicated.
j.
At day 1 (visit 2) thru week 8 (visit 4), excluding visits 2b and 5b, and weeks 16 (visit 6) thru week 48 (visit 14), a symptom directed physical exam will be conducted which 
includes weight and waist circumference. 
k.
Includes biochemistry, coagulation and hematology panel. Visits 2b & 5b will only include liver biochemistry and INR testing. 
Footnotes continued on next page


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l.
Includes oral/tympanic temperature, sitting blood pressure and pulse rate (after 5 minutes of rest). 
m. 12-lead ECG. The subject should rest in supine position for at least 10 minutes prior to the ECG measurement.
n.
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 9 months on record. 
o.
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 for up to 3 months from date of procedure 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. 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 HBsAG, anti-HCV antibodies, anti-HBs antibodies, anti-HBc antibodies and anti-HIV antibodies. 
q.
Pharmacodynamic samples will be taken predose at day 1 (visit 2), week 12 (visit 5), week 16 (visit 6), week 24 (visit 8) and EOT/ED week 52 (visit 15), as well as predose and 3 
hours postdose at week 4 (visit 3). The week 4 (visit 3) 3 hours postdose pharmacodynamic sample may be shifted to a later date (prior to week 12) in case the subject cannot 
accommodate the sampling schedule at that visit. The pharmacodynamic sample should be taken at the same time as the 3-hour postdose pharmacokinetic sample. A 
pharmacodynamic sample will be taken at the follow-up visit (week 55 [visit 16]) as well. Markers include LH, FSH, E2, SHBG, androstenedione, dehydroepiandrosterone, 
estrone and testosterone. 
r.
Pharmacokinetic samples to be taken at predose (1 hour), 1 h (30 min) post dose and 3 h (30 min) postdose week 4 (visit 3) and week 16 (visit 6), as well as predose, week 12 
(visit 5), week 24 (visit 8) and EOT/ED week 52 (visit 15). The indicated time windows for week 4 (visit 3) pharmacokinetic sampling will allow for flexibility. If this visit is
missed, the samples can be taken at the next visit (prior to week 12). A pre-dose sample will be collected for any subject with a signal of elevated transaminases (> 3 × ULN) when 
she returns for a repeat blood draw.
s.
While scheduled for week 4 (visit 3), PGx sample can be taken at any time during the study after signed informed consent and enrollment into the study.
t.
The VMS diary will be kept by subjects. Subjects will record the VMS frequency and severity of each VMS in the ePRO diary on a daily basis from the screening visit (days -35 to 
-1 [visit 1]) through the follow-up visit (week 55 [visit 16]). Night sweats should be recorded no later than in the morning upon awakening to start a new day.
u.
Includes BSAP, P1NP and CTX.
v.
Subjects will be assigned study drug as a kit in blister packaging. 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 dose of 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 interactive response technology.
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 with home healthcare, telemedicine conferences 
or 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 (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 lasts 4 to 10 minutes 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 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 
demonstrated that the gonadotropin-releasing hormone (GnRH) pulse frequency is modulated 


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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 (human neurokinin 1 and human neurokinin) 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-0009) 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 orally intake, fezolinetant showed generally dose proportional 
pharmacokinetics at doses between 20 and 60 mg once daily in female subjects. Peak 
concentration (Cmax) was generally reached within 1 to 4 hours postdose with terminal half-
life (t1/2) ranging between 4 to 6 hours in healthy subjects and patients. With a once daily 
dose regimen, steady state in plasma concentrations are approximately achieved by 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 CYP1A2 enzyme, to form the 
major metabolite ES259564. A strong CYP1A2 inhibitor (fluvoxamine) increased 
fezolinetant AUC and Cmax approximately 9-fold and 1.8-fold, respectively, while smoking 
can decrease AUC and Cmax to a geometric LS mean ratio of 48.29% and 71.74%, 
respectively (study 2693-CL-0006). 
In a recently completed mass balance study (ESN364_CPK_103), the routes of excretion of 
fezolinetant were 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 (study 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, comparing 
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 the 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 of 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
Table continued on next page


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Study Number
Development 
Phase
Description
Location
Number of 
Subjects/Patients 
Randomized
ESN364_HF_204
2a
Proof of concept study in 
MR-VMS
Belgium
Fezolinetant 90 mg 
twice daily = 43
Placebo = 44
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
Fezolinetnat 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
14C-ESN-364 ADME: absorption, disposition, metabolism and excretion of 14C-ESN-364; MAD: multiple 
ascending dose; MR-VMS: menopause-related vasomotor symptoms; SAD: single ascending dose; VMS: 
vasomotor symptoms
Source: Fezolinetant (ESN364) Investigator’s Brochure
In patients, 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.


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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 HF 
(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 
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 HF 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 to 
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 Study Drugs
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 (AUC) at this dose level 
in Cynomolgus monkeys 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.


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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 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 pre-dose 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, paraesthesia and nausea. The highest incidence for headache was after 360 and 
900 mg intake, for paraesthesia 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 


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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.
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 SAEs were reported. The most common 
MedDRA 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 aspartate aminotransferase (AST) > 3× 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 (ECGs), 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.


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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/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 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 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 above 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 12.4. Increased transaminases have not been 
observed at the dose selected for the phase 3 studies (i.e., 30 mg fezolinetant qd). 
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 mild, 
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, 
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 


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described as either plain paresthesia (oral, facial skin, tongue, scalp and/or lips), as a 
prickling sensation of the face, as a numbness of the tongue or as a tingling sensation (face, 
mouth and/or tongue). 
Circumoral paraesthesia has been recognized in the phase 1 and 2 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 12 week placebo treatment, which also is 
associated with improvement in VMS, is justifiable.
2
STUDY OBJECTIVES, DESIGN AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
●
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of 
moderate to severe VMS. 
o
The estimand of the primary objective will use a hypothetical strategy and compare 
patients as though they had continued on the assigned treatment. 
2.1.2
Key Secondary Objective
●
To evaluate the efficacy of fezolinetant versus placebo on patient-reported sleep 
disturbance.
2.1.3
Secondary Objectives
●
To evaluate the effect of fezolinetant versus placebo on the frequency and severity of
moderate to severe VMS at weekly time points.
●
To evaluate the safety and tolerability of fezolinetant.
2.1.4
Exploratory Objectives
●
To evaluate pharmacokinetics of fezolinetant and metabolite ES259564.
●
To evaluate the effect of fezolinetant on pharmacodynamic markers.
●
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of 
mild, moderate and severe VMS. 
●
To evaluate the short-term and sustained effects of fezolinetant versus placebo on patient-
reported sleep disturbance.
●
To evaluate the effect of fezolinetant versus placebo on the following patient-reported 
outcomes (PROs): global assessments of VMS and sleep disturbance, overall sleep-wake 
function, quality of life and work productivity. 




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Eligibility will be assessed via physical examination; clinical laboratory testing; vital signs; 
ECG; Papanicolaou (Pap) test (or equivalent cervical cytology); mammography; transvaginal 
ultrasound (TVU); and endometrial biopsy. Endometrial biopsy will be performed at 
screening and at week 52/EOT, for subjects with uterine bleeding, and for subjects who are 
withdrawn from the study prior to completion. If a subject discontinues from the study, an 
endometrial biopsy will be performed at the discontinuation visit along with all other EOT 
procedures. During treatment, 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. 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.
Subjects may be retested up to 1 time, retaining the same screening number, upon approval of 
the medical monitor within the 35-day screening window. Subjects may be rescreened up to 
1 time, with a new screening number, upon the approval of the medical monitor, which will 
result in a new 35-day screening window. Subjects may not rescreen if the VMS eligibility 
report has been run. The following assessments do not need to be repeated at the rescreen 
provided they fall within the acceptable procedure competed timeframe 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 findings mammogram obtained within the prior 12 months of study 
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.
Within the 10 days prior to randomization, subjects must have a minimum average of 7 to 
8 moderate to severe HFs (VMS) per day, or 50 to 60 per week. Subjects are to record HFs 
for the entirety of the screening period. The electronic diary will be reviewed by study site 
staff at visit 2 to confirm study eligibility. 
During the 52-week treatment period, subjects will return to the study site from visit 2 through 
visit 15 for assessments as indicated in the Schedule of Assessments [Table 1]. Subjects will 
record their VMS via their electronic dairy on a daily basis throughout their study participation.
Site-based PRO measures will be self-administered via an electronic device as indicated in 
the Schedule of Assessments [Table 1]. Assessments at visit 2 must occur prior to 
randomization/first dosing; assessments at weeks 4, 12, 24 and 52 must occur prior to dosing. 
All self-administered assessments will be performed first upon arrival at the site and prior to 
all other procedures. In the event a subject withdraws from the study, efforts to collect 


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information on the site-based PRO measures should be made before or shortly after 
discontinuation.
A Data Monitoring Committee (DMC) and a Liver Safety Monitoring Panel 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 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.
●
Subjects should be instructed to continue entering their hot flashes in the daily handheld 
diary as instructed regardless of site closure.
●
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 
using all or some of the following services: home healthcare, telemedicine conferences 
(telephone visits) and 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.
2.2.2
Dose Rationale
A phase 2b dose-ranging study (ESN364_HF_205) assessing the effects of the potent and 
selective NK3 antagonist, fezolinetant, on VMS in post-menopausal females was recently 
completed. 
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 week 4 and week 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 


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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 total bilirubin > 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 
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 enrollment if they experienced more than 
an average 7 hot flashes 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 


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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 hot flashes 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 hot flashes, 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 hot flash 
severity and the increased sample size planned in the phase 3 studies, these proposed doses 
are anticipated that a statistically significant reduction in hot flash severity can be achieved 
compared to placebo.
In addition to the dose- and exposure-response analyses, 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-times the upper limit of 
normal 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
Co-primary Endpoints
The primary efficacy objective requires the evaluation of 4 co-primary endpoints: 
●
Mean change in the frequency of moderate to severe VMS from baseline to week 4
●
Mean change in the frequency of moderate to severe VMS from baseline to week 12
●
Mean change in the severity of moderate to severe VMS from baseline to week 4
●
Mean change in the severity of moderate to severe VMS from baseline to week 12
2.3.2
Key Secondary Endpoints
The key secondary efficacy objective examines the effect of fezolinetant versus placebo on 
the following:
●
Mean change in the Patient-reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8b (PROMIS SD SF 8b) total score from baseline to week 12


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2.3.3
Secondary Endpoints
The secondary efficacy objectives examine the effect of fezolinetant versus placebo on the 
following: 
●
Mean change in the frequency of moderate and severe VMS from baseline to each week 
up to week 12
●
Mean change in the severity of moderate and severe VMS from baseline to each week up 
to week 12
●
Mean percent reduction in the frequency of moderate and severe VMS from baseline to 
each week up to week 12
●
Percent reduction ≥ 50% and at 100% in the frequency of moderate and severe VMS 
from baseline to each week up to week 12
●
Mean change in the frequency of moderate to severe VMS from baseline to week 24 
(descriptive)
●
Mean change in the severity of moderate to severe VMS from baseline to week 24 
(descriptive)
●
Mean score on the Patient Global Impression of Change (PGI-C) in VMS from baseline 
to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
2.3.4
Exploratory Endpoints
●
Mean change in the frequency of mild, moderate and severe VMS from baseline to each 
week up to week 12
●
Mean change in the severity of mild, moderate and severe VMS from baseline to each 
week up to week 12 
●
Mean percent reduction in the frequency of mild, moderate and severe VMS from 
baseline to each week up to week 12
●
Percent reduction ≥ 50% and at 100% in the frequency of mild, moderate and severe 
VMS from baseline to each week up to week 12
●
Mean change in the frequency and severity of moderate and severe VMS from baseline 
to each visit in the non-controlled extension period and the follow-up visit (week 16, 20, 
24, 28, 32, 36, 40, 44, 48, 52, 55)
●
Change in serum concentrations of sex hormones and sex hormone-binding globulin 
(SHBG) from baseline to each visit (week 4, 12, 16, 24, 52, 55)
●
Mean change in serum concentrations of bone specific alkaline phosphatase (BSAP), 
procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal telopeptide 
of type I collagen (CTX) from baseline to each visit (week 52, 55)
●
Plasma concentrations of fezolinetant and metabolite ES259564 at pre-specified time 
points (week 4, 12, 16, 24, 52)
●
Mean change on the PROMIS SD SF 8b total score from baseline to each visit (week 4, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)


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●
Mean change on the Patient-reported Outcomes Measurement Information System 
Sleep-Related Impairment – Short Form 8a (PROMIS SRI SF 8a) total score from 
baseline to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
●
Mean change on the Patient Global Impression of Severity in Sleep Disturbance (PGI-S 
SD) from baseline to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
●
Mean score on the Patient Global Impression of Change in Sleep Disturbance (PGI-C 
SD) from baseline to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
●
Mean change on the Menopause-Specific Quality of Life (MENQOL) total score from 
baseline to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
●
Mean change on the MENQOL domain scores from baseline to each visit (week 4, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, 52
●
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) total score and Visual Analog Scale 
(VAS) from baseline to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
●
Mean change on the Work Productivity and Activity Impairment questionnaire specific 
to VMS (WPAI-VMS) domain scores from baseline to each visit (week 4, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52)
NOTE: Assessments after the 12 week placebo-controlled period are descriptive only,
because there is no placebo control.
2.3.5
Safety Endpoints
Safety evaluations will include the following endpoints, but are not limited to:
●
Frequency and severity of AEs
●
TVUs and endometrial biopsy findings
●
Change from baseline to each time point in vital signs: sitting systolic and diastolic blood 
pressure and pulse rate
●
Change from baseline to each time point in ECG parameters
●
Change from baseline to each time point in laboratory tests: hematology, biochemistry 
and urinalysis
NOTE: Details of the safety assessments and time points for the assessments throughout the 
study are described in [Section 5.4 Safety Assessment].
3
STUDY POPULATION
3.1
Selection of Study Population 
The patient population for this study is women ≥ 40 years and ≤ 65 years of age with 
moderate to severe VMS (≥ 50/week) associated with menopause.


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3.2
Inclusion Criteria
Subject who meets 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 
●
Having had bilateral oophorectomy 6 weeks prior to the screening visit. 
5.
Within the 10 days prior to randomization, subject must have a minimum average of 7 to 
8 moderate to severe HFs (VMS) per day, or 50 to 60 per week.
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 findings 
mammogram (obtained at screening or within the prior 12 months of study 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), and for subjects who are withdrawn from the study prior to 
completion, a TVU at the ED visit. 
9.
Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), 
for subjects with uterine bleeding, and for subjects who are withdrawn from the study 
prior to completion. 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.


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Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
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 CYP1A2 inhibitors, HRT, 
hormonal contraceptive or any treatment for VMS [prescription, over the counter or 
herbal]) or is not willing to wash out and discontinue use of such drugs for the full 
duration of study conduct.
2.
Subject has known substance abuse or alcohol addiction within 6 months of screening, as 
assessed by the 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 these 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 clear (stable and compliant).
5.
Subject has 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, elevated 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 are normal. Patients with 
mildly elevated ALP (up to 1.5 x 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 may be enrolled as long as direct bilirubin, 
hemoglobin, and reticulocytes are normal.


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12. Subject has creatinine > 1.5 × ULN; or estimated glomerular filtration rate (eGFR) using 
the Modification of Diet in Renal Disease formula 59 mL/min per 1.73 m2 at 
screening.
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 question 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 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. This criterion has been removed.
18. This criterion has been removed.
19. Subject has any condition, which in the investigator’s opinion, makes the subject 
unsuitable for study participation.
20. Subject has had a partial or full hysterectomy.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug(s)
Fezolinetant study drug will be supplied in a blinded form by Astellas as fezolinetant 30 mg 
and 15 mg once daily tablets. 
4.1.2
Comparative Drug(s) 
Placebo will be supplied by Astellas in a blinded form to match the active fezolinetant 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 Astellas Pharma Global Development, Inc. (APGD) or 
sponsor’s designee in accordance with APGD or sponsor’s designee Standard Operating 
Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH 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 BV or sponsor’s designee will perform the 
final release of the medication according to the requirements of the 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 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 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. 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 termination of this study, the investigator or designee 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 
The first 12 weeks of the study are double blind. Subjects will be randomized to receive 
fezolinetant 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 the fezolinetant are identical 
to those of their matching placebo.


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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 
an SAE the investigator is to follow the instructions in [Section 5.5.5 Reporting of Serious 
Adverse Events]. 
Care should be taken to limit knowledge of the randomization arm, in case this could affect 
the blinding of other subjects or future study 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 to a treatment arm according to the 
randomization schedules and stratified by smoking status (active smoker or non-smoker) 
through IRT. Subjects who complete the 12-week treatment period and received placebo will 
be randomized to either fezolinetant 30 mg or 45 mg. The extension period will remain 
blinded to the site personnel and participating subjects. 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 screened up to 35 days prior to randomization. Informed consent/ authorization 
will be obtained prior to randomization and before any study-related procedures are performed.
Subjects will be assigned study drug as a kit at visits indicated in the Schedule of 
Assessments [Table 1]. Each kit will contain blister wallets containing either fezolinetant or 
placebo. Study drug intake will be done with a glass of 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 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, in the morning with 
water. 
In the case 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)
Medication for VMS 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 through the last study-related 
activity will be documented on the appropriate eCRF 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) and over the counter and prescription medication. 
Subjects are 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 and 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 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) 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.
●
Strong or moderate CYP1A2 inhibitors.
Refer to [Appendix 12.3 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. 
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 considered for 
withdrawal 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 protocol restrictions. 


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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] and will include age, sex, race, smoking 
status and prior HT use.
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. 
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 
ICF 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); or 
●
Having had bilateral oophorectomy 6 weeks prior to the screening; 
●
Within the 10 days prior to randomization, subject has a minimum average of 7 to 
8 moderate to severe HFs (VMS) per day, or 50 to 60 per week.
5.3
Efficacy | Pharmacodynamics | Pharmacokinetics | Assessments
5.3.1
Efficacy Assessment
5.3.1.1 Vasomotor Symptom Diary
Daily HF data will be collected using an electronic HF diary [Section 8.1 Data Collection], 
which should be completed daily by study participants from screening (visit 1) through the 
follow-up visit (visit 16). The HF diary is a validated, interactive, real-time vendor hosted 
system available for use 24 hours per day for data entry. This electronic diary will be the only 
source document for the 4 co-primary endpoints. Subjects will be provided with a reference 
guide within the diary, which includes the definitions of mild, moderate and severe HFs. These 
definitions are as follows [FDA Guidance for Industry, 2003]: 
●
Mild: sensation of heat without sweating
●
Moderate: sensation of heat with sweating, able to continue activity
●
Severe: sensation of heat with sweating, causing cessation of activity
The real-time system will generate daily compliance reports for each subject. The compliance 
reports tabulate the date and time of each HF entry and the number of HFs entered at each 
time point.


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5.3.2
Key Secondary Efficacy Assessment
The PROMIS is a National Institutes of Health Roadmap initiative designed to improve PRO
measures using state-of-the-science methods. The PROMIS SD SF 8b [PROMIS SD, 2015] 
assesses self-reported sleep disturbance over the past 7 days and includes perceptions of 
restless sleep; satisfaction with sleep; refreshing sleep; difficulties sleeping, getting to sleep 
or staying asleep; amount of sleep; and sleep quality. Because it assesses the patient’s 
experience of sleep disturbance, the measure does not focus on specific sleep-disorder 
symptoms or ask patients to report objective measures of sleep (e.g., total amount of sleep, 
time to fall asleep and amount of wakefulness during sleep). Responses to each of the 8 items 
range from 1 to 5, and the range of possible summed raw scores is 8 to 40. Higher scores on 
the PROMIS SD SF 8b indicate more of the concept measured (disturbed sleep).
Subjects will complete the PROMIS SD SF 8b electronically via a tablet at each site and 
without assistance from anyone else. This instrument will be self-administered; proxy 
responses will not be allowed.
While administration time for the PROMIS SD SF 8b has not been quantified, it is 
anticipated that the measure can be completed in approximately 2 minutes. In a study of 
patients with systemic sclerosis [Khanna et al, 2012], 11 PROMIS item banks, including the 
SD item bank, were administered via computerized adaptive test (CAT). The average number 
of items completed for each CAT-administered item bank ranged from 5 to 8, and the 
average time to complete each CAT-administered item bank ranged from 48 seconds to 
1.9 minutes per subject (average time = 11.9 minutes per subject for 11 banks) [Khanna et al, 
2012]. The expected administration time of approximately 2 minutes is also in line with the 
‘rule of thumb’ that 3 to 5 items can be completed per minute [Hays & Reeve, 2008]. The 
PROMIS SD SF 8b should take approximately 2 minutes to complete.
Due to the electronic administration of this PRO, risk for missing data is mitigated.
5.3.3
Patient-reported Outcome Assessments
The following PROs will be self-administered electronically at the site visit:
●
PROMIS SD SF 8b – assesses sleep disturbance
●
PROMIS SRI SF 8a – assesses sleep-related impairment
●
PGI scales – assess patient-perceived global impressions of severity in sleep disturbance 
and change in VMS and sleep disturbance 
●
MENQOL – assesses quality of life as it relates to menopausal symptoms
●
EQ-5D-5L – assesses general health-related quality of life
●
WPAI-VMS – assesses VMS-related work productivity and activity impairment
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 will be self-administered at the site and prior to performing all other 
procedures including the C-SSRS. 


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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 
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.
5.3.3.1 Patient Global Impression Scale
The PGI is comprised of 2 companion 1-item PRO measures analogous to the Clinical Global 
Impression (CGI) scales [Busner J & Targum SD, 2007]. These measures provide brief, 
stand-alone global assessments prior to and after initiating a study medication. The Patient 
Global Impression evaluates the following: (a) patient-perceived severity of a condition 
(PGI-S) and (2) patient-perceived change from the initiation of treatment (PGI-C). In this 
study, PGI scales will be used to evaluate meaningful within-person changes over time in 
VMS (PGI-C) and sleep disturbance (PGI-S and PGI-C).
The PGI-C VMS asks: “Compared to the beginning of this study, how would you rate your 
HFs/night sweats now?” Subject ratings range from (1) much better to (7) much worse. The 
PGI-C SD asks: Compared to the beginning of this study, how well are you sleeping now?” 
Subject ratings range from (1) much better to (7) much worse. The PGI-S SD asks: “How 
would you rate the severity of any problems you currently have while sleeping at night?” 
Subject ratings range from (1) no problems to (4) severe problems. 
Each PGI measure should take less than 1 minute to complete. Due to the electronic 
administration of these PROs, risk for missing data is mitigated.
5.3.3.2 PROMIS SRI SF 8a
The PROMIS SRI SF 8a [PROMIS Sleep-Related Impairment, 2015] is an 8-item PRO 
measure that evaluates self-reported perceptions of alertness, sleepiness and tiredness during 
usual waking hours and the perceived functional impairments during wakefulness associated 
with sleep problems or impaired alertness. Though this measure does not directly assess 
cognitive, affective or performance impairment, it does measure waking alertness, sleepiness 
and function within the context of overall sleep-wake function. The PROMIS SRI SF 8a is a 
universal rather than disease-specific instrument, and has a 7-day recall period.
Responses to each of the 8 items on the PROMIS SRI SF 8a range from 1 to 5, and the range 
of possible summed raw scores is 8 to 40. Higher scores indicate more of the concept 
measured (sleep-related impairment).
The PROMIS SRI SF 8a should take up to 2 minutes to complete. Due to the electronic 
administration of this PRO, risk for missing data is mitigated.


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5.3.3.3 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 pre-tests [Lewis et al, 2005; 
Hilditch et al, 1996].
5.3.3.4 EQ-5D-5L with Visual Analog Scale
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 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.
5.3.3.5 WPAI-VMS
The WPAI-VMS is a 6-item PRO measure that examines VMS-related work productivity and 
activity in the preceding 7 days [Reilly Associates, 2013; Reily et al, 1993]. It consists of 
4 domains: absenteeism (the percentage of work time missed because of VMS in the past 
7 days), presenteeism (the percentage of impairment experienced while at work in the past 
7 days because of VMS), overall work productivity loss (overall work impairment measured 
by combining absenteeism and presenteeism to determine the total percentage of missed 
time) and activity impairment (the percentage of impairment in daily activities because of 


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VMS in the past 7 days). If the subject is unemployed, only 2 of the 6 items on this 
questionnaire require completion.
WPAI-VMS outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity (i.e., worse outcomes) [Reilly Associates, 
2013].
The WPAI-VMS should take 2 minutes to complete. Due to the electronic administration of 
this PRO, risk for missing data is mitigated.
5.3.4
Pharmacodynamic Assessments
Venous blood samples will be collected for pharmacodynamic assessments starting at day 1 
(visit 2), through week 52 (visit 15/EOT) and at the follow-up visit (week 55 [visit 16]). 
Pharmacodynamic samples will be taken predose at day 1 (visit 2), week 12 (visit 5), week 
16 (visit 6), week 24 (visit 8) and week 52 (visit 15), as well as predose and 3 hours postdose 
at week 4 (visit 3). The week 4 (visit 3) 3 hours postdose pharmacodynamic sample should be 
shifted to a later date (prior to week 12) in case the subject cannot accommodate the sampling 
schedule at that visit. The pharmacodynamic sample should be taken at the same time as the 
3-hour postdose pharmacokinetic sample. A pharmacodynamic sample will be taken at the 
follow-up visit (week 55 [visit 16]), as well. 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 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.
5.3.5
Pharmacokinetic Assessments
Venous blood samples will be collected for pharmacokinetic analysis of fezolinetant and 
metabolite ES259564 in plasma predose, 1 h (± 30 min) postdose and 3 h (± 30 min) 
postdose at week 4 (visit 3) and week 16 (visit 6), as well as predose week 12 (visit 5), 
week 24 (visit 8) and week 52 (visit 15) [see Table 1 Schedule of Assessments]. The 
indicated time windows for week 4 (visit 3) pharmacokinetic sampling will allow for 
flexibility. If this visit is missed, the samples can be taken at the next visit. 
A predose PK 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 


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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. 
5.3.6
Pharmacogenomic sample
While pharmacogenomic (PGx) sampling is scheduled for week 4 (visit 3), PGx sample can 
be taken at any time during the study after signed ICF and enrollment into the study [see 
Table 1 Schedule of Assessments]. PGx samples will be stored for potential future analysis. 
Any PGx sample taken during screening will be destroyed in the event of a screen failure.
5.4
Safety Assessment
Safety will be assessed by examining the incidence of AEs, physical examinations findings, 
the clinician-administered C-SSRS, TVU’s, endometrial biopsies, vital signs, ECGs, clinical 
laboratory tests and bone marker concentrations over time.
5.4.1
Vital Signs
Vital sign parameters will be assessed at each study visit [see Table 1 Schedule of 
Assessments].
The vital sign parameters that will be assessed are body temperature (oral/tympanic), blood 
pressure 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 administered at screening (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]) [see 
Table 1 Schedule of Assessments]. 
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. 


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Table 3
Clinical Laboratory Tests
Panel/Assessments
Parameters to be Analyzed
Screening
Urine Pregnancy Test
β-HCG
All Visits
Hematology
CBC: white blood cell count with 
differential (neutrophils, lymphocytes, 
eosinophils, monocytes and basophils) 
Hemoglobin 
Hematocrit
Red blood cell count
Platelets
Reticulocytes
All Visits
Biochemistry
Blood urea nitrogen
Chloride
Creatinine 
Inorganic phosphorus
Sodium
Bicarbonate
Calcium
Creatine kinase
Estimated glomerular filtration rate
Glucose
Lactate dehydrogenase
Potassium
Uric acid
All Visits
Liver Biochemistry
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
Albumin
Gamma-glutamyl transferase
Direct bilirubin
Total bilirubin
Reference Lab 
Manual
All Visits
Urinalysis 
Protein
Glucose
pH
Blood
All Visits
Coagulation Panel
International normalized ratio/prothrombin 
time
Activated partial thromboplastin time
Screening
Serology
HBsAg
HCV antibody
HIV antibody
Anti-HBs
Anti-HBc
Table continued on next page


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Panel/Assessments
Parameters to be Analyzed
Visit 2
Visit 15/EOT
Visit 16/FU
Bone Marker
BSAP
PINP
CTX
Visit 2
Visit 3
Visit 5
Visit 6
Visit 8
Visit 15/EOT
Visit 16/FU
Hormone Levels
LH
FSH
E2
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; CTX: 
carboxy-terminal telopeptide of type I collagen; DHEA: dehydroepiandrosterone; E2: estradiol; EOT: end of 
treatment; FSH: follicle-stimulating hormone; FU: follow-up; HBsAG: hepatitis B virus surface antigen; 
HCV: hepatitis C virus; HIV: human immunodeficiency virus; LH: luteinizing hormone; PINP: Procollagen 
Type 1 N-Terminal Propeptide; 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.
5.4.4
Physical Examination 
A full physical examination will be performed at screening (visit 1), week 12 (visit 5), end-
of-treatment week 52 (visit 15) and at the follow-up week 55 (visit 16), 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 
day 1 (visit 2) through week 8 (visit 4), excluding visits 2b and 5b, and week 16 (visit 6) 
through week 48 (visit 14) a symptom directed physical exam will be conducted, which 
includes weight and waist circumference.
5.4.5
Electrocardiogram 
The 12-lead ECGs will be captured at the time points shown in the Schedule of Assessments 
[Table 1]. The subject should rest in supine position for at least 10 minutes prior to the first ECG.
5.4.6
Imaging 
5.4.6.1 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 


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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.
5.4.6.2 Transvaginal Ultrasound
All other subjects will undergo a TVU to assess endometrial thickness 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 read by a local reader followed by a central reading.
5.4.7
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 endometrial biopsy performed at screening must be evaluable. 
Subjects that require a retest biopsy for insufficient material or unevaluable results 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 per screening is allowed.
Screening biopsy results are valid for study entry for up to 3 months from date of procedure 
for applicable subjects.
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. 
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 and all 


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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 Guidance for Industry, Estrogen and 
Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal 
Atrophy Symptoms – Recommendations for Clinical Evaluation, 2003.
5.4.8
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. 
5.4.9
Order of Assessments 
All PRO measures must be self-administered at the site first upon arrival 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 day 1, week 4, week 12, week 24 and week 52.
The following sequence order will be in effect when more than 1 assessment is required at a 
time point:
Screening (day -35 to day -1)
1.
All screening procedures (except biopsy)
2.
Endometrial biopsy
After Randomization (day 1 to day 386)
1. All PRO measures will be administered in the following order, at visits indicated in the 
Schedule of Assessments [Table 1]:
●
PGI-C VMS 
●
PROMIS SD SF 8b 
●
PGI-S SD 
●
PGI-C SD 
●
PROMIS SRI SF 8b 
●
MENQOL 
●
EQ-5D-5L 
●
WPAI-VMS 


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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.
5.5
Adverse Events and Other Safety Aspects
5.5.1
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 ICF 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.
5.5.1.1 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, 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 (adverse event or serious adverse event).
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.
5.5.1.2 Potential Cases of Drug-induced Liver Injury
Refer to [Appendix 12.4 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 12.4 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 


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to be considered important medical events and reported per [Section 5.5.5 Reporting of 
Serious Adverse Events].
5.5.1.3 Disease Progression and Study Endpoints
Under this protocol, the following event(s) will not be considered as an (S)AE:
●
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 study. These procedures are collected per the eCRFs Completion Guidelines.
5.5.2
Definition of Serious Adverse Events
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)
●
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 1 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.
5.5.2.1 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. 


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5.5.3
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 Reference Safety Information [see Section 1.4 Summary of 
Key Safety Information for Study Drugs] to determine the relationship. The causality 
assessment is 1 of the criteria used when determining regulatory reporting requirements.
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 


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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. 
5.5.4
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
5.5.5
Reporting of Serious Adverse Events
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
ICF and will continue until 21 days after the 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 in 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


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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 eCRF.
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)
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, Council for International 
Organizations of Medical Sciences-I (CIOMS-I) form] to Competent Authorities (CAs) 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, which require submission per local requirements to IRB/local 
IEC.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor.
The investigator may contact the sponsor's medical monitor/study physician for any other 
problem related to the safety, welfare or rights of the subject.
5.5.6
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 5.5.1 Definition of Adverse 
Events], an AE progresses to a SAE, or the investigator learns of any (S)AE including death, 


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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.
5.5.7
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 
below and should be reported on the eCRF as SAEs. AEs of special interest in this study will 
include:
●
AE of uterine bleeding
●
Endometrial hyperplasia/cancer or disordered proliferative endometrium
●
AE of thrombocytopenia or platelets < 150,000/uL 
●
AE of liver test elevations
●
AE of bone fractures
●
AE of abuse liability
●
AE of depression
●
AE of wakefulness
●
AE of effect on memory
5.5.8
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 deviations 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 5.5.5 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 
●
Medication error, overdose and “off-label use”
●
Misuse/abuse
●
Suspected drug-drug interaction
5.5.8.1 Pregnancy
If a female subject becomes pregnant during the study dosing period or within 28 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 5.5.5 Reporting of Serious Adverse Events] using the 
Pregnancy Reporting Form and in the eCRF.


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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.
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 5.5.5 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.
5.5.8.2 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 5.5.5 Reporting of Serious Adverse Events] 
together with the details of the medication error, overdose and/or “off-label use”.
In the event of suspected overdose, the subject should receive supportive care and monitoring.
The medical monitor/expert should be contacted as applicable.
5.5.8.3 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 5.5.5 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s).
5.5.8.4 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 


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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 5.5.5 Reporting of Serious Adverse Events] together with details of the suspected 
drug-drug interaction.
5.5.9
Supply of New Information Affecting the Conduct of the Study
When new information becomes available and/or 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 ICF in 
order to continue in the clinical study.
5.5.10
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 CAs, 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. 
5.5.11
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 study 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.
5.6
Test Drug Concentration
Blood plasma samples for pharmacokinetics of fezolinetant and metabolite ES259564 will be 
collected from every subject.
A single pharmacokinetic sample will be collected at each of the following time points, as 
well as pre-dose in any subject with a signal of elevated aminotransferases (Appendix 12.4)
[Table 4]. 


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Table 4
Pharmacokinetic Time Points
Week
Time Point
Weeks 4 and 16
pre-dose, 1 hour and 3 hour postdose
Weeks 12, 24 and 52
pre-dose
Unscheduled
Pre-dose
Details on sampling, processing, storage and shipment procedures will be provided in a 
separate central laboratory manual. 
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for Future Pharmacogenetic Analysis (Retrospective 
Pharmacogenetic Analysis)
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety issues. After randomization [see 
Table 1 Schedule of Assessments], a sample of whole blood for possible retrospective PGx 
analysis will be collected. Samples will be shipped to a sponsor designated banking contract 
research organization (CRO). PGx samples will be kept for up to 15 years, or as specified in 
the ICF.
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See [Appendix 12.6 Pharmacogenetic Analysis With Banked Sample] for further details on 
the banking procedures.
5.7.2
Caffeinated Beverage Intake
Subject’s intake of caffeinated beverages (e.g., coffee) will be recorded to explore the 
interaction of fezolinetant with caffeine (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. 
5.8
Total Amount of Blood
Blood samples will be taken for the purposes of clinical laboratory tests, serology tests 
(screening only), pharmacokinetic samples, pharmacodynamic samples, PGx samples (if 
applicable) and bone markers. Repeat and additional blood samples may be taken if required. For 
each patient, the expected blood volume to be drawn will be approximately 250 mL over the 
course of the clinical study.


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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 defined as 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 International Normalized Ratio 
(INR) > 1.5
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 
above 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. 


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6.3
Discontinuation of the Study
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.  
7
STATISTICAL METHODOLOGY
As described above, the first 12 weeks of treatment will be double-blind, with a 12-week
analysis conducted after all subjects complete 12 weeks of treatment. After completing 
12 weeks of treatment, subjects will receive active treatment through end of 52-week study.
Given the design, a 12-week treatment analysis will occur to assess efficacy and safety during 
the double-blind treatment phase. This will occur after all subjects have completed 12 weeks 
of treatment. Efficacy and safety data will be analyzed, excluding the endpoints measured 
after 12 weeks. Since all primary and secondary analyses only based on data through week 12, 
no alpha adjustment is required as the information fraction at the 12-week analysis is 100%. 
Data from the extension treatment period will be summarized without statistical comparison 
to placebo.
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 hard lock for the12-week treatment analysis at the latest. Changes from the analyses 
planned in SAP that affect the statistical analyses will be documented in the clinical study 
report.
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
A total of 450 subjects are planned to be randomized; 150 subjects in each treatment arm.
The phase 2b dose-ranging study included 7 active doses. In this study, the observed 
least-squares mean difference between fezolinetant and placebo in change from baseline to 
week 12 (and week 4) in mean daily frequency of moderate to severe VMS ranged from 
-1.8 to -3.0.


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For a pairwise comparison using a 2-sample t-test at a 2-sided 2.5% alpha (adjusting for 
2 active doses), 120 subjects would provide 79% or more power to detect the following effect 
sizes assuming a SD of 5:
Assumed treatment difference in mean daily frequency
Power for pairwise test
-2.0
79%
-2.3
90%
-2.5
94%
For change from baseline to week 12 (and week 4) in mean severity of moderate to severe 
VMS, the observed mean treatment differences in the phase 2b study ranged from 
-0.2 and -1.0. 
For a pairwise comparison using a 2-sample t-test at a 2-sided 2.5% alpha (adjusting for 
2 active doses), 120 subjects would provide the at least 79% power to detect the following 
effect sizes assuming a SD of 1:
Assumed treatment difference in mean severity
Power for pairwise test
-0.40
79%
-0.46
90%
-0.50
94%
NOTE: The combined power for testing all 4 co-primary endpoints will be lower than the 
power for each considered individually; however, the co-primary endpoints are correlated 
(especially the same endpoint at different time points) and this will serve to limit the potential 
reduction of power. 
Assuming approximately 20% of subjects discontinue prematurely, the number of subjects 
will be increased from 120 to 150 subjects per arm.
This sample size would also provide over 95% power to detect a difference of 4.3 from 
placebo on the key secondary endpoint of the PROMIS sleep disturbance questionnaire, using 
a 2-sample t-test at a 2-sided 2.5% alpha (adjusting for 2 active doses) assuming a SD of 
7 [Avis et al, 2016].
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in classification specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
For each treatment group, the number and percentage of subjects will be characterized for all 
randomized subjects and by each analysis set.
7.2.1
Full Analysis Set
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.


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7.2.2
Per Protocol Set
The per protocol set (PPS) will consist of the subset of the FAS who do not meet criteria for 
PPS exclusion. These criteria are to capture relevant non-adherence to the protocol, in a 
manner that might reasonably impact the primary analysis, and will be defined in the SAP. A 
full list of criteria will be decided and assessed prior to database lock and unblinding. There 
are 2 PPS populations; one specific to the co-primary analyses at week 4 and another specific 
to week 12. Final judgments on exclusion of subjects from Per Protocol Set - Week 4 (PPS4) 
and Per Protocol Analysis Set - Week 12 (PPS12) will be made prior to randomization 
unblinding. 
7.2.3
Safety Analysis Set
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.
7.2.4
Pharmacokinetic Analysis Set
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 
PKAS will be documented in the in the Classification Specifications and determined the 
Classification Meeting. The PKAS will be used for all summaries and analyses of the 
pharmacokinetic data.
7.3
Demographics and Baseline Characteristics 
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 and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented for all randomized subjects and for 
subjects in the SAF by treatment group and overall. Similar tables for screening disposition
and investigational period disposition will also be presented for all randomized subjects 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 presented in a listing.
7.3.3
Medical History 
Medical history for each subject will be presented in a listing.


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7.4
Analysis of Efficacy 
Efficacy analysis will be conducted on the FAS and PPS. The interpretation of results from 
statistical tests will be based on the FAS. The PPS will be used to assess the robustness of the 
results from the statistical tests based on the FAS.
All statistical comparisons will be conducted using 2-sided tests at the α = 0.05 significance 
level unless specifically stated otherwise. There are additional testing details below regarding 
the 4 co-primary endpoints. All null hypotheses will be of no treatment difference, all 
alternative hypotheses will be 2-sided and control for 2 comparisons to placebo using the 
Hochberg approach, unless specifically stated otherwise.
7.4.1
Analysis of Co-primary Endpoint 
7.4.1.1 Co-primary Analysis
The 4 co-primary efficacy endpoints are the mean change in the frequency of moderate to 
severe VMS and the mean change in severity of VMS (per 24 hours) from baseline to week 4 
and week 12.
For each of the 4 co-primary efficacy endpoints, a mixed models repeated measures analysis 
of covariance (MMRM) will be used with treatment group, week 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 week and an interaction of baseline measurement by 
week. An unstructured covariance structure shared across treatment groups will be used to 
model the within-patient errors. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom and adjust standard errors. This analysis will use a restricted
maximum likelihood–based repeated-measures approach. The treatment difference will be 
estimated at all study weeks. MMRM will use all available on-treatment data to inform mean 
treatment effect estimates without requiring explicit imputation for missing data (i.e., for 
discontinued subjects). This approach is consistent with the hypothetical strategy used for the 
estimand, which is to compare patients as though they had continued on the assigned 
treatment.
Comparisons between the fezolinetant and placebo will be calculated based on least-squares 
mean contrasts using a 2-tailed 95% confidence interval (CI).
The hypothesis for each pairwise comparison is given as follows:
H0: The change from baseline at week 4 (or 12) for fezolinetant and placebo are the same
H1: The change from baseline at week 4 (or 12) for fezolinetant and placebo are not the same
The co-primary analysis will use the FAS.
Frequency of moderate or severe VMS events will be calculated as the sum of moderate or 
severe VMS events per day.


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Severity of post-baseline co-primary severity endpoints will be calculated using a weighted 
average defined as shown below. Note that the calculation for severity at baseline uses a 
similar formula, but does not include mild VMS events in the numerator or denominator.
([number of mild hot flashes/day × 1] + [number of moderate hot flashes/day × 2] + 
[number of severe hot flashes/day × 3])/total number of daily (or weekly) 
mild/moderate/severe hot flashes
Daily frequency and severity per week (e.g., week 4, week 12) will be calculated as the 
average frequency or severity over 7 days. The specific windows will be defined in the SAP.
The family-wise type I error rate for the 2 active dose groups compared to placebo for the 
4 co-primary efficacy endpoints will be controlled using a Hochberg approach. All 
4 co-primary endpoints must be statistically significant for a given dose to be considered 
successful. Given that, the largest p-value from the 4 co-primary endpoints in each dose 
group will be used to test that dose because it represents the least significant of the 
co-primary endpoints. If the larger of the 2 maximum P values, one from each dose, is less 
than 0.05, then both dose groups are considered statistically significant. If not, then if the 
smaller of the P values is less than 0.025, the second compared dose is considered statistically 
significant. Otherwise, neither dose is considered statistically significant. The trial will be 
considered successful if at least one dose is statistically significant. 
7.4.1.2 Sensitivity Analysis of Co-primary Endpoints
Sensitivity analyses will be carried out for the co-primary efficacy endpoints based on the 
PPS populations. The data will be analyzed using the same MMRM model as the primary 
analyses, but the comparison of interest is a particular week within each population (week 4 
when using PPS4, and week 12 when using PPS12).
The analysis for each of the co-primary endpoints also will be conducted using a simplified 
MMRM model with treatment group and week as factors, with baseline measurement as a 
covariate, as well as an interaction of treatment by week and baseline by week.
7.4.1.3 Subgroup Analysis
The simplified MMRM for the co-primary efficacy endpoints analyses will be repeated,
including but not limited to, smoking status, body mass index and race.
7.4.2
Analysis of Secondary Endpoints 
The analysis of secondary efficacy endpoints will be based on the FAS. For efficacy 
endpoints collected at visits, the last non-missing assessment prior to the first dose of study 
treatment (investigational product or placebo) is the baseline.
7.4.2.1 Key Secondary Endpoint
The PROMIS SD SF 8b scale will be analyzed using MMRM, similar to the primary analysis 
of the co-primary endpoints.


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If all the co-primary endpoints are statistically significant between fezolinetant and placebo at 
both doses, then the 5% alpha from the analysis of the co-primary endpoints will be passed to 
the key secondary endpoint as part of the family-wise error rate.
7.4.2.2 Secondary Endpoints
For percent reduction at weeks 4 and 12, an MMRM model as described in [Section 7.4.1.1
Co-Primary Analysis] will be used. Additional calculations of severity will be described in 
the SAP and will also be analyzed as described in Section 7.4.1.1 Co-Primary Analysis.
For each of the secondary responder endpoints, logistic regression will be used for the 
analysis for each week and endpoint. A missing value will be imputed as a nonresponder.
PGI-C will be analyzed using Cochran Mantel Haenszel test.
7.4.3
Analysis of Exploratory Endpoints 
Percent reduction, PROMIS (SD and SRI total scores), MENQOL total, EQ-5D domain 
scores and WPAI-VMS total score will be assessed using an MMRM model as described in 
[Section 7.4.1.1 Co-Primary Analysis]. Percent reduction and absolute reduction will be 
analyzed as described for the secondary responder endpoints. PGI-S will be analyzed using 
Cochran Mantel Haenszel test adjusted for baseline score. The median change in serum 
concentrations of sex hormones and sex hormone-binding globulin (SHBG) from baseline to 
weeks 4 and 12 and the mean change in serum concentrations of BSAP, P1NP and CTX from 
baseline to week 12 will be summarized. 
NOTE: Assessments after the 12-week placebo-controlled period are descriptive only, 
because there is no placebo control.
7.5
Analysis of Safety
Safety will be assessed by examining the incidence of AEs, physical examinations findings, 
the clinician-administered C-SSRS, TVU’s, endometrial biopsies, vital signs, ECGs, clinical 
laboratory tests and bone marker concentrations over time.
7.5.1
Adverse Events 
AEs will be coded using MedDRA. 
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 system organ 
class, preferred term and treatment group. The number and percentage of AEs by severity 
will also be summarized. 
A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator.


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7.5.2
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.
The liver safety assessments will be summarized by the categories below based on the 
measurements from alkaline phosphatase (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.
7.5.3
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 time point. 
7.5.4
Physical Examination 
Physical examination will be listed by treatment group.
7.5.5
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.
7.5.6
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.
7.6
Analysis of Pharmacokinetics
Descriptive statistics (e.g., n, mean, SD, minimum, median, maximum, coefficient of 
variation [CV], geometric mean and geometric CV) will be provided for plasma 
concentrations of fezolinetant and the major metabolite ES259564 by time point. Plasma 
concentration data of fezolinetant may be subjected to population pharmacokinetic analysis. 


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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. The results of the population pharmacokinetic analysis will not be 
reported in the clinical study report, but in a separate population pharmacokinetic report.
7.7
Analysis of Pharmacodynamics
Serum concentrations of sex hormones and 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 applicable. Detailed 
information on the statistical analysis of pharmacodynamic data, such as transformations and 
nature of descriptive statistics used, will be provided in the SAP for this study.
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned for this study.
7.9
Additional Conventions
Missing data may be the result of missing week 4/week 12 frequency/severity of VMS 
measurements or the result of patients discontinuing treatment prior to week 4/week 12. 
Missing at random will be assumed. Details will be provided in the SAP.
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 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. 


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ECG results are performed at a central ECG reading facility. 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.
All procedures conducted under the protocol must be documented. For screen failures, the 
minimum demographic data (sex, birth date/age, race and ICF 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 diaries and questionnaires as described in [Section 5.3.3 Patient-reported Outcomes 
Assessments] 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 will 
review the diaries and questionnaire data throughout the study to ensure completion and 
protocol compliance.
The diary and 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 (DCF) to the vendor. The requested change must be supported by 
documented evidence at site. For this study, it has been decided that there are justifiable 
scientific reasons (e.g., recall bias) for not allowing the following variables or type of data to 
be added to or changed greater than one calendar day after the original daily diary data has 
been entered and submitted, as a change could potentially impact the data integrity of this 
study: HF diary entries and associated severities. Subjects’ diaries will be set up with a 
24 hour window for daily entry. If there are no entries during the 24-hour window, upon their 
next interaction with the diary, subjects will be asked to confirm no hot flash entries for the 
previous day or to record the missed entries that occurred up to 24 hours ago. Within one 
calendar day of the daily diary entry missed or entry requiring changes, subjects may request
the site to initiate changes or additions to that entry through the vendor’s DCF process. The 
requested change to the HF diary or associated severities must be supported by documented 
evidence at site.
The daily diary compliance threshold for each individual subject should not fall below 85%. 
In cases where a subject’s compliance falls below this threshold, the site should immediately 
retrain the subject and document this training in the subject’s source.


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8.2
Screen Failures
For screen failures the demographic data, reason for failing, ICF, 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. All 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 one 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 
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 applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file. 
9
END OF STUDY
The end of the study is defined as the last visit or scheduled procedure shown in the Schedule 
of Assessments [Table 1] for the last study participant in the study.


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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 and are not investigators participating in the study or 
Astellas employees. A statistician will also be an 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 Panel consisting of independent hepatologists experienced in the 
assessment of DILI 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
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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;34:211-27.
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.
Reilly Associates. Work Productivity and Activity Impairment (WPAI) General Information. Updated
04 Feb 2013. Available at http://www.reillyassociates.net/WPAI_General.html. Accessed 
11 Oct 2018.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmaco Economics. 1993;4:353-65.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, 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;157:752-63.
Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of 
menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289:2827-34.


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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.
Thurston RC, Joffe H. Vasomotor symptoms and menopause: Findings from the study of women’s 
health across the nation. Obstet Gynecol Clin North Am. 2011;38:489-501.
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.


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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/Independent Ethics Committee/Competent 
Authorities
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the IB, the ICF 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, ICF 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 non-substantial amendments. 
Depending on the nature of the amendment, either IRB/IEC, CA 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 ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor. An approved copy of the new ICF 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 or 
her guardian or legal representative, and answer all questions regarding this study. Prior to 
any study-related screening procedures being performed on the subject, the ICF will be 
reviewed and signed and dated by the subject or her guardian or legal representative, the 
person who administered the ICF 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 ICFs 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.
12.1.5.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
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 their 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 study 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, 
eCRFs 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 is approved or if the IND 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
The privacy of subjects must always be respected. Every possible measure should be taken to 
ensure the privacy of subjects and to minimize the potential impact of the clinical study on 
the subject. The specific measures should be provided in this section.
For clinical research performed at a facility that is not a covered entity under Health 
Insurance Portability and Accountability Act (HIPAA), language consistent with the 
principles of HIPAA should be included in the ICF to describe the provisions in place to 
protect subject privacy and to seek consent for use of private information obtained during the 
study.


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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.
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 sponsor shall serve as the controller of such 
data, as defined by the EU Data Protection Directive, and investigator and/or third party shall 
act only under the instructions of the sponsor in regard to personal data. If sponsor is not 
based in the EEA, 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.


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12.1.10 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 
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 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 Data Science or designee 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 WHO Drug Dictionary, respectively.
12.2.4
Quality Assurance
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(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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12.4
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 test 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)
elevations should be followed as described below.
Moderate liver test abnormalities as defined above should be repeated 2 to 3 times weekly, 
and 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, direct bilirubin.
●
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 aminotransferase (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 be 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
●
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 of 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 transaminases 
(> 3 × ULN) will have a pre-dose PK sample 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) with concurrent transaminase elevations at 
least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
ALP) or Gilbert’s syndrome [Temple, 2006].
FDA Guidance for Industry, “Drug-Induced Liver Injury: Premarketing Clinical Evaluation,”
2009:
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 study subjects showing such AT elevations, often with ATs much greater than 
3 × ULN, 1 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):241-43.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 


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12.5
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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12.6
Pharmacogenomic Analysis with Banked Sample 
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring differences in a 
subject’s gene and/or expression of genes based on genetic variation may impact what 
treatment options are best suited for the subject. Through investigation of PGx by 
technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association Studies, the relationship between gene profiles and a drug’s kinetics, efficacy or 
toxicity may be better understood. As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and/or toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study participate in this PGx sub-study. 
Subjects must provide written consent prior to providing any blood samples that may be used 
at a later time for PGx analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide 1 tube of whole blood of 
approximately 4 to 6 mL per Astellas’ instructions. Each sample will be identified by the 
unique subject number. Samples will be shipped to a designated banking CRO as directed by 
Astellas.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis if evidence suggests that genetic variants may be influencing the drug’s kinetics, 
efficacy and/or safety. 
DISPOSAL OF PGx SAMPLES/DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely unless otherwise specified by local regulation.


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INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the PGx analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas. 


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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Substantial Changes
1.
Update Inclusion Criteria #4, #8, #9 and #10
DESCRIPTION OF CHANGE:
Inclusion criterion #4 is updated to remove with or without hysterectomy from the bilateral 
oophorectomy screening criteria. Inclusion criteria #8 and #10 are aligned to account for the 
exclusion of subjects who have had a hysterectomy. Inclusion criterion #9 is updated to 
specify that the endometrial biopsy obtained at screening must be considered evaluable; this 
criterion is now required for all subjects. 
RATIONALE:
These inclusion criteria are being updated to ensure that only patients with a uterus and an 
evaluable screening endometrial biopsy are to be enrolled in the study moving forward.
2.
Add COVID-19 Considerations
DESCRIPTION OF CHANGE:
Alternate measures that may be implemented due to site closures related to the COVID-19 
pandemic are added to the protocol. These include telemedicine conferences (by telephone), 
home healthcare services, and laboratory assessments performed at local laboratories.
It is noted that subjects who screen fail due to a COVID-19 pandemic study suspension and 
have an evaluable endometrial biopsy will not require a repeat biopsy if they rescreen.
RATIONALE:
These measures will provide an alternative for conducting the study visits when scheduled 
visits cannot be conducted at the clinical site due to the COVID-19 pandemic.
3.
Update Exclusion Criteria #6 and #7, and Add Exclusion Criterion #20
DESCRIPTION OF CHANGE:
Exclusion criteria #6 and #7 are updated so that they apply to all subjects, not just subjects 
with a uterus, and the exception for endometrial thickness less than 4 mm is removed from 
exclusion criterion #7. Exclusion criterion #20 is added to exclude subjects who have had 
partial or full hysterectomies.
RATIONALE:
These exclusion criteria are updated to ensure that only patients with a uterus and an 
evaluable screening endometrial biopsy are to be enrolled in the study moving forward.


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4.
Update Endometrial Biopsy Requirements
DESCRIPTION OF CHANGE:
Language is added to specify that the screening endometrial biopsy must be evaluable. Retest 
biopsies may only be performed for insufficient material or unevaluable biopsies, and a 
maximum of one retest biopsy during screening is allowed. It is noted that subjects will be 
allowed into the study based on the primary endometrial result/diagnosis, but a second and 
tertiary diagnosis will also be reported.
RATIONALE:
This change is made to clarify that only patients with an evaluable screening endometrial 
biopsy are to be enrolled in the study moving forward.
5.
Update Adverse Events of Special Interest
DESCRIPTION OF CHANGE:
Adverse events (AEs) of abuse liability, depression, wakefulness and effect on memory are 
added to the protocol as AEs of special interest. AEs of liver test elevation are clarified. 
RATIONALE:
These AEs of special interest are added per the request of the European Medicines Agency. 
Liver test elevations criterion is removed from this section as they are located in the 
laboratory analysis section.
6.
Update Subject Discontinuation Criteria
DESCRIPTION OF CHANGE:
Category 2 results of secondary or tertiary screening endometrial biopsy diagnosis are added 
to the list of reasons for subject discontinuation.
RATIONALE:
To clarify a subject’s need to be discontinued if the results of the secondary or tertiary 
reading of his/her screening endometrial biopsy indicates Category 2 results.
7.
Change Patient Global Impression of Change (PGI-C) in VMS to Secondary 
Endpoint
DESCRIPTION OF CHANGE:
The exploratory endpoint of “Mean score on the PGI-C in VMS from baseline to each visit”
is re-categorized as a secondary endpoint. Sections 7.4.2.2 Secondary Endpoints and 7.4.3 
Exploratory Endpoints are updated to move the PGI-C analysis to Section 7.4.2.2.
RATIONALE:
This endpoint is moved to secondary endpoints as it will be potentially used for the anchor-
based method for psychometric analysis in evaluating clinically meaningful within-patient 


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change from baseline in hot flash frequency. The revision to Sections 7.4.2.2 and 7.4.3 are 
made to split one sentence that includes both PGI-C and Patient Global Impression of 
Severity (PGI-S) into two: one for PGI-C and one for PGI-S.
8.
Add Daily Diary Compliance
DESCRIPTION OF CHANGE:
Language is added to instruct sites about daily diary compliance.
RATIONALE:
This language is added to provide the compliance threshold to sites at which additional 
retraining and documentation of retraining is required for subjects that are not completing 
daily diary entries as required.
Nonsubstantial Changes
1.
Update Key Sponsor Personnel
DESCRIPTION OF CHANGE: 
Contact details for medical monitor/study physician are added.
RATIONALE:
Contact details of sponsor personnel are updated based on changes to study personnel.
2.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol).
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.


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II.  Amendment Summary of Changes:
IIA. Substantial Changes
V. Flow Chart and Schedule of Assessments
Table 1 Schedule of Assessments
WAS:
Assessments
Screening 
Visit
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/ED
Visit 16
n.
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 9 months on record, except for subjects who 
have had a full hysterectomy.
o.
Endometrial biopsy will be performed at screening and at week 52/EOT and in the case of uterine bleeding during treatment, except for subjects who have had a partial (supra-cervical) or full 
hysterectomy. Subject may schedule the endometrial biopsy on a separate day, within the screening period. Subjects that require a retest biopsy 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. 
q.
Pharmacodynamic samples will be taken predose at day 1 (visit 2), week 12 (visit 5), week 16 (visit 6), week 24 (visit 8) and week 52 (visit 15), as well as predose and 3 hours postdose at week 4 
(visit 3). The week 4 (visit 3) 3 hours postdose pharmacodynamic sample may be shifted to a later date (prior to week 12) in case the subject cannot accommodate the sampling schedule at that visit. 
The pharmacodynamic sample should be taken at the same time as the 3-hour postdose pharmacokinetic sample. A pharmacodynamic sample will be taken at the follow-up visit (week 55 [visit 16]) 
as well. Markers include LH, FSH, E2, SHBG, androstenedione, dehydroepiandrosterone, estrone and testosterone. 
r.
Pharmacokinetic samples to be taken at predose (1 hour), 1 h (± 30 min) post dose and 3 h (± 30 min) postdose week 4 (visit 3) and week 16 (visit 6), as well as predose, week 12 (visit 5), week 24 
(visit 8) and week 52 (visit 15). The indicated time windows for week 4 (visit 3) pharmacokinetic sampling will allow for flexibility. If this visit is missed, the samples can be taken at the next visit 
(prior to week 12). A pre-dose sample will be collected for any subject with a signal of elevated transaminases (> 3 × ULN) when she returns for a repeat blood draw.


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IS AMENDED TO:
Assessments
Screening 
Visity
Randomi-
zationy
Treatment Period
Follow-
Up Visit
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
n.
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 9 months on record, except for subjects who 
have had a full hysterectomy.
o.
Endometrial biopsy will be performed at screening and at week 52/EOT and in the case of uterine bleeding during treatment, except for subjects who have had a partial (supra cervical) or full 
hysterectomy. 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.
q.
Pharmacodynamic samples will be taken predose at day 1 (visit 2), week 12 (visit 5), week 16 (visit 6), week 24 (visit 8) and EOT/ED week 52 (visit 15), as well as predose and 3 hours postdose at 
week 4 (visit 3). The week 4 (visit 3) 3 hours postdose pharmacodynamic sample may be shifted to a later date (prior to week 12) in case the subject cannot accommodate the sampling schedule at that 
visit. The pharmacodynamic sample should be taken at the same time as the 3-hour postdose pharmacokinetic sample. A pharmacodynamic sample will be taken at the follow-up visit (week 55 [visit 
16]) as well. Markers include LH, FSH, E2, SHBG, androstenedione, dehydroepiandrosterone, estrone and testosterone. 
r.
Pharmacokinetic samples to be taken at predose (1 hour), 1 h (± 30 min) post dose and 3 h (± 30 min) postdose week 4 (visit 3) and week 16 (visit 6), as well as predose, week 12 (visit 5), week 24 
(visit 8) and EOT/ED week 52 (visit 15). The indicated time windows for week 4 (visit 3) pharmacokinetic sampling will allow for flexibility. If this visit is missed, the samples can be taken at the 
next visit (prior to week 12). A pre-dose sample will be collected for any subject with a signal of elevated transaminases (> 3 × ULN) when she returns for a repeat blood draw.
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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IV. Synopsis, Study Design Overview and 2 Study Objective(s), Design, and Endpoints
2.2.1 Study Design
WAS:
Eligibility will be assessed via physical examination; clinical laboratory testing; vital signs; 
electrocardiogram (ECG); Papanicolaou (Pap) test (or equivalent cervical cytology), except 
for subjects who have had a full hysterectomy; mammography; transvaginal ultrasound 
(TVU), except for subjects who have had a partial [supracervical] or full hysterectomy; and 
endometrial biopsy (except for subjects who have had a partial [supracervical] or full 
hysterectomy). Endometrial biopsy will be performed at screening and at week 52/EOT, for 
subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to 
completion. If a subject discountinues from the study, an endometrial biopsy will be 
performed at the discontinuation visit along with all other EOT procedures.
IS AMENDED TO:
Eligibility will be assessed via physical examination; clinical laboratory testing; vital signs; 
electrocardiogram (ECG); Papanicolaou (Pap) test (or equivalent cervical cytology), except 
for subjects who have had a full hysterectomy; mammography; transvaginal ultrasound 
(TVU), except for subjects who have had a partial [supracervical] or full hysterectomy; and 
endometrial biopsy (except for subjects who have had a partial [supracervical] or full 
hysterectomy). Endometrial biopsy will be performed at screening and at week 52/EOT, for 
subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to 
completion. If a subject discountinuesdiscontinues from the study, an endometrial biopsy 
will be performed at the discontinuation visit along with all other EOT procedures.
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.
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 including biochemistry, hematology, 
liver biochemistry and coagulation panel testing.
●
Subjects should be instructed to continue entering their hot flashes in the daily 
handheld diary as instructed regardless of site closure.
●
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 


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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) and safety laboratory tests collected at a local laboratory.  
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.
IV. Synopsis, Endpoints for Evaluation and 2 Study Objective(s), Design, and Endpoints
2.3.3 Secondary Endpoints, 2.3.4 Exploratory Endpoints
WAS:
2.3.3 Secondary Endpoints
2.3.4 Exploratory Endpoints

Mean score on the Patient Global Impression of Change (PGI-C) in VMS from baseline 
to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
IS AMENDED TO:
2.3.3 Secondary Endpoints

Mean score on the Patient Global Impression of Change (PGI-C) in VMS from 
baseline to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
2.3.4 Exploratory Endpoints

Mean score on the Patient Global Impression of Change (PGI C) in VMS from baseline 
to each visit (week 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
IV. Synopsis, Inclusion Criteria and 3 Study Population
3.2 Inclusion Criteria
WAS:
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 
●
Having had bilateral oophorectomy 6 weeks prior to the screening visit (with or 
without hysterectomy).
8.
Subject is willing to undergo a TVU to evaluate the uterus and ovaries at screening and 
at week 52 (EOT), and for subjects who are withdrawn from the study prior to 
completion, a TVU at the ED visit. This is not required for subjects who have had a 
partial (supra-cervical) or full hysterectomy.
9.
Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), 
for subjects with uterine bleeding, and for subjects who are withdrawn from the study 
prior to completion. This is not required for subjects who have had a partial (supra-
cervical) or full hysterectomy.


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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. This is not required for subjects who have had a full 
hysterectomy.
IS AMENDED TO:
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 
●
Having had bilateral oophorectomy 6 weeks prior to the screening visit (with or 
without hysterectomy).
8.
Subject is willing to undergo a TVU to evaluate the uterus and ovaries at screening and 
at week 52 (EOT), and for subjects who are withdrawn from the study prior to 
completion, a TVU at the ED visit. This is not required for subjects who have had a 
partial (supra cervical) or full hysterectomy.
9.
Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), 
for subjects with uterine bleeding, and for subjects who are withdrawn from the study 
prior to completion. The endometrial biopsy obtained at screening must be 
considered evaluable. This is not required for subjects who have had a partial (supra
cervical) or full hysterectomy.
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. This is not required for subjects who have had a full 
hysterectomy.
IV. Synopsis, Exclusion Criteria and 3 Study Population
3.3 Exclusion Criteria
WAS:
6. For subjects with a uterus: 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. For subjects with a uterus:  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.  A 
biopsy with insufficient material for evaluation or unevaluable material is acceptable 
provided the endometrial thickness is < 4 mm.
IS AMENDED TO:
6. For subjects with a uterus: 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. For subjects with a uterus:  Subject has an endometrial biopsy confirming presence of 


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disordered proliferative endometrium, endometrial hyperplasia, endometrial cancer or 
other clinically significant findings in the opinion of the investigator at screening. A 
biopsy with insufficient material for evaluation or unevaluable material is acceptable 
provided the endometrial thickness is < 4 mm.
20. Subject has had partial or full hysterectomy.
5 Treatments and Evaluation
5.2.3 Diagnosis of the Target Disease, Severity and Duration of Disease
WAS:

Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (with or without 
hysterectomy);
IS AMENDED TO:

Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (with or without 
hysterectomy);
5 Treatments and Evaluation
5.4.6.2 Transvaginal Ultrasound
DELETED:
This is not required for subjects who have had a partial (supra cervical) or full hysterectomy.
5 Treatments and Evaluation
5.4.7 Endometrial Biopsy
WAS:
Subjects will undergo a suction endometrial biopsy at the following time points (except for 
subjects who have had a partial [supra-cervical] or full hysterectomy):
●
Screening 
●
At week 52/EOT 
●
Early discontinuation/ED
●
All cases of uterine bleeding during treatment
A repeat biopsy will be required for subjects with insufficient material for evaluation, or 
unevaluable material, provided the endometrial thickness equal to or greater than 4 mm. 
An additional biopsy will not be required  for subjects with insufficient material for 
evaluation, or unevaluable material, provided the endometrial thickness is less than 4 mm. 
Subjects that require a retest biopsy will have an extended screening period and will be 
allowed an additional 15 days of screening (i.e., days -50 to -1). 
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.  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.  


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IS AMENDED TO:
Subjects will undergo a suction endometrial biopsy at the following time points (except for 
subjects who have had a partial [supra cervical] or full hysterectomy):
●
Screening 
●
At week 52/EOT/ED
●
All cases of uterine bleeding during treatment
The endometrial biopsy performed at screening must be evaluable.  A repeat biopsy will 
be required for subjects with insufficient material for evaluation, or unevaluable material, 
provided the endometrial thickness equal to or greater than 4 mm.
An additional biopsy will not be required for subjects with insufficient material for 
evaluation, or unevaluable material, provided the endometrial thickness is less than 4 mm. 
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. 
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, Tthe 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.  
5 Treatments and Evaluation
5.4.8 Papanicolaou Test
DELETED:
This is not required for subjects who have had a full hysterectomy.
5 Treatments and Evaluation
5.8.7 Adverse Events of Special Interest
WAS:
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 < 150000/uL
●
AE of liver test elevations or elevation in ALT and/or AST > 3 × ULN
●
AE of bone fractures/bone loss ≥ 7%


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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 < 150000/uL
●
AE of liver test elevations or elevation in ALT and/or AST > 3 × ULN
●
AE of bone fractures/bone loss ≥ 7%
●
AEs of abuse liability
●
AEs of depression
●
AEs of wakefulness 
●
AEs of effect on memory
IV. Synopsis, Subject Discontinuation and 6 Discontinuation
6.1 Discontinuation of Individual Subject(s) From Study Treatment
ADDED:
●
Category 2 results of secondary or tertiary screening endometrial biopsy diagnosis.
8 Operational Considerations
8.1.1 Electronic Clinical Outcome Assessment/Electronic Patient-reported Outcome
ADDED:
The daily diary compliance threshold for each individual subject should not fall below 
85%. In cases where a subject’s compliance falls below this threshold, the site should 
immediately retrain the subject and document this training in the subject’s source.
7 Statistical Methodology
7.4.2.2 Secondary Endpoints
ADDED:
PGI-C will be analyzed using Cochran Mantel Haenszel test.
7 Statistical Methodology
7.4.3 Analysis of Exploratory Endpoints
WAS:
PGI-S and PGI-C will be analyzed using Cochran Mantel Haenszel test with PGI S using the 
baseline score.
IS AMENDED TO:
PGI-S and PGI-C will be analyzed using Cochran Mantel Haenszel test with PGI S using the
adjusted for baseline score.




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5 Treatments and Evaluation
5.1.4 Treatment Compliance
WAS:
Subjects who are less than 80% compliant with the dosage regimen for any 2 consecutive 
visit periods during the study should be considered withdrawn from the study.
IS AMENDED TO:
Subjects who are less than 80% compliant with the dosage regimen for any 2 consecutive 
visit periods during the study should be considered for withdrawalwithdrawn from the 
study.
PPD


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14
SPONSOR SIGNATURES

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc. 
SAP Version 2.0 
ISN/Protocol 2693-CL-0302 
27APR2021 
Astellas 
Page 1 of 29 
STATISTICAL ANALYSIS PLAN (52-Week)  
(analysis for fezolinetant exposure up to 52 week) 
Version 2.0, dated 27APR2021 
A Phase 3, Randomized, Placebo-controlled, 12-week Double-
blind Study, followed by a Non-Controlled Extension Treatment 
Period, to Assess the Efficacy and Safety of Fezolinetant in 
Women Suffering from Moderate to Severe Vasomotor 
Symptoms (Hot Flashes) Associated with Menopause 
Skylight 2 
ISN: 2693-CL-0302 
IND number: 130277 
EudraCT 2018-003529-27 
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. 
NCT04003142


Sponsor: Astellas Pharma Inc. 
SAP Version 2.0 
ISN/Protocol 2693-CL-0302 
27APR2021 
Astellas 
Page 2 of 29 
Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 4 
1 
INTRODUCTION ································
································
··················
 6 
2 
STUDY OBJECTIVE(S) AND DESIGN ································
·······················
 6 
2.1 
Study Objective(s) ································
································
·············
 6 
2.2 
Study Design ································
································
····················
 7 
2.3 
Randomization ································
································
··················
 7 
3 
SAMPLE SIZE································
································
······················
 8 
4 
ANALYSIS SETS ································
································
··················
 8 
4.1 
Full Analysis Set ································
································
···············
 8 
4.2 
Safety Analysis Set ································
································
············
 8 
4.3 
Per Protocol Set ································
································
················
 8 
4.4 
Pharmacokinetics Analysis Set ································
·······························
 8 
4.5 
Pharmacodynamic Analysis Set ································
······························
 8 
5 
ENDPOINTS ································
································
························
 9 
5.1 
Primary Efficacy Endpoints ································
································
··  10 
5.2 
Secondary Efficacy Endpoints ································
·······························
 10 
5.2.1 
Key Secondary Endpoint ································
·······························
 10 
5.2.2 
Secondary Endpoints ································
································
····  10 
5.3 
Exploratory Efficacy Endpoints ································
·····························
 10 
5.4 
Safety Endpoints ································
································
··············
 11 
6 
STATISTICAL METHODOLOGY ································
···························
 11 
6.1 
General Considerations ································
································
·······  11 
6.2 
Study Population ································
································
··············
 12 
6.2.1 
Disposition of Subjects ································
································
· 12 
6.2.2 
Protocol Deviations ································
································
·····  12 
6.2.3 
Demographic and Other Baseline Characteristics ································
···  13 
6.2.4 
Previous and Concomitant Medications ································
··············
 13 
6.3 
Study Drug Exposure and Compliance ································
·····················
 14 
6.4 
Analysis of Efficacy ································
································
··········
 14 
6.4.1 
Analysis of Secondary Efficacy Endpoints ································
···········
 15 
6.4.2 
Analysis of Exploratory Endpoints ································
····················
 15 


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6.5 
Analysis of Safety ································
································
·············
 15 
6.5.1 
Adverse Events ································
································
··········
 16 
6.5.2 
Clinical Laboratory Evaluation ································
························
 17 
6.5.3 
Vital Signs ································
································
················
 19 
6.5.4 
Electrocardiograms ································
································
······  19 
6.5.5 
Other Safety-Related Assessments ································
····················
 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 ································
···············
 23 
7 
REVISION AND RATIONALE ································
································
 25 
7.1 
List of Changes in SAP Version 2.0 ································
························
 25 
8 
REFERENCES ································
································
····················
 26 
9 
APPENDICES ································
································
·····················
 28 
9.1 
Appendix 1: Additional Statistical Analysis due to COVID-19 ·························
 28 
9.2 
Appendix 2: Author and Approver Signatures ································
············
 29 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations  
Abbreviations 
Description of abbreviations 
ANCOVA 
Analysis of Covariance 
ASCM 
Analysis Set Classification Meeting  
CI 
Confidence Intervals 
CMH 
Cochran Mantel Haenszel 
CSR 
Clinical Study Report 
ED 
Early Discontinuation 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life 5 Dimensions-5 Levels 
FAS 
Full Analysis Set 
FAS_F 
Full Analysis Set for Fezolinetant 
FD 
Fezolinetant Day (study day relative to first dose of Fezolinetant) 
FUD 
Follow-up Day (study day relative to last dose date of study treatment)  
ICH 
International Conference on Harmonization 
IRT 
Interactive Response Technology 
MAR 
Missing at Random 
MENQOL 
Menopause-specific Quality of Life Questionnaire 
MMRM 
Mixed Model Repeated Measures 
PDAS 
Pharmacodynamics Analysis Set 
PDAS_F 
Pharmacodynamics Analysis Set for Fezolinetant 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PKAS 
Pharmacokinetics Analysis Set 
PRO 
Patient-Reported Outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
SAF 
Safety Analysis Set 
SAF_F 
Safety Analysis Set for Fezolinetant 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SD 
PROMIS Sleep Disturbance 
SRI 
PROMIS Sleep Related Impairment 
TLF 
Tables, Listings and Figures 
VMS 
Vasomotor Symptoms 
WPAI 
Work Productivity and Activity Impairment 
 


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List of Key Terms  
Terms 
Definition of terms 
Double-blind Treatment 
Period 
The 12 weeks of treatment after the first administration of study drug 
and prior to first administration of study drug in the extension period. 
Only this period contains a placebo treatment.  
Extension Treatment 
Period 
Period of time after the first administration of study drug in the 
extension period after completing 12 weeks of placebo-controlled 
double-blind treatment until the last dose of the study drug (at 
Week-52 or early discontinuation). 
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. 
 


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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.  
This SAP describes the plans for data summary of the 52-week study including the 40-week 
extension treatment period after completing 12-week double-blind placebo-controlled 
treatment period. These analyses may be conducted prior to all subjects completing the full 
52-week study, if needed. A separate SAP describes the analysis of the 12-week double-blind 
study data period.  
The SAP v1.0 was approved prior to the database lock for the 12-week analysis. This updated 
SAP will be approved prior to the final study database lock.  The SAP will be finalized 
before unblinding the subject treatment assignments. 
Changes from the planned analyses in the finalized SAP that impact the statistical analyses 
will be documented and justified in the Clinical Study Report (CSR).  
2 
STUDY OBJECTIVE(S) AND DESIGN 
2.1 
Study Objective(s) 
Note that the analyses for many of these objectives have been described in the SAP for the 
double-blind placebo-controlled study period for 12-week analysis. All protocol objectives 
are listed below but the specific endpoints in this SAP have been restricted to those extending 
beyond the double-blind treatment period. The objectives of the study beyond the 
double-blind treatment period are to describe efficacy and safety for subjects exposed to 
fezolinetant for up to 52 weeks. 
Primary objective: 
● 
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of 
moderate to severe vasomotor symptoms (VMS).  
o 
The estimand of the primary objective will use a hypothetical strategy and compare 
patients as though they had continued on the assigned treatment.  
Key secondary objective: 
● 
To evaluate the efficacy of fezolinetant versus placebo on patient-reported sleep 
disturbance. 
Secondary objectives:  
● 
To evaluate the effect of fezolinetant versus placebo on the frequency and severity of 
moderate to severe VMS at weekly time points.  
● 
To evaluate the safety and tolerability of fezolinetant. 


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Exploratory objectives:  
● 
To evaluate population pharmacokinetics (popPK) of fezolinetant and metabolite 
ES259564. 
● 
To evaluate the effect of fezolinetant on pharmacodynamic markers. 
● 
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of 
mild, moderate and severe VMS.  
● 
To evaluate the short-term and sustained effects of fezolinetant versus placebo on 
patient-reported sleep disturbance. 
● 
To evaluate the effect of fezolinetant versus placebo on the following patient-reported 
outcomes (PROs): global assessments of VMS and sleep disturbance, overall sleep-wake 
function, quality of life and work productivity. 
2.2 
Study Design 
This is a randomized, 12-week double-blind, placebo-controlled, parallel group, multicenter 
clinical study to assess the efficacy and safety of fezolinetant in women suffering from 
moderate to severe VMS associated with menopause. Approximately 450 subjects will be 
enrolled into this study, 150 subjects per treatment arm. Duration of treatment is 52 weeks. 
After completing 12 weeks of treatment, subjects on placebo will be reassigned to 30 mg or 
45 mg of active treatment in an extension treatment period through end of study. Subjects 
who were already randomized on an active arm will continue on their assigned dose for the 
remaining 40 weeks of treatment. Following the completion (or early discontinuation [ED]) 
of the treatment period (week 52), subjects will complete an end of treatment (EOT; or ED) 
visit and final safety follow-up visit 3 weeks after the last dose of study drug is administered 
(week 55). 
Details of the schedule of clinical assessments are available in the protocol. 
2.3 
Randomization 
The first 12 weeks of the study are double blind. Subjects will be randomized to receive 
fezolinetant or placebo in a blinded fashion such that neither 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). 
Subjects will be randomized in a 1:1:1 ratio to a treatment arm according to the 
randomization schedules and stratified by smoking status (current smoker vs former/never) 
through IRT. Subjects who complete the 12-week treatment period and have received 
placebo will be re-randomized to either fezolinetant 30 mg or 45 mg for the extension period. 
The assigned treatment in the extension period will remain blinded to the site personnel and 
participating subjects. 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 IRT specifications manual. 


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3 
SAMPLE SIZE  
A total of 450 subjects are planned to be randomized; 150 subjects in each of the three 
treatment arms. The subjects for the analyses covered in this SAP are determined by the 
number of subjects who receive at least one dose of fezolinetant during the study. Subjects 
originally randomized to placebo will only be included if they complete the double-blind 
treatment phase, are re-randomized, and receive at least one dose of fezolinetant during the 
study, unless otherwise specified. 
The sample size of 450 subjects was driven by the double-blind comparisons to placebo at 
week 4 and week 12. See the 12-week analysis SAP for sample size details. 
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. 
4.1 
Full Analysis Set 
The full analysis set for the 52-week analysis will consist of all subjects who are randomized 
and receive at least 1 dose of fezolinetant during either the double-blind or the extension 
period (FAS_F). This will be the primary analysis set for descriptive efficacy analyses. The 
randomized treatment for each subject will be used for summaries by treatment group based 
on the FAS_F, even if a subject erroneously received a different treatment. 
4.2 
Safety Analysis Set 
The safety analysis set for the 52-week analysis will consist of all subjects who are 
randomized and receive at least 1 dose of fezolinetant during either the double-blind or the 
extension period (SAF_F), 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 subject received as first dose. 
The SAF_F will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables. 
4.3 
Per Protocol Set 
Per protocol analysis sets are not applicable beyond the double-blind treatment period. 
4.4 
Pharmacokinetics Analysis Set 
The PKAS will be defined 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. 
4.5 
Pharmacodynamic Analysis Set  
The pharmacodynamic analysis set for the extension (PDAS_F) will include the subjects 
from the administered population (received at least 1 dose of fezolinetant during either the 
double-blind or the extension period) for whom sufficient pharmacodynamic measurements 


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were collected during the study.  The PDAS_F will be used for all analyses of 
pharmacodynamic data (e.g., sex hormones).  
5 
ENDPOINTS  
The calculation of efficacy baseline for VMS frequency and severity is described in the 
12-week analysis SAP, and will be calculated based on the number of moderate to severe hot 
flashes in the 10 days immediately prior to randomization. 
For general efficacy endpoints collected at visits, the last non-missing assessment on or prior 
to the first dose of study treatment (investigational product or placebo) is the baseline. 
For all general safety endpoints, in contrast, the baseline value will be the last non-missing 
value taken on or prior to first dose of fezolinetant. 
Note that the baseline calculations differ between efficacy and safety analyses. The efficacy 
endpoints are subjective and there is expected to be a non-ignorable placebo effect, so the 
entire double-blind portion of the study is considered post-baseline for all subjects. For safety 
endpoints, any changes while on placebo during the double-blind portion of the study are 
expected to be within-subject variation and changes from baseline will be assessed beginning 
with exposure to fezolinetant.  
The table below provides additional details regarding the baselines for specific endpoints. 
The terms RBL and WK12BL indicate where the baseline is established, where RBL is initial 
randomization and WK12BL is the start of the extension period at Week 12. 
Endpoint 
Baseline 
fezolinetant / 
fezolinetant 
placebo / 
fezolinetant 
General efficacy 
RBL 
RBL 
General safety and TVU 
RBL 
WK12BL 
Hormones 
RBL 
WK12BL 
Demographics 
RBL 
RBL 
Medical history 
RBL 
RBL 
Prior medications 
RBL 
WK12BL 
Concomitant medications 
RBL 
WK12BL 
Study drug exposure and compliance 
RBL 
WK12BL 
TEAE 
RBL 
WK12BL 
Clinical lab summary shifts and liver safety assessments 
RBL 
WK12BL 
Protocol deviations 
RBL 
RBL 
Biopsy (Listing only) 
RBL 
RBL 
 
The 12-week double-blind placebo period will be completely described as part of the 
treatment comparisons within the 12-week double-blind analyses. As a result, all endpoints in 
the 52-week analysis are from the first dose of fezolinetant and onward (see Section 6.10 for 
additional details).  
The ePRO daily diary, ePRO visit-based questionnaires, and CRF-based endpoints are all 
described in the 12-week analysis SAP. 


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Only analyses pertaining to endpoints that extend to time points beyond the 12-week double-
blind period will be described in this SAP for the 52-week study.  
The analysis visits for each endpoint and their corresponding definitions of calculation 
windows are in Section 6.10.1.1 (Efficacy Analysis Windows).   
5.1 
Primary Efficacy Endpoints 
There is no primary efficacy endpoint beyond the double-blind treatment period. However, 
some VMS definitions from the 12-week analysis  SAP are repeated below as the subjects 
continue to record their VMS symptoms in their electronic diary during the extension 
treatment period. 
Subjects will record the number of vasomotor symptoms and severity of each vasomotor 
symptom via the ePRO daily diary. 
The severity of an individual VMS is defined as follows [FDA Draft Guidance for Industry, 
2003 and EMA CHMP Guideline, 2005]:  
● Mild: sensation of heat without sweating 
● Moderate: sensation of heat with sweating, able to continue activity 
● Severe: sensation of heat with sweating, causing cessation of activity 
For both post-baseline frequency and severity, a daily average per week will be derived if any 
information for 4 or more days was reported. 
5.2 
Secondary Efficacy Endpoints 
5.2.1 
Key Secondary Endpoint 
There is no key secondary efficacy endpoint beyond the double-blind treatment period. 
5.2.2 
Secondary Endpoints 
The secondary efficacy objectives that extend beyond the double-blind treatment period and 
examine the effect of fezolinetant over time are the following:  
● 
Mean change in the frequency of moderate to severe VMS from baseline to week 24 
(descriptive)  
● 
Mean change in the Severity of moderate to severe VMS from baseline to week 24 
(descriptive) 
These will be described as a time point of particular interest within the exploratory VMS 
endpoint below. 
5.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy objectives that extend beyond the double-blind treatment period and 
examine the effect of fezolinetant over time are the following:  
● 
Mean change in the frequency and severity of moderate and severe VMS from baseline 
to each analysis visit in the extension period and the follow-up visit 
○ Earlier time points will also be presented for completeness 


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● 
Change in serum concentrations of sex hormones  and sex hormone-binding globulin 
(SHBG) from baseline to each analysis visit 
● 
Mean change in serum concentrations of bone specific alkaline phosphatase (BSAP), 
procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal telopeptide 
of type I collagen (CTX) from baseline to each analysis visit  
● 
Plasma concentrations of fezolinetant and metabolite ES259564 at pre-specified time 
points 
● 
Score on the Patient Global Impression of Change (PGI-C) in VMS at each visit 
● 
Mean change on the PROMIS SD SF 8b total score from baseline to each visit 
● 
Mean change on the Patient-Reported Outcomes Measurement Information System 
Sleep-Related Impairment – Short Form 8a (PROMIS SRI SF 8a) total score from 
baseline to each visit 
● 
Score on the Patient Global Impression of Severity in Sleep Disturbance (PGI-S SD) at 
each visit 
● 
Score on the Patient Global Impression of Change in Sleep Disturbance (PGI-C SD) to 
each visit 
● 
Mean change on the Menopause-Specific Quality of Life (MENQOL) total score from 
baseline to each visit 
● 
Mean change on the MENQOL domain scores from baseline to each visit 
● 
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) Visual Analog Scale (VAS) from 
baseline to each visit 
● 
Mean change on the Work Productivity and Activity Impairment questionnaire specific 
to VMS (WPAI-VMS) domain scores from baseline to each visit.  
5.4 
Safety Endpoints 
Safety evaluations will include the following endpoints, but are not limited to: 
● 
Frequency and severity of AEs 
● 
TVUs and endometrial biopsy findings  
● 
Change from baseline to each timepoint in vital signs: sitting systolic and diastolic blood 
pressure and pulse rate 
● 
Change from baseline to each timepoint in ECG parameters 
● 
Change from baseline to each timepoint in laboratory tests: hematology, biochemistry 
and urinalysis 
6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
As a result of this study design and the re-randomization of subjects originally assigned to 
placebo, there are four treatment groups which will be described in the 52-week analysis: 
● 
Subjects originally randomized to 30 mg: 30 mg => 30 mg; per protocol, these subjects 
will have up to 12 months of fezolinetant exposure. 


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● 
Subjects randomized to placebo who will be re-randomized to 30 mg: placebo => 30 mg; 
per protocol, these subjects will have up to 9 months of fezolinetant exposure. 
● 
Subjects originally randomized to 45 mg: 45 mg => 45 mg; per protocol, these subjects 
will have up to 12 months of fezolinetant exposure. 
● 
Subjects randomized to placebo who will be re-randomized to 45 mg: placebo => 45 mg; 
per protocol, these subjects will have up to 9 months of fezolinetant exposure. 
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%. 
All summaries are descriptive and there are no statistical comparisons within the 52-week 
analyses.  
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. 
As mentioned in the introduction, this analysis plan describes the analyses of the entire 
52-week study for subjects who received fezolinetant, excluding the 12-week double blind 
analyses which is planned in a separate SAP. 
Listings will include baseline data and data from first dose of fezolinetant, unless otherwise 
noted.   
6.2 
Study Population 
In general, data such as patient disposition, demographics and baseline characteristics will be 
summarized for FAS_F population as the definition of FAS_F is identical to SAF_F if no 
patients were given wrong study drug. In the event when FAS_F is not identical to SAF_F 
then data will be summarized for both FAS_F and SAF_F as specified in the relevant 
sections. 
6.2.1 
Disposition of Subjects 
Disposition of subjects will be summarized for the FAS_F by treatment group and overall. 
For the discontinuations, 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 the complete SAF population for each criterion and overall, by treatment 
group at the time the deviation occurs and total as well as by investigative site. Subjects 
deviating from a criterion more than once will be counted once for the corresponding 
criterion within a treatment group. The summary will include a column for PD during the 


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12-week placebo period. Placebo subjects deviating from a criterion while on placebo and 
again while on active treatment will be counted once in each treatment (e.g., placebo and 
fezolinetant) for the corresponding criterion, and the subject will be described in a footnote. 
However, such a subject would only be counted once in the Total column. 
The listing will be based on the complete SAF population including all placebo data and 
subjects randomized to placebo who never received fezolinetant. 
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 affected by the COVID-19 pandemic 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 including missed visit windows 
due to COVID-19, and impacted diary data due to COVID-19.  
An overview listing of subjects who were affected by the COVID-19 pandemic will be 
generated by the impact items.   
Detailed information on how these assessments are affected by the COVID-19 pandemic can 
be found in relevant data listings with a flag for COVID-19.   
6.2.3 
Demographic and Other Baseline Characteristics 
Demographics, tobacco history (smoking status), substance use (e-cigarette, alcohol, 
cannabis), caffeine beverage intake, height and weight, and targeted medical history  will be 
summarized descriptively by treatment group and total group for FAS_F and SAF_F. 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. Note that 
current versus former or never smoking status is a stratification factor for randomization. 
Hormone replacement therapy history will be summarized descriptively by treatment group 
and total group for SAF_F.  
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_F. 
These parameters will be summarized using the data collected at baseline. 
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 FAS_F and SAF_F. Subjects taking the same medication multiple times will be 
counted once per medication and investigational period.  


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Previous medications are defined as medications that patients started prior to first 
administration of fezolinetant. Concomitant medications are defined as any medications that 
patients took after the first dose of fezolinetant and through 30 days from last dose of study 
drug. Medications that started prior to first administration of fezolinetant 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_F by treatment group 
and overall.  
Number and percentages of subjects with the following categories of study drug duration will 
be summarized: >0 to ≤ 1 day, >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 ≤ 112 days, >112 to ≤ 140 
days, >140 to ≤ 168 days, >168 to ≤ 196 days, >196 to ≤ 224 days, >224 to ≤ 252 days, >252 
to ≤ 280 days, >280 to ≤ 308 days, >308 to ≤ 336 days, >336 to ≤ 364 days, and >364 days. 
Number and percentages of subjects with the following cumulative categories of study drug 
duration will be summarized: ≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 42 days, 
≥ 56 days,  ≥ 84 days, ≥ 112 days, ≥ 140 days, ≥ 168 days, ≥ 196 days, ≥ 224 days,  
≥ 252 days, ≥ 280 days, ≥ 308 days, ≥ 336 days, and ≥ 364 days. 
Overall treatment compliance with the dosing schedule will be examined for subjects in the 
SAF_F 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 fezolinetant), not to the planned treatment period. 
Percent overall compliance while on fezolinetant will be summarized in two ways for the 
SAF_F: 
● 
Descriptive statistics will be presented by treatment group. 
● 
Percent compliance will be categorized according to the following categories by 
treatment group: 
○ Less than 50%, 
○ at least 50%, less than or equal to 85%, 
○ greater than 85%, less than or equal to 120%, 
○ Over 120%, and 
○ Unknown. 
To explore the impact of the COVID-19 pandemic, additional analysis will be performed by 
excluding the days of missing study drug/drug interruption due to COVID-19 pandemic in 
the duration and compliance calculation, according to the study drug interruption CRF page.  
6.4 
Analysis of Efficacy  
All efficacy endpoints will be descriptively summarized by the four treatment groups, as 
described in Section 6.1 (General Considerations), for FAS_F, unless specified otherwise. 


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For efficacy analyses, the visit windows from Section 6.10.1.1 and 6.10.1.2 will be applied, 
and they are all defined relative to the start of fezolinetant.  
6.4.1 
Analysis of Secondary Efficacy Endpoints 
The mean change in the frequency and severity of moderate and severe VMS from baseline 
to week 24 will be summarized descriptively, as part of the output specified below and in 
Section 6.10.1.1.  
The analysis will be repeated by excluding diary data that are impacted by COVID-19 
pandemic, which includes the diary data recorded after the subjects were diagnosed of 
COVID-19, after study drug discontinuation due to COVID-19, and during dose interruption 
due to COVID-19.   
6.4.2 
Analysis of Exploratory Endpoints 
The mean change in the frequency and severity of moderate and severe VMS from baseline 
to each analysis week up to week 12, and specified weeks thereafter (as specified in 
Section 6.10.1.1) will be summarized, including the secondary endpoint of Week 24. 
For non-diary efficacy endpoints analysis visits are used rather than weeks, as described in 
Section 6.10.1.1. 
PROMIS (SD and SRI total scores), MENQOL (domain and total scores), and WPAI-VMS 
domain scores will be summarized descriptively.  
PGI-S and PGI-C (both VMS and SD) and EQ-5D domain scores will be summarized 
descriptively. The mean and standard deviation of the EQ-5D domain scores will be 
presented.  
Change on the Euro-Qol 5D-5L (EQ-5D-5L) Visual Analog Scale (VAS) from baseline will 
be summarized descriptively. 
The median change in serum concentrations of sex hormones and sex hormone-binding 
globulin (SHBG) from baseline to each analysis visit and the mean change in serum 
concentrations of BSAP, P1NP and CTX from baseline to each analysis visit will be 
summarized.  
6.5 
Analysis of Safety 
All analysis of safety will be presented by the four treatment groups, as described in 
Section 6.1 (General Considerations), for SAF_F, unless specified otherwise. For analyses by 
visit, the visit windows from Section 6.10.1.2 will be applied, and they are all defined relative 
to the start of fezolinetant. 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 fezolinetant unless otherwise noted. 


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6.5.1 
Adverse Events 
TEAE is defined as an AE observed after starting administration of fezolinetant and up to 
21 days after the last dose of study drug.  
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 drug related TEAEs, 
● 
Number of serious TEAEs, 
● 
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.  
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. 


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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 
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.  
Following adverse events of special interest are defined: 
● Adverse event of uterine bleeding 
● Endometrial hyperplasia/cancer or disordered proliferative endometrium 
● Adverse event of thrombocytopenia  
● Adverse event of liver test elevations  
● Adverse event of bone fractures  
● Adverse events of abuse liability 
● Adverse events of depression 
● Adverse events of wakefulness  
● Adverse events 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 and listings of these adverse events will be provided. 
The number and percentage of subjects with TEAEs associated with COVID-19, as classified 
by SOC and PT, will be summarized for each treatment group 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. 
The number and percentage of subjects below and above reference range will be summarized 
for each treatment group at each visit. 
Number and percentage of subjects with platelets < 150000/uL (150,000/µL (150 × 109/L) 
will also be summarized.  
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit. 
For hematology and biochemistry shift tables will be presented for each treatment group: 


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● 
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]). 
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. 
6.5.2.1 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 
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 entire active-dose study period (from day of first dose 
of fezolinetant until last dose of extension 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 > 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 active-dose study period. The number and 
percentage of subjects meeting the criteria during the active-dose study period  will be 
summarized by treatment group.  
Due to the COVID-19 pandemic, subjects might not have been 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 were performed taken by a local laboratory. 
The liver biochemistry safety assessments will be summarized including central and locally 
collected laboratory data due to the COVID-19 pandemic. This analysis is considered the 
primary analysis for the liver safety assessment.   
As a secondary analysis for liver biochemistry, the analysis will be repeated with the data 
evaluated by the central laboratory but excluding the data that are impacted by COVID-19 
pandemic, 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 windows or data collected via home visits due 
to COVID-19 recorded in the eCRF.  


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6.5.3 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by treatment 
group and analysis visit. Additionally, a within-subject change will be calculated per analysis 
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 analysis visit, including changes from baseline. 
Number and percent of subjects with normal and abnormal results as assessed by the central 
reader for the 12 lead ECG will be tabulated by treatment group at each analysis visit. 
The QTc interval will be summarized using frequency tables for each analysis 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 analysis visit. 
6.5.5 
Other Safety-Related Assessments 
C-SSRS results will be summarized by treatment group and analysis visit based on SAF_F. 
Ultrasound results (endometrial thickness) and bone marker results will be summarized for 
the SAF_F population 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. The listing will be based on the complete SAF population, including all placebo 
data and subjects randomized to placebo who never received fezolinetant, because these data 
were not included in the double-blind 12-week analysis. 
Baseline biopsy will be defined as the non-missing value on or prior to first dose of study 
drug. Biopsy results will be listed based on the complete SAF population, including all 
placebo data and subjects randomized to placebo who never received fezolinetant, because 
biopsy data was not included in the double-blind 12-week analysis. Post-baseline biopsy 
results for subjects originally randomized to placebo will still be listed.  


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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 (LH, FSH, E2, Testosterone Total/Free, 
Androstenedione, DHEA, Estrone) and SHBG will be summarized using descriptive statistics 
(number of subjects, mean, SD, median, minimum and maximum) for each analysis 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  
In case of data issues or findings pertaining to the 12-week period after the 12-week lock and 
before the final lock, an errata form will be issued to document those data discrepancies.  
6.10.1 Analysis Windows 
Study Day for analysis windows during the double-blind treatment phase will be calculated 
as date of visit/assessment – first dose date +1.   
Study Day during the extension phase will be calculated as date of visit/assessment – first 
dose date of the extension phase +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). 
Fezolinetant Study Day (FD) will be calculated as date of visit/assessment – first dose date of 
fezolinetant +1. Note that this is the same as Study Day for subjects randomized to 
fezolinetant in the double-blind treatment phase. Post-baseline data prior to first dose of 
fezolinetant Day 1 is excluded from the analyses described in this SAP unless otherwise 
noted. 
6.10.1.1 Efficacy Analysis Windows 
For the analysis windows, the last day is always the last day of exposure to overall study 
treatment. For VMS diary data the last day of exposure includes events reported until 


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8:00AM the following day. For example, the Week 1 average will include diary data from 
8AM on Day 1 through 7:59AM on Day 8. 
For both VMS and non-VMS efficacy, the end of overall treatment is defined as the last day 
of treatment (e.g., discontinued study or entered follow-up period) and the follow-up period 
begins at last overall treatment + 1 day. 
The study week determination for the vasomotor symptoms data is based on the following: 
Analysis study week 
Analysis window 
Baseline 
Non-missing days from D-10 up to and including D-1 
Week 1 
FD1 to FD7 
Week 2 
FD8 to FD14 
Week 3 
FD15 to FD21 
Week 4 
FD22 to FD28 
Week 5 
FD29 to FD35 
Week 6 
FD36 to FD42 
Week 7 
FD43 to FD49 
Week 8 
FD50 to FD56 
Week 9 
FD57 to FD63 
Week 10 
FD64 to FD70 
Week 11 
FD71 to FD77 
Week 12 
FD78 to FD84  
Week 16 
FD110 to FD116 
Week 20 
FD138 to FD144 
Week 24 
FD166 to FD172 
Week 28 
FD194 to FD200 
Week 32 
FD222 to FD228 
Week 36 
FD250 to FD256 
Week 40 
FD278 to FD284 
Week 44 
FD306 to FD312 
Week 48 
FD334 to FD340 
Week 52 
FD362 to FD368 
Week 53 (Follow-up) 
FUD1 to FUD7 
Week 54 (Follow-up) 
FUD8 to FUD14 
Week 55 (Follow-up) 
FUD15 to FUD21 
 
Calculations for weeks up through Week 12 end on the last day of the study week. 
Calculations for weeks beyond the double-blind treatment period are centered about 
protocol-specified visits to match visit-based efficacy assessments. For example, the 
Week 12 analysis window ends on FD84 (7*12=84), but the Week 16 visit is centered around 


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protocol specified FD113 (FD110 to FD116). Calculations in the follow-up period end on the 
last day of the study week, based on study days in the follow-up period. 
Weeks 44, 48 and 52 will be missing for subjects randomized to placebo during the double-
blind treatment period because they are only on active treatment for 40 weeks.  
A weekly average will be calculated if any information, including zero VMS events, was 
reported for 4 or more days. 
All other efficacy assessments, including those from unscheduled visits and regardless of 
visit label, will be allocated to analysis visits based on the table below: 
Target day 
Analysis window 
Analysis visit 
D1  
last non-missing value on or prior to day 1 
Baseline 
D29 
FD22 to FD36 
Week 4 
D85  
FD72 to FD 92 
Week 12 
D113 
FD106 to FD120 
Week 16 
D141 
FD134 to FD148 
Week 20 
D169 
FD162 to FD176 
Week 24 
D197 
FD190 to FD204 
Week 28 
D225 
FD218 to FD232 
Week 32 
D253 
FD246 to FD 260 
Week 36 
D281 
FD274 to FD288 
Week 40 
D309 
FD302 to FD316 
Week 44 
D337 
FD330 to FD344 
Week 48 
D365 
FD358 to FD372 
Week 52 
 
The VMS efficacy windows are smaller because they are calculated from daily data and are 
not dependent on the scheduling of visits. The non-VMS efficacy endpoint are not collected 
during the follow-up period.  
If more than one observation exists within the analysis window, the observation closest to the 
scheduled visit day will be selected for that visit.  If there are two observations that have the 
same distance from the scheduled day, the value that is before the scheduled day will be 
selected in the analysis.  If more than one observation is made on the same day, an average 
value if continuous, or the worst value if categorical, will be included in the analysis. 
6.10.1.2 Safety Analysis Windows 
Except for adverse events, for the analysis window, the last day is always 1 day after the last 
day of exposure to overall study treatment. 
The end of overall treatment is defined as the last day of treatment (e.g., discontinued study 
or entered follow-up period) +1 and the follow-up period for analysis windows begins at last 
overall treatment + 2 days and onward (Follow-up Study Day 2). 




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● 
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 
The changes from the Version 1 to Version 2 that may impact the statistical analyses are 
listed in the table below:  
SAP Sections 
Description 
Rationale 
Relevant sections 
(see Section 9.1 
Appendix 1)   
Added additional statistical analyses 
due to the COVID-19 pandemic  
To evaluate potential impact of the 
COVID-19 pandemic 
6.5.1  
Modified the list of AESIs  
To be consistent with the protocol 
amendments (version 3.0)   
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      
6.10.12 
Upper bound of the Week 52 analysis 
window is modified to 376.  
The analysis window for the Week 52 
TVU and biopsy assessments is 
Fezolinetant Study Day 2 (FD2) until 
last treatment + 30 days. 
To be consistent with other study 
(0304) in the program.  
 


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8 
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Khanna D, Maranian P, Rothrock N, Cella D, Gershon R, Khanna PP, et al. Feasibility and construct 
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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 characterized 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, all planned subjects were randomized into the study before Astellas paused 
recruitment in all their clinical studies on March 30, 2020. In order to capture the relevant 
impact of the COVID-19 pandemic, dedicated CRF pages, the risk benefit plans, and 
alternative measures were implemented in the study as described in the study protocol. Since 
the study data may be impacted by the COVID-19 pandemic, additional statistical analyses 
are planned for this study.   
The additional statistical analyses due to the COVID-19 pandemic are planned in the 
following sections of this SAP.  
Section 
Topic  
6.2.2  
Study population  
6.3 
Study Drug Exposure and Compliance 
6.4.1 
Analysis of Secondary Efficacy Endpoints 
6.5.1 
Adverse Events 
6.5.2.1 
Clinical Laboratory Evaluation/Liver Safety Assessment    
 
 
 


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


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STATISTICAL ANALYSIS PLAN
(for the 12-week Double-Blind Treatment Period)
Version 3.0, dated 30 September 2020
A Phase 3, Randomized, Placebo-controlled, 12-week Double-
blind Study, followed by a Non-Controlled Extension Treatment 
Period, to Assess the Efficacy and Safety of Fezolinetant in 
Women Suffering from Moderate to Severe Vasomotor 
Symptoms (Hot Flashes) Associated with Menopause
Skylight 2
ISN: 2693-CL-0302
IND number: 130277
EudraCT 018-003529-27
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.  
NCT04003142


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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 6
2
STUDY OBJECTIVE(S) AND DESIGN······················································· 6
2.1
Study Objective(s) ············································································· 6
2.2
Study Design···················································································· 7
2.3
Randomization·················································································· 7
3
SAMPLE SIZE······················································································ 8
4
ANALYSIS SETS ·················································································· 9
4.1
Full Analysis Set ··············································································· 9
4.2
Safety Analysis Set ············································································ 9
4.3
Per Protocol Set ················································································ 9
4.3.1
Reasons for Exclusion From PPS4 ····················································· 9
4.3.2
Reasons for Exclusion From PPS12 ··················································· 9
4.4
Pharmacokinetics Analysis Set (PKAS)····················································10
4.5
Pharmacodynamic Analysis Set (PDAS)···················································10
5
ENDPOINTS ·······················································································10
5.1
Primary Efficacy Endpoints··································································10
5.2
Secondary Efficacy Endpoints·······························································11
5.2.1
Key Secondary Endpoint ·······························································11
5.2.2
Secondary Endpoints····································································12
5.3
Exploratory Efficacy Endpoints ·····························································13
5.3.1
VMS events ··············································································14
5.3.2
Hormones·················································································14
5.3.3
Bone Markers ············································································14
5.3.4
Patient Global Impression Scales (PGI-C VMS, PGI-S SD, PGI-C SD) ·········14
5.3.5
Patient-Reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8b (PROMIS SD SF 8b) ································15
5.3.6
Patient-Reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8a (PROMIS SRI SF 8a)································15
5.3.7
Menopause-Specific Quality of Life (MENQOL)···································15
5.3.8
Euro-QoL 5D-5L (EQ-5D-5L) with Visual Analog Scale (VAS)·················15


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5.3.9
Work Productivity and Activity Impairment questionnaire specific to VMS 
(WPAI-VMS)············································································16
5.4
Safety Endpoints ··············································································16
6
STATISTICAL METHODOLOGY ···························································16
6.1
General Considerations·······································································16
6.2
Study Population ··············································································17
6.2.1
Disposition of Subjects ·································································17
6.2.2
Protocol Deviations ·····································································17
6.2.3
Demographic and Other Baseline Characteristics ···································18
6.2.4
Previous and Concomitant Medications ··············································18
6.3
Study Drug Exposure and Compliance·····················································18
6.4
Analysis of Efficacy ··········································································19
6.4.1
Analysis of Primary Efficacy Endpoints··············································20
6.4.2
Analysis of Key Secondary Efficacy Endpoint ······································22
6.4.3
Analysis of Secondary Efficacy Endpoints···········································23
6.4.4
Analysis of Exploratory Endpoints····················································23
6.5
Analysis of Safety·············································································25
6.5.1
Adverse Events ··········································································25
6.5.2
Clinical Laboratory Evaluation ························································27
6.5.3
Vital Signs················································································28
6.5.4
Electrocardiograms······································································28
6.5.5
Other Safety-Related Assessments ····················································29
6.6
Analysis of Pharmacokinetics ·······························································29
6.6.1
Estimation of Pharmacokinetic Parameters ··········································29
6.7
Analysis of Pharmacodynamics ·····························································29
6.8
Other Analyses ················································································29
6.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················29
6.10
Additional Conventions ······································································29
6.10.1
Analysis Windows ······································································29
6.10.2
Imputation Rules for Incomplete Dates···············································31
7
REVISION AND RATIONALE································································33
7.1
List of Changes in SAP Version 2.0 ························································33
7.2
List of Changes in SAP Version 3.0 ························································34


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8
REFERENCES ····················································································35
9
APPENDICES ·····················································································37
9.1
Appendix 1 Additional Statistical Analysis due to COVID-19··························37
9.2
Appendix 2 Author and Approver Signatures ·············································38


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ANCOVA
Analysis of Covariance
ASCM
Analysis Set Classification Meeting 
ATE
Active Treatment Extension
CI
Confidence Intervals
CMH
Cochran Mantel Haenszel
COVID-19
Coronavirus Disease 2019
FAS
Full Analysis Set
GCP
Good Clinical Practice
ISE
Integrated Summary of Efficacy
MAR
Missing at Random
MMRM
Mixed Model Repeated Measures
PAP
Psychometric Analysis Plan
PKAS
Pharmacokinetics Analysis Set
PPS
Per-Protocol Analysis Set
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
TLF
Tables, Listings and Figures
VMS
Vasomotor Symptoms
List of Key Terms
Terms
Definition of terms
Double-blind Treatment 
Period
The 12 weeks of treatment after the first administration of study drug 
and prior to first administration of study drug in the active treatment
extension period. Only this period contains a placebo treatment. 
Active Treatment 
Extension Period
Period of time after the first administration of study drug in the active 
treatment extension period after completing 12 weeks of placebo-
controlled double-blind treatment until the last dose of the study drug 
(at Week 52 or early discontinuation).
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.


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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 analyses described in the SAP will be conducted after all subjects complete the 
double-blind treatment period at 12 weeks. Only data pertaining to the double-blind treatment 
period (all data for subjects early discontinued during the double-blind period, or data from 
12-week double-blind period prior to first dose of study drug in the active treatment 
extension period for subjects entered the extension period) will be used. A separate SAP will 
describe the analysis of the 52-week study data period, including the active treatment 
extension period. 
This SAP will be approved prior to the database lock for the 12-week double-blind period.
Changes from the planned analyses in the finalized SAP that impact the statistical analyses 
will be documented and justified in the Clinical Study Report (CSR).
2
STUDY OBJECTIVE(S) AND DESIGN
2.1
Study Objective(s)
Primary objective:
●
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of 
moderate to severe vasomotor symptoms (VMS). 
o
The estimand of the primary objective will use a hypothetical strategy and compare 
patients as though they had continued on the assigned treatment. 
Key secondary objective:
●
To evaluate the efficacy of fezolinetant versus placebo on patient-reported sleep 
disturbance.
Secondary objectives: 
●
To evaluate the effect of fezolinetant versus placebo on the frequency and severity of 
moderate to severe VMS at weekly time points. 
●
To evaluate the safety and tolerability of fezolinetant.
Exploratory objectives: 
●
To evaluate population pharmacokinetics (popPK) of fezolinetant and metabolite 
ES259564.
●
To evaluate the effect of fezolinetant on pharmacodynamic markers.
●
To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of 
mild, moderate and severe VMS. 
●
To evaluate the short-term and sustained effects of fezolinetant versus placebo on 
patient-reported sleep disturbance.


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●
To evaluate the effect of fezolinetant versus placebo on the following patient-reported 
outcomes (PROs): global assessments of VMS and sleep disturbance, overall sleep-wake 
function, quality of life and work productivity.
2.2
Study Design
This is a randomized, 12-week double-blind, placebo-controlled, parallel group, multicenter 
clinical study to assess the efficacy and safety of fezolinetant in women suffering from 
moderate to severe VMS associated with menopause. Approximately 450 subjects will be 
enrolled into this study, 150 subjects per treatment arm. Duration of treatment is 52 weeks. 
After completing 12 weeks of treatment, subjects on placebo will be reassigned to 30 mg or 
45 mg of fezolinetant in the active treatment extension period through end of study. Subjects 
who were already randomized on an active arm will continue on their assigned dose for the 
remaining 40 weeks of treatment. Following the completion (or early discontinuation [ED]) 
of the treatment period (week 52), subjects will complete an end of treatment (EOT; or ED) 
visit and final safety follow-up visit 3 weeks after the last dose of study drug is administered 
(week 55). 
Given the design, a 12-week treatment analysis will occur to assess efficacy and safety 
during the double-blind treatment phase. This will occur after all subjects have completed 
12 weeks of treatment. Efficacy and safety data will be analyzed, excluding the endpoints 
measured after 12 weeks. Since all primary and secondary analyses only based on data 
through Week 12, no alpha adjustment is required as the information fraction at the 12-week 
analysis is 100%. 
Details of the schedule of clinical assessments are available in the protocol.
2.3
Randomization
The first 12 weeks of the study are double blind. Subjects will be randomized to receive 
fezolinetant or placebo in a blinded fashion such that neither 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).
Subjects will be randomized in a 1:1:1 ratio to a treatment arm according to the 
randomization schedules and stratified by smoking status (current smoker vs former/never) 
through IRT. Subjects who complete the 12-week treatment period and have received 
placebo will be randomized to either fezolinetant 30 mg or 45 mg for the extension period. 
The assigned treatment in the extension period will remain blinded to the site personnel and 
participating subjects. 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 IRT specifications manual.


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3
SAMPLE SIZE
A total of 450 subjects are planned to be randomized; 150 subjects in each treatment arm.
The phase 2b dose-ranging study (ESN_HF_205) included 7 active doses. In this study, the 
observed least-squares mean difference between fezolinetant and placebo in change from 
baseline to week 12 (and week 4) in mean daily frequency of moderate to severe VMS 
ranged from -1.8 to -3.0.
For a pairwise comparison using a 2-sample t-test at a 2-sided 2.5% alpha (adjusting for 
2 active doses within study -0302), 120 subjects would provide 79% or more power to detect 
the following effect sizes assuming a SD of 5:
Assumed treatment difference in mean daily frequency
Power for pairwise test
-2.0
79%
-2.3
90%
-2.5
94%
For change from baseline to week 12 (and week 4) in mean severity of moderate to severe 
VMS, the observed mean treatment differences in the phase 2b study ranged from 
-0.2 and -1.0. 
For a pairwise comparison using a 2-sample t-test at a 2-sided 2.5% alpha (adjusting for 
2 active doses within study -0302), 120 subjects would provide the at least 79% power to 
detect the following effect sizes assuming a SD of 1:
Assumed treatment difference in mean severity
Power for pairwise test
-0.40
79%
-0.46
90%
-0.50
94%
NOTE: The combined power for testing all 4 co-primary endpoints will be lower than the 
power for each considered individually; however, the co-primary endpoints are correlated 
(especially the same endpoint at different time points) and this will serve to limit the potential 
reduction of power. 
Assuming approximately 20% of subjects discontinue prematurely prior to 12 weeks of 
treatment in study -0302, the number of subjects will be increased from 120 to 150 subjects 
per arm. This should enable the analysis of the primary efficacy endpoints with sufficient 
power.
This sample size would also provide over 95% power to detect a difference of 4.3 from 
placebo on the key secondary endpoint of the PROMIS sleep disturbance questionnaire, 
using a 2-sample t-test at a 2-sided 2.5% alpha (adjusting for 2 active doses) assuming a SD 
of 7 [Avis et al, 2016].


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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 and efficacy
analysis sets will be made prior to database unblinding for the 12-week double-blind period.
4.1
Full Analysis Set
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.
4.2
Safety Analysis Set
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.
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables.
4.3
Per Protocol Set
The per protocol sets (PPS) will consist of the subset of the FAS who do not meet criteria for 
exclusion from PPS listed in Section 4.3.1 below. 
Final judgments on exclusion of subjects from Per Protocol Analysis Set - Week 4 (PPS4) 
and Per Protocol Analysis Set - Week 12 (PPS12) will be made prior to randomization 
unblinding.  
The PPS will be a secondary analysis set for efficacy analyses. Select demographic and 
baseline characteristics may also be summarized for the PPS.
4.3.1
Reasons for Exclusion From PPS4
The following reasons may lead to subject’s exclusion from PPS4:
●
No measurement of the primary efficacy endpoint available at Week 4.
●
<85% interactive diary compliance during the 4 week treatment period.
●
Treatment compliance less than or equal to 85% between randomization and Week 4. 
4.3.2
Reasons for Exclusion From PPS12
The following reasons may lead to subject’s exclusion from PPS12:
●
No measurement of the primary efficacy endpoint available at Week 12.
●
<85% interactive diary compliance during the 12 week treatment period.
●
Treatment compliance less than or equal to 85% between randomization and Week 12. 


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4.4
Pharmacokinetics Analysis Set (PKAS)
The PKAS will be defined 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.
4.5
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. 
5
ENDPOINTS 
For VMS symptoms, baseline frequency is calculated based on the number of moderate to 
severe hot flashes in the 10 days immediately prior to randomization. Subjects are required to 
have reported VMS symptoms on at least 7 of these 10 days to meet the eligibility criterion, 
and the average is based on all the non-missing days. The value is calculated within the 
ePRO device and used to assess the VMS frequency eligibility criterion, as well as for the 
analysis of VMS efficacy baseline. Baseline severity is calculated based on these same days, 
but is not provided by the ePRO device because it is not used for eligibility. 
For efficacy endpoints collected at visits, the last non-missing assessment on or prior to the 
first dose of study treatment (investigational product or placebo) is the baseline.
For completeness, all protocol-specified endpoints are listed in the following subsections. 
However, analyses pertaining to endpoints at time points beyond the 12-week double-blind 
period will be described in the SAP for the active treatment extension period.
5.1
Primary Efficacy Endpoints
The primary efficacy objective requires the evaluation of 4 co-primary endpoints: 
●
Mean change in the frequency of moderate to severe VMS from baseline to week 4
●
Mean change in the frequency of moderate to severe VMS from baseline to week 12
●
Mean change in the severity of moderate to severe VMS from baseline to week 4
●
Mean change in the severity of moderate to severe VMS from baseline to week 12
Subjects will record the number of vasomotor symptoms and severity of each vasomotor
symptom via the ePRO daily diary.
The 24 hour vasomotor symptoms time frame runs from 08:00 AM to 07:59 AM (next day).
Frequency of moderate to severe vasomotor symptoms is the number of moderate to severe
vasomotor symptoms per 24h.
The severity of an individual vasomotor symptom (VMS) is defined as follows [FDA Draft 
Guidance for Industry, 2003 and EMA CHMP Guideline, 2005]:
●
Mild: sensation of heat without sweating
●
Moderate: sensation of heat with sweating, able to continue activity
●
Severe: sensation of heat with sweating, causing cessation of activity


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Severity of post-baseline co-primary severity endpoints will be calculated using a weighted 
average defined as shown below. Note that the calculation for severity at baseline uses a 
similar formula, but does not include mild VMS events in the numerator or denominator. The 
calculation of baseline and post-baseline severity is based on specific direction from the FDA 
during the Type B end-of-phase 2 meeting of April 17, 2019. This calculation allows for the 
capture all hot flashes on treatment, including mild.
([number of mild hot flashes/day × 1] + [number of moderate hot flashes/day × 2] + 
[number of severe hot flashes/day × 3]) / total number of daily  mild/moderate/severe hot
flashes
At baseline, severity is zero for any individual days on which subjects have zero moderate or 
severe symptoms. Severity for post-baseline individual days is zero for subjects who have 
zero mild, moderate or severe vasomotor symptoms. 
At baseline, as mentioned at the start of Section 5, frequency and severity are based on the 
non-missing values in the 10 days immediately prior to randomization. After baseline, daily 
frequency and severity for specific weeks (e.g., week 4, week 12) will be calculated as the 
average over non-missing days over 7 days period. Days without any reporting of VMS 
events will be considered missing for that day. For both post-baseline frequency and severity, 
a daily average per week will be derived if any information for 4 or more days was reported.
All 4 co-primary endpoints must be statistically significant for a given dose to be considered 
successful. Details regarding determination of statistical significance are provided in 
Section 6.4. 
5.2
Secondary Efficacy Endpoints
5.2.1
Key Secondary Endpoint
The key secondary efficacy objective examines the effect of fezolinetant versus placebo on 
the following:
●
Mean change in the Patient-Reported Outcomes Measurement Information System Sleep 
Disturbance – Short Form 8b (PROMIS SD SF 8b) total score from baseline to week 12
Alpha will only be propagated to the key secondary endpoint if all co-primary endpoints are 
statistically significant at both dose levels. If all the co-primary endpoints are statistically 
significant between fezolinetant and placebo at both doses, the statistical testing will be 
performed on the key secondary efficacy endpoint between fezolinetant and placebo, using 
Hochberg with alpha = 0.05, as part of the family-wise (overall) error rate.
5.2.1.1
Patient-Reported Outcomes Measurement Information System Sleep Disturbance –
Short Form 8b (PROMIS SD SF 8b)
The PROMIS is a National Institutes of Health Roadmap initiative designed to improve PRO 
measures using state-of-the-science methods. The PROMIS SD SF 8b [PROMIS 
Sleep-Disturbance, 2015; Khanna, 2012] assesses self-reported sleep disturbance over the 
past 7 days and includes perceptions of restless sleep; satisfaction with sleep; refreshing 


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sleep; difficulties sleeping, getting to sleep or staying asleep; amount of sleep; and sleep 
quality. Because it assesses the patient’s experience of sleep disturbance, the measure does 
not focus on specific sleep-disorder symptoms or ask patients to report objective measures of 
sleep (e.g., total amount of sleep, time to fall asleep and amount of wakefulness during 
sleep). Responses to each of the 8 items range from 1 to 5, and the range of possible summed 
raw scores is 8 to 40. Higher scores on the PROMIS SD SF 8b indicate more of the concept 
measured (disturbed sleep).
5.2.2
Secondary Endpoints
The secondary efficacy objectives examine the effect of fezolinetant versus placebo on the 
following: 
●
Mean change in the frequency of moderate and severe VMS from baseline to each week 
up to week 12
●
Mean change in the severity of moderate and severe VMS from baseline to each week up 
to week 12
●
Mean percent reduction in the frequency of moderate and severe VMS from baseline to 
each week up to week 12
●
Percent reduction ≥ 50% and at 100% in the frequency of moderate and severe VMS 
from baseline to each week up to week 12
●
Mean change in the frequency of moderate to severe VMS from baseline to week 24 
(descriptive) [Analysis to be described in the 52-Week SAP]
●
Mean change in the Severity of moderate to severe VMS from baseline to week 24 
(descriptive) [Analysis to be described in the 52-Week SAP]
●
Score on the Patient Global Impression of Change (PGI-C) in VMS at each visit
The severity of moderate to severe VMS for all secondary endpoints in this Section will be 
calculated as described in Section 5.1, where baseline severity include moderate and severe 
VMS events, while post-baseline severity includes mild, moderate and severe VMS events in 
the calculation. 
5.2.2.1 VMS responder 
Two separate definitions of the frequency of moderate and severe VMS responder will be 
used to assess each subject. The derivations at each week are as follows, using Week 12 as an 
example:
●
Subject has ≥50% reduction from baseline to week 12.
○
(VMSweek12 – VMSBL)/ VMSBL ≤-0.5
where VMSweek12 and VMSBL are the frequency of moderate and severe VMS
at week 12 and baseline, respectively;
●
Subject has 100% reduction from baseline to week 12 if frequency at week 12 = 0 
VMS events.
Subjects with missing data will be considered as a non-responder.


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Percent reduction ≥ 75%  ≥ 90% in the frequency of moderate and severe VMS from 
baseline to each week, and the frequency of mild, moderate and severe VMS responder will 
be defined in a similar way (see exploratory endpoints).
5.3
Exploratory Efficacy Endpoints
●
Mean change in the frequency of mild, moderate and severe VMS from baseline to each 
week up to week 12
●
Mean change in the severity of mild, moderate and severe VMS from baseline to each 
week up to week 12 
●
Mean percent reduction in the frequency of mild, moderate and severe VMS from 
baseline to each week up to week 12
●
Percent reduction ≥ 75% and ≥ 90% in the frequency of moderate and severe VMS from 
baseline to each week up to week 12 (VMS responder, which will be calculated in a 
similar way as stated in Section 5.2.2.1)
●
Percent reduction ≥ 50%, ≥ 75%, ≥ 90%, and at 100% in the frequency of mild, 
moderate and severe VMS from baseline to each week up to week 12 (VMS responder, 
which will be calculated in a similar way as stated in Section 5.2.2.1)
●
Mean change in the frequency and severity of moderate and severe VMS from baseline 
to each visit in the active treatment extension period and the follow-up visit [Analysis to 
be described in the 52-Week SAP] 
●
Change in serum concentrations of sex hormones and sex hormone-binding globulin 
(SHBG) from baseline to each visit
●
Mean change in serum concentrations of BSAP, P1NP and CTX from baseline to each 
visit [Analysis to be described in the 52-Week SAP]
●
Plasma concentrations of fezolinetant and metabolite ES259564 at pre-specified time 
points [Analysis to be described in the 52-Week SAP]
●
Mean change on the PROMIS SD SF 8b total score from baseline to each visit
●
Mean change on the Patient-Reported Outcomes Measurement Information System 
Sleep-Related Impairment – Short Form 8a (PROMIS SRI SF 8a) total score from 
baseline to each visit
●
Score on Patient Global Impression of Severity in Sleep Disturbance (PGI-S SD) at each 
visit
●
Score on Patient Global Impression of Change in Sleep Disturbance (PGI-C SD) to each 
visit
●
Mean change on the Menopause-Specific Quality of Life (MENQOL) total score from 
baseline to each visit
●
Mean change on the MENQOL domain scores from baseline to each week up to week 12
●
Mean change on the Euro-Qol 5D-5L (EQ-5D-5L) Visual Analog Scale (VAS) from 
baseline to each visit
●
Mean change on the Work Productivity and Activity Impairment questionnaire specific 
to VMS (WPAI-VMS) domain scores from baseline to each visit. 


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●
Mean change in the severity of moderate and severe VMS from baseline to each week up 
to week 12 (see specification in Section 5.3.1) 
●
Mean and mean change from baseline in the daily frequency of moderate and severe 
VMS for the first week (see specification in Section 5.3.1)
Note that many of the above protocol-specified exploratory endpoints are scheduled beyond 
the 12-week double-blind treatment period and, as mentioned earlier, will be described in the 
SAP for the active treatment extension period. 
5.3.1
VMS events
Exploratory endpoints that include mild post-baseline VMS events (frequency, severity, 
percent reduction, and responder analyses) also consider mild VMS at baseline.
The severity of moderate to severe VMS in this Section will be calculated as described in 
Section 5.1, where both baseline and post-baseline severity include only moderate and severe 
VMS events in the calculation. 
For the daily frequency of moderate and severe VMS endpoint, the baseline frequency and 
post-baseline daily frequency will be calculated as described in Section 5.1. In addition, the 
co-primary endpoints will also be re-derived excluding data affected by COVID-19.
5.3.2
Hormones
Hormones being collected include estradiol (E2), follicle stimulating hormone (FSH), 
luteinizing hormone (LH), sex hormone-binding globulin (SHBG), total and free 
testosterone, androstenedione, dehydroepiandrosterone (DHEA), and estrone.
5.3.3
Bone Markers
Bone markers being collected include Bone Specific Alkaline Phosphatase (BSAP), carboxy-
terminal telopeptide of Type I Collagen (CTX), Procollagen 1 N-Terminal Propeptide
(P1NP). However, they only collected at the randomization and Week 52/end of treatment 
visit, so analyses will be described in the active treatment extension period SAP.
5.3.4
Patient Global Impression Scales (PGI-C VMS, PGI-S SD, PGI-C SD)
The PGI is comprised of 2 companion 1-item PRO measures analogous to the Clinical Global 
Impression (CGI) scales [Busner J & Targum SD, 2007]. These measures provide brief, 
stand-alone global assessments prior to and after initiating a study medication. The Patient 
Global Impression evaluates the following: (1) patient-perceived severity of a condition 
(PGI-S) and (2) patient-perceived change from the initiation of treatment (PGI-C). In this 
study, PGI scales will be used to evaluate meaningful within-person changes over time in 
VMS (PGI-C) and sleep disturbance (PGI-S and PGI-C).
The PGI-C VMS asks: “Compared to the beginning of this study, how would you rate your 
HFs/night sweats now?” Subject ratings range from (1) much better to (7) much worse. 
The PGI-C SD asks: Compared to the beginning of this study, how well are you sleeping 
now?” Subject ratings range from (1) much better to (7) much worse. 


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The PGI-S SD asks: “How would you rate the severity of any problems you currently have 
while sleeping at night?” Subject ratings range from (1) no problems to (4) severe problems.
5.3.5
Patient-Reported Outcomes Measurement Information System Sleep Disturbance –
Short Form 8b (PROMIS SD SF 8b)
See Section 5.2.1.1. PROMIS SD SG 8b total score will be analyzed at each visit. Based on 
the correspondence from the FDA in the Type B meeting minutes from April 2019, it also 
will be analyzed at each visit after removing question #4 - I had difficulty falling asleep. 
5.3.6
Patient-Reported Outcomes Measurement Information System Sleep Disturbance –
Short Form 8a (PROMIS SRI SF 8a)
The PROMIS SRI SF 8a [PROMIS Sleep-Related Impairment, 2015] is an 8-item PRO 
measure that evaluates self-reported perceptions of alertness, sleepiness and tiredness during 
usual waking hours and the perceived functional impairments during wakefulness associated 
with sleep problems or impaired alertness. Though this measure does not directly assess 
cognitive, affective or performance impairment, it does measure waking alertness, sleepiness 
and function within the context of overall sleep-wake function. The PROMIS SRI SF 8a is a 
universal rather than disease-specific instrument, and has a 7-day recall period.
Responses to each of the 8 items on the PROMIS SRI SF 8a range from 1 to 5, and the range 
of possible summed raw scores is 8 to 40. Higher scores indicate more of the concept 
measured (sleep-related impairment).
5.3.7
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.
5.3.8
Euro-QoL 5D-5L (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 


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can be combined into a 5-digit number that describes the patient’s health state. The data from 
each of the 5 dimensions will be summarized. 
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.
5.3.9
Work Productivity and Activity Impairment questionnaire specific to VMS 
(WPAI-VMS)
The WPAI-VMS is a 6-item PRO measure that examines VMS-related work productivity and 
activity in the preceding 7 days [Reilly Associates, 2013; Reily et al, 1993]. It consists of 
4 domains: absenteeism (the percentage of work time missed because of VMS in the past 
7 days), presenteeism (the percentage of impairment experienced while at work in the past 
7 days because of VMS), overall work productivity loss (overall work impairment measured 
by combining absenteeism and presenteeism to determine the total percentage of missed 
time) and activity impairment (the percentage of impairment in daily activities because of 
VMS in the past 7 days). If the subject is unemployed, only 2 of the 6 items on this 
questionnaire require completion.
WPAI-VMS outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity (i.e., worse outcomes) [Reilly Associates, 
2013].
5.4
Safety Endpoints
Safety evaluations will include the following endpoints and other safety-related assessments:
●
Frequency and severity of AEs
●
TVUs and endometrial biopsy findings [Analysis to be described in the 52-Week SAP]
●
Change from baseline to each timepoint in vital signs: sitting systolic and diastolic blood 
pressure and pulse rate
●
Change from baseline to each timepoint in ECG parameters
●
Change from baseline to each timepoint in laboratory tests: hematology, biochemistry 
and urinalysis
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 will be conducted using 2-sided tests controlling the overall error 
rate at the 5% significance level, as described in Section 6.4.
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.
As mentioned in the introduction, this analysis plan describes the analyses of the 12-week 
double-blind treatment period.
6.2
Study Population
In general, data such as patient disposition, demographics and baseline characteristics will be 
summarized for FAS population as the definition of FAS is identical to SAF if no patients 
were given wrong study drug. In the event when FAS is not identical to SAF then data will 
be summarized for both FAS and SAF as specified in the relevant sections.
6.2.1
Disposition of Subjects
Disposition of subjects will be summarized for the FAS by treatment group and overall. 
Number of subjects who complete or prematurely discontinue from the 12-week treatment 
period will be summarized by treatment group and overall. For the discontinuations, 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. In addition, number and percentage of subjects excluded from the PPS4 
and PPS12 by reason for exclusion will be summarized for FAS. 
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 including missed visit windows due to COVID-19, and 
impacted diary data due to COVID-19. 


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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
Demographics, tobacco history (smoking status), substance use (e-cigarette, alcohol, 
cannabis), caffeine beverage intake, height and weight, and targeted medical history will be 
summarized descriptively by treatment group and total group for SAF. Note that current 
versus former or never smoking status is a stratification factor for randomization. Age group 
categories include ages within <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. 
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 subjects took after the first dose of study medication and either up to 30 days from last 
dose of study drug, or first dose of study drug during the active treatment extension period, 
whichever comes sooner. 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 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, and >84 days.
Number and percentages of subjects with the following cumulative categories of study drug 
duration will be summarized: ≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 42 days, 
≥56 days and ≥ 84 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 
double-blind treatment period), not to the planned treatment period.


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Percent overall compliance over the 12-week double-blind treatment period will be 
summarized in two ways for the SAF:
●
Descriptive statistics will be presented by treatment group.
●
Percent compliance will be categorized according to the following categories by 
treatment group:
○
< 50%,
○
≥ 50% to < 85%,
○
≥ 85% to < 120%,
○
≥ 120%, and
○
Unknown.
Overall treatment compliance through Week 4 (study day 28 of exposure) will be analyzed in 
a similar manner. 
To explore the impact of the COVID-19 pandemic, additional analysis 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 
All statistical comparisons will be conducted using 2-sided tests at the α = 0.05 significance 
level unless specifically stated otherwise. There are additional testing details below regarding 
the 4 co-primary endpoints. All null hypotheses will be of no treatment difference, all 
alternative hypotheses will be 2-sided and control for 2 comparisons to placebo using the 
Hochberg approach, unless specifically stated otherwise.
The family-wise type I error rate for the 2 active dose groups compared to placebo for the 
4 co-primary efficacy endpoints will be controlled using a Hochberg approach. All 
4 co-primary endpoints must be statistically significant for a given dose to be considered 
successful. Given that, the largest p-value in each dose group will be used to test that dose 
because it represents the least significant of the co-primary endpoints. 
If the larger of the two maximum p-values, one from each dose, is less than 0.05, then both 
dose groups are considered statistically significant. If not, then if the smaller of the p-values 
is less than 0.025, the second compared dose is considered statistically significant. Othewise, 
neither dose is considered statistically significant. The trial will be considered successful if at 
least one dose is statistically significant.
All analysis of efficacy will be presented by treatment group for FAS, unless specified 
otherwise.
In general, the mechanism of missing data due to COVID-19 will be assumed to be missing 
at random (MAR).


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6.4.1
Analysis of Primary Efficacy Endpoints
6.4.1.1 Primary Analysis for Primary Efficacy Endpoints
For each of the 4 co-primary efficacy endpoints, a mixed models repeated measures analysis 
of covariance (MMRM) will be used with treatment group, week (Week 1 through Week 12) 
and smoking status (current vs former/never) as factors, with baseline weight and baseline 
VMS as covariates, as well as an interaction of treatment by week and an interaction of 
baseline measurement by week. 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. This analysis will use a restricted maximum 
likelihood–based repeated-measures approach. The treatment difference will be estimated at 
all study weeks (subtract placebo change from baseline from each fezolinetant response).
MMRM will use all available on-treatment data to inform mean treatment effect estimates 
without requiring explicit imputation for missing data due to intercurrent events (i.e., for 
discontinued subjects). This approach is consistent with the hypothetical strategy used for the 
estimand, which is to compare subjects as though they had continued on the assigned 
treatment. Given the primary objective of the study, the analysis should describe the 
pharmacologic effect of the randomized treatments. The MMRM approach, and the missing 
at random (MAR) assumption, allows us to hypothesize that subjects had continued on 
assigned treatment while not being influenced by how subjects might have done without 
treatment or with alternative treatment(s). 
Comparisons between the fezolinetant and placebo at Week 4 and Week 12 will be calculated 
based on least-squares mean contrasts using a 2-tailed 95% confidence interval (CI) and 
p-values. The LS Means will be estimated using weights proportional to the percentage of 
women who were randomized as current smokers.  Details regarding determination of 
statistical significance can be found in Section 6.4. 
The hypothesis for each pairwise comparison is given as follows:
H0: The change from baseline at week 4 (or 12) for fezolinetant and placebo are the same
H1: The change from baseline at week 4 (or 12) for fezolinetant and placebo are not the same
6.4.1.2 Sensitivity Analysis for Primary Efficacy Endpoints
The following sensitivity analyses will be performed for the primary efficacy endpoints to 
assess the robustness of the primary analysis.
MMRM model based on PPS populations
Supportive analyses will be carried out for the co-primary efficacy endpoints based on the 
PPS populations. The data will be analyzed using the same MMRM model as the primary 
analyses, but the comparison of interest is a particular week within each population (Week 4 
when using PPS4, and Week 12 when using PPS12).


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Simplified MMRM model
The analysis for each of the co-primary endpoints also will be conducted using a simplified 
MMRM model with treatment group and week as factors, with baseline measurement as a 
covariate as well as an interaction of treatment by week and baseline by week.
Discontinuation-reason based multiple imputation
The MMRM analysis that will be used to perform the primary analysis of the primary 
endpoint assumes that missingness is at random. That is, the model assumes that the 
trajectory of VMS events over time for subjects who prematurely discontinue is similar to the 
trajectory for those observed in their own treatment arm which is valid so long as that 
assumption is reasonable.
Discontinuation-reason based multiple imputation (MI) will be used to examine the 
sensitivity of the primary analysis results to departures from that underlying assumption and 
will assess a situation where data for subjects who discontinue early follow a pattern which is 
missing not at random. Specifically, MI will be used for imputation of missing data, using 
“Jump to Reference” algorithm (where placebo is the reference group) [Carpenter et al. 2013] 
for subjects who discontinue active treatment due to AEs (AE reported as primary study drug 
treatment status in the End of Treatment eCRF). The analysis will be implemented using the 
general three-step process (imputation phase, followed by analysis phase, followed by 
pooling phase) described in O’Kelly and Ratitch, 2014.
1.
The imputation phase will implement MI via sequential modelling for the “Jump to 
Reference” algorithm. In particular, when implementing the “Jump to Reference” 
algorithm via sequential modelling, this means that only baseline values are used in the 
imputation of missing values for subjects in the fezolinetant 30 mg or 45 mg groups who 
discontinue due to AEs (this variation of the “Jump to Reference” algorithm is also 
referred to as the “Unconditional Reference” approach). The imputation phase will 
generate M imputed datasets, where M=30.
2.
The analysis phase will perform the primary MMRM analysis model of the primary 
efficacy endpoint as described in Section 6.4.1.1 for each of the M imputed datasets.
3.
Rubin’s rules will be used to generate an overall set of pooled results which combines 
the analysis results from the M imputed datasets.
The overall set of pooled results will present:
●
Least squares (LS) mean estimates, SE and 2-sided 90% confidence interval (CI) for 
mean change from baseline to Week 12 within a treatment group (fezolinetant 30 mg or 
45 mg, placebo),
●
The difference in LS means for fezolinetant 30 mg or 45 mg versus placebo, SE for the 
difference and 2-sided 90% CI for the difference at Week 4 and Week 12,
●
Two-sided p-value for fezolinetant 30 mg or 45 mg versus placebo at Week 4 and 
Week 12, obtained using the difference in the LS means.
●
Descriptive summary statistics at Week 4 and Week 12 will be derived using the mean of 
the M imputed datasets. 


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COVID-19 Impact 
The primary analysis will be repeated by excluding diary data that are impacted by 
COVID-19, which includes the diary data recorded after the subjects were diagnosed of 
COVID-19, after study drug discontinuation due to COVID-19, and during dose interruption 
due to COVID-19.  
6.4.1.3 Subgroup Analysis for Primary Efficacy Endpoint
The co-primary efficacy endpoint analyses will be repeated for the following subgroups using 
the simplified MMRM model. However, p-values for treatment difference will not be 
provided. Descriptive statistics and least square mean (SE) will be provided for each 
subgroup. 
The subgroups will be defined below. 
●
Smoking status (current versus former/never), per randomization strata.
●
Race (African-American vs Non-African-American, Asian vs Non-Asian, White vs 
Non-White) 
●
BMI (>=18.5 kg/m2 to <25 kg/m2, >=25 kg/m2 to <30 kg/m2, >=30 kg/m2)
●
Age (<55, >=55)
For subjects who are recorded more than one race, the subjects will be excluded from the 
race subgroups, except: 
●
If no African-American is recorded, then the subject is included in Non-African-
American subgroup 
●
If no Asian is recorded, then the subject is included in Non-Asian subgroup
●
If no White is recorded, then the subject is included in Non-White subgroup.
6.4.2
Analysis of Key Secondary Efficacy Endpoint
The PROMIS SD SF 8b scale will be analyzed using MMRM, similar to the primary analysis 
of the co-primary endpoints, with spatial power as the backup covariance structure.
If all the co-primary endpoints are statistically significant between fezolinetant and placebo at 
both doses, then the 5% alpha from the analysis of the co-primary endpoints will be passed to 
the key secondary endpoint as part of the family-wise error rate.
As a sensitivity analysis, the analysis will be repeated by excluding data that are impacted by 
COVID-19, which includes 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 due to COVID-19 recorded in the 
eCRF. 


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6.4.3
Analysis of Secondary Efficacy Endpoints
The mean change in the frequency and severity of moderate and severe VMS from baseline 
to each week up to week 12 comes from the same model as the co-primary analyses, but 
examines the results at all weeks.
For percent reduction at weeks 4 and 12, an MMRM model as described in Section 6.4.1.1
will be used.
For each of the secondary responder endpoints, logistic regression will be used for the 
analysis for each week and endpoint. The analyses will include the treatment group and 
smoking status (current vs. former/never) as factors and baseline measurement (mean 
frequency of vasomotor symptoms) as a covariate.
For these responder endpoints, the number of subjects who achieve the reduction will be 
summarized by study week with descriptive statistics for each treatment arm. A 
Kaplan-Meier estimate will be used to estimate the time to response. Smooth average (SA)
will be used for the time to response. SA value for day X-1, day X and Day X+1 would be 
assigned to day X. The time to response will be the first day with at least 50% (or 100%, or 
the exploratory endpoints 75%, 90%) response for both original numbers and SA number.
For the non-responders, it will be censored at the end of the last day of the double-blind 
treatment (e.g., 8am the following day).
Comparisons between the fezolinetant and placebo will be calculated based on the odds ratio
using a 2-tailed 95% confidence interval (CI) and p-values. 
PGI-C VMS score will be analyzed using Cochran Mantel Haenszel (CMH) test with 
modified ridit scores. 
For the changes in the frequency and severity of moderate and severe VMS from baseline to 
each week up to week 12 that are derived from diary data, the analysis will be repeated by 
excluding diary data that are impacted by COVID-19, which includes the diary data recorded 
after the subjects were diagnosed of COVID-19, after study drug discontinuation due to 
COVID-19, and during dose interruption due to COVID-19.  
For the PGI-C VMS scores that are collected by visit, the analysis will be repeated by 
excluding data that are impacted by COVID-19, which includes 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 due to 
COVID-19 recorded in the eCRF. 
6.4.4
Analysis of Exploratory Endpoints
Assessment of the mean change in the frequency and severity of mild, moderate and severe 
VMS from baseline to each week up to week 12 will be analyzed using the same MMRM 
model as the primary analyses.
For non-VMS efficacy endpoints Visits are used rather than weeks, as described in 
Section 6.10.1.1.


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Percent reduction, PROMIS (SD and SRI total scores), MENQOL (domain and total scores), 
and WPAI-VMS domain scores will be assessed using an MMRM model as described in 
[Section 6.4.1.1 Co-Primary Analysis]. 
VMS responders will be analyzed as described for the secondary responder endpoints. 
PGI-S and PGI-C (SD) and EQ-5D domain scores will be summarized and analyzed using 
Cochran Mantel Haenszel (CMH) test with modified ridit scores. PGI-S and EQ-5D will also 
be adjusted for the baseline score. The mean and standard deviation will also be provided for 
the EQ-5D domain scores.  
The severity calculation excludes mild events at both baseline and post-baseline, using the 
same model as the primary analyses.
The mean change in the severity of moderate and severe VMS from baseline to each week up 
to week 12 (both baseline and post-baseline severity include only moderate and severe VMS 
events in the calculation) will be analyzed using the same MMRM model as the primary 
analyses. 
The median change in serum concentrations of sex hormones and sex hormone-binding 
globulin (SHBG) from baseline to weeks 4 and 12 will be summarized.
The daily frequency of moderate and severe VMS for the first week will be summarized and 
graphically displayed by each day.  
Anexploratory analysis will be conducted using the thresholds for clinical meaningful within 
subject change from an anchor based analysis.
In order to provide further context for interpretation of change in the frequency of hot flashes, 
the anchor based analysis will be conducted to empirically define the threshold for 
meaningful within-subject reduction. A separate Psychometric Analysis Plan (PAP) [RTI 
Health Solutions] will provide the detailed description of the psychometric analytic methods 
to be used in determining the clinically meaningful within-subject reductions at week 4 and 
week 12. The thresholds will be estimated according to the prespecified PAP. 
A subject will be classified as a responder if her change from baseline to Week 4 is equal or 
larger than the threshold at Week 4. Similarly, a subject will be classified as a responder if 
her change from baseline to Week 12 is equal or larger than the threshold at Week 12. 
A logistic regression analysis will be conducted to compare each dose of fezolinetant to 
placebo. The logistic regression model will include the treatment group and smoking status 
(current vs. former/never) as factors, and baseline mean frequency of vasomotor symptoms as 
a covariate. Missing data will be imputed by considering the following approaches: 
(1) last-observation-carried-forward (primary), (2) missing as a non-responder, and (3) 
including observed cases only. Odds ratio (fezolinetant over placebo), its 2-sided 95% CI and 
nominal p-value will be presented. 
This analysis will be conducted using the thresholds that are calculated from the pooled 
studies (ASP2693-CL-0301 and ASP2693-CL-0302) in the Integrated Summary of Efficacy 


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(ISE). An additional analysis will be conducted using the thresholds that are calculated from 
each study to further characterize the study results.
6.5
Analysis of Safety
All analysis of safety will be presented by treatment group for SAF, unless specified 
otherwise. For analyses by visit, the visit windows from Section 6.10.1.2 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.
6.5.1
Adverse Events
Per protocol, a TEAE is defined as an AE observed after starting administration of the study 
drug and up to 21 days after the last dose of the study drug. 
A TEAE during the DB period, is defined as an AE observed after starting administration of 
the study drug and up to 21 days after the last dose of the double-blind study drug, and before 
the first dose of  treatment for extension phase for subjects who entered extension treatment 
period. 
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 drug related TEAEs,
●
Number of serious TEAEs,
●
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.


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The number and percentage of subjects with TEAEs in the following AE categories will be 
summarized 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% 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 
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.
Following adverse events of special interest are defined:
●
Adverse event of uterine bleeding
●
Endometrial hyperplasia, cancer, or disordered proliferative endometrium
●
Adverse event of thrombocytopenia
●
Adverse event of liver test elevations 
●
Adverse event of bone fractures
●
Adverse events of abuse liability
●
Adverse events of depression
●
Adverse events of wakefulness 
●
Adverse events of effect on memory  
Search terms defining the AESIs will be pre-specified and separately documented.  
The number and percentage of subjects with AESIs, as classified by PT will be separately 
summarized for each treatment group and listings of these adverse events will be provided.
The number and percentage of subjects with TEAEs associated with COVID-19, as classified 
by SOC and PT, will be summarized for each treatment group and overall. 


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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.
The number and percentage of subjects below and above reference range will be summarized 
for each treatment group at each visit.
Number and percentage of subjects with platelets < 150000/uL (150 109/L) will also be 
summarized. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit.
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]).
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. 
6.5.2.1 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 
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 double-blind investigational period (from day of first 
dose of study drug until first dose of double-blind treatment period) 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 > 3xULN) and ALP< 2xULN and Total Bilirubin > 2xULN


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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 period. The number and 
percentage of subjects meeting the criteria during the double-blind 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) 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 and time point, including changes 
from baseline.
Number and percent of subjects with normal and abnormal results as assessed by the central 
reader for the 12 lead ECG will be tabulated by treatment group at each treatment visit and 
time point.
The QTc interval will be summarized using frequency tables for each treatment visit and time 
point 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.


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6.5.5
Other Safety-Related Assessments
C-SSRS results will be summarized by treatment group and visit.
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 (LH, FSH, E2, Testosterone Total/Free, 
Androstenedione, DHEA, Estrone) and 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 during the double-blind treatment phase will be calculated 
as date of visit/assessment – first dose date +1.  
Study Day for the follow-up phase will be calculated as date of visit/assessment – last dose 
date of double-blind treatment.
As noted in Section 1, only data pertaining to the double-blind treatment phase will be used
in the 12-week treatment phase analysis:
●
The active treatment extension period data (beginning from the second day of the
active treatment extension period) will be excluded, assuming the Week 12 
assessments are done before the first dose of active treatment extension period.
●
Follow-up data that also falls into the active treatment extension period will be 
excluded (i.e., early discontinuations within the active treatment extension period
phase).


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6.10.1.1 Efficacy Analysis Windows
For the analysis windows (weeks prior to the extension period), the last day is always the last 
day of exposure to double-blind treatment. For VMS diary data the last day of exposure 
includes events reported until 8:00AM the following day. For example, the Week 1 average 
will include diary data from 8AM on Day 1 through 7:59AM on Day 8.
For both VMS and non-VMS efficacy, the end of overall treatment is defined as the last day 
of treatment (e.g., discontinued study or entered follow-up period) and the follow-up period 
begins at last overall treatment + 1 day.
The study week determination for the vasomotor symptoms data is based on the following:
Analysis study week
Analysis window
Baseline
Non-missing days from D-10 up to and including D-1
Week 1
D1 to D7
Week 2
D8 to D14
Week 3
D15 to D21
Week 4
D22 to D28
Week 5
D29 to D35
Week 6
D36 to D42
Week 7
D43 to D49
Week 8
D50 to D56
Week 9
D57 to D63
Week 10
D64 to D70
Week 11
D71 to D77
Week 12
D78 to D84 
Extension period visits
Defined in extension period SAP
A weekly average will be calculated if any information, including zero VMS events, for 4 or 
more days was reported.
All other efficacy assessments, including those from unscheduled visits and regardless of 
visit label, will be allocated to analysis visits based on the table below:
Target day
Analysis window
Analysis visit
D1 
last non-missing value on or prior to day 1
Baseline
D29
D22 to D36
Week 4
D85
D72 to Day 92
Week 12
Beginning on Day 99
Defined in extension period SAP
Extension period visits
If more than one observation exists within the analysis window, the observation closest to the 
scheduled visit day will be selected for that visit. If there are two observations that have the 
same distance from the scheduled day, the value that is before the scheduled day will be 
selected in the analysis. If more than one observation is made on the same day, an average 
value if continuous, or the worst value if categorical, will be included in the analysis.




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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 
The changes from the Version 1 to Version 2 that may impact the statistical analyses are 
listed in the table below: 
SAP Sections
Description
Rationale
Relevant 
sections 
Added additional statistical analysis due to 
COVID-19 
To evaluate potential impact of 
COVID-19
5.2.2
Moved PGI-C to Secondary endpoints 
Section 
To be consistent with the protocol 
amendments (version 3.0)
5.3
Added 75%, 90% responder endpoints
To add clinically relevant 
exploratory endpoints 
5.3, 5.3.1 
Added an endpoint in the severity of 
moderate and severe VMS (include only 
moderate and severe VMS events in the 
calculation) 
To extend the endpoints in a 
sensitivity analysis to exploratory 
endpoints for all visits
5.3, 5.3.1, 
6.4.4  
Added an endpoint in daily frequency of 
moderate and severe VMS for the first 
week
To explore early onset by adding 
daily VMS frequency for the first 
week
5.3.1, 6.4.4
Removed Frequency and severity of 12-
hour daytime and nighttime VMS events.
Planned not to perform analysis on 
the 12-hour daytime and nighttime 
VMS events
6.2.3, 6.2.4
Removed analysis on FAS from 
demographics and baseline characteristics, 
medical history/medication Sections 
The planned analysis on SAF is 
sufficient to provide information
6.4.1.3
Added subgroup on Age (<55, >=55)
To add medically meaningful 
subgroups    
6.4.1.4
Added conditional analysis based on 
clinical meaningfulness of the statistical 
change in moderate to severe hot flash 
frequency  
Potentially in supporting the 
primary endpoints  
6.5.1 
Modified the list of AESIs 
To be consistent with the protocol 
amendments (version 3.0)
6.5.2.1
Added a category for liver assessment, 
(ALT or AST > 3xULN) and ALP< 
2xULN and Total Bilirubin > 1.5xULN
To be aligned with CIOMS 
Guidance 2020 
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     


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7.2
List of Changes in SAP Version 3.0 
The changes from the Version 2 to Version 3 that may impact the statistical analyses are 
listed in the table below: 
SAP Sections
Description
Rationale
6.4.1.4, 6.4.4
Removed Section 6.4.1.4 on conditional 
analysis based on clinical meaningfulness of 
the statistical change in moderate to severe 
hot flash frequency, and added the analysis to 
Section 6.4.4 (Analysis of Exploratory 
Endpoints)  
To reflect FDA’s feedback.
6.5.2.1
Removed the category for liver assessment, 
(ALT or AST > 3xULN) and ALP< 2xULN 
and Total Bilirubin > 1.5xULN
The analysis of this category is 
only planned for Integrated 
Summary of Safety.  


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8
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JoAnn V. Pinkerton, Ginger Constantine, Eunhee Hwang, Ru-fong J. Cheng Desvenlafaxine 
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Sponsor: Astellas Pharma Inc.
SAP Version 3.0
ISN/Protocol 2693-CL-0302
30-Sep-2020
Astellas
Page 37 of 38
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, all planned subjects were randomized into the study before Astellas paused 
recruitment in all their clinical studies on March 30, 2020. 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
6.4
Analysis of Efficacy
6.4.1.2
Sensitivity Analysis for Primary Efficacy Endpoints
6.4.2
Key Secondary Endpoints
6.4.3
Secondary Endpoints
6.5.1
Adverse Events
6.5.2.1
Clinical Laboratory Evaluation 


Sponsor: Astellas Pharma Inc.
SAP Version 3.0
ISN/Protocol 2693-CL-0302
30-Sep-2020
Astellas
Page 38 of 38
9.2
Appendix 2
Author and Approver Signatures
E-signatures are attached at the end of document. 
Signatures: 
Prepared by:
E-signatures are attached at end of document
Date:
 
Date (DD Mmm YYYY)
Approved by:
E-signatures are attached at end of document
Date:
Date (DD Mmm YYYY)
Approved by:
E-signatures are attached at end of document
Date:
Date (DD Mmm YYYY)
PPD
PPD
PPD