Clinical trial NCT03192176
Conditions: Menopause Hot Flashes
Keywords: Vasomotor symptoms Menopause Hot flashes Perimenopause
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2017-07-19; Completion date: 2018-09-19
Enrollment: 356 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study determined the effects of different doses and dosing regimens of ESN364 on the frequency and severity of hot flashes. The treatment was administered for 12 weeks to postmenopausal women, aged 40 to 65, suffering at least 50 moderate to severe hot flashes per week.

Detailed description:
This was a 12-week randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multi-center study to assess the efficacy of ESN364 in postmenopausal women suffering from vasomotor symptoms (hot flashes).

This study consisted of a screening period (Days -35 to -1, including the screening visit \[Visit 1\] and a minimum 7-day collection of baseline vasomotor symptom frequency and severity assessments), a 12 week treatment period (Day 1 \[Visit 2\] to Week 12 \[Visit 5\]), and a follow up visit (Week 15 \[Visit 6\]) 3 weeks after the last dose of study drug.

The study was performed on an ambulatory basis. The screening visit (Visit 1) occurred up to 35 days prior to randomization. Eligibility was assessed via physical examination, clinical laboratory testing, vital signs, ECG, Pap smear, mammography, and endometrial biopsy. Subjects received an electronic diary to record daily vasomotor symptoms during the duration of the screening period. Subjects who had ≥7 consecutive days of vasomotor symptom recordings participated in the study. Subjects are encouraged to continue recording for the duration of the whole screening period. The electronic diary was reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects were rescreened 1 time upon approval of the medical monitor.

During the treatment period, subjects returned to the study site every 4 weeks for assessments.

The follow-up visit occurred approximately 3 weeks following the last dose of study drug.

Arms: arm 1: Participants received fezolinetant matching placebo capsules orally, BID for a period of 12 weeks. arm 2: Participants received fezolinetant 15 mg capsules orally, BID for a period of 12 weeks. arm 3: Participants received fezolinetant 30 mg capsules orally, BID for a period of 12 weeks. arm 4: Participants received fezolinetant 60 mg capsules orally, BID for a period of 12 weeks. arm 5: Participants received fezolinetant 90 mg capsules orally, BID for a period of 12 weeks. arm 6: Participants received fezolinetant 30 mg capsules orally, QD and matching placebo QD for a period of 12 weeks. arm 7: Participants received fezolinetant 60 mg capsules orally, QD and matching placebo QD for a period of 12 weeks. arm 8: Participants received fezolinetant 120 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.
Interventions: intervention 1: Fezolinetant intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Capsule intervention 2: Oral Capsule

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging, 
Phase 2b Study to Investigate the Efficacy of ESN364 in 
Postmenopausal Women Suffering From Vasomotor Symptoms 
(Hot Flashes) 
Investigational Product: ESN364 
Protocol Number: ESN364_HF_205 
Sponsor: 
Ogeda S.A.  
47 Rue Adrienne Bolland  
6047 Gosselies, Belgium 
Telephone: +32 71 348 510 
Fax: +32 71 348 519 
Version Number: 4.0 
Date: 01 Aug 2018 
Original Protocol: 27 April 2017 
Amendment 1: 06 December 2017 
Amendment 2: 05 March 2018 
Amendment 3: 01 Aug 2018 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Ogeda S.A. except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Ogeda S.A. You are allowed to 
disclose the contents of this document only to your Institutional Review Board (IRB) and study 
personnel directly involved with conducting this protocol. Persons to whom the information is 
disclosed must be informed that the information is confidential and proprietary to Ogeda S.A. 
and that it may not be further disclosed to third parties. 
NCT03192176




Ogeda S.A. 
Clinical Study Protocol ESN364_HF_205 
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Protocol Version 4.0 (incl. Amendments) 
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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Ogeda S.A. to study personnel under my supervision. I will discuss this material with them to 
ensure they are fully informed about the study product and study procedures. I will let them know 
that this information is confidential and proprietary to Ogeda S.A. and that it may not be further 
disclosed to third parties. I understand that the study may be terminated or enrollment suspended 
at any time by Ogeda S.A., with or without cause, or by me if it becomes necessary to protect the 
best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration (FDA) 
Regulations, IRB Regulations, and International Council for Harmonisation (ICH) Guidelines for 
Good Clinical Practice (GCP). 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  


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SYNOPSIS 
TITLE:  A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging, Phase 2b Study to 
Investigate the Efficacy of ESN364 in Postmenopausal Women Suffering From Vasomotor 
Symptoms (Hot Flashes)  
PROTOCOL NUMBER:  ESN364_HF_205 
INVESTIGATIONAL PRODUCT:  ESN364 (International nonproprietary name: Fezolinetant)
PHASE:  2b 
INDICATION:  Postmenopausal vasomotor symptoms (hot flashes) 
OBJECTIVES: 
The primary objective of this study is to evaluate the effect of different doses and dosing regimens 
of ESN364 on frequency and severity of vasomotor symptoms (hot flashes).  
The secondary objectives of this study are the following: 
• To evaluate the effect of different doses and dosing regimens of ESN364 on the frequency, 
severity, and hot flash score of mild, moderate, and severe vasomotor symptoms;  
• To evaluate the effect of different doses and dosing regimens of ESN364 on responder rates 
using variation of responder definitions;  
• To evaluate the effect of different doses and dosing regimens of ESN364 on patient-reported 
outcomes;  
• To evaluate the effect of different doses and dosing 
regimens of ESN364 on 
pharmacodynamics markers (hormones and bone markers); and 
• To evaluate the effect of different doses and dosing regimens of ESN364 on safety and 
tolerability.  
The exploratory objectives of this study are the following: 
• 
 
  
• To evaluate the pharmacokinetic (PK) plasma concentrations of ESN364 and metabolite 
  
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POPULATION: 
The population for this study is postmenopausal women >40 years and 65 years of age with at 
least 50 moderate to severe vasomotor symptoms (hot flashes) per week.  
Inclusion Criteria: 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Women >40 years and 65 years of age at the screening visit; 
2. A body mass index between 18 kg/m2 to 38 kg/m2 (extremes included);  
3. Spontaneous amenorrhea for 12 consecutive months; or 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 (with 
or without hysterectomy);  
4. At least 50 moderate to severe vasomotor symptoms per week (ie, 7 consecutive days), as 
recorded in the daily diary during the screening period; 
5. 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 electrocardiogram (ECG)
within the reference range for the population studied, or showing no clinically relevant 
deviations, as judged by the Investigator; 
6. Women >40 years of age who have documentation of a normal/negative or no clinically 
significant findings mammogram (obtained at Screening or within the prior 9 months of trial 
enrollment). Appropriate documentation includes a written report or an electronic report 
indicating normal/negative or no clinically significant mammographic findings; 
7. Willing to undergo a transvaginal ultrasound to assess endometrial thickness at screening and
at Week 12 (end-of-treatment), and for subjects who are withdrawn from the study prior to 
completion, at the Early Termination (ET) Visit. This is not required for subjects who have 
had a partial (supracervical) or full hysterectomy; 
8. Willing to undergo an endometrial biopsy at screening (in the event that the subject’s 
transvaginal 
ultrasound 
shows endometrial 
thickness 
4 mm) and at Week 12 
(end-of-treatment – all subjects), for subjects with uterine bleeding, and for subjects who are 
withdrawn from the study prior to completion, at the ET Visit if study drug exposure is
10 weeks. This is not required for subjects who have had a partial (supracervical) or full 
hysterectomy;  
9. Negative alcohol breath test and negative urine test for selected drugs of abuse (amphetamines, 
tricyclic antidepressants, cocaine, or opiates) at the screening visit; 
10. Negative urine pregnancy test;  
11. Negative serology panel (including hepatitis B surface antigen, hepatitis C virus antibody, and 
human immunodeficiency virus antibody screens); 


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12. Informed Consent Form signed voluntarily before any study-related procedure is performed, 
indicating that the subject understands the purpose of and procedures required for the study 
and is willing to participate in the study; and 
13. Documentation of a normal Pap smear (or equivalent cervical cytology) or of no clinical 
significance in the opinion of the Investigator within the previous 9 months or at screening. 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Use of a prohibited therapy (hormone therapy, hormonal contraceptive, or vasomotor 
symptom medication [prescription, over the counter, or herbal]) or not willing to wash out 
drugs; 
2. History (in the past year) or presence of drug or alcohol abuse; 
3. Previous or current history of a malignant tumor, except for basal cell carcinoma; 
4. Uncontrolled hypertension and a systolic blood pressure 140 mmHg and/or a diastolic blood 
pressure 90 mmHg; 
5. Judged by the Investigator to be unsuited to participate in the study based on findings observed 
during physical examination, vital sign assessment, or 12-lead ECG; 
6. History of severe allergy, hypersensitivity, or intolerance to drugs in general, including the 
study drug and any of its excipients; 
7. Exclusion criterion 7 has been removed in Amendment 1; 
8. An unacceptable result from endometrial biopsy (performed when endometrial thickness is 
4 mm measured by transvaginal ultrasound) of endometrial hyperplasia, endometrial cancer, 
or inadequate specimen at screening (1 repeat biopsy permitted if technically possible);  
9. History of endometrial hyperplasia or uterine/endometrial cancer; 
10. History of unexplained uterine bleeding; 
11. History of seizures or other convulsive disorders; 
12. Medical condition or chronic disease (including history of neurological [including cognitive], 
hepatic, renal, cardiovascular, gastrointestinal, pulmonary [eg, moderate asthma], endocrine,
or gynecological disease) or malignancy that could confound interpretation of the study 
outcome; 
13. Presence or sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere 
with the absorption, distribution, metabolism, or excretion mechanisms of drugs as judged by 
the Investigator;  
14. Active liver disease or jaundice, or values of alanine aminotransferase and aspartate 
aminotransferase >1.5  the upper limit of normal (ULN); or total bilirubin >1.5  ULN; or 
creatinine >1.5  ULN; or estimated glomerular filtration rate (eGFR) using the Modification 
of Diet in Renal Disease formula 59 mL/min/1.73 m2 at the screening visit; 


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15. Concurrent participation in another interventional study (or participation within 3 months prior 
to screening in this study); 
16. Suicide attempt in the past 3 years;  
17. Unable or unwilling to complete the study procedures; or 
18. Subject is the Investigator or any sub-Investigator, research assistant, pharmacist, study 
coordinator, or other staff or relative thereof, who is directly involved in the conduct of the 
study. 
STUDY DESIGN AND DURATION: 
This is a 12-week randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, 
multicenter study to assess the efficacy of ESN364 in postmenopausal women suffering from 
vasomotor symptoms (hot flashes).  
This study will consist of a screening period (Days -35 to -1, including the screening visit [Visit 1] 
and a minimum 7-day collection of baseline vasomotor symptom frequency and severity 
assessments), a 12-week treatment period (Day 1 [Visit 2] to Week 12 [Visit 5], including safety 
visits at Week 2 [Visit 2A], Week 6 [Visit 3A], and Week 10 [Visit 4A]), and a follow-up visit
(Week 15 [Visit 6]) approximately 3 weeks after the last dose of study drug, for a total of 9 visits. 
The study will be performed on an ambulatory basis.  
The screening visit (Visit 1) will occur up to 35 days prior to randomization. Eligibility will be 
assessed via physical examination, clinical laboratory testing, vital signs, ECG, Pap smear, 
mammography, and endometrial biopsy. Subjects will receive an electronic diary in which to 
record daily vasomotor symptoms during the duration of the screening period. Subjects must have
7 consecutive days of vasomotor symptom recordings to participate in the study. Subjects are 
encouraged to continue recording for the duration of the whole screening period. The electronic 
diary will be reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects 
may be rescreened 1 time upon approval of the medical monitor. 
During the treatment period, subjects will return to the study site every 2 weeks for assessments.  
The follow-up visit will occur approximately 3 weeks following the last dose of study drug.  
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Subjects will be randomized to 1 of 8 treatment groups in an equal ratio:  
• ESN364 15 mg twice daily (BID), 
• ESN364 30 mg BID, 
• ESN364 60 mg BID, 
• ESN364 90 mg BID, 
• ESN364 30 mg once daily (QD) + placebo QD, 
• ESN364 60 mg QD + placebo QD, 


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• ESN364 120 mg QD + placebo QD, or 
• Placebo BID. 
ESN364 capsules will be taken orally with a glass of room temperature tap water.  
ENDPOINTS FOR EVALUATION: 
Co-Primary Efficacy Variables  
The primary efficacy objective will require the evaluation of the effect of ESN364 on the 
following 4 co-primary variables:  
• Mean change in the frequency of moderate to severe vasomotor symptoms from baseline to 
Week 4; 
• Mean change in the frequency of moderate to severe vasomotor symptoms from baseline to 
Week 12;  
• Mean change in the severity of moderate to severe vasomotor symptoms from baseline to 
Week 4; and 
• Mean change in the severity of moderate to severe vasomotor symptoms from baseline to 
Week 12.  
Secondary Efficacy Variables 
The secondary efficacy variables include the effect of ESN364 on the following:  
Vasomotor Symptom Variables:  
• Mean change in the frequency of mild, moderate, and severe vasomotor symptoms from
baseline to each study week;  
• Mean change in the frequency of moderate and severe vasomotor symptoms from baseline to 
each study week;  
• Mean change in the severity of mild, moderate, and severe vasomotor symptoms from baseline 
to each study week;  
• Mean change in the severity of moderate and severe vasomotor symptoms from baseline to 
each study week;  
• Mean change in the hot flash score of mild, moderate, and severe vasomotor symptoms from 
baseline to each study week;  
• Mean change in the hot flash score of moderate and severe vasomotor symptoms from baseline 
to each study week; 
• Mean percent reduction of mild, moderate, and severe vasomotor symptoms from baseline to 
each study week; and 
• Mean percent reduction of moderate and severe vasomotor symptoms from baseline to each 
study week. 


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Responder Variables:  
• Mean percent reduction of 50%, 70%, 90%, and 100% of mild, moderate, and severe 
vasomotor symptoms from baseline to each study week; 
• Mean percent reduction of 50%, 70%, 90%, and 100% of moderate and severe vasomotor 
symptoms from baseline to each study week; 
• Absolute reduction of 2, 3, 4, and 5 in mean number of mild, moderate, and severe vasomotor 
symptoms per day from baseline to each study week; and 
• Absolute reduction of 2, 3, 4, and 5 in mean number of moderate and severe vasomotor 
symptoms per day from baseline to each study week.  
Patient-Reported Outcome Variables:  
• Change in Hot Flash-Related Daily Interference Scale (HFRDIS), Leeds Sleep Evaluation 
Questionnaire (LSEQ), Greene Climacteric Scale (GCS), and Menopause-Specific Quality of 
Life (MENQoL) questionnaire from baseline to Weeks 4, 8, 12, and 15.  
Pharmacodynamic Variables: 
• Change over time from baseline to Week 12 in plasma concentrations of luteinizing hormone
(LH), follicle-stimulating hormone (FSH), estradiol (E2), and sex hormone-binding globulin
(SHBG).  
Exploratory Variables 
  
 
 
 
 
• Level of PK plasma concentrations of ESN364 and metabolite 
 at pre-specified 
timepoints.   
Safety Variables 
The safety variables include the following:   
• Incidence and severity of treatment-emergent adverse events; 
• Endometrial health assessment (transvaginal ultrasound  endometrial biopsy); 
• Vital signs (sitting systolic and diastolic blood pressure and pulse rate); 
• Laboratory tests (hematology, biochemistry, urinalysis, and coagulation); 
• ECG parameters; 
• Plasma bone density marker concentrations; 
• Physical examinations; and 
• Columbia Suicide Severity Rating Scale (C-SSRS). 
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STATISTICAL ANALYSES: 
Analysis Populations 
All primary and secondary efficacy endpoints will be analyzed using the Full Analysis Set (FAS). 
The Per Protocol Analysis Set (PPAS) will be used only for the analysis of the selected endpoints
to examine the robustness of the primary analysis. 
Safety and tolerability will be analyzed using the Safety Analysis Set. 
Safety Analysis Set: The Safety Analysis Set comprises all subjects who receive at least 1 dose of 
study drug. 
Full Analysis Set: The FAS comprises the subset of the Safety Analysis Set who have a baseline 
and post-baseline efficacy evaluation.  
Per Protocol Analysis Set: The PPAS comprises the subset of subjects from the FAS who are 
treated according to the protocol without any major deviations. A full list of inclusion criteria will 
be decided and assessed prior to database lock and unblinding. 
Pharmacokinetic Analysis Set: The PK Analysis Set comprises the subset of the Safety Analysis 
Set who provide evaluable PK assessments. 
Efficacy Analysis 
Primary Efficacy Analysis: The 4 co-primary efficacy endpoints are the mean change in the 
frequency of moderate to severe vasomotor symptoms and the mean change in severity of 
vasomotor symptoms from baseline to Week 4 and Week 12. 
For each of the 4 co-primary efficacy endpoints, an analysis of covariance model will be used with 
treatment group, pooled center, and smoking status as factors, with baseline weight and baseline 
measurement as covariates. Pairwise comparisons between the active doses and placebo will be 
calculated based on least-squares mean contrasts using a 2-tailed 95% confidence interval (CI).
For subjects in the efficacy analysis populations with missing primary efficacy endpoints, multiple 
imputation by fully conditional specification methods will be used. The imputation model will use 
subject demographics (age, sex, race, baseline weight, and smoking status) and baseline and 
post-baseline mean number and severity of vasomotor symptoms. Sensitivity analyses will be 
performed with other multiple imputation methods and mixed model for repeat measurements.  
Since the study design requires the comparison of 7 active dose groups with placebo for 
4 co-primary efficacy variables, a two-tier closed testing procedure will be used to control the 
family-wise error. A step-down testing procedure will be followed. The following testing order of 
doses will be employed: 
a. Placebo versus 90 mg BID (daily dose 180 mg), 
b. Placebo versus 60 mg BID (daily dose 120 mg), 
c. Placebo versus 120 mg QD (daily dose 120 mg), 
d. Placebo versus 30 mg BID (daily dose 60 mg), 
e. Placebo versus 60 mg QD (daily dose 60 mg), 
f. Placebo versus 15 mg BID (daily dose 30 mg), and 
g. Placebo versus 30 mg QD (daily dose 30 mg). 


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The 4 co-primary efficacy endpoints will be compared at each dose level. Only when ESN364 is 
proved to be significantly better than placebo at a 2-sided alpha level of 0.05 for all 4 co-primary 
efficacy endpoints will this dose level be claimed to be superior to placebo. A failure to prove the 
significance for 1 or more co-primary efficacy endpoints will lead to a failure to claim superiority 
to placebo at this dose level, and the other dose levels after this one in the sequence will not be 
tested. 
The primary efficacy analysis will be based on the FAS. A supportive analysis will be carried out 
for the co-primary efficacy variables based on the PPAS to examine the impact of premature 
dropouts and/or major protocol deviations. 
Secondary Efficacy Analysis: Efficacy will be further assessed based on the secondary endpoints 
described above using the FAS. 
Safety Analysis 
Safety will be assessed by examining the incidence of adverse events, physical examination
findings, C-SSRS, vital signs, ECGs, clinical laboratory tests, and bone density marker 
concentrations over time using the Safety Analysis Set. 
SAMPLE SIZE DETERMINATION: 
A total of 352 subjects are planned to be randomized, 44 subjects in each treatment arm. This is 
based on the observed data for severity and frequency of moderate and severe vasomotor 
symptoms from the Phase 2a study. Sample size calculations from statistical analysis software 
were based on 2-sample t-tests, assuming 2-sided 5% alpha and power of >90% for expected effect 
sizes.  
SITES: Approximately 55 sites in the United States 
SPONSOR: 
Ogeda S.A.  
47 Rue Adrienne Bolland  
6047 Gosselies, Belgium 
Telephone: +32 71 348 510 
Fax: +32 71 348 519 


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TABLE OF CONTENTS 
Signature Page......................................................................................................................... 2 
Investigator Agreement............................................................................................................ 3 
Synopsis.................................................................................................................................. 4 
Table of Contents ...................................................................................................................12 
List of Tables .........................................................................................................................17 
List of Figures ........................................................................................................................18 
List of Abbreviations and Definition of Terms .........................................................................19 
1 
Introduction and Background Information .........................................................................21 
1.1 
Background Information ..........................................................................................21 
1.1.1 
Vasomotor Symptoms (Hot Flashes) .............................................................21 
1.1.2 
Introduction to ESN364 (International Nonproprietary Name: Fezolinetant) ...21 
1.2 
Summary of Nonclinical Studies ..............................................................................24 
1.3 
Clinical Studies........................................................................................................25 
1.3.1 
Summary of Clinical Studies.........................................................................25 
1.3.2 
Effects of ESN364 (Fezolinetant) ..................................................................26 
1.4 
Rationale .................................................................................................................28 
1.5 
Risk/Benefit ............................................................................................................28 
2 
Study Objectives...............................................................................................................30 
2.1 
Primary Objective ....................................................................................................30 
2.2 
Secondary Objectives...............................................................................................30 
2.3 
Exploratory Objectives ............................................................................................30 
3 
Study Description .............................................................................................................31 
3.1 
Summary of Study Design .......................................................................................31 
3.2 
Study Indication ......................................................................................................32 
4 
Selection and Withdrawal of Subjects................................................................................33 
4.1 
Inclusion Criteria .....................................................................................................33 
4.2 
Exclusion Criteria ....................................................................................................34 
4.3 
Study Drug Interruption ...........................................................................................35 
4.4 
Withdrawal Criteria .................................................................................................35 
5 
Study Treatments ..............................................................................................................37 


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5.1 
Treatment Groups ....................................................................................................37 
5.2 
Rationale for Dosing ................................................................................................37 
5.3 
Randomization and Blinding ....................................................................................38 
5.4 
Breaking the Blind ...................................................................................................38 
5.5 
Drug Supplies ..........................................................................................................39 
5.5.1 
Formulation and Packaging...........................................................................39 
5.5.2 
Study Drug Preparation and Dispensing ........................................................40 
5.5.3 
Study Drug Administration ...........................................................................40 
5.5.4 
Treatment Compliance..................................................................................41 
5.5.5 
Storage and Accountability ...........................................................................41 
5.6 
Prior and Concomitant Medications and/or Procedures..............................................42 
5.6.1 
Excluded Medications and/or Procedures ......................................................42 
5.6.2 
Restricted Medications and/or Procedures .....................................................42 
5.6.3 
Documentation of Prior and Concomitant Medication Use .............................43 
6 
Study Procedures ..............................................................................................................44 
6.1 
Informed Consent ....................................................................................................44 
6.2 
Screening Visit (Days -35 to -1 [Visit 1])..................................................................45 
6.3 
Treatment Period (Visits 2 through 5) .......................................................................46 
6.3.1 
Day 1 (Visit 2)..............................................................................................46 
6.3.2 
Week 2 (Visit 2A) ........................................................................................47 
6.3.3 
Week 4 (Visit 3) ...........................................................................................47 
6.3.4 
Week 6 (Visit 3A) ........................................................................................48 
6.3.5 
Week 8 (Visit 4) ...........................................................................................48 
6.3.6 
Week 10 (Visit 4A) ......................................................................................48 
6.3.7 
Week 12 (Visit 5) .........................................................................................48 
6.4 
Follow-Up Visit (Week 15 [Visit 6]) ........................................................................49 
6.5 
Early Termination Visit and Withdrawal Procedures .................................................50 
6.6 
Unscheduled Visits ..................................................................................................51 
7 
Endpoints for Evaluation...................................................................................................52 
7.1 
Co-Primary Efficacy Variables.................................................................................52 
7.2 
Secondary Efficacy Variables...................................................................................52 
7.3 
Exploratory Variables ..............................................................................................53 


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7.4 
Safety Variables ......................................................................................................53 
8 
Efficacy and Other Assessments........................................................................................54 
8.1 
Efficacy Assessments...............................................................................................54 
8.1.1 
Hot Flash Frequency and Severity .................................................................54 
8.1.2 
Hot Flash Related Daily Interference Scale....................................................55 
8.1.3 
Leeds Sleep Evaluation Questionnaire...........................................................55 
8.1.4 
Greene Climacteric Scale ..............................................................................56 
8.1.5 
Menopause-Specific Quality of Life ..............................................................56 
8.1.6 
Body Composition........................................................................................56 
8.2 
Pharmacokinetic Assessments ..................................................................................57 
8.3 
Pharmacodynamic Assessments ...............................................................................58 
8.4 
Pharmacogenomic Assessments ...............................................................................58 
9 
Safety Assessments...........................................................................................................59 
9.1 
Adverse Events........................................................................................................59 
9.1.1 
Unexpected Adverse Drug Reaction ..............................................................59 
9.1.2 
Adverse (Drug) Reaction ..............................................................................60 
9.1.3 
Assessment of Adverse Events by the Investigator.........................................60 
9.2 
Serious Adverse Events............................................................................................61 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators ...............................62 
9.4 
Stopping Rules or Discontinuation Criteria ...............................................................62 
9.5 
Pregnancy Reporting................................................................................................63 
9.6 
Expedited Reporting ................................................................................................63 
9.7 
Clinical Laboratory Evaluations ...............................................................................63 
9.8 
Bone Turnover Markers ...........................................................................................64 
9.9 
Vital Signs...............................................................................................................65 
9.10 Electrocardiograms ..................................................................................................65 
9.11 Physical Examinations .............................................................................................65 
9.12 Pap Smear ...............................................................................................................66 
9.13 Mammograms..........................................................................................................66 
9.14 Abnormal Liver Function Monitoring and Drug-Induced Liver Injury Monitoring .....66 
9.14.1 Abnormal Liver Function..............................................................................66 
9.14.2 Suspected Drug-Induced Liver Injury ............................................................67 


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9.15 Adverse Events of Special Interest............................................................................67 
9.16 Columbia Suicide Severity Rating Scale ...................................................................67 
9.17 Transvaginal Ultrasound ..........................................................................................67 
9.18 Endometrial Biopsy .................................................................................................68 
10 Statistics ...........................................................................................................................69 
10.1 Analysis Populations................................................................................................69 
10.1.1 Safety Analysis Set .......................................................................................69 
10.1.2 Full Analysis Set ..........................................................................................69 
10.1.3 Per Protocol Analysis Set..............................................................................69 
10.1.4 Pharmacokinetic Analysis Set .......................................................................69 
10.2 Statistical Methods...................................................................................................69 
10.2.1 Analysis of Efficacy .....................................................................................69 
10.2.1.1 Primary efficacy analysis.................................................................69 
10.2.1.2 Secondary efficacy analysis .............................................................70 
10.2.1.3 Pharmacodynamic analysis..............................................................70 
10.2.1.4 Exploratory efficacy analysis...........................................................70 
10.2.2 Analysis of Safety ........................................................................................71 
10.2.3 Interim Analysis ...........................................................................................71 
10.2.4 Sample Size Determination ...........................................................................71 
11 Data Management and Record Keeping .............................................................................72 
11.1 Data Management ....................................................................................................72 
11.1.1 Data Handling ..............................................................................................72 
11.1.2 Computer Systems........................................................................................72 
11.1.3 Data Entry ....................................................................................................72 
11.1.4 Medical Information Coding .........................................................................72 
11.1.5 Data Validation ............................................................................................72 
11.2 Record Keeping .......................................................................................................72 
12 Investigator Requirements and Quality Control ..................................................................73 
12.1 Ethical Conduct of the Study ....................................................................................73 
12.2 Institutional Review Board .......................................................................................73 
12.3 Informed Consent ....................................................................................................73 
12.4 Study Monitoring Requirements ...............................................................................73 


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12.5 Disclosure of Data ...................................................................................................74 
12.6 Retention of Records................................................................................................74 
12.7 Publication Policy ....................................................................................................74 
12.8 Financial Disclosure ................................................................................................75 
13 Study Administrative Information .....................................................................................76 
13.1 Protocol Amendments..............................................................................................76 
13.2 Address List ............................................................................................................76 
13.2.1 Sponsor ........................................................................................................76 
13.2.2 Contract Research Organization ....................................................................76 
13.2.3 Drug Safety ..................................................................................................76 
13.2.4 Biological Specimens ...................................................................................76 
13.2.5 Pharmacokinetic Samples .............................................................................77 
13.2.6 12-Lead Electrocardiograms .........................................................................77 
14 References........................................................................................................................78 
Appendix A. Schedule of Procedures ......................................................................................81 
Appendix B. Clinical Laboratory Analytes ..............................................................................84 
Appendix C. Waist Circumference Measurement.....................................................................86 
Appendix D. Events of Clinical Interest Guidance for Potential Drug-Induced Liver Injury.......87 
Appendix E. Normal Ranges for Vital Signs and Electrocardiograms .......................................98 


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LIST OF TABLES 
Table 1. 
Treatment Groups..................................................................................................37 
Table 2. 
Qualitative Composition of ESN364 Hard Gelatin Capsules....................................40 
 
 


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LIST OF FIGURES 
Figure 1. NK3 Modulatory Role on GnRH Neurons ..............................................................22 
Figure 2.  Relationship Between KNDy Neurons, GnRH Neurons, and the Heat-Defense 
Pathway in Rat ......................................................................................................23 
Figure 3. Vasomotor Symptom Frequency Reported in the eDiary at Baseline, Week 4, and 
Week 12 of Treatment ...........................................................................................26 
Figure 4. Vasomotor Symptom Score Reported in the eDiary at Baseline, Week 4, and 
Week 12 of Treatment ...........................................................................................27 
Figure 5. The Evolution of Mean Daily Vasomotor Symptom Score (A) and Vasomotor 
Symptom Frequency (B) ........................................................................................27 
Figure 6. Overview of the Study Design................................................................................32 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ADME 
Absorption, distribution, metabolism, and excretion 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BALP 
Bone alkaline phosphatase 
BID 
Bis in die; twice daily 
CI 
Confidence interval 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTX 
Carboxy-terminal telopeptide of type I collagen 
DILI 
Drug-Induced Liver Injury 
DXA 
Dual-energy x-ray absorptiometry 
E2 
Estradiol 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ePRO 
Electronic Patient-Reported Outcome 
ET 
Early Termination  
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 
HFRDIS 
Hot Flash Related Daily Interference Scale 
HIV 
Human immunodeficiency virus 
HPG 
Hypothalamic-pituitary-gonadal 
HRT 
Hormone replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
INR 
International Normalized Ratio 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KNDy 
Kisspeptin/neurokinin B/dynorphin 
LH 
Luteinizing hormone 
LSEQ 
Leeds Sleep Evaluation Questionnaire 
MENQoL 
Menopause-Specific Quality of Life 
MTD 
Maximum tolerated dose 
NIH 
National Institutes of Health 
NK3 
Neurokinin 3 
NK3R 
Neurokinin 3 receptor 
NKB 
Neurokinin B 
NOAEL 
No observed adverse effect level 
P1NP 
Procollagen type 1 amino-terminal propeptide 
P4 
Progesterone 
PD 
Pharmacodynamic(s) 
PGX 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PPAS 
Per Protocol Analysis Set 
QD 
Quaque die; once daily 
SAE 
Serious adverse event 
SHBG 
Sex hormone-binding globulin  
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Background Information 
1.1.1 
Vasomotor Symptoms (Hot Flashes) 
Vasomotor symptoms (hot flashes) are the most common complaint among women entering 
menopause and, for many women, may continue to occur for up to 5 years (although about 20% of 
women may have them for up to 15 years).1–3 Approximately 75% of peri-menopausal women will 
experience vasomotor symptoms (hot flashes), with 10% to 20% of those enduring severe 
symptoms.4 Today, more than 25 million women in the United States alone experience symptoms 
of vasomotor symptoms (hot flashes), and 4 million women report severe symptoms.5  
Vasomotor symptoms (hot flashes) can have a significant negative impact on the 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 vasomotor symptoms (hot flashes) is not 
fully understood; although, a disturbance in normal thermoregulatory function is thought to be the 
main underlying cause. 
The primary symptom of vasomotor symptoms (hot flashes) is a subjective and transient sensation 
of heat, flushing, and sweating that usually lasts 4 to 10 minutes and may be accompanied by 
palpitations, feelings of anxiety, irritability, and in rare occurrence, panic.4  
The most effective and commonly used pharmacological treatment for vasomotor symptoms (hot 
flashes) is hormone replacement therapy (HRT), but a Women’s Health Initiative study raised 
questions about the long-term safety of this treatment. Current guidelines recommend a limited 
duration of HRT due to associated risks of breast cancer, coronary artery disease, stroke, and 
thromboembolism.1,6 Furthermore, the current safety data do not support the use of HRT in many 
patients (eg, patients with breast/endometrial cancer or liver disease). 
The perceived limitations of HRT coupled with the lack of efficacy and the adverse effects 
observed with non-hormonal therapies have led clinicians to search for other treatment options for 
vasomotor symptoms. Recent studies of venlafaxine and fluoxetine in women with a prior history 
of breast cancer have suggested that certain antidepressants with the ability to inhibit serotonin 
reuptake may significantly reduce vasomotor symptoms of menopause.7–9 However, the clinical 
benefit of these antidepressants is not as great as that observed for estrogen. 
1.1.2 
Introduction to ESN364 (International Nonproprietary Name: Fezolinetant) 
ESN364 is an orally-available, potent, and selective small molecule neurokinin 3 receptor (NK3R) 
antagonist shown to significantly modulate the hypothalamic-pituitary-gonadal (HPG) axis to 
lower the circulating levels of sex hormones in nonclinical studies and in clinical trials. The 
mechanism-of-action of ESN364 is to decrease the luteinizing hormone (LH) pulse frequency, a 
response indicative of a decrease in the gonadotropin-releasing hormone (GnRH) pulse 
frequency.10 Moreover, the finding that the drug action selectively affected LH but not 
follicle-stimulating hormone (FSH) provides additional evidence that ESN364 does not block 
GnRH signaling but merely decreases the GnRH pulse frequency. The selective effect of ESN364 
to lower LH but not FSH is consistent in rats, sheep, monkeys, and male and female humans.10,11 


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Recent advances in the field have demonstrated that the GnRH pulse frequency is modulated by 
the Kisspeptin/neurokinin B (NKB)/dynorphin (KNDy) neurons (also known as “KiSS Neuron”) 
in the arcuate nucleus of the hypothalamus.12 Neuroanatomical studies have shown that these 
neurons are sensitive to NKB/NK3R signal.13 These data support the hypothesis that ESN364 
antagonism of NK3R on the KNDy neuron decreases the GnRH pulse frequency as the basis of 
the downstream effects observed on LH, FSH, and the sex hormones. The schematic of the 
neurokinin 3 (NK3) modulatory role on GnRH neurons to inhibit GnRH release and consequent 
release of sex hormones is presented in Figure 1.  
Figure 1. NK3 Modulatory Role on GnRH Neurons 
 
Select abbreviations: FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; 
KiSS = kisspeptin/neurokinin B/dynorphin; LH = luteinizing hormone; NK3 = neurokinin 3.  
Source: Investigator’s Brochure14 
Furthermore, the proposed pharmacological action of ESN364 is consistent with the findings of a 
landmark publication revealing that a human population identified to have a loss-of-function 
mutation in NK3R presents a phenotype of reduced circulating levels of sex hormones, but with 
the important distinction that the levels of these hormones are above castration levels in women.15 
A follow-up article demonstrates this point clearly by showing that patients with a loss-of-function 
mutation in NK3 present very low levels of LH but that FSH levels are not significantly altered. 
In contrast, patients expressing a GnRH receptor loss-of-function mutation exhibit castration levels 
of both LH and FSH.16 Luteinizing hormone and FSH function independently to stimulate estradiol 
(E2) release from the ovaries. In total, these human mutant studies predict that ESN364 antagonism 
of NK3R will diminish levels of E2 due to reduction of the LH pulse frequency but will not affect 
FSH levels. Therefore, there is a natural safety margin in place that protects against over-inhibition 
of E2 and the attenuation side effects of chemical castration such as the maintenance of bone 
density as well as maintenance of a normal, healthy sex life. This safety margin is based on the 
NK3-selective modulation of LH, but not FSH, and this is the anticipated advantage of ESN364 
over the existing GnRH products currently prescribed (eg, Lupron®, Zoladex®, etc.). 
In addition to the precedent established by the human population study, an additional clinical 
precedence has been established by the historic testing of NK3 antagonists in clinical studies by 
various pharmaceutical companies. The therapeutic goal at the time was the treatment of 
schizophrenia, wherein all compounds failed due to lack of convincing efficacy in Phase 2 studies. 
Importantly, these development programs report dose-related changes in LH, testosterone, and 
various reproductive 
organs (testes, epididymis, 
and prostate) in male dogs and a 


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testosterone-lowering effect in male volunteers.17 This history indicates that NK3 antagonism is a 
target concept for drug development with clinical precedence to reversibly lower sex hormones.  
As described above, the KNDy neurons are sensitive to NKB/NK3R signaling that is susceptible 
to pharmacological blockade by ESN364 to decrease KNDy neuron activity. Importantly, estrogen 
also acts directly on the alpha estrogen receptor expressed on KNDy neurons to similarly decrease 
KNDy neuron activity.18,19 Thus, ESN364 and estrogen have common pharmacological effects to 
decrease KNDy neuron activity. 
In physiological situations where there is a change toward lower estrogen levels, such as in 
menopause or in the case of therapies used to lower estrogen to treat estrogen-dependent cancers, 
estrogen feedback control of KNDy neuron activity is lost. The KNDy neuron is known to synapse 
at 2 sites: (1) the GnRH neuron, as explained earlier, and (2) the median preoptic nucleus which is 
an area of the brain critical for autonomic thermoregulation.20 Furthermore, additional evidence 
linking NK3R signaling on KNDy neuron activity to vasomotor symptom/thermoregulation 
includes the observations that (1) administration of NKB (NK3R agonist) provoked vasomotor 
symptoms in premenopausal women,21 (2) administration of ESN364 (NK3 antagonist) prevented 
body temperature changes in ovariectomized ewe,10 and (3) the demonstration of a significant 
association between risk of vasomotor symptoms and genetic variation in tachykinin receptor 322 
(see Figure 2).  
Figure 2.  Relationship Between KNDy Neurons, GnRH Neurons, and the Heat-Defense 
Pathway in Rat 
 
Select abbreviations: ERα = estrogen receptor alpha; GnRH = gonadotropin-releasing hormone; 
KNDy = kisspeptin/neurokinin B/dynorphin; LH = luteinizing hormone; MnPO = median preoptic nucleus; 
NK3R = neurokinin 3 receptor.  
Source: Rance NE20 


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1.2 
Summary of Nonclinical Studies  
A series of non-Good Laboratory Practice (GLP) and GLP nonclinical studies were carried out in 
order to define the pharmacodynamics (PD), pharmacokinetics (PK), and toxicity of the test 
product ESN364. Compound affinity to human NK3R and to rat and monkey NK3R orthologs 
were confirmed via in vitro studies. Receptor-ligand affinity for ESN364 has been confirmed as 
essentially equipotent for the human and monkey NK3R orthologs. Also, the metabolic stability 
of the test item was determined to be similar in human and monkey liver microsomes. These 
preliminary studies justified the use of rat and monkey species in nonclinical testing. Since castrate 
animals exhibit high and stable levels of plasma LH, castrated rats and monkeys were used as the 
animal model of choice to measure the PD response to ESN364 in the modulation of plasma LH. 
Rats and monkeys were used for GLP toxicity studies, and monkeys, as the most sensitive species, 
were used to define the no observed adverse effect level (NOAEL) and to determine the starting 
dose in the Phase 1 clinical study. 
In the nonclinical toxicology studies in rats and monkeys, ESN364 was well tolerated and the 
NOAEL was considered to be 25 mg/kg/day in Cynomolgus monkeys, the most relevant species; 
drug exposure (ie, AUC) at this dose level in Cynomolgus monkey was similar to drug exposure 
levels measured in premenopausal women dosed at 540 mg/day. The main events that were 
observed in the nonclinical studies were considered to be related to the pharmacology of ESN364, 
including reduction of the ovarian activity in female monkeys. Adverse events were only observed 
at the very high doses used in the nonclinical studies. The NOAEL exceeded the intended clinical 
doses by a factor of 20. In monkeys, high doses of ESN364 resulted in weight loss and 
histopathological changes such as hyperplasia of lymphocytes in lymph nodes, spleen, and lung, 
as well as perivascular inflammation in the kidney. In addition, a reduction in platelet counts 
considered to be due to decreased production in bone marrow 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 
(including lethargy, reduced activity, labored respiration, and staggering), and body weight loss 
during the first few days of treatment. 
In a 3-month toxicology study in rats, convulsive episodes were reported with no dose- or 
time-dependent trends or concurrent ESN364 exposure. Convulsive episodes were reduced 
significantly by changing the handling procedures. In an independent assessment of the convulsive 
episodes in this study, it was concluded that the event was not linked to the test drug ESN364, but 
rather a stress-and-fear reaction (expert report from Brunner Naga Health Science Consulting, 
Switzerland, available upon request). In order to evaluate the potential of ESN364 to produce 
seizures in rats, a long-term central nervous system toxicity study was conducted. In this study, no 
seizures were detected throughout the study based on review of video-electroencephalogram 
records. In addition, no convulsions were observed in a subsequent 6-month study in rat conducted 
at exactly the same dose levels (NOAEL of 200 mg/kg/d). Therefore, it was concluded that the 
convulsive episodes observed in the 3-month study were unlikely to be related to ESN364 
administration. Notably, no signs of convulsive activity were observed in 3-month and 9-month 
toxicology studies in nonhuman primates, nor in any of the clinical studies conducted. 
Reproductive toxicology studies on both rats and rabbits demonstrated significant litter loss in both 
animal species at high dose levels; however, the surviving embryos did not show any adverse effect 
on development. The litter loss in this case is to be regarded as a pharmacologic effect on the 


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hormonal and reproductive status. A fertility and early embryonic development study was also 
completed in rat without any reported adverse events (NOAEL of 100 mg/kg/d). 
For more detailed information on ESN364 and the nonclinical toxicology studies, see the current 
Investigator’s Brochure.14 
1.3 
Clinical Studies 
1.3.1 
Summary of Clinical Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A second Phase 1 clinical trial exploring the maximum tolerated dose (MTD) of ESN364 in healthy 
female and healthy male volunteers has been recently completed (ESN-364-CPK-102). Dose 
ranges between 180 mg and 900 mg have been tested as single doses. Doses up to 720 mg have 
been given in a multiple dose fashion for 7 consecutive days. It was decided that 900 mg ESN364 
was to be the MTD because of the occurrence of headache and facial paresthesia (a feeling of 
numbness around the mouth and face). This complaint was reported at 540 mg (reported start times 
around 40 minutes postdose). The reported paresthesia tended to become more pronounced and 
prolonged with increasing doses. The apparent dose-dependent nature of the event, together with 
the occurrence of some moderate headaches, led to the decision to stop further escalation. The 
subsequent 7-day multiple dose part was conducted using 540 mg and 720 mg of ESN364 once 
daily (QD) in healthy female volunteers. These dose levels were well tolerated and safe. 
Three Phase 2a trials (proof-of-concept) have been initiated in 3 separate therapeutic indications: 
polycystic ovary syndrome (ESN-364-PCO-201), heavy menstrual bleeding due to uterine fibroids 
(ESN-364-UF-02), and 
  
Based on the collected clinical and nonclinical safety data, it can be concluded that doses up to 
360 mg/day can be safely administered over a 3-month dosing period. Dose ranges that cover an 
appropriate 10-fold range between 20 mg/day and 180 mg/day will allow exploration of a dose 
response in the patients. 
For more detailed information on ESN364 and the clinical studies, see the current Investigator’s 
Brochure.14  
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1.3.2 
Effects of ESN364 (Fezolinetant) 
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t 
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Two other Phase 2a trials (proof-of-concept) have been initiated in 2 separate therapeutic 
indications: polycystic ovary syndrome (ESN-364-PCO-201) and heavy menstrual bleeding due 
to uterine fibroids (ESN-364-UF-02). The results of these Phase 2 clinical trials are not yet 
available. 
Please see the most current version of the Investigator’s Brochure for additional details.  
1.4 
Rationale 
ESN364 has been selected as the development candidate molecule based on its superior PK profile, 
oral bioavailability, and selective target potency. The summary of clinical studies supports the 
rationale for the current trial to refine both the dose-level and dosing regimen in order to define 
the minimal effective dose level of fezolinetant to treat moderate and severe vasomotor symptoms.  
1.5 
Risk/Benefit 
ESN364 is being developed for the treatment of women’s health disorders such as menopausal 
vasomotor symptoms, endometriosis, polycystic ovarian syndrome, and uterine fibroids. The 
compound may also be developed for sex hormone disorders affecting men, such as benign 
prostate hyperplasia. 
Due to recent advances in science, there are reasons to believe that ESN364 can be an effective 
treatment for the symptoms and morbidity associated with menopause. 
A key feature of NK3 antagonism is the selective decrease of LH secretion without compromising 
FSH secretion by decreasing the firing rate of the KNDy neuron. 
When given to normally cycling healthy women, ESN364 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 postmenopausal volunteers, these effects will become 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 menopause.  
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Treatment with ESN364 can cause adverse effects or other symptoms. Adverse effects that can be 
expected are those adverse events that presented in ESN364 clinical trials in healthy male and 
female volunteers as well as in menopausal women.  
Details of the adverse event profile from the proof-of-concept study are presented in Section 1.3. 
All recorded treatment-related TEAEs were mild to moderate in severity. All adverse events 
resolved spontaneously without sequelae. The reported palpitations were short-lived and were not 
accompanied by other signs/symptoms of cardiac involvement (vital signs and electrocardiogram 
[ECG] findings were normal). Current knowledge of the side effect profile of ESN364 is still 
limited. 
 
 
  
Indirectly, subjects could benefit from participating in this clinical trial because of the intense 
medical follow-up demanded by the protocol for the duration of the trial. 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the effect of different doses and dosing regimens 
of ESN364 on frequency and severity of vasomotor symptoms (hot flashes).  
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
• To evaluate the effect of different doses and dosing regimens of ESN364 on the frequency, 
severity, and hot flash score of mild, moderate, and severe vasomotor symptoms;  
• To evaluate the effect of different doses and dosing regimens of ESN364 on responder rates 
using variation of responder definitions;  
• To evaluate the effect of different doses and dosing regimens of ESN364 on patient-reported 
outcomes;  
• To evaluate the effect of different doses and dosing regimens of ESN364 on PD markers 
(hormones and bone markers); and 
• To evaluate the effect of different doses and dosing regimens of ESN364 on safety and 
tolerability.  
2.3 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
• 
 
  
• To evaluate the PK plasma concentrations of ESN364 and metabolite 
     
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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a 12-week, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, 
multicenter study to assess the efficacy of ESN364 in postmenopausal women suffering from 
vasomotor symptoms (hot flashes).  
This study will consist of a screening period (Days -35 to -1, including the screening visit [Visit 1] 
and a minimum 7-day collection of baseline vasomotor symptom frequency and severity 
assessments), a 12-week treatment period (Day 1 [Visit 2] to Week 12 [Visit 5], including safety 
visits at Week 2 [Visit 2A], Week 6 [Visit 3A], and Week 10 [Visit 4A]), and a follow-up visit 
(Week 15 [Visit 6]) approximately 3 weeks after the last dose of study drug, for a total of 9 visits.  
The study will be performed on an ambulatory basis.  
The screening visit (Visit 1) will occur up to 35 days prior to randomization. Eligibility will be 
assessed via physical examination, clinical laboratory testing, vital signs, ECG, Pap smear, 
mammography, and endometrial biopsy. Subjects will receive an electronic diary in which to 
record daily vasomotor symptoms during the duration of the screening period. Subjects must have 
7 consecutive days of vasomotor symptom recordings to participate in the study. Subjects are 
encouraged to continue recording for the duration of the whole screening period. The electronic 
diary will be reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects 
may be rescreened 1 time upon approval of the medical monitor (see Section 6.2).   
A total of 352 subjects will be enrolled in the study. Subjects will be randomized to 1 of 8 treatment 
groups (ie, 44 subjects in each arm).  
Subjects and study personnel will be blinded to the treatment (placebo or ESN364), dosage (30 mg, 
60 mg, etc.), and dosing regimen (QD or twice daily [BID]). 
For a schematic overview of the study design, see Figure 6. 




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4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Women >40 years and 65 years of age at the screening visit; 
2. A body mass index between 18 kg/m2 to 38 kg/m2 (extremes included);  
3. Spontaneous amenorrhea for 12 consecutive months; or 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);  
4. At least 50 moderate to severe vasomotor symptoms per week (ie, 7 consecutive days), as 
recorded in the daily diary during the screening period; 
5. 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; 
6. Women >40 years of age who have documentation of a normal/negative or no clinically 
significant findings mammogram (obtained at screening or within the prior 9 months of trial 
enrollment). Appropriate documentation includes a written report or an electronic report 
indicating normal/negative or no clinically significant mammographic findings; 
7. Willing to undergo a transvaginal ultrasound to assess endometrial thickness at screening and 
at Week 12 (end-of-treatment), and for subjects who are withdrawn from the study prior to 
completion, at the Early Termination (ET) Visit. This is not required for subjects who have 
had a partial (supracervical) or full hysterectomy; 
8. Willing to undergo an endometrial biopsy at screening (in the event that the subject’s 
transvaginal 
ultrasound 
shows endometrial 
thickness 
4 mm) 
and at Week 12 
(end-of-treatment – all subjects), for subjects with uterine bleeding, and, for subjects who are 
withdrawn from the study prior to completion, at the ET Visit if study drug exposure is 
10 weeks. This is not required for subjects who have had a partial (supracervical) or full 
hysterectomy;  
9. Negative alcohol breath test and negative urine test for selected drugs of abuse (amphetamines, 
tricyclic antidepressants, cocaine, or opiates) at the screening visit; 
10. Negative urine pregnancy test;  
11. Negative serology panel (including hepatitis B surface antigen, hepatitis C virus antibody, and 
human immunodeficiency virus antibody screens); 


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12. Informed Consent Form (ICF) signed voluntarily before any study-related procedure is 
performed, indicating that the subject understands the purpose of and procedures required for 
the study and is willing to participate in the study; and 
13. Documentation of a normal Pap smear (or equivalent cervical cytology) or of no clinical 
significance in the opinion of the Investigator within the previous 9 months or at screening. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Use of a prohibited therapy (hormone therapy, hormonal contraceptive, or vasomotor symptom 
medication [prescription, over the counter, or herbal]) or not willing to wash out drugs; 
2. History (in the past year) or presence of drug or alcohol abuse; 
3. Previous or current history of a malignant tumor, except for basal cell carcinoma; 
4. Uncontrolled hypertension and a systolic blood pressure 140 mmHg and/or a diastolic blood 
pressure 90 mmHg; 
5. Judged by the Investigator to be unsuited to participate in the study based on findings observed 
during physical examination, vital sign assessment, or 12-lead ECG; 
6. History of severe allergy, hypersensitivity, or intolerance to drugs in general, including the 
study drug and any of its excipients; 
7. Exclusion criterion 7 has been removed in Amendment 1;  
8. An unacceptable result from endometrial biopsy (performed when endometrial thickness is 
4 mm measured by transvaginal ultrasound) of endometrial hyperplasia, endometrial cancer, 
or inadequate specimen at screening (1 repeat biopsy permitted if technically possible);  
9. History of endometrial hyperplasia or uterine/endometrial cancer; 
10. History of unexplained uterine bleeding; 
11. History of seizures or other convulsive disorders; 
12. Medical condition or chronic disease (including history of neurological [including cognitive], 
hepatic, renal, cardiovascular, gastrointestinal, pulmonary [eg, moderate asthma], endocrine, 
or gynecological disease) or malignancy that could confound interpretation of the study 
outcome; 
13. Presence or sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere 
with the absorption, distribution, metabolism, or excretion (ADME) mechanisms of drugs as 
judged by the Investigator;  
14. Active liver disease or jaundice, or values of alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) >1.5  the upper limit of normal (ULN); or total bilirubin >1.5  ULN; 
or creatinine >1.5  ULN; or estimated glomerular filtration rate (eGFR) using the 
Modification of Diet in Renal Disease formula 59 mL/min/1.73 m2 at the screening visit; 
15. Concurrent participation in another interventional study (or participation within 3 months prior 
to screening in this study); 


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16. Suicide attempt in the past 3 years;  
17. Unable or unwilling to complete the study procedures; or 
18. Subject is the Investigator or any sub-Investigator, research assistant, pharmacist, study 
coordinator, or other staff or relative thereof, who is directly involved in the conduct of the 
study.  
4.3 
Study Drug Interruption 
If a subject develops a liver function test abnormality, promptly investigate with repeat 
biochemical and physical evaluation and notify the CRA immediately. 
Interrupt study drug administration for any subject who also experiences any symptoms of 
abdominal pain, worsening or new fatigue, anorexia, nausea, rash, vomiting, or diarrhea. If prompt 
evaluation is not possible, then drug administration should be interrupted until this investigation 
has been done.  
Once the subject has been evaluated physically and liver function tests have returned to normal or 
baseline values, study drug can be restarted and the normal follow-up should be installed. 
If a subject requires to stop study drug for more than 7 days, this should be discussed with the 
medical monitor and/or sponsor with regards to re-starting study drug treatment.  
4.4 
Withdrawal Criteria 
Subjects have the right to withdraw from the study at any time for any reason, including personal 
reasons. A subject can withdraw without giving a reason. This will not affect the subject’s future 
care. The Investigator should, however, try to find out why a subject has withdrawn from the study 
and document the reason for withdrawal in the source documents and on the electronic Case Report 
Form (eCRF). 
A subject must be withdrawn from the study or treatment for any of the following reasons: 
• Withdrawal of informed consent; 
• Lost to follow-up; 
• If, for safety reasons, including meeting the requirement for interruption of study drug, 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 (see Section 5.6); 
• 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 timepoint analysis, the subject may remain in the study; 
• Confirmed decrease in platelets below 75,000 mm3, which does not normalize after 7 days; 
• ALT or AST >8  ULN; 
• ALT or AST >5  ULN for more than 2 weeks; 


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• ALT or AST >3  ULN AND total bilirubin >2  ULN or International Normalized Ratio 
(INR) >1.5  ULN; 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%). 
See Appendix D and Section 9.14 for the procedure to follow in case of suspected drug-induced 
liver injury (DILI). 
In the event that a subject is withdrawn from the study drug, the Medical Monitor and Sponsor or 
designee should be informed. In the event of withdrawal due to a serious adverse event (SAE), the 
Sponsor should be notified within 24 hours (for details on adverse event reporting see Section 9.3). 
In the event of withdrawal for other reasons, the Sponsor or designee should be notified within 
2 days of the event. 
Subjects who are withdrawn from the study prior to completion of the scheduled study procedures 
for any reason (adverse event, withdrawal of consent, etc.) should be invited to complete the 
ET assessments (see Section 6.5). As long as the subject consents, all relevant assessments of the 
day on which the subject withdrew from the study should be completed (at a minimum those 
related to safety) and the subject should return for a safety follow-up visit approximately 3 weeks 
after the last intake of study drug. As long as the subject consents, she will be asked to continue 
the completion of the eDiary up to the safety follow-up visit. In case of an adverse event, the 
appropriate follow-up will be done. 
Subjects who are withdrawn from the study will not be replaced. 
Study drug assigned to a withdrawn subject must not be assigned to another subject. 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Subjects will be randomized to 1 of 8 treatment groups in an equal ratio (see Table 1).  
Table 1. 
Treatment Groups 
Dose, Regimen, Route 
Number of Subjects 
Total ESN364 Daily Dose 
ESN364 15 mg BID, oral 
44 
30 mg 
ESN364 30 mg BID, oral 
44 
60 mg 
ESN364 60 mg BID, oral 
44 
120 mg 
ESN364 90 mg BID, oral 
44 
180 mg 
ESN364 30 mg QD + placebo QD, oral 
44 
30 mg 
ESN364 60 mg QD + placebo QD, oral 
44 
60 mg 
ESN364 120 mg QD + placebo QD, oral 
44 
120 mg 
Placebo BID, oral 
44 
N/A 
BID = twice daily; N/A = not applicable; QD = once daily.  
5.2 
Rationale for Dosing 
Luteinizing hormone secretion is a surrogate for the activity of the KNDy neuron. In the 
first-in-human Phase 1 study, the mid-range dose of ESN364 (60 mg/day) was demonstrated to be 
associated with a submaximal LH suppression, and thus a submaximal suppression of the KNDy 
neuron. ESN364 given as a dose of 180 mg/day was also tested in the first-in-human Phase 1 study 
and was demonstrated to be safe and well tolerated. Luteinizing hormone suppression was 
maximal with this dose level. Hence, the expectation is that the 180 mg dose represents the dose 
associated with maximal suppression of the KNDy neuron. 
During menopause, the negative feedback by E2 does not occur due to the cessation of estrogen 
production in the ovaries. The loss of negative E2 feedback causes the KNDy neuron to become 
hyperactive in an attempt to restore the needed E2 levels via the increased release of LH/FSH. 
When the KNDy neuron is in the hyperactive state, as it is presumed to be in the postmenopausal 
period, a QD morning dose of ESN364 is unlikely to yield the desired suppression of KNDy at 
night to prevent night sweats. For this reason, a high dose of ESN364 (total daily dose of 180 mg) 
given as 90 mg BID will be tested to investigate the possibility of completely suppressing LH 
secretion. 
The other doses are based on their ability to significantly decrease LH levels in healthy female 
volunteers, 
 
. The aim is to demonstrate an ESN364 dose 
response using BID dosing as well as QD dosing in the morning and to select the optimal dose for 
Phase 3. 
Placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment. Placebo control will be used to 
maintain blinding as well as to investigate the placebo effect that is widely seen in vasomotor 
symptom trials.  
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5.3 
Randomization and Blinding 
In total, 352 subjects will be randomized to 1 of 8 treatment groups in an equal ratio. 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment arms, and to enhance the validity of statistical 
comparisons across treatment arms. 
Subjects and study personnel will be blinded to the treatment (placebo or ESN364), dosage (30 mg, 
60 mg, etc.), and dosing regimen (QD or BID).  
Randomization will be based on a computer-generated randomization schedule prepared by 
Medpace, Inc. Biostatistics using SAS® software (SAS Institute Inc., Cary, NC, USA) prior to the 
start of the study. The randomization will be balanced using randomly permuted blocks across the 
treatment arms. The randomization list will be retained by Medpace Biostatistics until the end of 
the study (database lock). A copy will be sent in a sealed envelope to the bioanalytical laboratory 
responsible for plasma drug and serum hormone determination before the start of the study as 
applicable. Because of a planned early timepoint analysis (see Section 10.2.3) and because PK/PD 
modeling will start prior to database hard-lock, specific assigned Sponsor staff involved in these 
activities (or delegates, if outsourced to an external vendor) will be unblinded after recruitment 
has been completed. Details of the unblinding will be documented in a separate charter to ensure 
the direct study team remains blinded and that unblinded results are restricted to a very small group 
independent of the study team.  
Subjects will be assigned a randomization number from the Interactive Response Technology 
(IRT) system upon enrollment. The randomization list will be uploaded into the IRT system. Based 
on this randomization list, the study drug will be packaged and labeled. Medication numbers will 
be preprinted on the study drug labels. The study team, including those involved in data 
management, clinical, medical, or statistical review of the study data, will also be blinded during 
the study as they will not have access to the randomization list. Medpace, the Contract Research 
Organization (CRO) performing data management and statistical activities, will receive a copy of 
the randomization list at database lock. The study drug administered to a subject can be identified 
by the IRT system. The IRT system will allow rapid access to the treatment allocation codes when 
relevant for site or CRO personnel. 
5.4 
Breaking the Blind 
The randomization list will not be available to the Investigator or other employees of the study 
site, subjects, monitors, or blinded Medpace and Sponsor personnel before unblinding of the data, 
unless in case of emergency. Blinding will be maintained unless unblinding is considered 
mandatory because of a life-threatening situation for management of medical treatment. In such 
case, the date at which breaking of the code occurs, the person who breaks the code, and the reason 
why the code is broken will need to be documented in the subject’s file. Sites will use IRT to break 
the blind. The Medpace IRT team will supply a passcode (6 digits) in a sealed envelope for each 
site in order to break the blind in the IRT system. Site personnel should inform the Medical Monitor 
immediately. If the Investigator accidentally breaks the code, the Medical Monitor and the Clinical 
Trial Manager must be also informed as soon as possible. If the code is broken by the Investigator 
or by someone of his/her clinical staff, the subject must be withdrawn from the study and must be 


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followed as appropriate. If the code is broken by the Sponsor or designee for safety reporting 
purposes or the planned early timepoint analysis, the subject may remain in the study. 
Because of a planned early timepoint analysis (see Section 10.2.3) and because PK/PD modeling 
will start prior to database hard-lock, specific assigned Sponsor staff involved in these activities 
(or delegates, if outsourced to an external vendor) will be unblinded after recruitment has been 
completed. Details of the unblinding will be documented in a separate charter to ensure the direct 
study team remains blinded and that unblinded results are restricted to a very small group 
independent of the study team. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
ESN364 and placebo will be manufactured, packaged, and labeled under the responsibility of 
Ogeda S.A. The study drug and placebo are manufactured under current Good Manufacturing 
Practice (GMP), as required by the current Good Clinical Practice (GCP), at Pharmavize N.V. 
(Mariakerke, Belgium). The packaging and labeling of study drug will be in accordance with 
applicable local regulatory requirements.  
The ESN364 and placebo capsules will be packaged in high-density polyethylene bottles with 
polypropylene closure. Subjects will be assigned 2 bottles as a kit (1 bottle labeled “morning” and 
1 bottle labeled “evening”) at Day 1 (Visit 2), Week 4 (Visit 3), and Week 8 (Visit 4). Each bottle 
will contain 34 capsules of ESN364 or placebo.  
Labels will be printed in the local language of the countries in which the study takes place in 
accordance with applicable local regulations and will contain the following: 
• Protocol number; 
• Medication number; 
• Visit number; 
• Batch number; 
• Storage conditions; 
• Contents; 
• The statements “Keep out of reach and sight of children,” “For oral route only,” and “For 
clinical study use only”; and 
• Sponsor (or sponsor representative) name. 
ESN364 will be supplied as immediate-release Coni cap size 0 white opaque hard gelatin capsules 
for oral administration in active dosage strength ranges of 15 mg to 180 mg. Capsules will be 
prepared according to the dosing scheme in Table 1. A copy of the certificate of analysis will be 
provided to study sites. The qualitative composition of the ESN64 capsules is provided in Table 2.  


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Table 2. 
Qualitative Composition of ESN364 Hard Gelatin Capsules 
Component 
Function 
ESN364 
Active pharmaceutical ingredient 
Starch, pregelatinized 
Filler 
Croscarmellose sodium 
Disintegrant 
Silicon dioxide 
Glidant 
Magnesium stearate 
Lubricant 
Placebo will be supplied as hard gelatin capsules that are visually indistinguishable from the 
investigational product. The placebo capsules contain the same excipients as ESN364 and will be 
supplied in capsules shells identical to ESN364.  
5.5.2 
Study Drug Preparation and Dispensing 
ESN364 and placebo are manufactured under current GMP, as required by the current GCP, at 
Pharmavize N.V. (Mariakerke, Belgium). Study drug will be assigned by the IRT to study 
sites/subjects.  
5.5.3 
Study Drug Administration 
Subjects will be assigned 2 bottles of study drug as a kit (1 bottle labeled “morning” and 1 bottle 
labeled “evening”) at Day 1 (Visit 2), Week 4 (Visit 3), and Week 8 (Visit 4). Each bottle will 
contain 34 capsules of ESN364 or placebo. Study drug should be dispensed under the supervision 
of the Investigator, a qualified member of the clinical staff, or the hospital/clinic pharmacist.  
All study visits should be conducted in the morning. Subjects should be fasted (defined as nothing 
by mouth except for water [up to 1 hour before study drug intake] for at least 10 hours prior to 
study visit). Day 1 (Visit 2) should be planned to allow for first intake of study drug (“morning” 
dose) at the study site between 7:00 AM and 10:00 AM. Following Day 1 (Visit 2), each 
subsequent visit should be planned at the same time of day (morning) for each subject.  
Study drug intake will be done with a glass of room temperature tap water. The first intake of study 
drug will take place at the study site on Day 1 (Visit 2) between 7:00 AM and 10:00 AM under the 
supervision of the study staff. On study visit days (Day 1 [Visit 2], Week 4 [Visit 3], and Week 8 
[Visit 4], only), the morning dose of study drug will be taken at the study site under the supervision 
of the study staff, after collection of predose blood samples. Subjects will be instructed to arrive 
at the study site fasted (defined as nothing by mouth except water [up to 1 hour prior to study drug 
intake] for at least 10 hours prior to study visit). On all other days throughout the treatment period, 
subjects will be instructed to take their morning dose of study drug at home, around the same time 
of the day and spaced as near to 12 hours apart as possible (preferably between 7:00 AM and 
10:00 AM and 7:00 PM and 10:00 PM). Intake of study drug should be preferably 1 hour before 
or 2 hours after meals.   
Subjects need to record all home study drug intake in the electronic Patient-Reported Outcome 
(ePRO) diary. 
In the event a subject accidentally misses a scheduled dose of the study drug, the missed dose 
should be skipped and the subject should resume the usual dosing schedule. 
Any deviation from the treatment regimen defined in the protocol must be documented in the 
eCRF. 


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5.5.4 
Treatment Compliance 
Subjects will be assigned 2 bottles of study drug as a kit (1 bottle labeled “morning” and 1 bottle 
labeled “evening”) at Day 1 (Visit 2), Week 4 (Visit 3), and Week 8 (Visit 4). Each bottle will 
contain 34 capsules of ESN364 or placebo. 
On visit days during the treatment period (Day 1 [Visit 2], Week 4 [Visit 3], and Week 8 [Visit 4], 
only), the morning dose of study drug will be taken at the study site under the supervision of the 
clinical staff. All other study drug intakes (evening dose and morning dose on all days without 
visits) will take place at home. When taking study drug at home, subjects will be asked to record 
their home study drug intake in the ePRO diary. Subjects will also be asked to return all unused 
study drug. 
Compliance of study drug intake will be assessed by counting returned study drug in addition to 
reviewing ePRO entries of study drug intake. Any discrepancies between returned study drug 
number and dosing in the ePRO diary will be discussed with the subject for whom a discrepancy 
was seen and recorded in the source documents and the eCRF. If a subject demonstrates continued 
non-compliance with study drug dosing (85% compliance) despite educational efforts, the 
Investigator should contact the Sponsor to discuss withdrawal of the subject from the study. 
5.5.5 
Storage and Accountability 
The Investigator (or his/her designee) is responsible for the safe storage of all study drug assigned 
to the study site. Study drug will be stored in a locked, secure storage facility with access limited 
to those individuals authorized to dispense the study drug and maintained within the appropriate 
ranges of temperature. All study drug must be stored as specified at delivery and in the original 
packaging. Instructions for the subjects regarding the storage and handling of the study drug will 
also be provided to the study sites. 
ESN364 must be stored at ambient conditions (15°C to 30°C or 59°F to 86°F), should not be 
exposed to freezing temperatures, and should be protected from light during storage at the study 
site. Study drug is stable up to 24 months at 25°C with 60% relative humidity.  
Daily temperature logging of the study drug storage room at the study site should be performed. 
In the event a deviation in storage conditions should occur, the site must discontinue dispensing 
the affected study drug and notify the Clinical Research Associate (CRA). The same instruction 
applies for temperature deviations occurring during shipment of study drug to the sites.  
The Investigator is responsible for ensuring that all study drug received at the study site is 
inventoried and accounted for throughout the study. As misallocations of study drug will have an 
impact on study execution and will jeopardize the validity of the data obtained, utmost care should 
be taken to correctly dispense the study drug as assigned by the randomization system. 
Subjects will be assigned 2 bottles of study drug as a kit (1 bottle labeled “morning” and 1 bottle 
labeled “evening”) at Day 1 (Visit 2), Week 4 (Visit 3), and Week 8 (Visit 4). Each bottle will 
contain 34 capsules of ESN364 or placebo. Study drug should be dispensed under the supervision 
of the Investigator, a qualified member of the clinical staff, or the hospital/clinic pharmacist. The 
Investigator must maintain accurate records demonstrating date and amount of study drug supplied 
to whom and by whom. Study drug will be supplied only to subjects participating in the study. 


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The site monitor will periodically check the supplies of study drug held by the Investigator or 
pharmacist to ensure accountability and appropriate storage conditions of all study drug used. 
Subjects must be instructed to return all unused study drug at Day 1 (Visit 2), Week 4 (Visit 3), 
Week 8 (Visit 4), and Week 12 (Visit 5)/ET. A record of any returned study drug will be kept for 
each subject. Returned study drug must not be relabeled or dispensed again. 
Unused study drug and study drug returned by the subject (if applicable) must be available for 
verification by the site monitor during on-site monitoring visits. Any discrepancies between 
returned and expected returned study drug should be explained and documented. 
After the last visit of the last subject in the study (Last Subject Last Visit), any unused study drug 
(including any study drug returned by the subject) will be returned to the Sponsor or designee. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Current use of hormonal medications such as hormone therapy or hormonal contraception or any 
treatment for vasomotor symptoms (prescription, over the counter, or herbal) is not allowed during 
the study. Prescription medications for the treatment of vasomotor symptoms should be washed 
out after consultation with the prescribing physician and as per package insert guidance to ensure 
clinical safety. A minimum of 5 half-lives is required prior to screening. For women who recently 
discontinued hormone therapy, the therapy must have been discontinued for at least the following 
durations prior to the screening visit: 
• 1 week or longer for prior vaginal hormonal products (rings, creams, gels, inserts); 
• 4 weeks or longer for prior transdermal estrogen alone or estrogen/progestin products; 
• 8 weeks or longer for prior oral estrogen and/or progestin therapy; 
• 8 weeks or longer for prior intrauterine progestin therapy; 
• 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. 
5.6.2 
Restricted Medications and/or Procedures 
Any medications, other than those excluded by the protocol (see Section 5.6.1), that are considered 
necessary for a subject’s welfare or will not interfere with the study drug may be given at the 
discretion of the Investigator. 
Analgesics are permitted on an as-needed basis. Long-term or prophylactic use is allowed if stable 
for >3 months. 
The use of stable doses (defined as no relevant dose changes within 3 months prior to screening) 
of thyroid replacement therapy is allowed.  
The use of stable doses (defined as no relevant dose changes within 3 months prior to screening) 
of antihypertensive medication (except clonidine) is allowed on the condition that hypertension is 
well controlled.  


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The use of stable doses (defined as no relevant dose changes within 3 months prior to screening) 
of antidepressants is allowed. 
Occasional use (defined as less than 3 times per week) of benzodiazepine or Z-drugs can be 
allowed on an as-needed basis.  
Restricted use (7 days) of topically applied corticosteroid containing cream/ointments is allowed.  
Active prescription for opiates is allowed at the discretion of the Investigator.  
The Sponsor or designee must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered. 
For any medication for which the Investigator is uncertain if it might interfere with the screening 
assessments or study drug, the Medical Monitor should be consulted. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
All therapies (prescriptions, over the counter, and herbal), other than the study drug, administered 
from informed consent until the last study-related activity must be recorded in the source 
documents and in the concomitant therapy section of the eCRF (name of the drug, dosage, route, 
and dates of administration). If a concomitant medication is started later than 2 weeks after the last 
intake of study drug, it will only be recorded when linked to an adverse event. 
In the event of observed liver enzyme elevations during the study, additional therapies will be 
recorded. All therapies (prescriptions, over the counter, and herbal) administered from 90 days 
prior to informed consent up to informed consent will be recorded in the source documents and in 
the concomitant therapy section of the eCRF (name of the drug, dosage, route, and dates of 
administration).  


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6 
STUDY PROCEDURES 
The screening visit (Days -35 to -1 [Visit 1]), Day 1 (Visit 2), Week 4 (Visit 3), Week 8 (Visit 4), 
Week 12 (Visit 5)/ET, and Week 15 (Visit 6) assessments should be conducted in the morning. 
Subjects should be fasted (defined as nothing by mouth except for water [up to 1 hour before study 
drug intake] for at least 10 hours prior to study visit). Day 1 (Visit 2) should be planned to allow 
for the first intake of study drug at the study site between 7:00 AM and 10:00 AM. Following 
Day 1 (Visit 2), each subsequent visit (excluding Visits 2A, 3A, and 4A) should be planned at the 
same time of day (morning) for each subject.  
Subjects may schedule Week 2 (Visit 2A), Week 6 (Visit 3A), and Week 10 (Visit 4A) assessments 
at their convenience within the visit window (see Section 6.3). Fasting is not required for these 
visits.  
 
 
 
 
 
 
 
 
 
  
 
 
  
An overview of the timing of study drug intake and assessments is given in the Schedule of 
Procedures (Appendix A). 
All assessments will be completed predose, except at Week 2 (Visit 2A), Week 6 (Visit 3A), and 
Week 10 (Visit 4A) and for postdose blood sampling for PK and PD assessments at Week 4 
(Visit 3). Administration of questionnaires will be completed at the respective visits prior to any 
invasive procedures.  
During the postdose assessment period, the subject may eat and drink, provided this is done at least 
1 hour after dosing.  
6.1 
Informed Consent 
Signed informed consent will be collected at or before the screening visit (Days -35 to -1 [Visit 1]) 
for all subjects before any study-related procedures are done. A separate signature will be collected 
for pharmacogenomics (PGX) sampling. Subjects who do not consent to PGX sampling are not 
excluded from participating in the study. The PGX sample can be taken at any time during the 
study following informed consent. Any PGX sample taken during screening will be destroyed in 
the event of a screen failure. 
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6.2 
Screening Visit (Days -35 to -1 [Visit 1]) 
The screening visit is to occur within 35 days of randomization (Day 1 [Visit 2]), with a minimum 
of 7 days to allow for baseline data collection of vasomotor symptom frequency and severity 
assessments. Subjects will receive an electronic diary in which to record daily vasomotor 
symptoms during the duration of the screening period. Subjects must have 7 consecutive days of 
vasomotor symptom recordings to participate in the study. Subjects are encouraged to continue 
recording for the duration of the whole screening period. Subjects will be instructed to arrive to 
the study site fasted (defined as nothing by mouth except water [up to 1 hour prior to study drug 
intake] for at least 10 hours). Subjects may be rescreened 1 time with approval of the Medical 
Monitor. The following assessments do not need to be repeated at the rescreen provided they still 
fall within the acceptable time window as outlined below: transvaginal ultrasound, endometrial 
biopsy, mammogram, 
, ECG, and Pap smear.  
The following procedures will be performed at the screening visit (Days -35 to -1 [Visit 1]): 
• Collect signed ICFs (see Section 6.1); 
• Determine eligibility (inclusion/exclusion criteria);  
• Perform mammogram (only in the event the subject does not have a normal/negative or no 
clinically significant findings mammogram from previous 9 months on record); 
• Perform Pap smear (only in the event the subject does not have a normal/negative or no 
clinically significant findings Pap smear from previous 9 months on record); 
• Perform transvaginal ultrasound;  
• Perform endometrial biopsy (only in the event the transvaginal ultrasound shows an 
endometrial thickness 4 mm);  
• Review medical history and concomitant diseases;  
• Collect demographic data;  
• Perform physical examination, including bimanual clinical pelvic and clinical breast 
examination, height, weight, and waist circumference;  
• Collect urine sample for: 
o Urine drug screen, 
o Urine pregnancy test, and 
o Urinalysis;  
• Collect blood sample for: 
o Clinical laboratory tests (biochemistry, coagulation, and hematology); 
o Endocrinology; and 
o Serology (HBsAG, HCV antibodies, and HIV antibodies); 
• Perform alcohol breath test;  
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• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes rest);  
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest); 
• Provide ePRO training;  
• 
 
 
 
 
 
 
; 
• Begin recording vasomotor symptom frequency and severity; and 
• Review concomitant medications.  
6.3 
Treatment Period (Visits 2 through 5) 
Following randomization to study drug, subjects will return to the study site for visits and 
procedures to occur within 3 days of the scheduled time. Except for Visits 2A, 3A, and 4A, 
subjects will be instructed to arrive to the study site fasted (defined as nothing by mouth except 
water [up to 1 hour prior to study drug intake] for at least 10 hours). Administration of 
questionnaires will be completed at the respective visits prior to any invasive procedures.  
6.3.1 
Day 1 (Visit 2) 
The following procedures will be performed at Day 1 (Visit 2): 
• Review inclusion/exclusion criteria (collect and review ePRO diary);  
• Review recorded vasomotor symptom frequency and severity;  
• Record Hot Flash Related Daily Interference Scale (HFRDIS);  
• Record baseline Leeds Sleep Evaluation Questionnaire (LSEQ);  
• Record Greene Climacteric Scale (GCS);  
• Record Menopause-Specific Quality of Life (MENQoL) Questionnaire; 
• Record Columbia Suicide Severity Rating Scale (C-SSRS); 
• Perform physical examination, including weight and waist circumference; 
• Collect blood sample for: 
o Clinical laboratory tests (including biochemistry and hematology); 
o PD (predose); and  
o Bone turnover markers (including bone alkaline phosphatase [BALP], procollagen type 1 
N-terminal propetide [P1NP], and carboxy-terminal telopeptide of type I collagen [CTX]);  
• Collect urine sample for urinalysis;  
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• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes of rest); 
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest); 
• Randomize subjects; 
• Dispense study drug;  
• Begin assessing study drug compliance and accountability; and 
• Review concomitant medications and assess adverse events.  
6.3.2 
Week 2 (Visit 2A) 
The following procedure will be performed at Week 2 (Visit 2A):  
• Collect blood sample for clinical laboratory tests (including biochemistry and hematology).  
6.3.3 
Week 4 (Visit 3) 
The following procedures will be performed at Week 4 (Visit 3):  
• Review recorded vasomotor symptom frequency and severity;  
• Record HFRDIS;  
• Record post-baseline LSEQ;  
• Record GCS;  
• Record MENQoL; 
• Perform limited physical examination (weight and waist circumference only);  
• Collect blood sample for: 
o Clinical laboratory tests (including biochemistry and hematology); 
o PD (predose and 3 h postdose). The Week 4 (Visit 3) 3 h postdose PD sample should be 
shifted to a later date in cases where the subject cannot accommodate the PK sampling 
schedule at that visit. The PD sample should be taken at the same time as the 3 h postdose 
PK sample (see Section 8.2); and  
o PK (predose and 1 h [30 min], 3 h [30 min], 5 h [-1 h/+30 min], and 7 h [-1 h/+2 h] 
postdose). The indicated time windows for Week 4 (Visit 3) PK sampling will allow for 
flexibility;  
• Collect urine sample for urinalysis;  
• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes of rest); 
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest);  
• Dispense study drug;  


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• Assess study drug compliance and accountability; and 
• Review concomitant medications and assess adverse events. 
6.3.4 
Week 6 (Visit 3A) 
The following procedure will be performed at Week 6 (Visit 3A):  
• Collect blood sample for Clinical laboratory tests (including biochemistry and hematology). 
6.3.5 
Week 8 (Visit 4) 
The following procedures will be performed at Week 8 (Visit 4):  
• Review recorded vasomotor symptom frequency and severity;  
• Record HFRDIS;  
• Record post-baseline LSEQ;  
• Record GCS;  
• Record MENQoL; 
• Perform limited physical examination (weight and waist circumference only);  
• Collect blood sample for: 
o Clinical laboratory tests (including biochemistry and hematology), and 
o PD (predose);  
• Collect urine sample for urinalysis;  
• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes of rest); 
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest);  
• Dispense study drug;  
• Assess study drug compliance and accountability; and 
• Review concomitant medications and assess adverse events. 
6.3.6 
Week 10 (Visit 4A) 
The following procedure will be performed at Week 10 (Visit 4A): 
• Collect blood sample for clinical laboratory tests (including biochemistry and hematology). 
6.3.7 
Week 12 (Visit 5) 
The following procedures will be performed at Week 12 (Visit 5):  
• Review recorded vasomotor symptom frequency and severity;  
• Record HFRDIS;  


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• Record post-baseline LSEQ;  
• Record GCS;  
• Record MENQoL; 
• Record C-SSRS; 
• Perform physical examination, including weight and waist circumference; 
• Collect blood sample for: 
o Clinical laboratory tests (including biochemistry, coagulation, and hematology); 
o PD (predose); 
o PK (predose); 
o PGX (can be taken at any time during the study following signed informed consent [see 
Section 6.1]); and  
o Bone turnover markers (including BALP, P1NP, and CTX);  
• Collect urine sample for urinalysis;  
• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes of rest); 
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest); 
• Perform transvaginal ultrasound;  
• Perform endometrial biopsy. If the Week 12 (Visit 5) biopsy is abnormal, subjects will have a 
repeat biopsy 4 weeks later, if clinically indicated;  
• 
 
 
 
;  
• Assess study drug compliance and accountability; and 
• Review concomitant medications and assess adverse events.   
6.4 
Follow-Up Visit (Week 15 [Visit 6]) 
The follow-up visit should occur approximately 3 weeks after the last intake of study drug. For 
subjects requiring a repeat biopsy, the follow-up visit will occur 4 weeks after Week 12 (Visit 5). 
The following procedures will be performed at the follow-up visit (Week 15 [Visit 6]): 
• Review recorded vasomotor symptom frequency and severity;  
• Record HFRDIS;  
• Record post-baseline LSEQ;  
• Record GCS;  
• Record MENQoL; 
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• Record C-SSRS; 
• Perform physical examination, including weight and waist circumference; 
• Collect blood sample for: 
o Clinical laboratory tests (including biochemistry and hematology); 
o PD;  
o PGX if not collected at previous visit (can be taken at any time during the study following 
signed informed consent [see Section 6.1]), and  
o Bone turnover markers (including BALP, P1NP, and CTX);  
• Collect urine sample for urinalysis;  
• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes of rest); 
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest); and 
• Review concomitant medications and assess adverse events. 
6.5 
Early Termination Visit and Withdrawal Procedures 
The end-of-treatment for subjects completing the study is Week 12 (Visit 5). For subjects who are 
withdrawn from the study prior to completion, all Week 15 (Visit 6) procedures will be performed 
at an ET visit. These procedures include the following:  
• Review recorded vasomotor symptom frequency and severity;  
• Record HFRDIS;  
• Record post-baseline LSEQ;  
• Record GCS;  
• Record MENQoL; 
• Record C-SSRS; 
• Perform physical examination, including weight and waist circumference; 
• Collect blood sample for: 
o Clinical laboratory tests (including biochemistry, coagulation, and hematology); 
o PD;   
o PK;  
o PGX if not collected at previous visit (can be taken at any time during the study following 
signed informed consent [see Section 6.1]); and  
o Bone turnover markers (including BALP, P1NP, and CTX);  
• Collect urine sample for urinalysis;  


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• Collect vital signs, including oral/tympanic temperature, blood pressure (sitting), and pulse 
rate (supine after 5 minutes of rest); 
• Perform triplicate 12-lead ECG (supine after 10 minutes of rest); 
• Perform transvaginal ultrasound;  
• Perform endometrial biopsy (only if exposure to study drug is 10 weeks or to assess adverse 
events of special interest [see Section 9.15]);  
• 
 
 
 
 
• Assess study drug compliance and accountability; and 
• Review concomitant medications and assess adverse events.   
6.6 
Unscheduled Visits 
Unscheduled visits can be planned outside the scheduled visits. The following are examples of 
reasons for unscheduled visits:  
• To obtain additional information to ensure safety of the subject. Additional blood and urine 
samples may be taken at the discretion of the Investigator; 
• To follow up on any abnormal liver function test result during the course of the study; 
• To collect an additional blood sample for PK assessment and/or if a subject discontinues the 
study drug due to an adverse event;  
• To assess, confirm, and follow up on an out-of-range clinical laboratory test, vital sign, or ECG 
value that will determine a subject’s eligibility, or in case of a positive drug screen at screening. 
Results of this retest must be available prior to randomization. The result of the retest will be 
considered for subject eligibility; 
• To investigate undiagnosed uterine bleeding after randomization (see Section 9.15); or 
• To follow up on further evaluation of abnormal transvaginal ultrasound, endometrial biopsy, 
or mammogram findings during the screening period.  
Findings made during unscheduled visits should be reported in the source documents and in the 
designated sections of the eCRF. 
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7 
ENDPOINTS FOR EVALUATION 
7.1 
Co-Primary Efficacy Variables  
The primary efficacy objectives will require the evaluation of the effect of ESN364 on the 
following 4 co-primary variables:  
• Mean change in the frequency of moderate to severe vasomotor symptoms from baseline to 
Week 4; 
• Mean change in the frequency of moderate to severe vasomotor symptoms from baseline to 
Week 12;  
• Mean change in the severity of moderate to severe vasomotor symptoms from baseline to 
Week 4; and 
• Mean change in the severity of moderate to severe vasomotor symptoms from baseline to 
Week 12. 
7.2 
Secondary Efficacy Variables 
The secondary efficacy variables include the effect of ESN364 on the following:  
Vasomotor Symptom Variables:  
• Mean change in the frequency of mild, moderate, and severe vasomotor symptoms from 
baseline to each study week;  
• Mean change in the frequency of moderate and severe vasomotor symptoms from baseline to 
each study week;  
• Mean change in the severity of mild, moderate, and severe vasomotor symptoms from baseline 
to each study week;  
• Mean change in the severity of moderate and severe vasomotor symptoms from baseline to 
each study week;  
• Mean change in the hot flash score of mild, moderate, and severe vasomotor symptoms from 
baseline to each study week;  
• Mean change in the hot flash score of moderate and severe vasomotor symptoms from baseline 
to each study week; 
• Mean percent reduction of mild, moderate, and severe vasomotor symptoms from baseline to 
each study week; and 
• Mean percent reduction of moderate and severe vasomotor symptoms from baseline to each 
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Responder Variables:  
• Mean percent reduction of 50%, 70%, 90%, and 100% of mild, moderate, and severe 
vasomotor symptoms from baseline to each study week; 
• Mean percent reduction of 50%, 70%, 90%, and 100% of moderate and severe vasomotor 
symptoms from baseline to each study week; 
• Absolute reduction of 2, 3, 4, and 5 in mean number of mild, moderate, and severe vasomotor 
symptoms per day from baseline to each study week; and 
• Absolute reduction of 2, 3, 4, and 5 in mean number of moderate and severe vasomotor 
symptoms per day from baseline to each study week.  
Patient-Reported Outcome Variables:  
• Change in Hot Flash-Related Daily Interference Scale (HFRDIS), Leeds Sleep Evaluation 
Questionnaire (LSEQ), Greene Climacteric Scale (GCS), and Menopause-Specific Quality of 
Life (MENQoL) questionnaire from baseline to Weeks 4, 8, 12, and 15.  
Pharmacodynamic Variables: 
• Change over time from baseline to Week 12 in plasma concentrations of luteinizing hormone 
(LH), follicle-stimulating hormone (FSH), estradiol (E2), and sex hormone-binding globulin 
(SHBG).  
7.3 
Exploratory Variables 
  
 
 
 
 
 
• Level of PK plasma concentrations of ESN364 and metabolite 
 at pre-specified 
timepoints.   
7.4 
Safety Variables 
Safety variables will include the following:  
• Incidence and severity of TEAEs; 
• Endometrial health assessment (transvaginal ultrasound  endometrial biopsy); 
• Vital signs (sitting systolic and diastolic blood pressure and pulse rate); 
• Laboratory tests (hematology, biochemistry, urinalysis, and coagulation); 
• ECG parameters; 
• Plasma bone density marker concentrations; 
• Physical examinations; and 
• Columbia Suicide Severity Rating Scale (C-SSRS). 
 
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8 
EFFICACY AND OTHER ASSESSMENTS 
8.1 
Efficacy Assessments 
8.1.1 
Hot Flash Frequency and Severity  
Subjects will record vasomotor symptom frequency and severity of each vasomotor symptom on 
an ad hoc basis, but at a minimum twice daily (morning and evening), via the ePRO diary from 
the screening visit (Days -35 to -1 [Visit 1]) through the follow-up visit (Week 15 [Visit 6]). At 
the screening visit, subjects will receive the ePRO diary in which to record daily vasomotor 
symptoms during the screening period. Subjects must have 7 consecutive days of vasomotor 
symptom recordings to participate in the study. Data on vasomotor symptom frequency and 
severity collected during the screening period (Days -35 to -1) will serve as baseline for vasomotor 
symptom frequency and severity. Vasomotor symptoms will be recorded by calendar day (ie, 1 day 
is midnight [12:00 AM (00:00 hours)] to 11:59 PM [23:59 hours]).  
Night sweats (vasomotor symptoms that disrupt the subject’s night sleep) should be recorded no 
later than in the morning upon awakening to start a new day. Subjects should take note of the time 
of the night sweat and record it on the appropriate calendar day (ie, before or after midnight).  
The severity of vasomotor symptoms is defined clinically as follows (according to the FDA and 
European Medicines Agency Guidances for Industry23,24 and the National Institutes of Health 
[NIH] Hot Flash Workshop25): 
• Mild: Sensation of heat without sweating/dampness. If at night, subject does not wake up but 
later notices damp sheets or clothing. 
• Moderate: Sensation of heat with sweating/dampness, but able to continue activity. If at night, 
subject wakes up because she is feeling hot and/or is sweating, but no action is necessary other 
than rearranging the bed sheets. 
• Severe: Sensation of intense heat with sweating, causing disruption of activity. If at night, 
subject wakes up hot and is sweating and needs to take action (eg, remove layers of clothes, 
open the window, or get out of bed). 
The definition of the main parameters are as follows:  
Frequency 
The frequency is the number of vasomotor symptoms per day.  
Severity 
Severity of moderate to severe vasomotor symptoms per day is calculated as follows: 
[(number of moderate vasomotor symptoms  2) + (number of severe vasomotor symptoms  3)]/ 
number of daily moderate/severe vasomotor symptoms  
Severity is zero for subjects that have no moderate or severe vasomotor symptoms.  
A weekly average severity is the average of the daily severity scores.  


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Severity of vasomotor symptoms per day is calculated as follows: 
[(number of mild vasomotor symptoms  1) + (number of moderate vasomotor symptoms  2) + 
(number of severe vasomotor symptoms  3)]/ number of daily mild/moderate/severe vasomotor 
symptoms 
Severity is zero for subjects that have no hot flashes.  
A weekly average severity is the average of the daily severity scores.  
Hot Flash Score 
Hot flash score per day is calculated as follows: 
(number of moderate vasomotor symptoms  2) + (number of severe vasomotor symptoms  3) 
Frequency, severity, and hot flash score will be assessed by taking the mean of the data over 7 days.  
8.1.2 
Hot Flash Related Daily Interference Scale 
Perceived vasomotor symptom interference on daily activities will be evaluated at Day 1 (Visit 2), 
Week 4 (Visit 3), Week 8 (Visit 4), Week 12 (Visit 5)/ET, and the follow-up visit (Week 15 
[Visit 6]) using the HFRDIS. The HFRDIS will be paper-based and administered at the study site 
prior to any invasive procedures.  
The HFRDIS is a 10-item scale that measures a woman’s perceptions of the degree to which 
vasomotor symptoms interfere with 9 daily life activities (work, social activities, leisure, sleep, 
mood, concentration, relations with others, sexuality, and enjoying life); the 10th item measures 
interference with overall quality of life.26 This scale was modeled after items on the Brief Pain 
Inventory27 and Brief Fatigue Inventory,28 which assess the extent to which pain or fatigue interfere 
with daily life. Subjects will be asked to rate the extent to which vasomotor symptoms have 
interfered with each item during the previous 2-week time interval using a 0 (do not interfere) to 
10 (completely interfere) scale. Recent structural equation modeling suggests this is a 
unidimensional scale best represented by an overall mean score (sum of items/10).29 
8.1.3 
Leeds Sleep Evaluation Questionnaire 
Subject sleep quality will be evaluated at Day 1 (Visit 2), Week 4 (Visit 3), Week 8 (Visit 4), 
Week 12 (Visit 5)/ET, and at the follow-up visit (Week 15 [Visit 6]) using the LSEQ. A baseline 
questionnaire will be used at Day 1 (Visit 2) and a post-baseline questionnaire will be used at all 
other visits. The questionnaire will be paper-based and administered at the study site prior to any 
invasive procedures. 
The LSEQ is a 10-item self-rated questionnaire that assesses a subject’s aspects of sleep and early 
morning behavior. The questions are grouped into 4 chronological areas: ease of getting to sleep, 
perceived quality of sleep, ease of awaking from sleep, and integrity of early morning behavior 
following wakefulness.30 The LSEQ is a visual analogue scale that requires respondents to place 
marks on a group of 10 cm lines representing the changes they have experienced in a variety of 
symptoms compared to usual (baseline version) versus since the beginning of treatment 
(post-baseline version). Lines extend between extremes like “more difficult than usual” and “easier 
than usual.” Responses are measured using a 100 mm scale and are averaged to provide a score 
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8.1.4 
Greene Climacteric Scale 
Changes in climacteric symptoms will be evaluated at Day 1 (Visit 2), Week 4 (Visit 3), Week 8 
(Visit 4), Week 12 (Visit 5)/ET, and at the follow-up visit (Week 15 [Visit 6]) using the GCS. The 
questionnaire will be paper-based and administered at the study site prior to any invasive 
procedures. 
The GCS is a 21-item scale that provides a brief but comprehensive and valid measure of 
climacteric symptomatology.31 Each item is rated by the subject according to its severity using a 
4-point rating scale from 0 (none) to 3 (severe). The first 20 items of the scale combine into 3 main 
independent symptom measures by summing up the individual item scores: psychological 
symptoms (items 1 to 11; score 0 to 33), physical symptoms (items 12 to 18; score 0 to 21), and 
vasomotor symptoms (items 19 to 20; score 0 to 6). Item 21 is a probe for sexual dysfunction. The 
total score can range from 0 to 63. Higher scores indicate worse symptoms. 
8.1.5 
Menopause-Specific Quality of Life 
The MENQoL questionnaire will be recorded at Day 1 (Visit 2), Week 4 (Visit 3), Week 8 
(Visit 4), Week 12 (Visit 5)/ET, and at the follow-up visit (Week 15 [Visit 6]). The questionnaire 
will be paper-based and administered at the study site prior to any invasive procedures. 
The MENQoL questionnaire was introduced in 1996 as a tool to assess health-related quality of 
life in the immediate postmenopausal period. An inherent assumption of the MENQoL is that 
disease states and conditions like menopause produce symptoms that may disrupt emotional, 
physical, and social aspects of an individual’s life, and must be considered concomitantly with 
treatment decisions. The MENQoL improves upon several instruments used to assess the impact 
of menopausal symptoms on quality of life, including the Kupperman Index and the General 
Well-Being Scale, in the following ways: 1) specificity to the condition of menopause; 2) item 
development based upon women’s own qualitative and quantitative accounts of menopausal 
symptoms; 3) inclusion of all pertinent domains of the menopause experience, including sexual 
symptoms; and 4) demonstrated reliability and validity. 
The MENQoL is self-administered and consists of a total of 29 items in a Likert-scale format. 
Each item assesses the impact of 1 of 4 domains of menopausal symptoms, as experienced over 
the last month: 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 0 (not bothersome) to 6 (extremely bothersome) 
scale.32,33 Means are computed for each subscale by dividing the sum of the domain’s items by the 
number of items within that domain.33 Non-endorsement of an item is scored a “1” and 
endorsement a “2,” plus the number of the particular rating, so that the possible score on any item 
ranges from 1 to 8.34 
8.1.6 
Body Composition 
 
  
 
 
 
 
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8.3 
Pharmacodynamic Assessments 
Venous blood samples will be collected for PD assessments at Day 1 (Visit 2), Week 4 (Visit 3), 
Week 8 (Visit 4), Week 12 (Visit 5)/ET, and at the follow-up visit (Week 15 [Visit 6]). Subjects 
should be fasted (defined as nothing by mouth except water [up to 1 hour before study drug intake] 
for at least 10 hours prior to study visit. During the postdose assessment period, the subject may 
eat and drink, provided this is done at least 1 hour after dosing. 
Samples will be taken predose at Day 1 (Visit 2), Week 8 (Visit 4), and Week 12 (Visit 5)/ET, as 
well as predose and 3 hours postdose at Week 4 (Visit 3). The Week 4 (Visit 3) 3-hour postdose 
PD sample should be shifted to a later date in cases where the subject cannot accommodate the 
PK sampling schedule at that visit. The PD sample should be taken at the same time as the 3-hour 
postdose PK sample (see Section 8.2). A PD sample will be taken at the follow-up visit (Week 15 
[Visit 6]) as well. Markers include LH, FSH, E2, and SHBG.  
The exact date and time of blood sampling must be recorded in the source documents and on the 
eCRF. Plasma will be collected and handled as specified in the central laboratory manual. After 
appropriate labeling, the plasma samples will be stored below -70°C at the study site. Thereafter, 
the frozen plasma samples will be transported/shipped on dry ice to the central laboratory for 
collection and storage below -70°C until analysis. 
Further procedures for sample collection, shipment, processing, and storage are described in the 
laboratory manual. 
8.4 
Pharmacogenomic Assessments 
Optional pharmacogenomic sampling is scheduled to occur at Week 12 (Visit 5)/ET; however, 
sampling can occur any time after subjects sign the PGX ICF and are enrolled into the study. 
Pharmacogenomic samples will be stored for potential future analysis. Any PGX sample taken 
during screening will be destroyed in the event of a screen failure. 


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9 
SAFETY ASSESSMENTS 
Safety variables will include adverse events, C-SSRS, endometrial health assessment (transvaginal 
ultrasound  endometrial biopsy), clinical laboratory tests, plasma bone density marker 
concentrations, ECGs, vital signs, and physical examinations, as described in the following 
sections.  
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of informed consent until study participation is complete. Subjects 
should be instructed to report any adverse event that they experience to the Investigator. 
Investigators should make an assessment for adverse events at each visit (excluding Visits 2A, 3A, 
and 4A) and record the event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at the screening visit will be recorded as medical history 
and should not be reported as an adverse event. Any medical condition or signs or symptoms 
present at screening that change in severity or seriousness at any time during the study should be 
reported as an adverse event.  
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at the screening visit and significantly worsen during the 
study should be reported as adverse events. The Investigator will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an adverse event. 
9.1.1 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. 


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9.1.2 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
9.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
• Concomitant drug- 
o The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 


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• Known response pattern for this class of study drug- 
o Clinical and/or nonclinical data may indicate whether a particular response is likely to be 
a class effect. 
• Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
• The pharmacology and PK of the study drug- 
o The known pharmacologic properties (ADME) of the study drug should be considered. 
9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death, 
• A life-threatening adverse event, 
o NOTE: An adverse event or adverse reaction 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 event that, had it occurred in a more severe form, might have 
caused death. 
• Requires hospitalization or prolongation of existing hospitalizations, 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (ie, no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions, 
• A congenital anomaly/birth defect, or 
• An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent 1 of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalizations, or the development 
of drug dependency. 


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9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent (see Section 9.1) until 30 days following 
the last administration of study drug must be reported to Medpace Clinical Safety within 24 hours 
of the knowledge of the occurrence (this refers to any adverse event that meets any of the 
aforementioned serious criteria). All SAEs that the Investigator considers related to study drug 
occurring after the 30-day follow-up period must be reported to the Sponsor. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access 
the 
EDC 
system, 
send 
an 
email 
to 
Medpace 
Safety 
at 
medpace-safetynotification@medpace.com or call the Medpace SAE hotline (phone number listed 
below), and fax the completed paper SAE form to Medpace (fax number listed below) within 
24 hours of awareness. When the EDC system becomes available, the SAE information must be 
entered within 24 hours of the system becoming available.  
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-579-0444 
E-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (eg, 
redacted subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or 
e-mail. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs.  
9.4 
Stopping Rules or Discontinuation Criteria 
The study may be stopped for any of the following reasons:  
• If 3 subjects are withdrawn from the study due to a confirmed study-related increase in: 
o ALT or AST >8  ULN; 
o ALT or AST >5  ULN for >2 weeks; 
o ALT or AST >3  ULN AND total bilirubin >2  ULN or INR >1.5  ULN; or 
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%);  
• If 3 subjects are withdrawn from the study due to a confirmed study-related decrease in 
platelets below 75,000 mm3, which does not normalize after 7 days; 


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• If 2 subjects develop seizures or other convulsive disorders that are not readily attributable to 
another underlying disease (eg, brain tumor, head trauma); or 
• If an increased frequency of unanticipated deaths or other SAEs is observed. 
9.5 
Pregnancy Reporting 
If the subject becomes pregnant during the study or within 30 days of discontinuing study drug, 
the Investigator should report the pregnancy to Medpace Clinical Safety within 24 hours of being 
notified. Medpace Clinical Safety will then forward the Exposure In Utero form to the Investigator 
for completion.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and ET study procedures will be performed. 
The subject should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify Medpace 
Clinical Safety/Sponsor. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
9.6 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected SAEs that are fatal 
or life-threatening as soon as possible to the FDA, and in any case no later than 7 days after 
knowledge by the Sponsor of such a case, and that relevant follow-up information will 
subsequently be communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all Investigators as required.  
9.7 
Clinical Laboratory Evaluations 
Blood samples for clinical laboratory tests will be collected at each visit. Urine samples for 
urinalysis will be collected at each visit (excluding Visits 2A, 3A, and 4A).  
Blood samples will be collected and handled as specified in the central laboratory manual. Except 
for Visits 2A, 3A, and 4A, all blood samples for clinical laboratory tests should be taken in a fasted 
state (defined as nothing by mouth except water [up to 1 hour before study drug intake] for at least 
10 hours). 
Standard laboratory tests will be performed by the central laboratory. Further procedures for 
sample collection, shipment, processing, and storage are described in the laboratory manual 
provided by the central laboratory. 


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The following clinical laboratory tests will be performed on the samples (see Appendix B): 
• Biochemistry: sodium, potassium, uric acid, creatinine, calcium, AST, ALT, blood urea 
nitrogen, eGFR, chloride, inorganic phosphorus, bicarbonate, lactate dehydrogenase, alkaline 
phosphatase, gamma-glutamyl aminotransferase, albumin, glucose, total bilirubin, creatine 
kinase, and total protein; 
• Coagulation (at the screening visit and Week 12 [Visit 5]/ET only): INR and activated partial 
thromboplastin time; and 
• Hematology: white blood cell count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, and basophils), hemoglobin, hematocrit, red blood cell count, and platelets. 
Serology (HBsAG, HCV, and HIV antibodies) will be completed at the screening visit.  
Urinalysis will be performed on site using a commercial urine dipstick. In the event the dipstick 
result is positive, a urine sample must be shipped to a central laboratory for urine sediment analysis 
(see Appendix B for list of urinalysis analytes). 
Urine drug screen for amphetamines, benzodiazepines, tricyclic antidepressants, cannabinoids, 
cocaine, or opiates will be performed at the screening visit. Note that testing positive for 
cannabinoids will not exclude a subject from participating the study. A subject with an active 
prescription for opiates may also participate in the study at the discretion of the Investigator.  
The Investigator must review the laboratory report, document this review, and record any change 
occurring during the study considered to be clinically relevant in the source documents and in the 
adverse events section of the eCRF. Laboratory values outside the laboratory normal range will be 
flagged and their clinical relevance will be assessed by the Investigator. A copy of all laboratory 
reports must be filed in the subject’s medical records. 
Samples that remain after protocol-specific assessments have been performed may be used for 
further exploratory work on PK, metabolites, plasma protein binding, protein analysis, and 
biochemistry. 
9.8 
Bone Turnover Markers 
Plasma concentrations of the bone turnover markers BALP, P1NP, and CTX will be assessed at 
Day 1 (Visit 2), Week 12 (Visit 5)/ET, and follow-up visit (Week 15 [Visit 6]). 
Blood samples for the assessment of BALP, P1NP, and CTX in plasma will be collected and 
handled as specified in the central laboratory manual. 
After appropriate labeling, the plasma samples will be stored below -70°C at the study site. 
Thereafter, the frozen plasma samples will be transported/shipped on dry ice to the central 
laboratory for collection and storage below -70°C until analysis. 
Further procedures for sample collection, shipment, processing, and storage are described in the 
laboratory manual. 


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9.9 
Vital Signs 
Vital sign parameters will be assessed at each study visit (excluding Visits 2A, 3A, and 4A). 
The vital sign parameters that will be assessed are body temperature (oral/tympanic), blood 
pressure (sitting), and pulse rate (supine after 5 minutes of rest). These parameters will be 
measured using a completely automated device consisting of an inflatable cuff and an oscillatory 
detection system. All values will be registered on a built-in recorder so that measurements are 
observer-independent. 
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 adverse event section of the eCRF. Refer to 
Appendix E for normal ranges for vital sign parameters.  
9.10 
Electrocardiograms 
Twelve-lead digital ECGs will be obtained at each study visit (excluding Visits 2A, 3A, and 4A) 
after 10 minutes in a supine position. 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. 
Skin preparation should be thorough and electrodes should be placed according to standard 12-lead 
ECG placement.  
Electrocardiograms will be digitally recorded and printed on paper. All 12-lead ECGs will be 
captured in triplicate (ie, 3 separate 12-lead ECGs at least 1 to 2 minutes apart within a 5-minute 
window). The printed paper ECGs will be used for “real time” bedside ECG assessment by the 
Investigator (or designee) who will be responsible for the overall interpretation and determination 
of the clinical significance of any potential ECG findings. Digital ECGs will be submitted to the 
ECG core laboratory, which will perform the digital ECG analysis and interpretation in this study 
using standard methodology. If the central reader identifies an abnormality, per the study alert 
criteria, the Investigator will be notified who will review the ECG and report any adverse events 
as necessary. 
The following variables will be reported: HR, RR, PR, QRS, QT, QTcB, and QTcF intervals. The 
Investigator may add additional 12-lead ECG safety assessments if there are any abnormal findings 
or if the Investigator considers it is required for any other safety reason. Refer to Appendix E for 
normal ranges for ECG parameters.  
9.11 
Physical Examinations 
Physical examinations will be performed at the screening visit (Days -35 to -1 [Visit 1]), Day 1 
(Visit 2), Week 12 (Visit 5)/ET, and the follow-up visit (Week 15 [Visit 6]). A limited physical 
examination (weight and waist circumference only) will be performed at Week 4 (Visit 3) and 
Week 8 (Visit 4).  
The physical examination includes height (at screening only), weight, and waist circumference. 
To obtain the actual body weight, subjects must be weighed lightly clothed. The height should be 
measured barefoot. Waist circumference will be measured according to NIH guidelines (see 
Appendix C). 


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Demographic data will be collected at screening only. This includes age, race, sex, and smoking 
status (smoker/non-smoker).  
A clinical breast examination will be performed at the screening visit only.  
A bimanual clinical pelvic examination will be performed at screening and at any time during the 
study where clinically indicated.  
Any change in physical examination occurring during the study that is considered to be clinically 
relevant by the Investigator should be recorded in the source documents and the adverse event 
section of the eCRF. 
9.12 
Pap Smear 
Pap smears 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 smear (or equivalent cervical cytology) within the prior 9 months. Pap smears must show no 
clinically significant findings in order for subjects to be included in the study (refer to guidance35). 
Samples will be analyzed at a central laboratory. For details on collection, handling, and shipment 
instructions, refer to the laboratory manual.  
9.13 
Mammograms 
Mammograms will be performed at the screening visit (Days -35 to -1 [Visit 1]) only in the event 
that the subject does not have documentation of a normal/negative or no clinically significant 
findings mammogram within the prior 9 months of trial enrollment. Mammograms must show no 
clinically significant findings in order for subjects to be included in the study.  
9.14 
Abnormal Liver Function Monitoring and Drug-Induced Liver Injury 
Monitoring  
Subjects will be monitored for liver function tests throughout the study, including transaminases, 
total bilirubin, complete blood count, serum alkaline phosphatase, prothrombin time/INR, and 
creatine kinase. If a subject develops a liver function test abnormality, promptly investigate with 
repeat biochemical and physical evaluation and notify the CRA immediately (refer to Section 4.3 
for detailed procedures). 
9.14.1 
Abnormal Liver Function  
Weekly monitoring of liver function tests is required under the following conditions:  
• Subject with a non-elevated liver function test at baseline is found to have any abnormal liver 
function test elevation that does not meet the stopping rules or discontinuation criteria 
(Section 9.4) or withdrawal criteria (Section 4.4); or  
• Subject who is enrolled with a baseline liver function test that is 1.5  ULN and subsequently 
has an elevation 2  that of the baseline value.  
Weekly monitoring shall continue for these subjects until their liver function tests return to below 
baseline value(s).  


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9.14.2 
Suspected Drug-Induced Liver Injury  
Subjects will be monitored for DILI from randomization to 21 days following the last 
administration of study drug (refer to Appendix D for detailed procedures). Subjects must be 
immediately withdrawn from the study and follow the evaluation for suspected DILI in 
Appendix D, if they meet any of the following criteria:   
• ALT or AST >8  ULN; 
• ALT or AST >5  ULN for more than 2 weeks;  
• ALT or AST >3  ULN AND total bilirubin >2  ULN or INR >1.5  ULN; 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%).  
9.15 
Adverse Events of Special Interest 
Adverse events of special interest are adverse events the Sponsor may wish to carefully monitor. 
These adverse events may be serious or non-serious and are not considered SAEs unless they meet 
the SAE definition in Section 9.2. Adverse events of special interest should be reported on the 
eCRF as such. Adverse events of special interest in this study will include: 
• Uterine bleeding,  
• Oral/facial paresthesia, and  
• Elevation in ALT and/or AST >3  ULN.  
9.16 
Columbia Suicide Severity Rating Scale 
The C-SSRS will be collected at Day 1 (Visit 2), Week 12 (Visit 5)/ET, and the follow-up visit 
(Week 15 [Visit 6]).  
The C-SSRS will be used to assess all suicidal events and provide a summary of suicidal ideation 
and behavior. It assesses the lethality of attempts and other features of ideation (frequency, 
duration, controllability, reasons for ideation, and deterrents), all of which are significantly 
predictive of completed suicide. The questionnaire will be paper-based and administered at the 
study site prior to any invasive procedures.  
9.17 
Transvaginal Ultrasound 
Subjects will undergo transvaginal ultrasound at screening, Week 12 (end-of-treatment), and, for 
subjects who are withdrawn from the study prior to completion, at the ET Visit. The endometrium 
should be measured in the long axis or sagittal plane. The measurement is of the thickest echogenic 
area from one 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 
transvaginal ultrasounds will be read by a local reader to determine endometrial biopsy eligibility 
followed by a central reading.  
In the event a subject has endometrial fibroids, the subject must undergo endometrial biopsy. 
Subjects with endometrial fibroids may be included in the study provided the endometrial biopsy 


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result at screening is satisfactory and the Investigator is confident no treatment will be required 
during the study. 
9.18 
Endometrial Biopsy  
Subjects will undergo endometrial biopsy (Pipelle) at the following timepoints:  
• At screening, if endometrial thickness is 4 mm determined by transvaginal ultrasound;  
• At Week 12 (end-of-treatment) – all subjects;  
• At the ET Visit for subjects who are withdrawn from the study prior to completion, if exposure 
to study drug is 10 weeks; and  
• In all cases of uterine bleeding.  
Although the transvaginal ultrasounds (see Section 9.17) will be read centrally, a local transvaginal 
ultrasound reading at screening should guide the decision to perform endometrial biopsy or not. In 
the event the local reader measures an endometrial thickness 4 mm, a single biopsy will be taken 
from the thickest part of the endometrium. Refer to the FDA draft guidance.23 In the event an 
inadequate specimen is obtained at screening, 1 repeat biopsy may be performed if technically 
possible. If the biopsy is abnormal at Week 12 (end-of-treatment), subjects will have a repeat 
biopsy 4 weeks later, if clinically indicated. All biopsies will be read by centrally by a blinded 
pathologist.  
In the event that subject’s biopsy indicates hyperplasia, biopsies will be assessed by 2 additional 
blinded pathologists. The participating study pathologists will be from different institutions with 
independent fiduciary and organizational reporting and will be blinded to each other’s assessments. 
Concurrence of 2 of the 3 pathologists will be accepted as the final diagnosis. If the 3 pathologists 
do not agree, the most severe pathologic diagnosis would be used as the final diagnosis.  
 


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10 
STATISTICS 
All statistical methods shall be detailed in the Statistical Analysis Plan that will be finalized before 
database lock.  
All data collected in the study will be documented using summary tables, figures, and subject data 
listings.  
10.1 
Analysis Populations 
All primary and secondary efficacy endpoints will be analyzed using the Full Analysis Set (FAS). 
The Per Protocol Analysis Set (PPAS) will be used only for the analysis of the selected endpoints 
to examine the robustness of the primary analysis. 
Safety and tolerability will be analyzed using the Safety Analysis Set. 
10.1.1 
Safety Analysis Set 
The Safety Analysis Set comprises all subjects who receive at least 1 dose of study drug. 
10.1.2 
Full Analysis Set 
The FAS comprises the subset of the Safety Analysis Set who have a baseline and post-baseline 
efficacy evaluation.  
10.1.3 
Per Protocol Analysis Set 
The PPAS comprises the subset of subjects from the FAS who are treated according to the protocol 
without any major deviations. A full list of inclusion criteria will be decided and assessed prior to 
database lock and unblinding. 
10.1.4 
Pharmacokinetic Analysis Set 
The PK Analysis Set comprises the subset of the Safety Analysis Set who provide evaluable PK 
assessments. 
10.2 
Statistical Methods 
10.2.1 
Analysis of Efficacy 
10.2.1.1 
Primary efficacy analysis 
Primary Efficacy Analysis: The 4 co-primary efficacy endpoints are the mean change in the 
frequency of moderate to severe vasomotor symptoms and the mean change in severity of 
vasomotor symptoms from baseline to Week 4 and Week 12. 
For each of the 4 co-primary efficacy endpoints, an analysis of covariance model will be used with 
treatment group, pooled center, and smoking status as factors, with baseline weight and baseline 
measurement as covariates. Pairwise comparisons between the active doses and placebo will be 
calculated based on least-squares mean contrasts using a 2-tailed 95% confidence interval (CI). 
For subjects in the efficacy analysis populations with missing primary efficacy endpoints, multiple 
imputation by fully conditional specification methods will be used. The imputation model will use 
subject demographics (age, sex, race, baseline weight, and smoking status) and baseline and 


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post-baseline mean number and severity of vasomotor symptoms. Sensitivity analyses will be 
performed with other multiple imputation methods and mixed model for repeat measurements.  
Since the study design requires the comparison of 7 active dose groups with placebo for 
4 co-primary efficacy variables, a two-tier closed testing procedure will be used to control the 
family-wise error. A step-down testing procedure will be followed. The following testing order of 
doses will be employed: 
a. Placebo versus 90 mg BID (daily dose 180 mg), 
b. Placebo versus 60 mg BID (daily dose 120 mg), 
c. Placebo versus 120 mg QD (daily dose 120 mg), 
d. Placebo versus 30 mg BID (daily dose 60 mg), 
e. Placebo versus 60 mg QD (daily dose 60 mg), 
f. Placebo versus 15 mg BID (daily dose 30 mg), and 
g. Placebo versus 30 mg QD (daily dose 30 mg). 
The 4 co-primary efficacy endpoints will be compared at each dose level. Only when ESN364 is 
proved to be significantly better than placebo at a 2-sided alpha level of 0.05 for all 4 co-primary 
efficacy endpoints will this dose level be claimed to be superior to placebo. A failure to prove the 
significance for 1 or more co-primary efficacy endpoints will lead to a failure to claim superiority 
to placebo at this dose level, and the other dose levels after this one in the sequence will not be 
tested. 
The primary efficacy analysis will be based on the FAS. A supportive analysis will be carried out 
for the co-primary efficacy variables based on the PPAS to examine the impact of premature 
dropouts and/or major protocol deviations. 
10.2.1.2 
Secondary efficacy analysis 
Efficacy will be further assessed based on the secondary endpoints described in Section 7.2 using 
the FAS.  
10.2.1.3 
Pharmacodynamic analysis 
Individual plasma hormone concentration values and actual sampling times relative to study drug 
intake will be listed. Descriptive statistics on the actual values and changes from baseline values 
will be summarized by assessment timepoint and by treatment arm.  
Descriptive statistics will include number of subjects, (arithmetic) mean, standard deviation (SD), 
median, minimum, and maximum, and a 95% CI. Frequency tabulations will show counts and 
percentages. Pharmacodynamic data and efficacy data may be evaluated by a population PD or 
population PK/PD 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.  
10.2.1.4 
Exploratory efficacy analysis 
 
 
 
 
. Pharmacokinetics may be 
CCI


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evaluated by a population PK 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.  
10.2.2 
Analysis of Safety 
Safety will be assessed by examining the incidence of adverse events, physical examinations 
findings, C-SSRS, vital signs, ECGs, clinical laboratory tests, and bone density marker 
concentrations over time using the Safety Analysis Set. 
10.2.3 
Interim Analysis 
An early timepoint analysis is planned 4 weeks after the last randomization. The unblinded results 
will be restricted to a very small group independent of the study team. No changes to the study or 
the statistical analysis plan will be made as a result of this analysis (which is intended to assist 
with internal decision making only). Full details will be documented in a separate charter to ensure 
the integrity of the trial blinding; all study team personnel, including all those involved in data 
management, clinical, medical, or statistical review of the data, will remain blinded until database 
hard-lock (see Section 5.3).   
10.2.4 
Sample Size Determination 
A total of 352 subjects are planned to be randomized, 44 subjects in each treatment arm.  
In the Phase 2a study, the observed least-squares mean difference between ESN364 90 mg BID 
(highest dose of this Phase 2b study) and placebo in change from baseline to Week 12 in mean 
daily frequency of moderate to severe vasomotor symptoms was -5.0 (95% CI: -6.8, -3.3) with 
similar results at Week 4. For any given pairwise comparison for a 2-sample t-test at a 2-sided 
5% alpha, 40 subjects provides the following power to detect the following effect sizes assuming 
an SD of 5: 
Assumed treatment difference in mean daily frequency 
Power for pairwise test 
3.3 
83% 
3.5 
87% 
4 
94% 
4.5 
97% 
5 
>99% 
For change from baseline to Week 12 in mean severity of moderate to severe vasomotor symptoms, 
the observed mean treatment different in the Phase 2a study was -1.12 (95% CI: -1.5, -0.74) with 
similar results at Week 4. For any given pairwise comparison for a 2-sample t-test at a 2-sided 
5% alpha, 40 subjects provides the following power to detect the following effect sizes assuming 
a SD of 1: 
Assumed treatment difference in mean severity 
Power for pairwise test 
0.64 
80% 
0.75 
91% 
1 
>99% 
Note that the combined power for testing all 4 co-primary endpoints will be lower than the power 
for each considered individually. Assuming approximately 10% of subjects discontinue 
prematurely, the number of 40 subjects is increased to 44 subjects per arm.  


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements.  
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of Medical Dictionary for Regulatory Activities for adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
12.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and wellbeing of study subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
12.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and wellbeing of subjects. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements 
(if applicable), written information given to the subjects, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the Investigator. 
Federal regulations and the International Conference on Harmonisation (ICH) require that 
approval be obtained from an IRB prior to participation of subjects in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject 
recruitment, and any other written information regarding this study to be provided to a subject or 
subject’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
12.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP 
requirements, local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of her rights to privacy. The Investigator will obtain written informed 
consent from each subject before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB, and/or regulatory agencies. 
A copy of the signed ICF will be given to the subject. 
12.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 


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the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
12.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
12.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.   
12.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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12.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for subject safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 
13.2 
Address List 
13.2.1 
Sponsor      
Ogeda S.A.  
47 Rue Adrienne Bolland 
6047 Gosselies, Belgium 
Telephone: +32 71 348 510 
Fax: +32 71 348 519 
13.2.2 
Contract Research Organization 
Medpace, Inc.  
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-513-579-9911 
Fax: +1-513-579-0444 
13.2.3 
Drug Safety 
Medpace Clinical Safety 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-800-730-5779, dial 3 
Fax: +1-866-336-5320 
Email: medpace-safetynotification@medpace.com 
PPD


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PPD


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14 
REFERENCES 
 
1. 
Rossouw, J. et al. Risks and Benefits of Estrogen Plus Progestin in Healthy 
Postmenopausal Women: Principal Results From the Women’s Health Initiative 
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2. 
Kronenberg, F. Hot flashes: phenomenology, quality of life, and search for treatment 
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3. 
Stearns, V., Beebe, K. L., Iyengar, M. & Dube, E. Paroxetine Controlled Release in the 
Treatment of Menopausal Hot Flashes. JAMA 289, 2827–2834 (2003). 
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Kronenberg, F. Hot flashes: epidemiology and physiology. Ann. N. Y. Acad. Sci. 592, 
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US Census Bureau. Resident population estimates of the United States by age and sex: 
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6. 
de Villiers, T. J. et al. Global Consensus Statement on menopausal hormone therapy. 
Maturitas 74, 391–2 (2013). 
7. 
Loprinzi, C. L. et al. Phase III evaluation of fluoxetine for treatment of hot flashes. 
J. Clin. Oncol. 20, 1578–83 (2002). 
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Loprinzi, C. L. et al. Venlafaxine in management of hot flashes in survivors of breast 
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9. 
Stearns, V. et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in 
controlling hot flashes in breast cancer survivors. Ann. Oncol. 11, 17–22 (2000). 
10. 
Fraser, G. L. et al. The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH 
Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle. 
Endocrinology 156, 4214–4225 (2015). 
11. 
Fraser, G. L., Ramael, S., Hoveyda, H. R., Gheyle, L. & Combalbert, J. The NK3 
Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women. J. Clin. 
Endocrinol. Metab. 101, 417–426 (2016). 
12. 
Millar, R. P. & Newton, C. L. Current and future applications of GnRH, kisspeptin and 
neurokinin B analogues. Nat. Rev. Endocrinol. 9, 451–466 (2013). 
13. 
Hrabovszky, E. Neuroanatomy of the Human Hypothalamic Kisspeptin System. 
Neuroendocrinology 99, 33–48 (2014). 
14. 
Ogeda S.A. Investigator’s Brochure. 
15. 
Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic 
hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. 
Nat. Genet. 41, 354–358 (2009). 
16. 
Francou, B. et al. Normosmic Congenital Hypogonadotropic Hypogonadism Due to 
TAC3/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel 
Mutations. PLoS One 6, 1–11 (2011). 


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17. 
Simpson, T. Discovery of AZD2624: a potent and selective NK3R antagonist to the NK3 
hypothesis in schizophrenia. in Oral Presentation, 239th ACS Meeting, (San Francisco, 
CA), paper ID: 17404 (2010). 
18. 
Lehman, M. N., Coolen, L. M. & Goodman, R. L. Minireview: kisspeptin/neurokinin 
B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of 
gonadotropin-releasing hormone secretion. Endocrinology 151, 3479–89 (2010). 
19. 
Ruka, K. A., Burger, L. L. & Moenter, S. M. Both Estrogen and Androgen Modify the 
Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin 
Neurons From Male Mice. Endocrinology 157, 752–763 (2016). 
20. 
Rance, N. E., Dacks, P. A., Mittelman-Smith, M. A., Romanovsky, A. A. & 
Krajewski-Hall, S. J. 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. 34, 211–227 (2013). 
21. 
Jayasena, C. N. et al. Neurokinin B Administration Induces Hot Flushes in Women. 
Sci. Rep. 5, 1–7 (2015). 
22. 
Crandall, C. J. et al. Association of genetic variation in the tachykinin receptor 3 locus 
with hot flashes and night sweats in the Womenʼs Health Initiative Study. Menopause 3, 
252–261 (2017). 
23. 
US Department of Health and Human Services 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). 
24. 
European Medicines Agency. Guideline of clinical investigation of medicinal products for 
hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal 
women. (2005). 
25. 
National Institutes of Health. Assessing and Improving Measures of Hot Flashes. (2004). 
26. 
Carpenter, J. S. The Hot Flash Related Daily Interference Scale: a tool for assessing the 
impact of hot flashes on quality of life following breast cancer. J. Pain Symptom Manage. 
22, 979–89 (2001). 
27. 
Daut, R. L., Cleeland, C. S. & Flanery, R. C. Development of the Wisconsin Brief Pain 
Questionnaire to assess pain in cancer and other diseases. Pain 17, 197–210 (1983). 
28. 
Hann, D. M. et al. Measurement of fatigue in cancer patients: development and validation 
of the Fatigue Symptom Inventory. Qual. Life Res. 7, 301–10 (1998). 
29. 
Rand, K. L. et al. Modeling hot flushes and quality of life in breast cancer survivors. 
Climacteric 14, 171–80 (2011). 
30. 
Parrott, A. C. & Hindmarch, I. Factor analysis of a sleep evaluation questionnaire. 
Psychol. Med. 8, 325–9 (1978). 
31. 
Greene, J. G. A factor analytic study of climacteric symptoms. J. Psychosom. Res. 20, 
425–430 (1976). 


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32. 
Hilditch, J., Lewis, J. & Peter, A. A menopause-specific quality of life questionnaire: 
development and psychometric properties. Maturitas 24, 161–175 (1996). 
33. 
Lewis, J. E., Hilditch, J. R. & Wong, C. J. Further psychometric property development of 
the Menopause-Specific Quality of Life questionnaire and development of a modified 
version, MENQOL-Intervention questionnaire. Maturitas 50, 209–221 (2005). 
34. 
Radtke, J., Terhorst, L. & Cohen, S. The Menopause-Specific Quality of Life (MENQOL) 
Questionnaire: Psychometric Evaluation among Breast Cancer Survivors. Menopause 18, 
289–295 (2011). 
35. 
Massad, L. S. et al. 2012 Updated Consensus Guidelines for the Management of 
Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J. Low. Genit. Tract 
Dis. 17, s1–s27 (2013). 


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APPENDIX A. SCHEDULE OF PROCEDURES 
Assessments 
Screening Visit 
Treatment Period 
Follow-Up 
Visit 
Study Visit 
Visit 1 
Visit 2 
Visit 2A 
Visit 3 
Visit 3A 
Visit 4 
Visit 4A 
Visit 5/ET 
Visit 6 
Time of Visit 
Days -35 to -1a,b 
Day 1a 
Week 2c 
Week 4a 
Week 6c 
Week 8a 
Week 10c 
Week 12a 
Week 15a,d  
Informed consente 
X 
 
 
 
 
 
 
 
 
Informed consent PGXe 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical history/concomitant diseases 
X 
 
 
 
 
 
 
 
 
Screening mammogramf 
X 
 
 
 
 
 
 
 
 
Demographic datag 
X 
 
 
 
 
 
 
 
 
Physical examinationh 
X 
X 
 
Xi 
 
Xi 
 
X 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
 
 
 
Clinical laboratoryj and urinalysis 
X 
X 
Xk 
X 
Xk 
X 
Xk 
X 
X 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
Vital signsl 
X 
X 
 
X 
 
X 
 
X 
X 
12-lead ECGm 
X 
X 
 
X 
 
X 
 
X 
X 
Pap smearn 
X 
 
 
 
 
 
 
 
 
Transvaginal ultrasound 
X 
 
 
 
 
 
 
X 
 
Endometrial biopsyo 
X 
 
 
 
 
 
 
X 
 
Serologyp 
X 
 
 
 
 
 
 
 
 
Blood PD sampleq 
 
X 
 
X 
 
X 
 
X 
X 
Blood PK sampler 
 
 
 
X 
 
 
 
X 
 
Blood PGX samples 
 
 
 
 
 
 
 
X 
 
Vasomotor symptom diaryt  
X 
X 
 
X 
 
X 
 
X 
X 
HFRDISu 
 
X 
 
X 
 
X 
 
X 
X 
LSEQu 
 
Xv 
 
Xv 
 
Xv 
 
Xv 
Xv 
GCSu 
 
X 
 
X 
 
X 
 
X 
X 
MENQoLu 
 
X 
 
X 
 
X 
 
X 
X 
C-SSRSu 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
Bone turnover markers x 
 
X 
 
 
 
 
 
X 
X 
ePRO training 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
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Assessments 
Screening Visit 
Treatment Period 
Follow-Up 
Visit 
Study Visit 
Visit 1 
Visit 2 
Visit 2A 
Visit 3 
Visit 3A 
Visit 4 
Visit 4A 
Visit 5/ET 
Visit 6 
Time of Visit 
Days -35 to -1a,b 
Day 1a 
Week 2c 
Week 4a 
Week 6c 
Week 8a 
Week 10c 
Week 12a 
Week 15a,d 
Dispense study drugy 
 
X 
 
X 
 
X 
 
 
 
Study drug compliance and 
accountabilityz 
 
X 
 
X 
 
X 
 
X 
 
Concomitant medications and 
adverse eventsaa 
X 
X 
 
X 
 
X 
 
X 
X 
a. 
Study visits should be conducted in the morning. Subjects should be fasted (defined as nothing by mouth except for water [up to 1 hour before study drug intake] for at least 
10 hours prior to study visit). All assessments will be completed predose, except for postdose blood sampling for PK and PD assessments at Week 4 (Visit 3). Administration 
of questionnaires will be completed at the respective visits prior to any invasive procedures. Day 1 (Visit 2) should be planned to allow for the first intake of study drug at the 
study site between 7:00 AM and 10:00 AM. Following Day 1 (Visit 2), each subsequent visit should be planned at the same time of day (morning) for each subject. Following 
randomization to study drug, subjects will return to the study site for visits and procedures to occur within 3 days of the scheduled time. Unscheduled visits can be planned 
outside the scheduled visits (see Section 6.6).  
b. 
The screening visit is to occur within 35 days of randomization (Day 1 [Visit 2]), with a minimum of 7 days to allow for baseline data collection of vasomotor symptom 
frequency and severity assessments. Subjects will receive an electronic diary in which to record daily vasomotor symptoms during the screening period. Subjects must have 
7 consecutive days of vasomotor symptom recordings to participate in the study. Subjects may be rescreened 1 time upon approval of the Medical Monitor. The following 
assessments do not need to be repeated at the rescreen provided they still fall within the acceptable time window: transvagin al ultrasound, endometrial biopsy, mammogram, 
, ECG, and Pap smear. 
c. 
Subjects may schedule Week 2 (Visit 2A), Week 6 (Visit 3A), and Week 10 (Visit 4A) assessments at their convenience within the visit window (3 days). Fasting is not 
required for these visits. 
d. 
The follow-up visit will occur approximately 3 weeks following the last dose of study drug. For subjects requiring a repeat biopsy, the follow-up visit will occur 4 weeks after 
Week 12 (Visit 5).   
e. 
Signed informed consent will be collected for all subjects before any study-related procedures are done. A separate signature will be collected for PGX sampling. Subjects 
who do not consent to PGX sampling are not excluded from participating in the study.  
f. 
Only in the event the subject does not have a normal/negative or no clinically significant findings mammogram from previous 9 months on record.  
g. 
Includes age, race, sex, and smoking status (smoker/non-smoker).   
h. 
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.   
i. 
Weight and waist circumference only.  
j. 
Includes biochemistry, coagulation (at the screening visit and Week 12 [Visit 5]/ET only), and hematology panel. Blood samples for clinical laboratory tests should be taken 
in a fasted state (defined as nothing by mouth except water for 10 hours), except for Week 2 (Visit 2A), Week 6 (Visit 3A), and Week 10 (Visit 4A). 
k. 
Includes biochemistry and hematology, only.  
l. 
Includes oral/tympanic temperature, sitting blood pressure, and pulse rate (supine after 5 minutes of rest).  
m. All 12-lead ECGs will be captured in triplicate (ie, 3 separate 12-lead ECGs at least 1 to 2 minutes apart within a 5-minute window). The subject should rest in supine position 
for at least 10 minutes prior to the first ECG. 
n. 
Only in the event the subject does not have a normal/negative or no clinically significant findings Pap smear from previous 9  months on record. 
o. 
Subjects will undergo endometrial biopsy at screening (if endometrial thickness is 4 mm), at Week 12 (end-of-treatment)-(all subjects), at the ET Visit for subjects who are 
withdrawn from the study prior to completion (if study drug exposure is 10 weeks), and in all cases of uterine bleeding. If the uterine biopsy is abnormal at Week 12 
(end-of-treatment), subjects will have a repeat biopsy 4 weeks later, if clinically indicated.  
p. 
For HBsAG, anti-HCV antibodies, and anti-HIV antibodies.  
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q. 
Samples will be taken predose at Day 1 (Visit 2), Week 8 (Visit 4), and Week 12 (Visit 5)/ET, as well as predose and 3 hours postdose at Week 4 (Visit 3). The Week 4 
(Visit 3) 3 hours postdose PD sample should be shifted to a later date in cases where the subject cannot accommodate the PK sampling schedule at that visit. The PD sample 
should be taken at the same time as the 3-hour postdose PK sample (see Section 8.2). A PD sample will be taken at the follow-up visit (Week 15 [Visit 6]) as well. Markers 
include LH, FSH, E2, and SHBG.  
r. 
Samples to be taken Week 4 (Visit 3) predose and 1 h (30 min), 3 h (30 min), 5 h (-1 h/+30 min), and 7 h (-1 h/+2 h) postdose as well as predose Week 12 (Visit 5). The 
indicated time windows for Week 4 (Visit 3) PK sampling will allow for flexibility.  
s. 
While scheduled for Week 12 (Visit 5), the PGX sample can be taken at any time during the study following signed informed consent and enrollment into the study. 
t. 
The vasomotor symptom diary will be kept by subjects. Subjects will record the vasomotor symptom frequency and severity of each vasomotor symptom in the ePRO diary 
on an ad hoc basis, but at a minimum twice daily (morning and evening), from the screening visit (Days -35 to -1 [Visit 1]) through the follow-up visit (Week 15 [Visit 6]). 
Night sweats should be recorded no later than in the morning upon awakening to start a new day. 
u. 
Paper-based, administered at the study site prior to any invasive procedures.  
v. 
A baseline LSEQ assessment will be collected at Day 1 (Visit 2). A post-baseline LSEQ assessment will be collected for all other indicated visits.  
w. 
 
 
 
  
x. 
Includes BALP, P1NP, and CTX.  
y. 
Subjects will be assigned 2 bottles of study drug as a kit (1 bottle labeled “morning” and 1 bottle labeled “evening”) at Day 1 (Visit 2), Week 4 (Visit 3), and Week 8 
(Visit 4). Each bottle will contain 34 capsules of ESN364 or placebo. Study drug intake will be done with a glass of room temperature tap water. The first intake of study drug 
will take place at the study site on Day 1 (Visit 2) between 7:00 AM and 10:00 AM, under the supervision of the study staff. On study visit days (Day 1 [Visit 2], Week 4 
[Visit 3], and Week 8 [Visit 4], only), the morning dose of study drug will be taken at the study site, under the supervision of the study staff, after collection of predose blood 
samples. Subjects will be instructed to arrive at the study site fasted (nothing by mouth except water [up to 1 hour prior to study drug intake] for at least 10 hours). On all 
other days throughout the treatment period, subjects will be instructed to take their morning dose of study drug at home, around the same time of the day spaced as near to 
12 hours apart as possible (preferably between 7:00 AM and 10:00 AM and 7:00 PM and 10:00 PM). Intake of study drug should be preferably 1 hour before or 2 hours after 
meals. Subjects need to record all home study drug intake in the ePRO diary.  
z. 
Includes compliance of study drug intake and ePRO completion. Subjects will be asked to return all unused study drug. Compliance of study drug intake will be assessed by 
counting returned study drug in addition to reviewing ePRO entries of study drug intake. Any discrepancies between returned study drug number and dosing in the ePRO 
diary will be discussed with the subject for whom a discrepancy was seen and recorded in the source documents and the eCRF. 
aa. Adverse events and intake of concomitant medication(s) will be monitored continuously from informed consent until the last st udy-related activity. 
 
BALP = bone alkaline phosphatase; C-SSRS = Columbia Suicide Severity Rating Scale; CTX = carboxy-terminal telopeptide of type I collagen; 
 
; E2 = estradiol; ECG = electrocardiogram; eCRF = electronic Case Report Form; ET = early termination; ePRO = electronic Patient-Reported Outcome; 
FSH = follicle-stimulating hormone; GCS = Greene Climacteric Scale; HBsAG = hepatitis B virus surface antigen; HCV = hepatitis C virus; HFRDIS = Hot Flash Related Daily 
Interference Scale; HIV = human immunodeficiency virus; LH = luteinizing hormone; LSEQ = Leeds Sleep Evaluation Questionnaire; MENQoL = Menopause-Specific Quality of 
Life; P1NP = procollagen type 1 amino-terminal propeptide; PD = pharmacodynamic; PGX = pharmacogenomic; PK = pharmacokinetic; SHBG = sex hormone-binding globulin.  
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APPENDIX B. CLINICAL LABORATORY ANALYTES 
Biochemistry 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Bicarbonate 
Aspartate aminotransferase 
Calcium 
Blood urea nitrogen 
Creatine kinase 
Chloride 
Estimated glomerular filtration rate 
Creatinine 
Glucose 
Gamma-glutamyl transferase 
Lactate dehydrogenase 
Inorganic phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
Endocrinology 
Estradiol 
Follicle-stimulating hormone 
Luteinizing hormone 
Sex hormone-binding globulin 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. 
Neutrophils, lymphocytes, eosinophils, monocytes, and basophils. Manual microscopic review is performed 
only if white blood cell count and/or differential values are out of reference range. 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
1. 
Microscopy is performed only as needed based on positive dipstick test results. 
 
Coagulation 
International normalized ratio 
Activated partial thromboplastin time 
Prothrombin time 
 
 
Serology 
Hepatitis B virus surface antigen 
Hepatitis C virus 
Human immunodeficiency virus 
 
 


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Bone Markers 
Procollagen type 1 amino-terminal 
propeptide 
Carboxy-terminal telopeptide of type 1 
collagen 
Bone alkaline phosphatase 
 
 
Urine Drug Screen 
Amphetamines 
Tricyclic antidepressants 
Cannabinoids 
Cocaine 
Opiates 
 
 


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APPENDIX C. WAIST CIRCUMFERENCE MEASUREMENT 
The National Institutes of Health provided a protocol for the measurement of waist 
circumference.  
 
Source: Adapted from the National Heart, Lung, and Blood Institute as a part of the National Institutes of Health and the U.S. 
Department of Health and Human Services. Available at: http://www nhlbi nih.gov/guidelines/obesity/prctgd_c.pdf  


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APPENDIX D. EVENTS OF CLINICAL INTEREST GUIDANCE FOR 
POTENTIAL DRUG-INDUCED LIVER INJURY 
 


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APPENDIX E. NORMAL RANGES FOR VITAL SIGNS AND 
ELECTROCARDIOGRAMS 
Normal Ranges for Vital Sign Parameters 
Systolic blood pressure 
(SBP) (mmHg) 
Diastolic blood pressure 
(DBP) (mmHg) 
Pulse rate 
(bpm) 
Oral/tympanic 
temperature (°C) 
90  SBP  160 
45  DBP  90 
40  pulse  100 
35.0  t°  37.5 
These normal ranges are applicable in supine position (after 5 minutes rest). 
 
Normal Ranges for Electrocardiogram Parameters 
PR 
(ms) 
QRS 
(ms) 
QTcF 
(ms) 
Heart rate 
(bpm) 
120  PR  220 
QRS  120 
QTcF  450 
40  HR  100 
 
 

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STATISTICAL ANALYSIS PLAN
Version 1.0, dated 30-May-2018
A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging, Phase 2b Study to 
Investigate the Efficacy of ESN364 in Postmenopausal Women Suffering From Vasomotor 
Symptoms (Hot Flashes)
ISN: ESN364_HF_205
IND number: 130277
Ogeda S.A.
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.
NCT03192176


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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
FLOW CHART AND VISIT SCHEDULE···················································· 6
2.1
Flow Chart ······················································································ 6
2.2
Schedule of Assessments······································································ 7
3
STUDY OBJECTIVE(S) AND DESIGN······················································11
3.1
Study Objective(s) ············································································11
3.1.1
Primary Objective ·······································································11
3.1.2
Secondary Objectives ···································································11
3.1.3
Exploratory Objectives ·································································11
3.2
Study Design···················································································11
3.3
Randomization·················································································12
4
SAMPLE SIZE·····················································································13
5
ANALYSIS SETS ·················································································13
5.1
Safety Analysis Set (SAF) ···································································13
5.2
Full Analysis Set (FAS) ······································································14
5.3
Per Protocol Analysis Sets (PPS)····························································14
5.3.1
Reasons for Exclusion From PPS4 ····················································14
5.3.2
Reasons for Exclusion From PPS12 ··················································14
5.4
Pharmacokinetics Analysis Set (PKAS)····················································14
6
ANALYSIS VARIABLES ·······································································14
6.1
Efficacy Endpoints············································································14
6.1.1
Co-Primary Efficacy Endpoints ·······················································14
6.1.2
Secondary Efficacy Endpoints·························································16
6.1.3
Exploratory Efficacy Endpoints ·······················································19
6.2
Safety Variables ···············································································19
6.3
Pharmacokinetic Variables···································································20
6.4
Other Variables················································································20
7
STATISTICAL METHODOLOGY ···························································21
7.1
General Considerations·······································································21
7.2
Study Population ··············································································22


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7.2.1
Disposition of Subjects ·································································22
7.2.2
Protocol Deviations ·····································································22
7.2.3
Demographic and Other Baseline Characteristics ···································22
7.2.4
Previous and Concomitant Medications ··············································23
7.3
Study Drugs····················································································23
7.3.1
Exposure··················································································23
7.3.2
Treatment Compliance··································································24
7.4
Analysis of Efficacy ··········································································24
7.4.1
Analysis of Primary Endpoints ························································24
7.4.2
Analysis of Secondary Endpoints ·····················································26
7.4.3
Analysis of Exploratory Endpoints····················································26
7.5
Analysis of Safety·············································································27
7.5.1
Adverse Events ··········································································27
7.5.2
Clinical Laboratory Evaluation ························································28
7.5.3
Vital Signs················································································29
7.5.4
Electrocardiograms (ECGs)····························································30
7.5.5
Pregnancies···············································································30
7.5.6
Other Safety-Related Observations ···················································30
7.6
Analysis of PK·················································································31
7.7
Subgroups of Interest ·········································································31
7.8
Other Analyses ················································································31
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················31
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········31
7.10.1
Missing Data ·············································································31
7.10.2
Pooled Center ············································································32
7.10.3
Electronic and Paper Diaries···························································33
7.10.4
Last Dose Date···········································································33
7.10.5
Outliers ···················································································33
7.10.6
Visit Windows ···········································································33
8
CHANGES FROM PROTOCOL ······························································35
9
DOCUMENT REVISION HISTORY ·························································35
10
REFERENCES ····················································································36
11
APPENDICES ·····················································································37
11.1
Appendix 1: Key Contributors and Approvers ············································37


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ASCM
Analysis Set Classification Meeting 
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
BALP
Bone alkaline phosphatase
BID
Bis in die; twice daily
BMC
Bone mineral content
BMD
Bone mineral density
BMI
Body mass index
BoT
Burden of Toxicity
CI
Confidence interval
CRF
Case Report Form
CRO
Contract Research Organization
CS
Classification Specifications
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTX
Carboxy-terminal telopeptide of type I collagen
CV
Coefficient of variation
DILI
Drug-induced liver injury
DXA
Dual-energy x-ray absorptiometry
E2
Estradiol
ECG
Electrocardiogram
eCRF
Electronic case report form
ePRO
Electronic Patient-Reported Outcome
ET
Early termination
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
FSI
First subject in
GCS
Greene Climacteric Scale
H
High
HBsAG
Hepatitis B virus surface antigen
HCV
Hepatitis C virus
HFRDIS
Hot Flash Related Daily Interference Scale
HIV
Human immunodeficiency virus
ICH
International Conference on Harmonization
IRT
Interactive Response Technology
L
Low
LH
Luteinizing hormone
LLN 
Lower limit of normal
LSEQ
Leeds Sleep Evaluation Questionnaire


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Abbreviations
Description of abbreviations
MedDRA
Medical Dictionary for Regulatory Activities
MENQoL
Menopause-Specific Quality of Life
MCP-Mod
Multiple Comparison Procedure – Modeling
mg
Milligram(s)
N
Normal
NIH
National Institutes of Health
P1NP
Procollagen type 1 amino-terminal propeptide
PD
Pharmacodynamic(s)
PGX
Pharmacogenomic(s)
PK
Pharmacokinetic(s)
PKAS
Pharmacokinetics Analysis Set
PPS
Per Protocol Analysis Set
PPS4
Per Protocol Analysis Set – Week 4
PPS12
Per Protocol Analysis Set – Week 12
PT
Preferred Term
QD
Quaque die; once daily
QT
Q-T Interval
QTcB
Corrected Q-T Interval (Bazett)
QTcF
Corrected Q-T Interval (Fridericia)
SA
Smooth average
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard deviation
SHBG
Sex hormone-binding globulin
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
TLF
Tables, listings and figures
ULN
Upper limit of normal
USA
United States of America
WHO-DD
World Health Organization Drug Dictionary
List of Key Terms
Terms
Definition of terms
Baseline
A variable that represents the efficacy and safety measurements and disease 
characteristics prior to the intervention with study medication. It can be a single 
measurement or a derived parameter (such as average frequency or severity of 
vasomotor symptom from 7 non-missing days prior to Day 1).
Endpoint
A variable that pertains to the trial objectives.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.
SAS ®
A statistical software package used for the analysis of data




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2.2
Schedule of Assessments
Assessments
Screening Visit
Treatment Period
Follow-Up 
Visit
Study Visit
Visit 1
Visit 2
Visit 2A
Visit 3
Visit 3A
Visit 4
Visit 4A
Visit 5/ET
Visit 6
Time of Visit
Days -35 to -10,b
Day 10
Week 2c
Week 40
Week 6c
Week 80
Week 10c
Week 120
Week 150,d
Informed consent0
X
Informed consent PGX0
X
Inclusion/exclusion criteria
X
X
Medical history/concomitant diseases
X
Screening mammogramf
X
Demographic datag
X
Physical examinationh
X
X
Xi
Xi
X
X
Urine drug screen
X
Urine pregnancy test
X
Clinical laboratoryj and urinalysis
X
X
Xk
X
Xk
X
Xk
X
X
Alcohol breath test
X
Vital signsl
X
X
X
X
X
X
12-lead ECG0
X
X
X
X
X
X
Pap smearn
X
Transvaginal ultrasound
X
X
Endometrial biopsyo
X
X
Serologyp
X
Blood PD sampleq
X
X
X
X
X
Blood PK sampler
X
X
Blood PGX samples
X
Vasomotor symptom diaryt
X
X
X
X
X
X
HFRDISu
X
X
X
X
X
LSEQu
Xv
Xv
Xv
Xv
Xv
GCSu
X
X
X
X
X
Table continued on next page


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Assessments
Screening Visit
Treatment Period
Follow-Up 
Visit
Study Visit
Visit 1
Visit 2
Visit 2A
Visit 3
Visit 3A
Visit 4
Visit 4A
Visit 5/ET
Visit 6
Time of Visit
Days -35 to -10,b
Day 10
Week 2c
Week 40
Week 6c
Week 80
Week 10c
Week 120
Week 150,d
MENQoLu
X
X
X
X
X
C-SSRSu
X
X
X
X
X
Bone turnover markersx
X
X
X
ePRO training
X
Randomization
X
Dispense study drugy
X
X
X
Study drug compliance and accountabilityz
X
X
X
X
Concomitant medications and adverse 
eventsaa
X
X
X
X
X
X
a.
Study visits should be conducted in the morning. Subjects should be fasted (defined as nothing by mouth except for water [up to 1 hour before study drug intake] for at least 
10 hours prior to study visit). All assessments will be completed predose, except for postdose blood sampling for PK and PD assessments at Week 4 (Visit 3). Administration of 
questionnaires will be completed at the respective visits prior to any invasive procedures. Day 1 (Visit 2) should be planned to allow for the first intake of study drug at the study
site between 7:00 AM and 10:00 AM. Following Day 1 (Visit 2), each subsequent visit should be planned at the same time of day (morning) for each subject. Following 
randomization to study drug, subjects will return to the study site for visits and procedures to occur within 3 days of the scheduled time. Unscheduled visits can be planned 
outside the scheduled visits (see Section 6.6). 
b.
The screening visit is to occur within 35 days of randomization (Day 1 [Visit 2]), with a minimum of 7 days to allow for baseline data collection of vasomotor symptom frequency 
and severity assessments. Subjects will receive an electronic diary in which to record daily vasomotor symptoms during the screening period. Subjects must have 7 consecutive 
days of vasomotor symptom recordings to participate in the study. Subjects may be rescreened 1 time upon approval of the Medical Monitor. The following assessments do not 
need to be repeated at the rescreen provided they still fall within the acceptable time window: transvaginal ultrasound, endometrial biopsy, mammogram, 
 ECG, and Pap 
smear.
c.
Subjects may schedule Week 2 (Visit 2A), Week 6 (Visit 3A), and Week 10 (Visit 4A) assessments at their convenience within the visit window (3 days). Fasting is not required 
for these visits.
d.
The follow-up visit will occur approximately 3 weeks following the last dose of study drug. For subjects requiring a repeat biopsy, the follow-up visit will occur 4 weeks after 
Week 12 (Visit 5).  
e.
Signed informed consent will be collected for all subjects before any study-related procedures are done. A separate signature will be collected for PGX sampling. Subjects who do 
not consent to PGX sampling are not excluded from participating in the study. 
f.
Only in the event the subject does not have a normal/negative or no clinically significant findings mammogram from previous 9 months on record. 
Footnotes continued on next page
CCI
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y.
Subjects will be assigned 2 bottles of study drug as a kit (1 bottle labeled “morning” and 1 bottle labeled “evening”) at Day 1 (Visit 2), Week 4 (Visit 3), and Week 8 (Visit 4). 
Each bottle will contain 34 capsules of ESN364 or placebo. Study drug intake will be done with a glass of room temperature tap water. The first intake of study drug will take 
place at the study site on Day 1 (Visit 2) between 7:00 AM and 10:00 AM, under the supervision of the study staff. On study visit days (Day 1 [Visit 2], Week 4 [Visit 3], and 
Week 8 [Visit 4], only), the morning dose of study drug will be taken at the study site, under the supervision of the study staff, after collection of predose blood samples. Subjects 
will be instructed to arrive at the study site fasted (nothing by mouth except water [up to 1 hour prior to study drug intake] for at least 10 hours). On all other days throughout the 
treatment period, subjects will be instructed to take their morning dose of study drug at home, around the same time of the day spaced as near to 12 hours apart as possible 
(preferably between 7:00 AM and 10:00 AM and 7:00 PM and 10:00 PM). Intake of study drug should be preferably 1 hour before or 2 hours after meals. Subjects need to record 
all home study drug intake in the ePRO diary. 
z.
Includes compliance of study drug intake and ePRO completion. Subjects will be asked to return all unused study drug. Compliance of study drug intake will be assessed by 
counting returned study drug in addition to reviewing ePRO entries of study drug intake. Any discrepancies between returned study drug number and dosing in the ePRO diary will 
be discussed with the subject for whom a discrepancy was seen and recorded in the source documents and the eCRF.
aa. Adverse events and intake of concomitant medication(s) will be monitored continuously from informed consent until the last study-related activity.
BALP = bone alkaline phosphatase; C-SSRS = Columbia Suicide Severity Rating Scale; CTX = carboxy-terminal telopeptide of type I collagen; 
 
 E2 = estradiol; ECG = electrocardiogram; eCRF = electronic Case Report Form; ET = early termination; ePRO = electronic Patient-Reported Outcome; 
FSH = follicle-stimulating hormone; GCS = Greene Climacteric Scale; HBsAG = hepatitis B virus surface antigen; HCV = hepatitis C virus; HFRDIS = Hot Flash Related Daily 
Interference Scale; HIV = human immunodeficiency virus; LH = luteinizing hormone; LSEQ = Leeds Sleep Evaluation Questionnaire; MENQoL = Menopause-Specific Quality of 
Life; P1NP = procollagen type 1 amino-terminal propeptide; PD = pharmacodynamic; PGX = pharmacogenomic; PK = pharmacokinetic; SHBG = sex hormone-binding globulin.
CCI


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
The primary objective of this study is to evaluate the effect of different doses and dosing 
regimens of ESN364 on frequency and severity of vasomotor symptoms (hot flashes).
3.1.2
Secondary Objectives
The secondary objectives of this study are the following:
●
To evaluate the effect of different doses and dosing regimens of ESN364 on the 
frequency, severity, and hot flash score of mild, moderate, and severe vasomotor 
symptoms;
●
To evaluate the effect of different doses and dosing regimens of ESN364 on responder 
rates using a variety of responder definitions;
●
To evaluate the effect of different doses and dosing regimens of ESN364 on 
patient-reported outcomes;
●
To evaluate the effect of different doses and dosing regimens of ESN364 on PD markers 
(hormone and bone markers); and
●
To evaluate the effect of different doses and dosing regimens of ESN364 on safety and 
tolerability.
3.1.3
Exploratory Objectives
The exploratory objectives of this study are the following:
●
 
●
To evaluate the PK plasma concentrations of ESN364 and metabolite 
3.2
Study Design
This is a 12-week, randomized, double-blind, placebo-controlled, dose-ranging, 
parallel-group, multicenter study to assess the efficacy of ESN364 in postmenopausal women 
suffering from vasomotor symptoms (hot flashes).
This study will consist of a screening period (Days -35 to -1, including the screening visit 
[Visit 1] and a minimum 7-day collection of baseline vasomotor symptom frequency and 
severity assessments), a 12-week treatment period (Day 1 [Visit 2] to Week 12 [Visit 5], 
including safety visits at Week 2 [Visit 2A], Week 6 [Visit 3A], and Week 10 [Visit 4A]), 
and a follow-up visit (Week 15 [Visit 6]) approximately 3 weeks after the last dose of study 
drug, for a total of 9 visits. 
The study will be performed on an ambulatory basis.
The screening visit (Visit 1) will occur up to 35 days prior to randomization.  Eligibility will 
be assessed via a physical examination, clinical laboratory testing, vital signs, ECG, Pap 
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smear, mammography, and endometrial biopsy.  Subjects will receive an electronic diary in 
which to record daily vasomotor symptoms during the duration of the screening period. 
Subjects must have ≥7 consecutive days of vasomotor symptom recordings to participate in 
the study.  Subjects are encouraged to continue recording for the duration of the whole 
screening period.  The electronic diary will be reviewed by study site staff on Day 1 (Visit 2) 
to confirm study eligibility. Subjects may be rescreened 1 time upon approval of the medical 
monitor. During the treatment period, subjects will return to the study site every 2 weeks for 
assessments. The follow-up visit will occur approximately 3 weeks following the last dose of 
study drug.
Approximately 352 subjects will be enrolled in the study.  Subjects will be randomized to 1 
of 8 treatment groups (i.e., 44 subjects in each arm).
Subjects and study personnel will be blinded to the treatment (placebo or ESN364), dosage 
(30 mg, 60 mg, etc.), and dosing regimen (QD or twice daily [BID]).
3.3
Randomization
In total, approximately 352 subjects will be randomized to 1 of 8 treatment groups in an 
equal ratio.  
Randomization will be based on a computer-generated randomization schedule prepared by 
an unblinded biostatistician from Medpace Biostatistics using SAS® software (SAS Institute 
Inc., Cary, North Carolina, USA) prior to the start of the study.  The randomization will be 
balanced using randomly permuted blocks across the treatment arms.  The randomization list 
will be retained by Medpace Randomization and Study Product Management until the end of 
the study (database lock). A copy will be sent in a sealed envelope to the bioanalytical 
laboratory responsible for plasma drug and serum hormone determination before the start of 
the study as applicable. Because of a planned early timepoint analysis (see Section 7.9) and
because PK/PD modeling will start prior to database hard-lock, specific assigned Sponsor 
staff involved in these activities (or delegates, if outsourced to an external vendor) will be 
unblinded after recruitment has been completed. Details of the unblinding will be 
documented in a separate charter to ensure the direct study team remains blinded and that 
unblinded results are restricted to a very small group independent of the study team. 
Subjects will be assigned a randomization number from the Interactive Response Technology 
(IRT) system upon enrollment.  The randomization list will be uploaded into the IRT system.  
Based on this randomization list, the study drug will be packaged and labeled.  Medication 
numbers will be preprinted on the study drug labels.  The study team, including those 
involved in data management, clinical, medical, or statistical review of the study data, will 
also be blinded during the study as they will not have access to the randomization list.  
Medpace, the Contract Research Organization (CRO) performing data management and 
statistical activities, will receive a copy of the randomization list after database lock.  The 
study drug administered to a subject can be identified by the IRT system.  The IRT system 
will allow rapid access to the treatment allocation codes when relevant for site or CRO 
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4
SAMPLE SIZE
A total of 352 subjects are planned to be randomized, 44 subjects in each treatment arm.
In the Phase 2a study, the observed least-squares mean difference between ESN364 90 mg 
BID (highest dose of this Phase 2b study) and placebo in change from baseline to Week 12 in 
mean daily frequency of moderate to severe vasomotor symptoms was -5.0 
(95% CI: - 6.8, -3.3) with similar results at Week 4.  For any given pairwise comparison for a 
2-sample t-test at a 2-sided 5% alpha, 40 subjects provides the following power to detect the 
following effect sizes assuming an SD of 5:
Assumed treatment difference in mean daily frequency
Power for pairwise test
3.3
83%
3.5
87%
4
94%
4.5
97%
5
>99%
For change from baseline to Week 12 in mean severity of moderate to severe vasomotor 
symptoms, the observed mean treatment difference in the Phase 2a study was -1.12 (95% CI: 
-1.5, -0.74) with similar results at Week 4.  For any given pairwise comparison for a 
2-sample t-test at a 2-sided 5% alpha, 40 subjects provides the following power to detect the 
following effect sizes assuming an SD of 1:
Assumed treatment difference in mean severity
Power for pairwise test
0.64
80%
0.75
91%
1
>99%
Note that the combined power for testing all 4 co-primary endpoints will be lower than the 
power for each considered individually.  Assuming approximately 10% of subjects 
discontinue prematurely, the number of 40 subjects is increased to 44 subjects per arm.
5
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.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
All primary and secondary efficacy endpoints will be analyzed using the Full Analysis Set 
(FAS).  The Per Protocol Analysis Set (PPS) will be used only for the analysis of selected 
endpoints to examine the robustness of the primary analysis.  Safety and tolerability will be 
analyzed using the Safety Analysis Set (SAF).
5.1
Safety Analysis Set (SAF)
The SAF comprises all randomized subjects who received at least one dose of study drug. 
The SAF will analyze patients as treated.  In case a subject erroneously received a treatment 
different from her randomized treatment, the subject will be assigned to the treatment group 


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that the subject received as first dose. The SAF will be used for summaries of demographic 
and baseline characteristics and all safety and tolerability related variables.
5.2
Full Analysis Set (FAS)
The FAS comprises the subset of subjects from the SAF who received at least one dose of 
study drug, had a baseline and at least one post-baseline efficacy evaluation. The FAS will 
analyze patients as randomized, irrespective of the actual treatment received. The FAS will 
be used for summaries and primary analyses of efficacy data, as well as selected 
demographic and baseline characteristics.
5.3
Per Protocol Analysis Sets (PPS)
The PPS comprises the subset of subjects from the FAS who are treated according to the 
protocol without any major deviations.  A full detail of inclusions and exclusions from Per 
Protocol Analysis Set - Week 4 (PPS4) and Per Protocol Analysis Set - Week 12 (PPS12) 
will be in the classifications specifications and finalized before unblinding.
5.3.1
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. 
5.3.2
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. 
5.4
Pharmacokinetics Analysis Set (PKAS)
The PKAS comprises the subset of subjects who receive study drug and provide at least one 
sample for the measurement of drug concentrations. Exclusion of subjects from the PKAS 
will be considered by the pharmacokineticist on a case-by-case basis.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Co-Primary Efficacy Endpoints
The primary efficacy objectives will require the evaluation of the effect of ESN364 on the 
following 4 co-primary endpoints:
●
Mean change in the frequency of moderate to severe vasomotor symptoms from baseline 
to Week 4;


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●
Mean change in the frequency of moderate to severe vasomotor symptoms from baseline 
to Week 12;
●
Mean change in the severity of moderate to severe vasomotor symptoms from baseline to 
Week 4; and
●
Mean change in the severity of moderate to severe vasomotor symptoms from baseline to 
Week 12.
Subjects will record the number of vasomotor symptoms and severity of each vasomotor 
symptom via the ePRO diary from the screening visit (Days -35 to -1 [Visit 1]) through the 
follow-up visit (Week 15 [Visit 6]). 
Night sweats (vasomotor symptoms that disrupt the subject’s night sleep) should be recorded 
no later than in the morning upon awakening to start a new day.  Subjects should take note of 
the time of the night sweat and record it on the appropriate calendar day (i.e., before or after 
midnight).
The 24 hour vasomotor symptoms runs from 08:00 AM to 07:59 AM (next day); the 12 hour
day time vasomotor symptoms is between 08:00 AM and 07:59 PM; the 12 hour night time
vasomotor symptoms is between 08:00 PM and 07:59 AM (next day) regardless of whether 
the patient was awake or woke up because of the event.
Frequency of moderate to severe vasomotor symptoms is the number of moderate to severe 
vasomotor symptoms per 24h (or 12h day time or 12h night time).
The severity of vasomotor symptoms is defined clinically as follows (according to the FDA 
and European Medicines Agency Guidances for Industry1,2 and the National Institutes of 
Health [NIH] Hot Flash Workshop3):
●
Mild:  Sensation of heat without sweating/dampness.  If at night, subject does not wake 
up but later notices damp sheets or clothing.
●
Moderate:  Sensation of heat with sweating/dampness, but able to continue activity.  If at 
night, subject wakes up because she is feeling hot and/or is sweating, but no action is 
necessary other than rearranging the bed sheets.
●
Severe:  Sensation of intense heat with sweating, causing disruption of activity.  If at 
night, subject wakes up hot and is sweating and needs to take action (e.g., remove layers 
of clothes, open the window, or get out of bed).
The severity of moderate and severe vasomotor symptoms per 24h (or 12h day time or 12h 
night time):
[(number of moderate vasomotor symptoms x 2) + 
(number of severe vasomotor symptoms x 3)] / number of moderate/severe vasomotor 
symptoms.
Severity is zero for subjects who have no moderate or severe vasomotor symptoms. 
A daily frequency and severity per week will be derived by taking the mean of the data over 
7 days. A daily average per week will be derived if any information for 3 or more days was 
reported (morning dose, evening dose, or vasomotor symptom).


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Because baseline data is preferably the most recent data prior to randomization and dosing, 
baseline for this study is the mean value of vasomotor symptoms calculated over the last 
7 calendar days with non-missing data prior to Day 1 (Visit 2). As a consequence, the 
baseline might be less than the required 50 moderate/severe hot flashes per week required for 
study entry, as these can occur anywhere during the 35 day screening period provided that 
they are the last 7 days with non-missing data prior to Day 1 (Visit 2).
See Section 7.10.6 for study week and endpoint derivations.
6.1.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints include the effect of ESN364 on the following:
6.1.2.1 Vasomotor Symptom Endpoints:
●
Mean change in the frequency of mild, moderate, and severe vasomotor symptoms from 
baseline to each study week;
●
Mean change in the frequency of moderate and severe vasomotor symptoms per 24h
from baseline to each study week;
●
Mean change in the severity of mild, moderate, and severe vasomotor symptoms from 
baseline to each study week;
●
Mean change in the severity of moderate and severe vasomotor symptoms from baseline 
to each study week;
●
Mean change in the hot flash score of mild, moderate, and severe vasomotor symptoms 
from baseline to each study week;
●
Mean change in the hot flash score of moderate and severe vasomotor symptoms from 
baseline to each study week;
●
Mean percent reduction of mild, moderate, and severe vasomotor symptoms from 
baseline to each study week; and
●
Mean percent reduction of moderate and severe vasomotor symptoms from baseline to 
each study week.
Frequency of mild, moderate and severe vasomotor symptoms is the number of mild, 
moderate and severe vasomotor symptoms per 24h (or 12h day time or 12h night time).
Severity of mild, moderate and severe vasomotor symptoms per 24h (or 12h day time or 12h 
night time):  
[(number of mild vasomotor symptoms x 1) + 
(number of moderate vasomotor symptoms x 2) + 
(number of severe vasomotor symptoms x 3)] / number of mild/moderate/severe
vasomotor symptoms
Severity is zero for subjects who have no hot flashes. 
Hot flash score per 24h (or 12 h day time or 12 h night time):  The hot flash score per 24h (or 
12 h day time or 12 h night time) of vasomotor symptoms (mild, moderate, and severe) is 
calculated as follows:


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(number of mild vasomotor symptoms x 1) + 
(number of moderate vasomotor symptoms x 2) + 
(number of severe vasomotor symptoms x 3).
The hot flash score per 24h (or 12 h day time or 12 h night time) of moderate and severe 
vasomotor symptoms is calculated as follows:
(number of moderate vasomotor symptoms x 2) + 
(number of severe vasomotor symptoms x 3).
A weekly frequency, severity, or hot flash score will be derived similar to the co-primary 
efficacy endpoints. See Section 7.10.6 for study week and endpoint derivations.
6.1.2.2 Responder Endpoints:
●
Mean percent reduction of 50%, 70%, 90%, and 100% of mild, moderate, and severe 
vasomotor symptoms from baseline to each study week;
●
Mean percent reduction of 50%, 70%, 90%, and 100% of moderate and severe 
vasomotor symptoms from baseline to each study week;
●
Absolute reduction of 2, 3, 4, and 5 in mean number of mild, moderate, and severe 
vasomotor symptoms per 24h from baseline to each study week; and
●
Absolute reduction of 2, 3, 4, and 5 in mean number of moderate and severe vasomotor 
symptoms per 24h from baseline to each study week.
6.1.2.3 Patient-Reported Outcome Endpoints:
●
Change in Hot Flash Related Daily Interference Scale (HFRDIS) from baseline to Weeks 
4, 8, 12, and 15;
●
Change in Leeds Sleep Evaluation Questionnaire (LSEQ) from baseline to Weeks 4, 8, 
12, and 15;
●
Change in Greene Climacteric Scale (GCS) from baseline to Weeks 4, 8, 12, and 15; and
●
Change in Menopause-Specific Quality of Life (MENQoL) from baseline to Weeks 4, 8, 
12, and 15.
HFRDIS:  The HFRDIS is a 10-item scale that measures a woman’s perceptions of the 
degree to which vasomotor symptoms interfere with 9 daily life activities (work, social 
activities, leisure, sleep, mood, concentration, relations with others, sexuality, and enjoying 
life); the 10th item measures interference with overall quality of life.5 This scale was modeled 
after items on the Brief Pain Inventory6 and Brief Fatigue Inventory,7 which assess the extent 
to which pain or fatigue interfere with daily life. Subjects will be asked to rate the extent to 
which vasomotor symptoms have interfered with each item during the previous 2-week time 
interval using a 0 (do not interfere) to 10 (completely interfere) scale.  Recent structural 
equation modeling suggests the HFRDIS is a unidimensional scale best represented by an 
overall mean score calculated as the sum of items/10.8 If any of the 10 items have missing 
values, the overall mean score will not be calculated.    
LSEQ:  The LSEQ is a 10-item self-rated questionnaire that assesses a subject’s aspects of 
sleep and early morning behavior.  The questions are grouped into 4 chronological domains:  
ease of getting to sleep (items 1 to 3), perceived quality of sleep (items 4 to 5), ease of 


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awaking from sleep (items 6 to 7) and integrity of early morning behavior following 
wakefulness (items 8 to 10).9 The LSEQ is a visual analogue scale that requires respondents 
to place marks on a group of 10 cm lines representing the changes they have experienced in a 
variety of symptoms compared to usual (baseline version) versus since the beginning of 
treatment (post-baseline version). Lines extend between extremes like “more difficult than 
usual” and “easier than usual.”  Responses are measured using a 100 mm scale and are 
averaged to provide a score for each domain. Note the questionnaire was reformatted for data 
collection to ensure precise measurements.  Visit 2 data not collected on the baseline version 
of the LSEQ will be excluded from the analysis and listings.  If any of the responses in a 
domain have missing values, the score for the domain will not be calculated.
GCS:  The GCS is a 21-item scale that provides a brief but comprehensive and valid measure 
of climacteric symptomatology.10 Each item is rated by the subject according to its severity 
using a 4-point rating scale from 0 (none) to 3 (severe).  The first 20 items of the scale 
combine into 3 main independent symptom measures by summing up the individual item 
scores:  
●
Psychological symptoms (items 1 to 11; score 0 to 33),
●
Physical symptoms (items 12 to 18; score 0 to 21), and 
●
Vasomotor symptoms (items 19 to 20; score 0 to 6).
Item 21 is a probe for sexual dysfunction. The total score can range from 0 to 63. Higher 
scores indicate worse symptoms.  If any of the contributing items have missing values, scores 
for psychological symptoms, physical symptoms, or vasomotor symptoms will not be 
calculated.  If any of the scores for psychological symptoms, physical symptoms, or 
vasomotor symptoms are missing, the total score will not be calculated. 
MENQoL:  The MENQoL is a self-administered questionnaire and consists of a total of 
29 items in a Likert-scale format.  Each item assesses the impact of 1 of 4 domains of 
menopausal symptoms, as experienced over the last month:  
●
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 0 (not bothersome) to 6 (extremely bothersome) scale.11,12  Non-
endorsement of an item is scored a “1” and endorsement a “2” plus the number of the 
particular rating, so that the possible score of any item ranges from 1 to 8.12  Mean scores are 
computed for each domain by dividing the sum of the domain’s items by the number of items 
within that domain.13 The overall mean score is the mean of the domain mean scores.  If any 
of the contributing items have missing values, the mean score for the domain will not be 
calculated.  If any of the domain mean scores are missing, the overall mean score will not be 
calculated.


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For all patient reported outcome endpoints, baseline is the value at Day 1 (Visit 2).
Questionnaires are completed at site prior to any invasive procedures are completed. 
6.1.2.4 Pharmacodynamics Markers
●
Change from baseline to Week 12 in plasma concentrations of luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), estradiol (E2), and sex hormone-binding globulin 
(SHBG).
6.1.3
Exploratory Efficacy Endpoints
The exploratory endpoints include the effect of ESN364 on the following:
●
 
 
●
Level of PK plasma concentrations of ESN364 and metabolite 
at 
pre-specified timepoints; 
●
Change in weight and waist circumference from baseline to Weeks 4, 8, 12, and 15;
●
Mean change in the frequency of moderate to severe 12h day time vasomotor symptoms
from baseline to Week 4;
●
Mean change in the frequency of moderate to severe 12h day time vasomotor symptoms
from baseline to Week 12;
●
Mean change in the severity of moderate to severe 12h day time vasomotor symptoms
from baseline to Week 4; 
●
Mean change in the severity of moderate to severe 12h day time vasomotor symptoms
from baseline to Week 12;
●
Mean change in the frequency of moderate to severe 12h night time from baseline to 
Week 4;
●
Mean change in the frequency of moderate to severe 12h night time from baseline to 
Week 12;
●
Mean change in the severity of moderate to severe 12h night time from baseline to 
Week 4; and
●
Mean change in the severity of moderate to severe 12h night time from baseline to 
Week 12.
6.2
Safety Variables
Safety variables will include the following:
●
Incidence and severity of treatment-emergent adverse events (TEAEs);
●
Endometrial health assessment (transvaginal ultrasound ± endometrial biopsy);
●
Vital signs (sitting systolic and diastolic blood pressure and pulse rate);
●
Laboratory tests (hematology, biochemistry, urinalysis, and coagulation);
●
12-lead electrocardiogram (ECG) parameters;
●
Plasma bone density marker concentrations;  
CCI
CCI


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●
Physical examinations; and
●
Columbia Suicide Severity Rating Scale (C-SSRS).
A TEAE is defined as an adverse event observed after starting administration of study drug
through 7 days after the last dose of study drug. If the adverse event occurs on the day of the 
first dose and the onset time is on or after the time of the first dose of study drug or the onset 
time is missing, then the adverse event will be considered treatment emergent. If the adverse 
event occurs on the day of first dose and the onset time is before the time of the first dose of 
study drug, then the adverse event will not be considered treatment emergent. If a subject 
experiences an event both during the pre-investigational period that continues into the 
investigational period, the event will be considered as TEAE only if it has worsened in 
severity (i.e. it is reported with a new start date). 
A drug-related TEAE is defined as any TEAE related to study treatment as assessed by the 
investigator or with missing assessment of the causal relationship. 
Other safety endpoints will be considered treatment emergent if observed after starting 
administration of study drug through 1 day after the last dose of study drug.
6.3
Pharmacokinetic Variables
The plasma concentration data may be used in a meta-population pharmacokinetic analysis.
The results of the population PK analysis for ESN364 and its active metabolite will be 
described in separate report.
6.4
Other Variables
Duration of treatment exposure
Duration of exposure to treatment will be calculated in days, using the following formula:
Days of exposure = date of last dose – date of first dose + 1
Study drug compliance
Study drug compliance will be calculated using the following formula:
Study drug compliance =
100 x
actual capsules consumed
expected capsules consumed
where 
Actual capsules consumed = total capsules dispensed – total capsules returned 
Expected capsules consumed = (last dose date – first dose date +1) x 2 capsules per 
day
Study drug compliance of morning dose
Study drug compliance of morning dose will be calculated using the following formula:


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Compliance of morning dose =
100 x
actual capsules consumed
expected capsules consumed
where 
Actual capsules consumed = morning capsules dispensed – morning capsules returned 
Expected capsules consumed = (last dose date – first dose date +1) capsules per day
Study drug compliance of evening dose
Study drug compliance of evening dose will be calculated using the following formula:
Compliance of evening dose =
100 x
actual capsules consumed
expected capsules consumed
where 
Actual capsules consumed = evening capsules dispensed – evening capsules returned 
Expected capsules consumed = (last dose date – first dose date +1) capsules per day
Diary interaction compliance during the treatment period
Diary compliance during the treatment period will be calculated using the following formula:
Diary interaction compliance =
100 x
actual diary days with data recorded
expected diary days with data recorded
where 
Actual diary days with data recorded = number of diary days with any morning or 
evening dose or hot flash data recorded from Visit 2 up to and including the 
last day of exposure to treatment
Expected diary days with data recorded = date of last dose – date of Visit 2 + 1
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken before the date of 
the first dose of study drug. 
Concomitant medication is defined as medication with at least one dose taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of study drug.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, minimum, median, maximum, 10%, 90%, and lower and upper quartiles. 
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e. will add up to 100%. 


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Summaries based on FAS and PPS (e.g. disposition, baseline and efficacy data) will be 
presented by planned treatment group, unless specifically stated otherwise. Safety analysis 
and other summaries based on SAF will be presented by actual treatment received. 
All statistical comparisons will be conducted using two sided tests at the α=0.05 significance 
level unless specifically stated otherwise.  All null hypotheses will be of no treatment 
difference, all alternative hypotheses will be two-sided, unless specifically stated otherwise.
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
or higher on Windows®.  Specifications for tables, figures, and data listing formats can be 
found in the TLF specifications.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number of subjects with informed consent, discontinued before randomization, 
randomized (overall only);
●
Number and percentage of subjects randomized in each analysis set, by treatment group
and overall;
●
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation for randomized subjects and by treatment group;
●
Number and percentage of subjects excluded from PPS4 and PPS12 by reason for 
exclusion defined in Section 5.3.1 and 5.3.2, by treatment group for FAS.
7.2.2
Protocol Deviations
Protocol deviations as defined in the Medpace Protocol Deviation Plan will be summarized
for all randomized subjects. The number and percentage of subjects meeting any criteria will 
be summarized for each criterion and overall, by treatment group and total as well as by 
study site. Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Any subjects who have more than one protocol deviation will be 
counted once in the overall summary. A data listing will be provided by site and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by descriptive statistics.
Number and percentage of subjects randomized in each country and site will be presented by 
treatment group for the SAF.
Descriptive statistics for age, weight, body mass index (BMI) and height at study entry will 
be presented.  Frequency tabulations for sex, ethnicity, and race will be presented. This will 
be done for the non-randomized subjects, as well as for the SAF and FAS, by treatment 
group.


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Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone, by treatment group for the SAF.
Disease-specific medical history including spontaneous amenorrhea and bilateral 
oophorectomy will be summarized by treatment group for the SAF. The number and 
percentage of subjects with amenorrhea <6 months, >=6 - <12 months or >=12 months will 
be presented by treatment group for the SAF.
Social history (smoking habits) will be summarized by treatment group for the SAF.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by anatomic main 
group (ATC 1st level), therapeutic subgroup (ATC 2nd level), chemical subgroup (ATC 4th 
level), and preferred WHO name by treatment group for the SAF. 
As with previous medications, concomitant medications will be summarized for each 
treatment group by anatomic main group (ATC 1st level), therapeutic subgroup (ATC 2nd 
level) and chemical subgroup (ATC 4th level) and preferred WHO name for the SAF. 
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period. A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for each treatment group for 
the SAF:
●
Descriptive statistics for cumulative amount of the drug subject was exposed to and 
average daily dose; and
●
Number and percent of subject with dose interruptions by treatment group.
Duration of exposure will be summarized in two ways.
●
Descriptive statistics will be presented by treatment group.
●
Exposure time will be categorized according to the following categories by treatment 
group:
○
less than 28 days
○
at least 28 days, less than 57 days 
○
at least 57 days, less than 72 days
○
at least 72 days, less than 93 days
○
At least 93 days
○
Unknown.
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment group for the SAF.


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7.3.2
Treatment Compliance
Overall treatment compliance with the dosing schedule, compliance of morning dose, and 
compliance of evening dose 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 treatment), not to the 
planned treatment period.
Percent overall compliance, percent compliance of morning dose, and percent compliance of 
evening dose 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:
○
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.
Overall treatment compliance, compliance of morning dose, and compliance of evening dose 
through Week 4 will be analyzed in a similar manner.
7.4
Analysis of Efficacy 
7.4.1
Analysis of Primary Endpoints
7.4.1.1 Primary Analysis of Co-Primary Endpoints
The primary efficacy analysis will be based on the FAS.
The mean frequency and severity of moderate to severe vasomotor symptoms as well as 
change from baseline will be summarized by study week and for the last on treatment week.
See Section 7.10.6 for study week and endpoint derivations. Weekly means will be plotted.
For each of the co-primary efficacy endpoints, an analysis of covariance (ANCOVA) model 
will be used with treatment group, pooled center, and smoking status (current vs. 
former/never) as factors, with baseline weight and baseline measurement as covariates. 
Pooled centers will be generated and documented prior to database lock. The algorithm for 
pooling centers can be found in Section 7.10.2  If the inclusion of pooled centers creates 
modeling problems, then dropping that factor will be considered.
Pairwise comparisons between the active doses and placebo will be calculated based on least-
squares mean contrasts using a 2-tailed 95% confidence interval (CI).  
For subjects in the efficacy analysis populations with missing primary efficacy endpoints, 
multiple imputation by fully conditional specification methods will be used. The multiple
imputation model is specified in Section 7.10.1  
Since the study design requires the comparison of 7 active dose groups with placebo for 4 
co-primary efficacy endpoints, a two-tier closed testing procedure will be used to control the 


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family-wise error rate.  A step-down testing procedure will be followed.  The following 
testing order of doses will be employed:
a.
Placebo versus 90 mg BID (daily dose 180 mg),
b. Placebo versus 60 mg BID (daily dose 120 mg),
c.
Placebo versus 120 mg QD (daily dose 120 mg),
d. Placebo versus 30 mg BID (daily dose 60 mg),
e.
Placebo versus 60 mg QD (daily dose 60 mg),
f.
Placebo versus 15 mg BID (daily dose 30 mg), and
g. Placebo versus 30 mg QD (daily dose 30 mg).
The 4 co-primary efficacy endpoints will be compared at each dose level.  If all 4 co-primary 
efficacy endpoints are statistically significantly better than placebo at a 2-sided alpha level of 
0.05 for a given dose this dose level will be considered superior to placebo.  A failure to 
prove the significance for one or more co-primary efficacy endpoints will lead to a failure to 
demonstrate superiority to placebo at this dose level, and the other dose levels after this one 
in the sequence will not be tested. In this testing sequence, if one comparison failed to 
provide the significance at this dose level, the comparisons at other dose levels following this 
sequence will not be tested. 
7.4.1.2 Secondary Analysis of Co-Primary Endpoints
The primary analysis for each of the co-primary endpoints will be repeated using an 
ANCOVA model with treatment group as a factor and baseline measurement as a covariate.
A supportive analysis will be carried out for the co-primary efficacy endpoints based on the 
PPS to examine the impact of premature dropouts and/or major protocol deviations.  The 
method used for this analysis will be identical to the primary analysis described in 
Section 7.4.1.1  The missing value imputation method for the early termination might not be 
applicable for the analysis on PPS since the analysis set only includes completed subjects.
Week 4 analyses will be performed on PPS4, and the Week 12 analyses will be performed on 
PPS12.
An analysis of the primary efficacy variable by week will be conducted with mixed model for 
repeated measurements (MMRM) on FAS. This analysis will use a restricted maximum 
likelihood (REML)–based repeated-measures approach. The analyses will include the 
treatment group, week and smoking status (current vs. former/never) as factors and baseline 
measurement as a covariate, 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. The treatment difference will be estimated at all study weeks. 
In addition, MCP-Mod analyses as described in the MCP-Mod SAP will be performed on co-
primary endpoints. 


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7.4.2
Analysis of Secondary Endpoints 
The analysis of secondary efficacy endpoints will be based on the FAS.
For each of the secondary vasomotor symptom and patient-reported outcome endpoints, an 
MMRM model as described in Section 7.4.1.2 will be used. The treatment difference will be 
estimated at all study weeks (week replaced by visit for patient-reported outcome endpoints).
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. The missing value will be imputed as a 
non-responder. 
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. For 50% and 
90% reduction responders, Kaplan-Meier estimate will be used to estimate the time to 
response and the time to sustained 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 90%) response for both original 
numbers and SA number. The time to sustained response will be the first day with at least 
50% (or 90%) response for both original numbers and SA number, and SA response from 
that day till the end of the treatment at least 50% (or 90%) response on each day. For the non-
responders, it will be censored at the end of treatment.
Diary interaction compliance will be summarized with descriptive statistics and presented by 
treatment group. 
Plasma concentrations of hormones and bone turnover markers will be summarized with 
descriptive statistics for each treatment group at each visit. Additionally, a within-subject 
change will be calculated as the post-baseline measurement minus the baseline measurement 
and summarized in the same way. Pharmacodynamic data and efficacy data may be evaluated 
by a population PD or population PK/PD approach. All details of population analyses will be 
described in a separate analysis plan and a separate report will be written. When deemed 
necessary, data from this study may be combined with data from other studies.
7.4.3
Analysis of Exploratory Endpoints 
 
 
Pharmacokinetics may be evaluated by a population PK 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.
CCI


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Weight and waist circumference will be summarized with descriptive statistics for each 
treatment group at Baseline and at Weeks 4, 8, 12, and 15.  Additionally, a within-subject 
change will be calculated as the post-baseline measurement minus the baseline measurement 
and summarized in the same way.  
The mean frequency of moderate to severe 12h day time and 12h night time vasomotor 
symptoms as well as change from baseline will be summarized by study week and for the 
Last on Treatment Week. See Section 7.10.6 for study week and endpoint derivations.
Additionally, the analysis of exploratory efficacy endpoints will be based on the FAS. An
analysis of covariance model as described in Section 7.4.1.1 will be used. 
7.5
Analysis of Safety
All analyses of safety will be presented by treatment group for SAF, unless specified 
otherwise. For analyses by visit, the visit windows from Section 7.10.6 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.
7.5.1
Adverse Events
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on review of the Sponsor’s list of Always Serious terms if any upgrade was done.
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
SOC and PT.
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with causally drug related TEAEs,
●
Number of serious TEAEs,
●
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, 
●
Number and percentage of subjects with TEAEs leading to study drug interruption, and
●
Number of deaths.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for:
●
TEAEs,
●
drug related TEAEs, 
●
serious TEAEs, 
●
drug related serious TEAEs, 


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●
TEAEs leading to permanent discontinuation of study drug, 
●
drug related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5% in any 
treatment group, and 
●
common TEAEs that equal to or exceed a threshold of 5% 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 also 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 only once with the worst severity 
and highest degree of relationship, however, if any of the severity or relationship values are 
missing then the subject will be counted only once with 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.
Adverse events of special interest oral/facial paresthesia, uterine bleeding and elevation in 
ALT and/or AST >3 x ULN. A summary table and detailed listing of adverse events of 
special interest will be provided. A burden of toxicity graph will be generated for the adverse 
events of special interest.
7.5.2
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to initial study drug administration.  
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, and urinalysis will 
be summarized using mean, standard deviation, minimum, median, maximum, 10%, 90%, 
and lower and upper quartiles for each treatment group at each 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. 
Shift tables will be generated for each treatment group at each visit.
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit (excluding Visits 2A, 3A, and 4A). 
7.5.2.1 Liver Enzymes and Total Bilirubin 
The liver safety assessments will be summarized by the following categories below based on 
the measurements from Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total 
bilirubin, Aspartate Transaminase (AST), and their combinations are defined. These 
parameters will be measured from a central lab. The subject’s highest value during the 
treatment period will be used.


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Parameter
Potentially Clinically Significant Criteria
ALT
>3 x ULN
>5 x ULN
>8 x ULN
>10 x ULN
>20 x ULN
AST
>3 x ULN
>5 x ULN
>8 x ULN
>10 x ULN
>20 x ULN
ALT or AST
>3 x ULN
>5 x ULN
>8 x ULN
>10 x ULN
>20 x ULN
ALP
>1.5 x ULN
Total bilirubin
>1.5 x ULN
>2 x ULN
ALT or AST and 
total bilirubin (*)
ALT or AST >3 x ULN and total bilirubin >2 x ULN
ALT or AST, ALP, 
and total bilirubin 
(*)
ALT or AST >3 x ULN, ALP <2 x ULN, and total bilirubin >2 x ULN
(*) Combination of values measured within the same day or up to one day apart.
The denominator for each criterion will be the number of subjects who have at least one 
value during the treatment period. The number and percentage of subjects meeting the critiera 
during the treatment and follow-up periods will be summarized by treatment group.
A detailed listing will be provided for subjects with suspected drug-induced liver injury 
(DILI).
7.5.3
Vital Signs
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, and temperature) will 
be summarized using mean, standard deviation, minimum, median, maximum, 10%, 90%, 
and lower and upper quartiles by treatment group and visit. Additionally, a within-subject 


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change will be calculated per visit as the post-baseline measurement minus the baseline 
measurement and summarized by treatment group and visit. 
7.5.4
Electrocardiograms (ECGs)
The baseline visit is the last measurement taken prior to initial study drug administration.  
ECG variables will be summarized using (n), mean, standard deviation, minimum, median, 
maximum, 10%, 90%, and lower and upper quartiles for each treatment group at each 
treatment visit, including changes from baseline. 
Number and percent of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the 12 lead ECG will be 
tabulated by treatment group at each treatment visit. Local readings and central readings will 
be summarized separately. 
The QT intervals (QT, QTcB, and QTcF) will be summarized using frequency tables for each 
treatment visit (excluding Visits 2A, 3A, and 4A) and time point for values of clinical 
importance using the range criteria below.
QT Interval Criteria (msec)
Description
≤450
Normal
>450
Borderline
>480
Prolonged
>500
Clinically significant
The QT intervals will also be summarized by the frequencies of subjects with a change from 
baseline of clinical importance using the criteria identified below. These summaries will be 
provided for each treatment visit and time point. 
Parameter
Change from Baseline Criteria
QT Interval (msec)
<0
≥0
>30 
>60
Number and percent of subjects whose 12 lead ECG reading changed from normal at baseline 
to abnormal will be tabulated by treatment group for each visit.
7.5.5
Pregnancies
A detailed listing of all pregnancies will be provided.
7.5.6
Other Safety-Related Observations
Endometrial health assessment results from transvaginal ultrasound and endometrial biopsy 
will be listed.
Mammogram results, plasma bone density marker concentration, and C-SSRS results will be 
listed.


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7.6
Analysis of PK
PK/PD analyses will be provided in a separate report.
7.7
Subgroups of Interest 
The primary efficacy endpoint summaries will be repeated by smoking status (current vs. 
former/never). The subgroup analyses for CYP1A2 inducers / inhibitors may be performed if 
data is available.
7.8
Other Analyses
Pharmacogenomic samples will be collected. Data will be analyzed and reported separately.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
An early timepoint analysis is planned 4 weeks after the last randomization. The unblinded 
results will be restricted to a very small group independent of the study team. No changes to 
the study or the statistical analysis plan will be made as a result of this analysis (which is 
intended to assist with internal decision making only). Full details will be documented in a 
separate charter to ensure the integrity of the trial blinding; all study team personnel, 
including all those involved in data management, clinical, medical or statistical review of the 
data, will remain blinded until database hard-lock (see Section 3.3).  
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.10.1
Missing Data
If there are no diary entries for a particular calendar day, and the patient reported receiving at 
least one morning dose of study medication or at least one evening dose of study medication 
on that day, the frequency of vasomotor symptoms will be imputed to 0; otherwise, the 
frequency of vasomotor symptoms will be considered missing.
If no vasomotor symptoms were recorded for the day, and the patient reported receiving at 
least one morning dose of study medication and at least one evening dose of study 
medication on that day, the severity will be 0.
Missing primary endpoints will be handled by multiple imputation for continuous variables, 
and non-responder imputation for binary variables. 
For study drug compliance, the capsules returned will be imputed to 0 at the visit if no bottle 
was returned for a visit.
Multiple Imputation Method:
Multiple imputation will be used to impute missing data and will be implemented using 
SAS® PROC MI. Missing data may be the result of missing Week 4/Week 12 
frequency/severity of vasomotor symptoms measurements or the result of patients 
discontinuing treatment prior to Week 4/Week 12. Missing at random will be assumed. 


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The imputation model will include the subject demographics (age [<median, ≥median], race 
[white, non-white], baseline weight [<median, ≥median], and smoking status), and baseline 
and post-baseline frequency/severity of vasomotor symptoms. Missing data will be imputed 
100 times to generate 100 complete data sets. The seed will be 98765. The fully conditional 
specification method will be used. The 100 complete data sets will then be analyzed using the 
same analysis method as the one used to analyze the primary endpoint. See Section 7.4.1.1  
The results from the 100 fitted models will be combined using SAS® PROC MIANALYZE.
If the model fails to converge, exclusion of subject demographics will be considered.
Safety Data Imputation:
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and concomitant medication in rare cases. The 
imputed dates will be used to allocate the concomitant medication and AEs to a treatment 
period, 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.
7.10.2
Pooled Center
Approximately 352 subjects will be randomized at approximately 48 sites. When “center” is 
included as a factor in a statistical model, sites that have less than 10 FAS subjects in total 
will be identified and then combined for statistical analysis purposes according to the 
following algorithm:

Step 1: Divide the sites into two groups with Group 1 including all sites that have at 
least 10 FAS subjects and Group 2 including all remaining sites. Sort each group in 
ascending order by total sample size and site number.

Step 2: Starting at the top of the Group 2 list (i.e., the first site with the smallest total 
sample size), combine the minimum number of sites required to achieve a “pooled 
center” that has at least 10 FAS subjects in total. Continue forming “pooled centers” 
in this manner until all Group 2 sites have been grouped or it is no longer possible to 
form a “pooled center” with at least 10 FAS subjects in total.

Step 3: If there is a site (or several sites) left after step 2, combine the site(s) with the 
last “pooled center” that is created. For the situation where no previous “pooled center” 
is created, combine the site(s) with the first site on the sorted Group 1 list.

“Pooled center” will be assigned names PoolSite01, PoolSite02, etc. For sites not 
needing to be pooled, the original site name will be used such as Site001. For all sites 
that have been combined into pooled centers, the assigned pooled center will be used 
instead of the original site identification in all statistical models that include “center” 
as a factor. However, the original site identification will be used in all summaries of 
subject disposition or discontinuation by site and in all data listings.


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7.10.3
Electronic and Paper Diaries
Subjects are to receive an electronic diary in which to record daily vasomotor symptoms 
during the study along with all home study drug intake. Paper diaries are to be used as back 
up to the electronic diary. In the case where there is an exact duplicate based on date and time 
between the electronic diary and the paper diary, the result from the electronic diary will be 
used. In the case where the date and/or time differs between electronic and paper diaries, 
results from both diaries will be used.
7.10.4
Last Dose Date
If the last dose date is missing from the eCRF, the last known dose date reported in the 
electronic diary will be used.
7.10.5
Outliers
All values will be included in the analyses.
7.10.6
Visit Windows
The study protocol gives the overall study schedule for these visits expressed as the number 
of days relative to Visit 2.  Study Day will be calculated as date of visit/assessment – first 
dose date +1.  There will be no Day 0. Visit 2 is scheduled to be Day 1 if the patient takes the 
first dose on Visit 2, and the day immediately prior to Visit 2 is Day -1.
Subjects will not be excluded from analyses due to the subject’s failure to comply with the 
visit schedule.
If baseline is missing, the screening assessment can be used.
7.10.6.1 Efficacy Visit Windows
For the weeks on treatment (weeks prior to the follow-up period), the last day is always the 
last day of exposure to treatment.
The study week determination for the vasomotor symptoms data is based on the following:


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Analysis study week
Actual assessment day
Baseline
7 non-missing days prior to D1
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 or last day of exposure to treatment, if this happened 
after day 84
Last on Treatment Week
Last 7 days of treatment 
Follow-up Week 1
Day 1 FU – Day 7 FU ^
Follow-up Week 2
Day 8 FU – Day 14 FU ^
Follow-up Week 3
Day 15 FU – Day 21 FU ^
^ Day X FU is defined as last day of exposure to treatment + X
The assessment of a week will be derived if any information for 3 or more days was reported 
(morning dose, evening dose, or vasomotor symptom).
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:
CRF visit
Target day
Actual assessment day
Analysis visit
Visit 1
D-35
D-35 to D-1
Screening
Visit 2
D1 
D1
Baseline
Visit 3
D29
D22 to D36
Week 4
Visit 4
D57
D50 to D64
Week 8
Visit 5
D85
D78 to Day 92
Week 12
End of treatment
Last dosing day
Closest observation to the date
EOT
Visit 6
D106
Last assessment after date of 
completion or termination of 
treatment period
Week 15 Follow-Up
The value which assessment day is the closest to the defined target day within these windows 
is used. If two values are equally close, the latter is used in the analysis.    
7.10.6.2 Safety Visit Windows
For the weeks on treatment (weeks prior to the follow-up period), the last day is always the 
day after the last day of exposure to treatment.
All safety assessments, including those from unscheduled visits and regardless of visit label,
will be allocated to analysis visits based on the table below:


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CRF visit
Target day
Actual assessment day
Analysis visit
Visit 1
D-35
D-35 to D-1
Screening
Visit 2
D1 
D1
Baseline
Visit 2A
D15
After first dose to D22
Week 2
Visit 3
D29
D23 to D36
Week 4
Visit 3A
D43
D37 to D50
Week 6
Visit 4
D57
D51 to D64
Week 8
Visit 4A
D71
D65 to D78
Week 10
Visit 5
D85
D79 to Day 92
Week 12
End of treatment
Last dosing day
+ 1 day
Closest observation to the date
EOT
Visit 6
D106
Last assessment after date of 
completion or termination of 
treatment period
Week 15 Follow-Up
The value which assessment day is the closest to the defined target day within these windows 
is used. If two values are equally close, the latter is used in the analysis.    
8
CHANGES FROM PROTOCOL
Protocol 
Version
Changes added in SAP
Comment/rationale for change
Amendment 
2: 05 March 
2018
Weight and waist 
circumference will be added as 
an Exploratory Efficacy 
Endpoint.
Weight and waist circumference will be analyzed as 
exploratory efficacy endpoints.
Amendment 
2: 05 March 
2018
The day time vasomotor 
symptoms and night time 
vasomotor symptoms of the 4 
co-primary endpoints will be 
added as an Exploratory 
Efficacy Endpoint.
Day time vasomotor symptoms and night time 
vasomotor symptoms of the 4 co-primary endpoints
will be analyzed as exploratory efficacy endpoints.
9
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.0
DD-Mmm-YYYY
N/A
Document finalized


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10
REFERENCES
1.
US Department of Health and Human Services 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).
2.
European Medicines Agency. Guideline of clinical investigation of medicinal products 
for hormone replacement therapy of oestrogen deficiency symptoms in menopausal 
women (2005).
3.
National Institutes of Health. Assessing and improving measures of hot flashes. (2004).
4.
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Page 37 of 39
11
APPENDICES
11.1
Appendix 1: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
Medpace Biostatistics
Contributors and Reviewers
Medpace Biostatistics
Medpace Medical Affairs
 
Astellas Biostatistics
Astellas Biostatistics
Ogeda, S.A.
Astellas Pharma Europe B.V.
Astellas Pharma Europe B.V
Astellas Pharma Europe B.V
Astellas Medical and 
Development
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD