Clinical trial NCT05419908
Conditions: Hot Flashes
Keywords: Hot flashes ESN364 ASP2693 fezolinetant menopause postmenopausal
Sponsor: Ogeda S.A.
Start date: 2015-09-21; Completion date: 2016-10-06
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study was to evaluate the effect of ESN364 on the severity and frequency of hot flashes in early postmenopausal women suffering from hot flashes, in terms of changes in weekly Hot Flash Score from baseline to Week 12.

This study also evaluated the effect of ESN364 on the severity and frequency of hot flashes at additional timepoints; hot flash interference on daily life, in terms of changes from baseline over time in Hot Flash Related Daily Interference Scale (HFRDIS); the effect of ESN364 on climacteric symptoms, in terms of changes from baseline over time in Leeds Sleep Evaluation Questionnaire (LSEQ), Greene Climacteric Scale (GCS), and Sheehan Disability Scale (SDS); pharmacodynamic (PD) effect; and safety and tolerability.

Detailed description:

Arms: arm 1: Participants received 90 milligrams (mg) fezolinetant capsules orally, twice daily (BID) for a period of 12 weeks arm 2: Participants received fezolinetant matching placebo capsules orally, BID 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: 










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CLINICAL STUDY PROTOCOL - ESN364_HF_204 10-December-2015 (Final 2.0) 
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6 
 
Signature of Principal (Site) Investigator 
 
Title: 
Pilot/Phase IIa Trial to Investigate the Effect of ESN364 in Early 
Postmenopausal Women Suffering From Hot Flashes 
 
Name: 
 
Affiliation: 
 
Address: 
 
 
 
‘I have read this Clinical Study Protocol and agree that it contains all information 
necessary for proper conduct of the study. I will carry out the study as outlined herein 
and will complete the study within the designated time.’ 
 
 
Signature: 
 
Date: 
 
 
 


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CLINICAL STUDY PROTOCOL - ESN364_HF_204 
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7 
PROTOCOL HISTORY 
Protocol History 
Euroscreen S.A. – ESN364_HF_204 
Document  
Issue Date 
Amendment Type 
Comments 
Initial Clinical Study Protocol 
25-June-2015 
- 
This document 
Revised Clinical Study Protocol 
10-December-2015 
General 
The overall reason for the revision is to liberalize the participant 
selection criteria to facilitate recruitment, and to allow for a lower 
number of subjects to be included in the interim analysis. For a 
detailed overview of the changes, please refer to the Protocol 
Amendments. 
 


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8 
TABLE OF CONTENTS 
Title Page ............................................................................................................................ 1 
Signatures ........................................................................................................................... 2 
Protocol History ................................................................................................................. 7 
Table of Contents ............................................................................................................... 8 
Protocol Amendments ..................................................................................................... 12 
Protocol Synopsis ............................................................................................................. 14 
Time and Events Schedule .............................................................................................. 18 
List of Abbreviations and Definitions of Terms ........................................................... 20 
Study Administrative Structure and Investigators ...................................................... 22 
1. 
Introduction ............................................................................................................. 23 
1.1 
Background Information ..................................................................................... 23 
1.1.1 
Hot Flashes ............................................................................................ 23 
1.1.2 
Introduction to ESN364 ........................................................................ 23 
1.2 
Non-Clinical Studies ........................................................................................... 25 
1.2.1 
Summary of Pharmacodynamics ........................................................... 25 
1.2.2 
Summary of Pharmacokinetics .............................................................. 26 
1.2.3 
Summary of Toxicology ........................................................................ 27 
1.3 
Clinical Studies .................................................................................................... 28 
1.4 
Overall Rationale for the Study ........................................................................... 31 
1.5 
Risk Benefit Analysis .......................................................................................... 32 
2. 
Study Objectives ...................................................................................................... 34 
2.1 
Primary Objective ................................................................................................ 34 
2.2 
Secondary Objectives .......................................................................................... 34 
3. 
Study Design ............................................................................................................. 35 
3.1 
Overview of Study Design .................................................................................. 35 
3.2 
Discussion of Study Design................................................................................. 36 
4. 
Selection of Study Population ................................................................................. 37 
4.1 
Inclusion Criteria ................................................................................................. 37 
4.2 
Exclusion Criteria ................................................................................................ 38 
5. 
Treatment(s) ............................................................................................................. 39 
5.1 
Physical Description of the Study Drug .............................................................. 39 
5.2 
Other Medication Administered in the Study ...................................................... 39 
5.3 
Packaging and Labeling ...................................................................................... 39 
5.4 
Storage and Drug Accountability ........................................................................ 40 
5.5 
Randomization ..................................................................................................... 41 
5.6 
Blinding ............................................................................................................... 41 
5.7 
Dose and Administration ..................................................................................... 42 
5.8 
Treatment Compliance ........................................................................................ 43 
6. 
Prior and Concomitant Therapy ............................................................................ 44 


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9 
6.1 
Permitted Concomitant Therapies ....................................................................... 44 
6.2 
Prohibited Concomitant Therapies ...................................................................... 44 
7. 
Assessments .............................................................................................................. 46 
7.1 
Timing of Assessments........................................................................................ 46 
7.1.1 
Screening Period (Visit 1) ..................................................................... 46 
7.1.2 
Treatment Period (Visits 2-5; Weeks 1-12) .......................................... 47 
7.1.3 
Follow-up Period (Visit 6) .................................................................... 48 
7.1.4 
Unscheduled Visits ................................................................................ 48 
7.2 
Pharmacokinetic Evaluations .............................................................................. 49 
7.2.1 
Blood Sample Collection and Handling ................................................ 49 
7.2.2 
Bioanalysis ............................................................................................ 49 
7.2.3 
Pharmacokinetic Endpoints ................................................................... 49 
7.3 
Pharmacodynamic Evaluations ........................................................................... 50 
7.3.1 
Blood Sample Collection and Handling ................................................ 50 
7.3.2 
Bioanalysis ............................................................................................ 50 
7.3.3 
Pharmacodynamic Endpoints ................................................................ 50 
7.4 
Efficacy Evaluations ............................................................................................ 50 
7.4.1 
Efficacy Variables ................................................................................. 50 
7.4.2 
Efficacy Endpoints ................................................................................ 53 
7.5 
Safety Evaluations ............................................................................................... 53 
7.5.1 
Safety Variables .................................................................................... 53 
7.5.2 
Safety Endpoints ................................................................................... 55 
7.6 
Appropriateness of Measurements ...................................................................... 56 
8. 
Study Termination/Completion .............................................................................. 57 
8.1 
Study Completion ................................................................................................ 57 
8.2 
Removal of Subjects From the Study or Treatment ............................................ 57 
8.3 
Stopping Rules or Discontinuation Criteria ........................................................ 58 
9. 
Statistical Methods................................................................................................... 59 
9.1 
Statistical Analysis .............................................................................................. 59 
9.1.1 
Initial Characteristics of the Subject Sample ........................................ 59 
9.1.2 
Pharmacokinetic Data ........................................................................... 60 
9.1.3 
Pharmacodynamic Data ......................................................................... 60 
9.1.4 
Efficacy Data ......................................................................................... 60 
9.1.5 
Safety Data ............................................................................................ 61 
9.1.6 
Interim Analysis .................................................................................... 62 
9.2 
Determination of Sample Size ............................................................................. 62 
10. Adverse Event Reporting ........................................................................................ 63 
10.1 
Definitions ........................................................................................................... 63 
10.2 
Intensity of Adverse Events................................................................................. 64 
10.3 
Causality Assessment .......................................................................................... 64 
10.4 
Action Taken Regarding the Study Drug ............................................................ 64 
10.5 
Outcome .............................................................................................................. 65 
10.6 
Recording of Adverse Events .............................................................................. 65 
10.7 
Reporting of Serious Adverse Events to SGS Life Science Services Medical 
Affairs .................................................................................................................. 65 


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10 
10.8 
Reporting of Serious Adverse Events to Competent Authorities/Ethics 
Committees .......................................................................................................... 66 
11. Ethical Aspects ......................................................................................................... 67 
11.1 
Study-Specific Design Considerations ................................................................ 67 
11.2 
Regulatory Ethics Compliance ............................................................................ 67 
11.2.1 
Investigator Responsibilities ................................................................. 67 
11.2.2 
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) .............................................................................................. 67 
11.2.3 
Informed Consent .................................................................................. 69 
11.2.4 
Privacy of Personal Data ....................................................................... 69 
12. Administrative Requirements ................................................................................ 71 
12.1 
Protocol Amendments ......................................................................................... 71 
12.2 
Subject Identification, Enrollment, and Screening Logs ..................................... 71 
12.3 
Source Documentation ........................................................................................ 71 
12.4 
Case Report Form Completion ............................................................................ 72 
12.5 
Monitoring ........................................................................................................... 72 
12.6 
Data Management ................................................................................................ 72 
12.7 
Data Quality Assurance ....................................................................................... 73 
12.8 
On-Site Audits ..................................................................................................... 73 
12.9 
Study Termination ............................................................................................... 74 
12.10 
Record Retention ................................................................................................. 74 
12.11 
Use of Information and Publication .................................................................... 75 
12.12 
Registration of Clinical Studies and Disclosure of Results ................................. 76 
12.13 
Investigator Indemnity......................................................................................... 76 
12.14 
Confidentiality ..................................................................................................... 76 
13. References ................................................................................................................. 77 
Attachment 1: Hot Flash Related Daily Interference Scale ......................................... 80 
Attachment 2: Leeds Sleep Evaluation Questionnaire ................................................. 81 
Attachment 3: Greene Climacteric Scale ...................................................................... 82 
Attachment 4: Sheehan Disability Scale ........................................................................ 83 
Attachment 5: Waist Circumference Measurement ..................................................... 84 
Attachment 6: Events of Clinical Interest Guidance For Potential Drug-Induced 
Liver Injury ........................................................................................................ 85 
Attachment 7: Normal Ranges for Vital Signs and ECG ............................................ 96 
 


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List of Tables 
Table 1: 
Qualitative Composition of ESN364 Hard Gelatin Capsules ........................ 37 
Table 2: 
Treatment Overview ...................................................................................... 40 
 
List of Figures 
Figure 1: 
Modulatory Role of NK3 on GnRH Neurons (Figure From [12]) ................ 22 
Figure 2: 
Inhibitory Effect of NK3 Antagonist on Testosterone Levels in Male 
Volunteers (Figure From [13]) ...................................................................... 23 
Figure 3: 
Core Body Temperature in Ovarectomized Ewes Injected With 1 mg/kg 
ESN364 or Placebo ........................................................................................ 29 
Figure 4: 
Schematic Diagram Showing the Relationship Between KNDy Neurons, 
GnRH Neurons and the Heat-Defense Pathway in the Rat. KNDy Neurons 
Branch and Project to GnRH Terminals in the Median Eminence and 
Preoptic Structures That Regulate Body Temperature (Figure from [18]) .... 30 
Figure 5: 
Schematic Overview of the Study ................................................................. 33 
 


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12 
PROTOCOL AMENDMENTS 
AMENDMENT 1 – REVISED CLINICAL STUDY PROTOCOL VERSION 2.0 
The overall reason for the revision is to liberalize the participant selection criteria to 
facilitate recruitment, and to allow for a lower number of subjects to be included in the 
interim analysis. 
Description and Rationale of Change 
• Change of the inclusion criteria with respect to age requirements, early 
post-menopause definitions and minimum frequency of hot flashes or night 
sweats. 
• Change of concomitant therapy restrictions. 
• Affected sections:  
o Section 4.1: Inclusion Criteria (inclusion criteria 1, 2, 3 and 5). 
o Section 6.1: Permitted Concomitant Therapies 
o Section 6.2: Prohibited Concomitant Therapies 
Description and Rationale of Change 
• Reduction of the number of subjects to be included in the interim analysis, to 
speed up the availability of interim analysis results.  
• Affected sections:  
o Section 3.1: Overview of Study Design 
o Section 5.6: Blinding 
o Section 9.1: Statistical Analysis 
o Section 9.1.6: Interim Analysis 
o Section 12.6: Data Management 
Description and Rationale of Change 
• Addition of dual-energy X-ray absorptiometry (DEXA) parameters to the list of 
endpoints analyzed during the interim analysis, to gather as much proof as 
possible to substantiate the conclusions of the interim analysis. 
• Affected sections:  
o Section 3.1: Overview of Study Design 
o Section 5.6: Blinding 
o Section 9.1: Statistical Analysis 
o Section 9.1.6: Interim Analysis 
o Section 12.6: Data Management 


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Description and Rationale of Change 
• Removal of benzodiazepines from the drugs of abuse list, since they are listed as 
permitted concomitant therapy (on an as-needed basis).  
• Affected sections: 
o Section 4.1: Inclusion Criteria 
o Section 7.5.1.2: Clinical Laboratory Tests 
Description and Rationale of Change 
• The protocol stated that certificates of analysis would accompany the study drug 
to the site. This statement was deleted since certificates of analysis are not 
provided to the sites because this is a blinded study and based on the certificates 
of analysis assumptions could be made about the nature of medication kits.  
• Affected sections: 
o Section 5.1: Physical Description of the Study Drug 
Description and Rationale of Change 
• Change of project manager. 
• Affected section: 
o Study Administrative Structure and Investigators  


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CLINICAL STUDY PROTOCOL - ESN364_HF_204 10-December-2015 (Final 2.0) 
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PROTOCOL SYNOPSIS 
Study Title 
Pilot/Phase IIa Trial to Investigate the Effect of ESN364 in Early 
Postmenopausal Women Suffering From Hot Flashes 
Product 
ESN364 
Clinical Phase 
IIa 
Protocol Number 
ESN364_HF_204 
Indication 
Hot flashes 
Eudract Number 
2015-002578-20 
 
Sponsor 
Euroscreen S.A. 
Sponsor Representative 
MD 
Clinical Center(s) 
Multi-center study in Belgium 
 
Objectives: 
The primary objective of the study is to evaluate the effect of ESN364 on the severity and frequency of 
hot flashes in early postmenopausal women suffering from hot flashes, in terms of changes in weekly Hot 
Flash Score from baseline to Week 12. 
Secondary objectives are to evaluate in early postmenopausal women suffering from hot flashes: 
- 
the effect of ESN364 on the severity and frequency of hot flashes, in terms of changes in weekly Hot 
Flash Score from baseline to Weeks 4 and 8, and at follow-up; 
- 
the effect of ESN364 on the frequency of hot flashes, in terms of changes in weekly Hot Flash 
Frequency from baseline to Weeks 4, 8, and 12, and at follow-up; 
- 
the effect of 12-week administration of ESN364 on hot flash interference on daily life, in terms of 
changes from baseline over time in Hot Flash Related Daily Interference Scale (HFRDIS); 
- 
the effect of 12-week administration of ESN364 on climacteric symptoms, in terms of changes from 
baseline over time in Leeds Sleep Evaluation Questionnaire (LSEQ), Greene Climacteric Scale 
(GCS), and Sheehan Disability Scale (SDS); 
- 
the pharmacodynamic (PD) effect of 12-week administration of ESN364, in terms of changes over 
time in plasma concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
estradiol (E2), sex hormone-binding globulin (SHBG), leptin, insulin, C-peptide, and glycated 
hemoglobin (HBA1c); 
- 
safety and tolerability of 12-week administration of ESN364, in terms of adverse events (AEs), 
physical examination, vital signs, electrocardiogram (ECG), clinical laboratory tests, and plasma 
bone density marker concentrations (bone alkaline phosphatase [BALP] and carboxy-terminal 
telopeptide of type I collagen [CTX]). 
Exploratory objectives are to: 
- 
evaluate the effect of 12-week administration of ESN364 on body composition (lean mass, fat mass, 
bone mass/density) assessed by dual-energy X-ray absorptiometry (DEXA); 
- 
assess ESN364 plasma concentrations from sparse pharmacokinetic (PK) sampling. 
Overview of Study Design: 
This is a 12-week double-blind, placebo-controlled, parallel-group, multicenter, proof-of-concept study to 
assess the effect of 12-week administration of ESN364 in early postmenopausal women suffering from hot 
flashes. 
The study will consist of a screening period of maximum 4 weeks and a 12-week double-blind treatment 
period (Weeks 1-12), followed by a follow-up visit 2-3 weeks after the last study drug intake. 
The study will be performed on an ambulatory basis. During the treatment period, subjects will be asked 
to come to the clinical site every 4 weeks (Day 1 and Weeks 4, 8, 12; Visits 2-5). 
PPD


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Study Population: 
In total 80 subjects are planned to be enrolled. Subjects will be randomized to one of 2 treatment arms in a 
1:1 ratio as per pregenerated randomization list: ESN364 90 mg twice daily (b.i.d.) (40 subjects) or 
placebo (40 subjects). 
Eligibility Criteria: 
Inclusion Criteria: 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1. Women, between 40 and 65 years old (extremes included) at screening; 
2. Spontaneous amenorrhea for at least 12 consecutive months; or spontaneous amenorrhea for at least 
6 months with biochemical criteria of menopause (FSH >40 IU/L); or spontaneous amenorrhea for at 
least 3 months with biochemical/physical criteria of menopause (FSH >40 IU/L and 
E2 <0.21 nmol/L); or having had bilateral oophorectomy at least 6 weeks prior to screening (with or 
without hysterectomy); 
3. At least 49 moderate or severe hot flashes or night sweats over a period of 7 consecutive days, as 
recorded in the daily diary during the screening period, with at least 4 of those days with 7 or more 
moderate or severe hot flashes per day; 
4. In good general health as determined on the basis of medical history and general physical 
examination performed at screening; Hematology and chemistry 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; 
5. Negative urine test for selected drugs of abuse (amphetamines, tricyclic antidepressants, 
cannabinoids, cocaine, tetrahydrocannabinol, or opiates) at screening; 
6. Negative serology panel (including hepatitis B surface antigen [HBsAg], anti-hepatitis C virus 
[HCV] and human immunodeficiency virus (HIV) antibody screens); 
7. Negative urine pregnancy test at screening; 
8. 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. 
Exclusion Criteria: 
Subjects meeting any of the following criteria are excluded from participation in this study: 
1. Use of a prohibited therapy or not willing to wash-out drugs as mentioned in the prohibited therapies 
section of the protocol; 
2. History (in the past year) or presence of drug or alcohol abuse; 
3. Suicide attempt in the past 3 years; 
4. Previous or current history of a malignant tumor, except basal cell carcinoma; 
5. Active liver disease or jaundice, or out-of-range values of alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST); or total bilirubin >1.3 times the upper limit of normal (ULN); or 
creatinine >1.5 times the ULN; or estimated glomerular filtration rate (eGFR) using the Modification 
of Diet in Renal Disease (MDRD) formula <60 mL/min/1.73 m2 at screening; 
6. Medical condition or chronic disease (including history of neurological [including cognitive], 
hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], or endocrine 
disease) or malignancy that could confound interpretation of the study outcome; 
7. Any psychological disorder according to the criteria indicated in the Diagnostics and Statistical 
Manual of Mental Disorders (DSM, 4th edition) within one year prior to screening. Such disorders 
include but are not limited to current major depression, alcohol (more than 3 glasses of wine, beer, or 
equivalent/day) or substance abuse/dependence; 
8. 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; 
9. History of severe allergy, hypersensitivity, or intolerance to drugs in general, including the study 
drug and any of its excipients; 


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CLINICAL STUDY PROTOCOL - ESN364_HF_204 10-December-2015 (Final 2.0) 
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10. Presence or sequellae 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; 
11. Concurrent participation in another interventional study (or participation within 3 months prior to 
screening in this study); 
12. History of poor compliance in clinical studies; 
13. Unable or unwilling to complete the study procedures; 
14. 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. 
Test Product, Dose, Mode of Administration: 
ESN364 capsules to be taken orally b.i.d. with a glass of tap water at room temperature. The dose level of 
ESN364 that will be investigated is 90 mg b.i.d. (total daily dose of 180 mg) 
Reference Product, Dose, Mode of Administration: 
Matching placebo capsules to be taken orally b.i.d. with a glass of tap water at room temperature. 
Study/Treatment Duration: 
The total duration of involvement for each subject, screening through study exit, will be at most 19 weeks: 
the study will consist of a screening period (screening is to be performed within 4 weeks prior to the first 
intake of study drug, with a minimum of 7 days to allow for baseline data collection of Hot Flash Score 
and Hot Flash Frequency) and a 12-week double-blind treatment period (Weeks 1-12). A follow-up visit 
will be scheduled 2-3 weeks after the last study drug intake. 
Criteria for Evaluation: 
Efficacy 
Primary endpoint: 
- 
Change from baseline to Week 12 in weekly Hot Flash Score 
Secondary endpoints: 
- 
Changes from baseline over time in weekly Hot Flash Score and Hot Flash Frequency; 
- 
Change from baseline over time in HFRDIS score; 
- 
Changes from baseline over time in LSEQ, GCS, and SDS. 
Exploratory endpoint: the change from baseline to Week 12 in body composition (lean mass, fat mass, 
bone mass/density) will be explored. 
Pharmacokinetics 
Assessment of plasma ESN364 concentrations will be exploratory. 
Pharmacodynamics 
Changes in plasma concentrations of LH, FSH, E2, SHBG, leptin, insulin, C-peptide, and HBA1c from 
baseline over time will be evaluated. 
Safety 
- 
AE frequency and severity from first dose of study drug through the last visit; 
- 
Changes from baseline over time in hematology and biochemistry concentrations; 
- 
Changes from baseline over time in vital sign and ECG assessments; 
- 
Changes from baseline over time in BALP and CTX levels. 
Statistical Methods: 
Sample size 
As this study is only the first proof-of-concept Phase IIa study in this therapeutic area, no formal power 
calculations have been done. All the statistical analyses involving testing for significance will be 
exploratory in nature and will serve as a basis for designing and powering a subsequent (dose-ranging) 
Phase IIb study. 
One (and actually the main reason) for the absence of such power calculation is the fact that this study is 
unprecedented. There are no references available that can give an indication of observed effect size of 


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NK3 antagonism on Hot Flash Score and Hot Flash Frequency. 
In a review article by Sloan et al., the authors propose the following general guideline regarding set-up of 
studies using hot flash diary data (severity and frequency): 
- 
For Phase III placebo-controlled studies, 50 patients per treatment arm seem appropriate to 
provide sufficient power specifications to detect a clinically meaningful change in hot flash 
activity. 
- 
For Phase II trials, 25 patients per study seem to provide reasonable estimates of eventual hot 
flash efficacy to screen potential agents for more definitive testing. 
Since the review article typically considers paroxetine and hormones, we would, in our specific case, 
expect the effect size to be larger and would therefore propose to be sufficiently powered to conduct a 
successful Phase II proof-of-concept study, while leaving some room for drop-outs and interim analysis. 
Efficacy 
Primary endpoint: 
Changes from baseline in Hot Flash Score will be analyzed using an Analysis of Covariance (ANCOVA) 
model with treatment as fixed effect and baseline as covariate. If a significant difference between the 
treatment arms is present, differences between each active treatment arm and placebo will be tested, 
correcting for multiplicity. 
Secondary endpoints: 
Hot Flash Score and Hot Flash Frequency at all time points will be evaluated by means of descriptive 
statistics (actual values and changes from baseline) by treatment arm. 
The percentage of subjects with at least 70% reduction from baseline in Hot Flash Score will be compared 
across the treatment arms, using chi-square or Fisher exact test, as appropriate. 
The percentage of subjects with at least 50% reduction in the number of moderate and severe hot flashes 
will be compared across the treatment arms, using chi-square or Fisher exact test, as appropriate. 
Questionnaires will be evaluated by means of descriptive statistics (actual values and changes from 
baseline) by treatment arm. HFRDIS, GCS, SDS and LSEQ total scores and subscores (if applicable) are 
to be reported. 
Change in lean body mass, fat mass, and bone mass/density will be explored by means of descriptive 
statistics on the actual values, at each assessment time point and by treatment arm. Changes from baseline 
to Week 12 will be summarized by treatment arm. 
Pharmacokinetics 
Individual plasma ESN364 concentration values and actual sampling times relative to study drug intake 
will be listed. Descriptive statistics will be summarized by assessment time point. 
Pharmacodynamics 
Individual plasma hormone concentration values and actual sampling times relative to study drug intake 
will be listed. Descriptive statistics of the actual values and changes from baseline values will be 
summarized by assessment time point and by treatment arm. 
Safety 
Safety parameters will be tabulated and analyzed descriptively. 


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18 
TIME AND EVENTS SCHEDULE 
Assessments 
Visit 1: 
Screeningb 
Treatment Period 
Visit 6: 
Follow-upc 
Study Visit 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Time of Visit (Weeks)a 
W1 
W4 
W8 
W12 
Informed consentd 
X 
 
 
 
 
 
In-/exclusion criteria 
X 
X 
 
 
 
 
Medical history/concomitant diseases 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Physical examinatione 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
Serologyf 
X 
 
 
 
 
 
Dual-energy X-ray absorptiometryg 
 
X 
 
 
X 
 
Sampling for pharmacokinetic assessmentsh 
 
X 
X 
X 
X 
 
Sampling for pharmacodynamic assessmentsh,i 
X 
X 
X 
X 
X 
X 
Hot Flashes Severity and Frequencyj 
X 
X 
X 
X 
X 
X 
Hot Flash Related Daily Interference Scalek 
 
X 
X 
X 
X 
X 
Leeds Sleep Evaluation Questionnairel 
 
X 
X 
X 
X 
X 
Greene Climacteric Scalel 
 
X 
X 
X 
X 
X 
Sheehan Disability Scalel 
 
X 
X 
X 
X 
X 
Clinical laboratory tests and urinalysism 
X 
X 
X 
X 
X 
X 
Bone density markersn 
 
X 
 
 
X 
 
Vital signso 
X 
X 
X 
X 
X 
X 
ECGp 
X 
X 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
 
ePRO training 
X 
 
 
 
 
 
Dispensing of study drugq 
 
X 
X 
X 
 
 
Intake of study drugr 
 
X 
X 
X 
X 
 
Compliances 
 
 
X 
X 
X 
 
Concomitant therapiest 
X 
X 
X 
X 
X 
X 
Adverse eventst 
X 
X 
X 
X 
X 
X 
Footnotes on the next page. 


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19 
a. All visits need to be planned in the morning, fasted (for unbiased glucose, insulin, and C-peptide determination). Visit 2 should be planned to allow for first intake of study drugs at 
the clinical site, between 7:00 and 10:00 AM. For each subject, all visits during the treatment period subsequent to Visit 2 should be planned at the same time of the day, in the 
morning. A deviation of ±1 day is allowed on the visits during the treatment period subsequent to the first study drug intake (Visits 3-5). 
b. Screening is to be performed within 4 weeks prior to the first intake of study drug, with a minimum of 7 days to allow for baseline data collection of Hot Flash Score and Hot Flash 
Frequency. 
c. Two to 3 weeks after the last intake of study drug. 
d. No study-related assessments are to be carried out before signing of the informed consent form. 
e. Includes height, weight, and waist circumference (height at screening only). 
f. Includes HBsAg, and anti-HCV and HIV antibodies. 
g. For practical reasons, the timing of DEXA may vary from the actual time of the visit, depending on DEXA availability (DEXA appointment).The Visit 2 DEXA can be performed 
prior to Visit 2 during the screening period, as well as at Visit 2 but must be performed before randomization. The Visit 5 DEXA can be performed ±4 days from the actual time of 
Visit 5. It is however to be performed before the last dose of the study drug; in case the DEXA appointment related to Visit 5 is scheduled later in time than Visit 5, study drug intake 
must be continued until DEXA has been performed. 
h. Predose at Visits 2, 3, and 4; predose and 3 hours postdose at Visit 5. 
i. Includes LH, FSH, E2, SHBG, leptin, insulin, C-peptide, and HBA1c (HBA1c at Visits 2 and 5 only). Additional back-up samples will be collected at every visit and stored for 
future, exploratory use. 
j. Recorded in the ePRO diary on an ad hoc basis, but at a minimum twice-daily (morning/evening) from screening to follow-up. Night sweats should be recorded no later than morning 
upon awakening to start a new day. 
k. Completed in the ePRO diary at the clinical site at any time during the visit. 
l. Paper-based, administered at the clinical site at any time during the visit. 
m. Includes biochemistry, coagulation, and hematology panel (coagulation panel only at screening). Blood samples for clinical laboratory tests should be taken in a fasted state 
(overnight fast for at least 10 h) for unbiased glucose, insulin, and C-peptide determination. 
n. Includes BALP and CTX. 
o. Includes body temperature (oral), sitting blood pressure and pulse rate (supine after 5 minutes of rest). 
p. Supine 12-lead after 5 minutes of rest. 
q. Study drugs will be dispensed to the subjects at Visits 2, 3, and 4 (one bottle containing 68 capsules at every visit). 
r. The first intake of study drugs (Day 1; Visit 2) will be done at the clinical site (between 7:00 and 10:00 AM), under the supervision of the clinical staff. Study drug intake will be 
done with a glass of tap water at room temperature. Also on other days of visits, the morning dose of study drug will be taken at the clinical site, under the supervision of the clinical 
staff, after collection of predose blood samples. Subjects will be instructed not to consume food/fluids for at least 10 hours before their visit to the clinical site (except water intake 
until 1 hour before). On all other days throughout the treatment period, subjects will be asked to take their morning dose of study drug at home, around the same time of day 
(preferably between 7:00 and 10:00 AM). Morning intake at home may be done together with a light meal. All evening doses of study drug will be taken at home (preferably between 
7:00 and 10:00 PM). Subjects need to record all home study drug intakes in the ePRO diary. 
s. Includes compliance towards study drug intake and ePRO completion. Subjects will be asked to return all unused study drugs at every visit during the treatment period and 
compliance towards study drug intake will be assessed by counting returned dosage units in addition to ePRO entries upon study drug intake. Any discrepancies between returned 
dosage units and dosing in the ePRO diary will be discussed with the subject for whom a discrepancy was seen. 
t. Adverse events and intake of concomitant medication(s) will be monitored continuously from informed consent until the last study-related activity. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
List of Abbreviations 
ADME 
Absorption, distribution, metabolism, or excretion 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC∞ 
Area under the plasma concentration-time curve extrapolated to infinity 
b.i.d. 
Bis in die; twice daily 
BALP 
Bone alkaline phosphatase 
BPH 
Benign prostate hyperplasia 
Cmax 
Maximum plasma concentration 
CRO 
Contract Research Organization 
CTX 
carboxy-terminal telopeptide of type I collagen 
DBP 
Diastolic blood pressure 
DEXA 
Dual-energy X-ray absorptiometry 
DNA 
Human deoxyribonucleic acid 
E2 
Estradiol 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ePRO 
Electronic Patient Reported Outcome 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCS 
Greene Climacteric Scale 
GnRH 
Gonadotropin-releasing hormone 
HBA1c 
Glycated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
hERG 
Human ether-à-go-go-related gene 
HFRDIS 
Hot Flash Related Daily Interference Scale 
HIV 
Human immunodeficiency virus 
hNK 
Human neurokinin 
HPG 
Hypothalamic-pituitary-gonadal 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
KNDy 
Kisspeptin/neurokinin B/dynorphin 
LH 
Luteinizing hormone 
LPLV 
Last Patient Last Visit 


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LSEQ 
Leeds Sleep Evaluation Questionnaire 
NK 
Neurokinin 
NIH 
National Institutes of Health 
NOAEL 
No observed adverse effect level 
P4 
Progesterone 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
q.d. 
Quaque die; once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected according to Fridericia’s formula 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SDO 
Secure Data Office 
SDS 
Sheehan Disability Scale 
SHBG 
Sex hormone-binding globulin 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
 
Definitions of Terms 
BMI 
Weight in kilogram divided by the square of height in meters 
QTcF 
QT interval corrected according to Fridericia’s formula:  
QTcF = QT/(1000/RR)1/3 
Study drug 
All drugs administered during the 12-week treatment period, i.e., the 
Investigational Medicinal Product (ESN364) and placebo 
 


Study Administrative page removed as out of scope


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1. 
INTRODUCTION 
1.1 
BACKGROUND INFORMATION 
1.1.1 
Hot Flashes 
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) [1,2,3]. Approximately 75% of perimenopausal 
women will experience 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 hot flashes, and 4 million women report severe symptoms [5]. 
Hot flashes can have a significant negative impact on the quality of life, causing hot 
flashes to be a major reason for menopausal women to seek medical attention. Despite 
the vast numbers of individuals affected, the physiology of 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 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, a rare occurrence, panic [2]. 
The most effective treatment of hot flashes is hormone replacement therapy (HRT), but a 
Women’s Health Initiative study raised questions about the long-term safety of this 
treatment. Hormone replacement therapy is also the most commonly used 
pharmacological treatment for hot flashes. However, 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 (e.g., breast/endometrial cancer, liver disease). 
The perceived limitations of HRT, coupled with the lack of efficacy and adverse effects 
observed with non-hormonal therapies, have led clinicians to search for other treatment 
options for hot flashes. 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 [7,8,9]. The clinical benefit of these antidepressants is not as great as that 
observed for estrogen however. 
1.1.2 
Introduction to ESN364 
ESN364 is an orally-available small molecule, potent and selective Neurokinin (NK) 3 
antagonist that significantly modulates the hypothalamic-pituitary-gonadal (HPG) axis to 
lower the circulating levels of sex hormones in animal models. The 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 the NK3 receptor 
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 [10]. 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 luteinizing hormone 




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Figure 2: 
Inhibitory Effect of NK3 Antagonist on Testosterone Levels in Male Volunteers 
(Figure From [13]) 
1.2 
NON-CLINICAL STUDIES 
1.2.1 
Summary of Pharmacodynamics 
Pharmacological assays characterized ESN364 as an NK3 receptor antagonist with 
activity to lower sex hormones via a reduction in LH, indicative of a centrally-mediated 
effect. In vitro studies demonstrated that ESN364 is a potent full inhibitor of human 
neurokinin (hNK) 3 receptor and is highly selective for hNK3 in comparison to the other 
members of tachykinin receptor family (hNK1 and hNK2) and other G-protein coupled 
receptors including the ones known to be implicated in modulation of GnRH axis. 
Further in vitro studies demonstrated that ESN364 have similar affinity for human and 
monkey NK3 receptors. The ESN364 affinity for rat NK3 receptor was high, however 
8-fold less than the affinity for human NK3 receptor. These data indicated that rat and 
specially monkey are useful animal models for in vivo non-clinical testing. 
In vivo studies demonstrated that ESN364 significantly reduces plasma LH levels in 
castrate male rats at a dose range of 3 to 20 mg/kg. At a dosage of 3 mg/kg, ESN364 
significantly reduced circulating testosterone levels in intact male rats. ESN364 
effectively reduced prostate size without concomitant effects to reduce testis weight in rat 
model of benign prostate hyperplasia (BPH) at dosages of 10 and 30 mg/kg (once daily 
[q.d.]; oral administration) after 21 days of treatment. 
In ovariectomized female rats, ESN364 significantly reduced the mean plasma levels and 
pulsatile LH secretion frequency and amplitude at 10 mg/kg dosage. ESN364 treatment 
at the dosage of 10 mg/kg twice daily (b.i.d.) for a period of 10 days reduced E2 levels 
and appeared to prolong the estrous cycle in adult intact female rats. ESN364 
significantly reduced circulating LH levels in castrate male monkeys following single 
and 5-day repeated oral dosing at 5 mg/kg/day. After five consecutive days of dosing, 
ESN364 had no effect on plasma FSH levels, demonstrating that antagonism of the NK3 
receptor is a means to selectively inhibit LH, but not FSH, as a novel and precise 
approach to modulate the HPG axis for the treatment of sex hormone disorders. 
ESN364 suppressed plasma LH levels 2 hours following bolus injection in 
ovariectomized female ewes at the 1 mg/kg dosage; pulsatile LH secretion restored 


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2-4 hours after the injection. ESN364 injection had no effect on FSH secretion in 
ovariectomized female ewes. 
ESN364 significantly reduced LH, E2, and progesterone (P4) levels in intact 
Cynomolgus female monkeys after oral administration at the dosages of 10, 25 and 
50 mg/kg/day during a treatment period of 35 days. The reduction in E2 was not to 
castration levels. With the same dosages and duration in female monkeys, ESN364 had 
no effect on FSH and testosterone levels. The LH, E2, and P4 levels were recovered in 
all compound treated animals after 28 days following cessation of treatment. In intact 
male Cynomolgus monkeys, following oral administration of ESN364 at the dosages of 
25 and 50 mg/kg/day, there was a small trend towards decrease levels of mean 
testosterone, LH and E2, whereas no test item-related effects were seen on male FSH 
levels. 
1.2.2 
Summary of Pharmacokinetics 
Pharmacokinetic (PK) and absorption, distribution, metabolism, and elimination 
(ADME) studies have been performed to demonstrate that ESN364 has a suitable profile 
for continued advancement through preclinical development as an oral product for the 
treatment of sex-hormone related disorders. 
Following oral administration of ESN364 at a dose range of 3 to 20 mg/kg in castrate 
male rats, plasma concentrations increased linearly with dose and remained stable up to 
300 minutes. ESN364 in methylcellulose formulation (0.5%) showed a good oral 
absorption in intact male rats at dosage of 3 mg/kg. In a BPH rat model, administration of 
ESN364 at dosages of 3, 10, 30 mg/kg q.d. (oral administration) for 21 days showed no 
significant accumulation, high absorption variability with relatively well-respected 
absorption ratios between the doses. 
ESN364 had a rapid oral absorption after 1.0 hour postdose with a maximum plasma 
concentration within 5.0 hours postdose in monkeys at dosages of 10, 25 and 50 mg/kg. 
There was little or no accumulation of ESN364 following repeated dose administration 
for 25 days. There were no notable trends in the plasma concentrations or toxicokinetic 
parameters which could be related to gender. 
ESN364 was devoid of significant inhibition of cytochrome P (CYP) 450 enzymes 
(>40 μM, standard panel). Plasma protein binding was low (<50%) and microsome 
stability was high (t1/2 >1000 min) with consistent values in matrices from rat, monkey 
and human. Also, metabolic stability in hepatocytes proved to be similar across species 
(rat, monkey, human). 
ESN364 had a good PK profile in rats with a low clearance, a good exposure, an 
elimination half-life longer than 4.0 hours, and bioavailability consistent with potential 
use via oral administration. Pharmacokinetic studies in rats and monkeys indicated that 
ESN364 undergoes low clearance and exhibits high oral exposure. In rats and monkeys, a 
single metabolite was predominantly observed resulting from an oxidation. The main 
route of excretion in both species was in the urine, with the oxidated metabolite being 
more rapidly excreted. Thus, the PK and excretory pathways appeared similar in rats and 
monkeys, the two species selected as models for the human safety profiling of this 
product. 


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High brain penetration was demonstrated in rat, consistent with the putative central 
mechanism of action of ESN364 to regulate LH release. 
Toxicokinetic studies in rats showed that mean plasma concentrations are at a maximum 
at between 1.0 and 8.0 hours postdose for both males and females in all dosage groups 
(30, 100, 300 mg/kg/day; oral administration). Exposure of ESN364 indicated no 
accumulation and appeared to be similar in males and females on both sampling 
occasions and at all dose levels. 
Toxicokinetic studies in monkeys demonstrated that ESN364 had a rapid oral absorption 
after 1.0 hour postdose (10, 25, 50 mg/kg/day; oral administration) with a maximum 
plasma concentration within 5.0 hours postdose. There was little or no accumulation of 
ESN364 following repeated dose administration for 25 days. There were no notable 
trends in the plasma concentrations or toxicokinetic parameters which could be related to 
gender. 
1.2.3 
Summary of Toxicology 
No cytotoxicity was observed for ESN364 using HEPG2 cells. ESN364 did not induce 
mutation in 5 histidine-requiring strains of Salmonella typhimurium (TA98, TA100, 
TA1535, TA1537, and TA102) in the absence and in the presence of a rat liver metabolic 
activation system S9. ESN364 did not induce chromosome aberrations in cultured human 
peripheral blood lymphocytes up to a concentration equivalent to 1 mM for 3+17 hours 
in the absence and presence of S9 and for 20+0 hours in the absence of S9. 
ESN364 did not exhibit any significant inhibition of human ether-à-go-go-related gene 
(hERG) channels nor did it significantly modulate either the electrical or the mechanical 
properties of the heart in a Langendorff model (rabbit) at tested concentrations up to 
30 μM. In the human embryonic kidney (HEK) 293 cells transfected with hERG, 
ESN364 exhibited a hERG inhibition liability which was more than 8000-fold lower than 
that of the reference compound (terfenadine). 
A study to investigate the effect of ESN364 on general activity, behavior and body 
temperature, oral administration of ESN364 to male and female Han Wistar rats 
demonstrated signs associated with sedation together with constricted pupils at the dose 
level of 250 mg/kg. At the dose level of 125 mg/kg, constricted pupils was the only sign 
seen and was present in 50% of the animals. These signs were judged to be of mild 
intensity and showed complete recovery at 24 hours postdose. No significant effect on 
body temperature was observed. 
Measurement of respiratory parameters using whole body plethysmography in rats 
showed a clear dose-related response in both male and female rats with minimal transient 
effects at the low dose (40 mg/kg) and increasing marked effects on tidal volume with 
increasing dose levels (80 and 125 mg/kg). In the context of this study, and the absence 
of respiratory-related clinical signs, the respiratory effects were not considered to be 
adverse. 
Electrocardiographic investigations in conscious male Cynomolgus monkeys showed that 
single oral doses of ESN364 at 10, 25, and 50 mg/kg were well-tolerated and elicited no 
significant changes. A slight decrease in mean +dP/dtmax and systolic and mean arterial 
blood pressure as well as a slight increase in heart rate (HR) were observed. No 
electrocardiogram (ECG) waveform morphologic abnormalities on qualitative 


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assessments and no effects on PR, QRS, and QTc (QT interval corrected for heart rate) 
interval following oral doses of ESN364 were noted. 
Repeated-dose toxicity studies in male and female HsdHan™: Wist rats demonstrate that 
daily oral administration of ESN364 for 28 days at dose levels of 30 and 100 mg/kg was 
well-tolerated. At the highest daily dosage of 300 mg/kg, two deaths and marked clinical 
signs (lethargy, reduced activity, labored respiration and staggering) and body weight 
loss during the first few days of treatment were observed. There were histopathological 
findings in the 100 and 300 mg/kg dosing groups in the lung, liver, bone marrow, uterus, 
ovary and prostate and some with corresponding changes in weight and macroscopic 
evaluation. These changes were considered to be adaptive or related to the pharmacology 
of the test article rather than being an adverse effect. Based on the findings from this 
study, the No observed adverse effect level (NOAEL) was considered to be 
100 mg/kg/day in rats. 
Repeated-dose toxicity studies in male and female Cynomolgus monkeys showed that 
daily oral administration of ESN364 for 5 weeks up to a dose of 50 mg/kg/day was 
tolerated with no mortality and no test item-related effects on hematology, clinical 
chemistry, urinalysis, respiratory rate, neurobehavioral observations, ophthalmic 
examinations, cardiovascular investigations and organ weights. Following oral 
administration of ESN364, a loss of body weight was observed, especially in male 
monkeys. One female monkey in the 50 mg/kg dosing group showed hyperplasia of 
lymphocytes in lymph nodes, spleen and lung and perivascular inflammation in the 
kidney. Therefore, the NOAEL for ESN364 was defined to be 25 mg/kg/day in monkeys. 
For more detailed information on ESN364 and the conducted long-term (13-week) 
toxicology studies, refer to the current Investigator’s Brochure [14]. 
1.3 
CLINICAL STUDIES 
To date, the development program of ESN364 includes only one recently completed 
study, conducted in 65 subjects. A dose range between 3 and 180 mg as single dose in 
fasted and fed conditions, and up to 21 days of dosing in a multiple dose setting was 
tested. Both sexes were included in this study. Male healthy volunteers have been dosed 
up to 10 consecutive days and healthy female subjects of childbearing potential have 
been dosed up to 21 consecutive days in accordance with their menstrual cycle. The 
highest dose in both multiple dose parts was 180 mg q.d. 
The results of the Phase I study demonstrated that administration of single and multiple 
ascending doses up to 180 mg of ESN364 were safe and well tolerated. 
No deaths occurred during the study. The majority of reported treatment-emergent 
adverse events (TEAEs) were mild to moderate in severity. A severe TEAE was reported 
in 1 (7.1%) subject in the placebo treatment group. One serious adverse event (SAE) 
(foot fracture) was reported in 1 (5.9%) subject during the follow-up period and led to 
withdrawal of the subject from the study. 
The most frequently reported TEAEs (i.e., those reported in >2 subjects per treatment 
group) following multiple ascending dosing for 21 days in healthy female subjects were 
abdominal pain in 3 (50.0%) subjects each in the placebo and 180 mg ESN364 treatment 
group, nausea in 3 (50.0%) subjects in the 20 mg ESN364 treatment group, headache in 
3 (50.0%) and 4 (66.7%) subjects in the 60 mg and 180 mg ESN364 treatment groups, 


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respectively, and dry skin in 3 (50.0%) subjects in the 180 mg ESN364 treatment group. 
Nausea and headache were only reported in the 20 mg, 60 mg, and 180 mg ESN364 
treatment groups and not in the placebo treatment group. 
All subjects had recovered or were recovering from the TEAEs by the end of the study. 
All treatment-emergent laboratory abnormalities (worst-case) were observed in at most 
2 subjects per treatment group, except for some isolated elevated abnormally high 
potassium levels and isolated low levels of total bilirubin. None of the laboratory 
abnormalities were considered to be of clinical relevance, and as a consequence none of 
the laboratory abnormalities were reported as adverse event (AE). 
No clinically relevant trends or changes were observed in median vital sign values and 
ECG parameters over time. None of the observed ECG related abnormalities were 
reported as AE. Vital sign abnormalities were reported as a AE in 2 subjects (palpitations 
in one subject after single dose administration and palpitations and orthostatic 
hypertension in one subject after multiple dose administration). 
None of the subjects were observed with new (i.e., not present at screening) abnormal 
findings during physical examination in the study. 
In female subjects, a dose-dependent decrease in detectable ovulations and a delay of the 
mid-cycle LH surges was observed, resulting in a prolonged or absent menstrual cycle. A 
84-day follow-up period showed a recovery of the normal menstrual pattern once the 
treatment with ESN364 had finished. 
Following single ascending dose administration of ESN364, the PK of ESN364 was dose 
proportional in terms of maximum plasma concentration (Cmax) and plasma exposure 
(AUC∞) over the 3 to 180 mg dose range. Median time to maximum plasma 
concentration (tmax) ranged between 1.25 to 2.00 hours, being longer in the 90 mg dose 
group compared to the 3 and 12 mg dose groups. Mean terminal half-life ranged between 
2.39 and 4.19 hours. No significant food effect was observed on ESN364 exposure and 
absorption rate measured in the 23 mg dose group. 
Single dose administration of ESN364 in the dose range from 3 to 180 mg induced a 
dose-dependent decrease in total and free testosterone, FSH and LH plasma 
concentrations within the 24 hours after administration, compared to placebo. Both 
minimum concentration (i.e., maximum effect) and plasma exposure were decreased 
after different single doses of ESN364. No clear effect on sex hormone-binding globulin 
(SHBG) plasma concentration was observed compared to placebo. 
Following multiple dose administration for 10 days in healthy males, it could be 
concluded that steady-state in ESN364 plasma concentrations was reached quickly, by 
Day 2, so after the first administration of study drug. The mean total amounts of ESN364 
excreted unchanged in urine over the 0-24 hour period were similar on Day 1 and Day 10 
(with a range of 1.53 to 2.16% of the dose). The bioavailability of ESN364 increased 
proportionally with the dose from 20 to 180 mg q.d, as measured by peak and plasma 
exposure. Time to peak concentration was similar after single and multiple 
administrations and for all tested doses, with median tmax of 2.50 or 3.00 hours. From 
descriptive data, the apparent elimination half-life seems to be comparable between the 
studied dose groups as well between single dosing and steady-state with mean values 
ranging between 2.84 and 4.20 hours. No accumulation of ESN364 was observed after 


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10 days of 60 or 180 mg q.d. administration. Renal clearance seems to be similar in the 
60 or 180 mg q.d. groups, with mean values of 11 and 9.93 mL/min, respectively. 
Single and multiple administration of ESN364, in the dose range from 20 to 180 mg q.d., 
induced a similar dose-dependent decrease in total and free testosterone within the 
24 hours after administration, compared to placebo. A decrease of a similar extent 
throughout the dose range (20 mg to 180 mg q.d.) was observed in LH and FSH plasma 
concentrations after single and multiple administration of ESN364, compared to placebo. 
After a single administration of ESN364 (Day 1), total testosterone plasma 
concentrations <5.2 nmol/L were found for 16.7% of the subjects at the dose of 20 mg 
q.d. (for a median extent of time of 5.58 hours), for 66.7% of the subjects at a dose of 
60 mg q.d. (for a median extent of time of 6.52 hours) and for 66.7% of the subjects at a 
dose of 180 mg q.d. (for a median extent of time of 11.5 hours). After multiple 
administration (Day 10) of ESN364 (Day 10), total testosterone plasma concentrations 
<5.2 nmol/L were found for 50% of the subjects at the dose of 20 mg q.d. (for a median 
extent of time of 1.77 hours), for 50% of the subjects at a dose of 60 mg q.d. (for a 
median extent of time of 4.21 hours) and for 66.7% of the subjects at a dose of 180 mg 
q.d. (for a median extent of time of 7.5 hours). After single and multiple dose 
administration of ESN364, no clear effect on plasma SHBG concentrations was 
observed, compared to placebo. Relatively high between-subject variability was observed 
for pharmacodynamic (PD) parameters. 
Following multiple dose administration for 21 days in healthy females, it could be 
concluded that steady-state in ESN364 plasma concentrations was reached quickly, by 
Day 2, so after the first administration of study drug. The bioavailability of ESN364 
increased dose proportionally between 20 and 60 mg q.d. but was above the dose 
proportionality for the highest 180 mg q.d. compared to 60 mg q.d., as measured by peak 
and plasma exposure, and this independently from PK sampling day (Day 1 and Day 21). 
No significant dose and day effects were observed on tmax with median tmax of 3.00 to 
4.00 hours. Plasma ESN364 exposure was higher at steady-state (Day 21) compared to 
Day 1. From descriptive data, the apparent elimination half-life seems to be comparable 
between the studied dose groups as well between single dosing and steady-state (mean 
half-life ranged between 4.22 and 4.84 hours), with the exception of the highest dose 
group where the half-life was prolonged on Day 1 (7.06 hours) and Day 21 (6.34 hours) 
compared to the other dose groups. No relevant accumulation of ESN364 was observed 
after 21 days of administration of 60 or 180 mg q.d. administration, with mean 
accumulation ratio (Rac) values of 1.23 and 1.18, respectively. Renal clearance seems to 
be comparable in the 60 or 180 mg q.d. groups, with mean values of 6.83 and 5.34 
mL/min, respectively. When comparing ESN364 exposure after single dosing or at 
steady-state following multiple dose administration for 10 days (healthy males) and 21 
days (healthy women), peak and plasma exposures were significantly lower in males. 
Time to peak exposure was similar for both genders. 
Based on plasma concentrations monitored from the first administration (Day 1) to 
24 hours after the last administration (Day 22) (i.e., over the time extent of the menstrual 
cycle during presence of study drug in the body), the time to reach the peak concentration 
in LH was lengthened with the 60 and 180 mg q.d. dosages (median time of ≈17 days) 
compared to placebo (median time of ≈ 8 days). No clear difference between active 
treatments and placebo could be evidenced in FSH plasma concentrations. The time to 
reach the peak concentration in total and free estradiol was lengthened with the 60 and 


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180 mg q.d. dosages (median time of between 17 and 19 days) compared to placebo 
(median time of ≈ 9 days). A dose-dependent decrease in P4 plasma concentration was 
observed with the 60 and 180 mg q.d. dosages, compared to placebo, and the 20 mg q.d. 
dosage; the calculated median time to reach P4 peak concentration was between around 
18 days for the 60 and 180 mg q.d. dosages, compared to 14 days for placebo and the 
20 mg q.d. dosage. However, for a majority of subjects in the 60 and 180 mg q.d. dose 
groups, the menstrual peak in P4 was not yet reached at Day 22. 
1.4 
OVERALL RATIONALE FOR THE STUDY 
Since 2012, there is an increasing number of articles and papers pointing towards a direct 
link between kisspeptin/neurokinin B/dynorphin (KNDy) neurons and the occurrence of 
hot flashes [15,16,17]. Mittelman-Smith and Rance linked the modulation of body 
temperature, estradiol and KNDy neurons to the occurrence of hot flashes [15,16]. 
Jayasena et al. demonstrated a direct causal relationship between the injection of NKB 
and the occurrence of hot flashes in the study participants [17]. 
Euroscreen did an experiment in 10 ovarectomized ewe (non-GLP study Monash 001) 
where the ewes were injected with either 1 mg/kg ESN364 or placebo. The study was 
used to demonstrate the suppression of the LH pulse frequency by ESN364. When 
analyzing the safety data from the ewes, there was a significant difference in core body 
temperature between the treated versus the placebo ewes, as shown in Figure 3. 
 
Figure 3: 
Core Body Temperature in Ovarectomized Ewes Injected With 1 mg/kg ESN364 or 
Placebo 
Our current hypothesis is that in menopause, the lack of E2 feedback to the KNDy 
neuron leads to an increased firing frequency of that neuron which in turn leads to the 
increase in plasma LH and FSH concentrations typically seen in postmenopause. 
Because of the projecting nerve endings from the KNDy neuron to the preoptic 
hypothalamus, this increase firing of the KNDy neuron also results in the generation of 
hot flashes. Our hypothesis is that ESN364 - via NK3 antagonism - will decrease this 
firing frequency of the KNDy neuron to normal ‘premenopausal’ levels thus eliminating 
the occurrence of hot flashes. 
A schematic diagram showing the anatomic relationship between KNDy neurons, GnRH 
neurons, and the heat-defense pathway in the rat is shown in Figure 4. 


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Figure 4: 
Schematic Diagram Showing the Relationship Between KNDy Neurons, GnRH 
Neurons and the Heat-Defense Pathway in the Rat. KNDy Neurons Branch and Project 
to GnRH Terminals in the Median Eminence and Preoptic Structures That Regulate 
Body Temperature (Figure from [18]) 
1.5 
RISK BENEFIT ANALYSIS 
ESN364 is being developed for the treatment of women’s health disorders such as 
endometriosis, polycystic ovarian syndrome, and uterine fibroids. The compound may 
also be developed for sex hormone disorders affecting men, such as BPH. 
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, P4 and testosterone. 
Since in this study we are aiming at including 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 we do anticipate a moderate decrease of the already 
elevated LH and FSH plasma levels, maybe even to premenopausal levels. There are no 
known risks associated with this quasi normalization of the gonadotropins. 
Treatment with ESN364 can cause adverse effects or other symptoms. Adverse effects 
that can be expected as derived from the AE profile of the first-in-human study in male 
and female healthy volunteers (see also Section 1.3) are as follows: 
During the Phase I study, following side effects have been recorded in the 41 male 
healthy volunteers who received ESN364: 
- 
Very Frequent (i.e., in more than 1/10 participants): none; 
- 
Frequent (i.e., in more than 1 in 100 but fewer than 1 in 10 participants): nausea 
and headache (both in 3/41 participants) and palpitations, abdominal discomfort, 
diarrhea, oral paresthesia (tingling sensation in the mouth), dizziness, 


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hyperhidrosis (increased sweating), abnormal skin odor, irritability, and fatigue 
(each in 1/41 participants). 
During the Phase I study, following side effects have been recorded in the 18 female 
healthy volunteers who received ESN364: 
- 
Very Frequent (i.e., in more than 1/10 participants): headache (7/18 participants), 
dry skin (3/18 participants), abdominal pain, metrorrhagia, vaginal discharge, and 
acne (each in 2/18 participants); 
- 
Frequent (i.e., in more than 1/100 but fewer than 1/10 participants): dry mouth, 
dysphagia (pain during swallowing), nausea, sensation of pressure, dizziness, 
breast pain, vulvovaginal itching, oropharyngeal pain, generalized itchy feeling, 
abnormal skin odor, palpitations, dry eye, abdominal discomfort, and abdominal 
distension (all in 1/18 participants). 
All recorded treatment-related AEs were mild to moderate in severity and had a short 
duration. All AEs resolved spontaneously without sequellae. Only 3 AEs were rated 
moderate in severity, being abdominal pain, headache and palpitations. The reported 
palpitations were short-lived and were not accompanied by other signs/symptoms of 
cardiac involvement (vital signs and ECG were normal). 
However, given the stage of drug development, our current knowledge of the side effect 
profile of ESN364 is still limited. 


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2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the effect of ESN364 on the severity 
and frequency of hot flashes in early postmenopausal women suffering from hot flashes, 
in terms of changes in weekly Hot Flash Score from baseline to Week 12. 
2.2 
SECONDARY OBJECTIVES 
Secondary objectives are to evaluate in early postmenopausal women suffering from hot 
flashes: 
- 
the effect of ESN364 on the severity and frequency of hot flashes, in terms of 
changes in weekly Hot Flash Score from baseline to Weeks 4 and 8, and at 
follow-up; 
- 
the effect of ESN364 on the frequency of hot flashes, in terms of changes in 
weekly Hot Flash Frequency from baseline to Weeks 4, 8, and 12, and at 
follow-up; 
- 
the effect of 12-week administration of ESN364 on hot flash interference on 
daily life, in terms of changes from baseline over time in Hot Flash Related 
Daily Interference Scale (HFRDIS); 
- 
the effect of 12-week administration of ESN364 on climacteric symptoms, in 
terms of changes from baseline over time in Leeds Sleep Evaluation 
Questionnaire (LSEQ), Greene Climacteric Scale (GCS), and Sheehan 
Disability Scale (SDS); 
- 
the PD effect of 12-week administration of ESN364, in terms of changes over 
time in plasma concentrations of LH, FSH, E2, SHBG, leptin, insulin, 
C-peptide, and glycated hemoglobin (HBA1c); 
- 
safety and tolerability of 12-week administration of ESN364, in terms of AEs, 
clinical laboratory tests, plasma bone density marker concentrations (bone 
alkaline phosphatase [BALP] and carboxy-terminal telopeptide of type I 
collagen [CTX]), vital signs, ECG, and physical examination. 
Exploratory objectives are to: 
- 
evaluate the effect of 12-week administration of ESN364 on body composition 
(lean mass, fat mass, bone mass/density) assessed by dual-energy X-ray 
absorptiometry (DEXA); 
- 
assess ESN364 plasma concentrations from sparse PK sampling. 




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3.2 
DISCUSSION OF STUDY DESIGN 
Dose Selection 
LH secretion is a surrogate for the activity of the KNDy neuron. In the first-in-human 
Phase I study (see Section 1.3), 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 I study and was demonstrated to be safe and 
well tolerated. LH suppression was maximal with this dose level. Hence, we expect that 
the 180-mg dose represents the dose associated with maximal suppression of the KNDy 
neuron. 
During menopause, the negative feedback by E2 is unexisting, due to the cessation of 
estrogen production in the ovaries. The lacking negative estradiol feedback will cause the 
KNDy neuron to become hyperactive in an attempt to restore the needed estradiol levels 
via the increased release of LH/FSH. When dealing with an hyperactive state of the 
KNDy neuron, as assumedly is the case in the postmenopause period, a once-daily 
morning dose of ESN364 will probably not yield the desired suppression of KNDy at 
night, preventing night sweats. For this reason, a high dose of ESN364 (total daily dose 
of 180 mg) given as 90 mg b.i.d. will be tested to investigate the possibility to completely 
suppress LH secretion. 
Placebo Control 
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. 
Randomization and Blinding 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to 
increase the likelihood that known and unknown subject attributes (e.g., demographic 
and baseline characteristics) are evenly balanced across treatment arms, and to enhance 
the validity of statistical comparisons across treatment arms. 
Blinded treatment will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints. 


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4. 
SELECTION OF STUDY POPULATION 
Screening for eligible subjects will be performed at a screening visit that is to be planned 
within 4 weeks prior to the first intake of study drug (with a minimum of 7 days to allow 
for baseline data collection of Hot Flash Score and Hot Flash Frequency). 
In total 80 subjects are planned to be enrolled. Subjects will be randomized to one of 
2 treatment arms in a 1:1 ratio: ESN364 90 mg b.i.d. (40 subjects) or placebo 
(40 subjects). 
In- and exclusion criteria will be checked during screening (Visit 1) and reassessed prior 
to randomization (Visit 2). 
Note: in case of 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, a retest 
can be done. Results of this retest must be available prior to randomization. The result of 
the retest will be considered for subject eligibility. 
4.1 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria are eligible to participate in this study: 
1. Women, between 40 and 65 years old (extremes included) at screening; 
2. Spontaneous amenorrhea for at least 12 consecutive months; or spontaneous 
amenorrhea for at least 6 months with biochemical criteria of menopause 
(FSH >40 IU/L); or spontaneous amenorrhea for at least 3 months with 
biochemical/physical criteria of menopause (FSH >40 IU/L and E2 <0.21 nmol/); 
or having had bilateral oophorectomy at least 6 weeks prior to screening (with or 
without hysterectomy); 
3. At least 49 moderate or severe hot flashes or night sweats over a period of 
7 consecutive days, as recorded in the daily diary during the screening period, 
with at least 4 of those days with 7 or more moderate or severe hot flashes per 
day; 
4. In good general health as determined on the basis of medical history and general 
physical examination performed at screening; hematology and chemistry 
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; 
5. Negative urine test for selected drugs of abuse (amphetamines, tricyclic 
antidepressants, cannabinoids, cocaine, tetrahydrocannabinol, or opiates) at 
screening; 
6. Negative serology panel (including hepatitis B surface antigen [HBsAg], anti-
hepatitis C virus [HCV] and human immunodeficiency virus (HIV) antibody 
screens); 
7. Negative urine pregnancy test at screening; 
8. 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. 


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4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria are excluded from participation in this 
study: 
1. Use of a prohibited therapy or not willing to wash-out drugs as mentioned in the 
prohibited therapies section (Section 6.2); 
2. History (in the past year) or presence of drug or alcohol abuse;  
3. Suicide attempt in the past 3 years; 
4. Previous or current history of a malignant tumor (except basal cell carcinoma); 
5. Active liver disease or jaundice, or out-of-range values of alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST); or total bilirubin 
>1.3 times the upper limit of normal (ULN); or creatinine >1.5 times the ULN; or 
estimated glomerular filtration rate (eGFR) using the Modification of Diet in 
Renal Disease (MDRD) formula <60 mL/min/1.73 m2 at screening; 
6. Medical condition or chronic disease (including history of neurological [including 
cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., 
moderate asthma], or endocrine disease) or malignancy that could confound 
interpretation of the study outcome, as judged by the Investigator; 
7. Any psychological disorder according to the criteria indicated in the Diagnostics 
and Statistical Manual of Mental Disorders (DSM, 4th edition) within one year 
prior to screening. Such disorders include but are not limited to current major 
depression, alcohol (more than 3 glasses of wine, beer, or equivalent/day) or 
substance abuse/dependence; 
8. 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; 
9. History of severe allergy, hypersensitivity, or intolerance to drugs in general, 
including the study drug and any of its excipients; 
10. Presence or sequellae of gastrointestinal, liver, kidney or other conditions known 
to interfere with the ADME mechanisms of drugs, as judged by the Investigator; 
11. Concurrent participation in another interventional study (or participation within 
3 months prior to screening in this study); 
12. History of poor compliance in clinical studies; 
13. Unable or unwilling to complete the study procedures; 
14. 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. 


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5. 
TREATMENT(S) 
Manufacturing, packaging, and labeling of the study drug, ESN364, will be done under 
the responsibility of the Sponsor. 
The ESN364 and placebo capsules are manufactured under current Good Manufacturing 
Practice (GMP), as required by the current Good Clinical Practice (GCP), at Pharmavize 
N.V. (Mariakerke, Belgium). 
5.1 
PHYSICAL DESCRIPTION OF THE STUDY DRUG 
The Investigational Medicinal Product (IMP), ESN364 capsules, is being developed as 
an immediate-release hard gelatin capsule for oral administration in an active dosage 
strength range of 2.25 mg to 180 mg. In this clinical study, only the 90 mg strength will 
be tested. The qualitative composition of the ESN364 capsules is provided in Table 1. 
Table 1: 
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 
Coni snap size 0 white opaque hard gelatin capsule 
(opaque white cap/opaque white body) 
Capsule shell 
5.2 
OTHER MEDICATION ADMINISTERED IN THE STUDY 
Placebo is supplied as hard gelatin capsules that match the IMP. Placebo capsules contain 
the same excipients as the IMP. The capsule shells used for manufacturing of placebo 
capsules are identical to the capsule shells used for manufacturing of ESN364 capsules. 
5.3 
PACKAGING AND LABELING 
The packaging and labeling of study drugs will be in accordance with applicable local 
regulatory requirements. 
The ESN364 and placebo capsules will be packaged in high-density polyethylene 
(HDPE) bottles with polypropylene closure. Each bottle will contain 68 capsules of 
ESN364 or placebo. A patient kit containing 3 bottles of study drug will be foreseen for 
each subject. 
Labels will be printed in the local language of the countries where the study takes place 
in accordance with applicable local regulations and will contain the following: 
- 
EudraCT number 
- 
Protocol number 
- 
Medication number 
- 
Visit number 
- 
Date of manufacture and/or expiration date 


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- 
Batch number 
- 
Storage conditions 
- 
Contents 
- 
The statements ‘Keep out of reach and sight of children’, ‘For oral route only’, 
‘For clinical trial use only’ 
- 
Sponsor (or sponsor representative) name 
5.4 
STORAGE AND DRUG ACCOUNTABILITY 
The Investigator (or his/her designee) is responsible for the safe storage of all study drugs 
assigned to the clinical site, in a locked, secure storage facility with access limited to 
those individuals authorized to dispense the study drugs, and maintained within the 
appropriate ranges of temperature. All study drugs must be stored as specified at delivery 
and in the original packaging. Instructions for the subjects, regarding the storage and 
handling of the study drugs, will also be provided to the clinical sites. 
ESN364 must be stored at ambient conditions (15-30°C or 59-86°F), should not be 
exposed to freezing temperatures, and should be protected from light during storage at 
the clinical site. 
Daily temperature logging of the study drug storage room at the clinical site should be 
performed. In case a deviation in storage conditions should occur, the site must not 
further dispense the affected study drug and notify the Clinical Research Associate 
(CRA) or Pharmavize N.V. 
For the available stability data of ESN364 capsules and placebo, please refer to the 
Investigational Medicinal Product Dossier (IMPD). 
The Investigator is responsible for ensuring that all study drugs received at the clinical 
site are inventoried and accounted for throughout the study. As misallocations of study 
drugs may have a detrimental effect on subjects' safety and/or the study drugs’ efficacy 
and are a potential source of bias, utmost care should be taken to correctly dispense the 
study drugs as assigned by the randomization system. 
Study drugs will be dispensed to the subjects at Visits 2, 3, and 4 (one bottle containing 
68 capsules at every visit). Study drugs 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 
drugs supplied to whom and by who. Study drugs will be supplied only to subjects 
participating in the study. 
The site monitor will periodically check the supplies of study drugs held by the 
Investigator or pharmacist to ensure accountability and appropriate storage conditions of 
all study drugs used. 
Subjects must be instructed to return all unused study drugs at every visit. A record of 
any returned study drugs will be kept for each subject. Returned study drugs must not be 
relabeled or dispensed again, not even to the same subject. 
Unused study drugs and study drugs returned by the subject (if applicable) must be 
available for verification by the site monitor during on-site monitoring visits. Any 


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discrepancies between returned and expected returned study drugs should be explained 
and documented. 
After the last visit of the last subject in the study (Last Patient Last Visit [LPLV]), any 
unused study drug will be returned to the Sponsor. 
5.5 
RANDOMIZATION 
In total 80 subjects are planned to be randomized to one of 2 treatment arms in a 
1:1 ratio: ESN364 90 mg b.i.d. (40 subjects) or placebo (40 subjects). 
Randomization will be based on a computer-generated randomization schedule prepared 
by the Secure Data Office (SDO) Department of SGS Life Science Services 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 uploaded into the randomization module of the Electronic 
Data Capture (EDC) system. Based on this randomization list, the study drugs will be 
packaged and labeled. Medication numbers will be preprinted on the study drug labels. 
At the clinical site, through the randomization module of the EDC system, subjects will 
automatically be assigned a randomization number as soon as they qualify for the study. 
5.6 
BLINDING 
Blinding will be achieved by the double-dummy method with placebo identical in smell, 
taste, and appearance. 
The randomization list will be retained by SDO 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 determination before the start of the study. 
The randomization list will not be available to the Investigator or other employees of the 
clinical site, subjects, monitors, or personnel of SGS Life Science Services departments 
other than SDO before unblinding of the data, unless in case of emergency. The 
Sponsor’s clinical team will also be blinded during the study as they will not have direct 
access to the randomization list. The Clinical 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 Interactive Web 
Response System (IWRS). IWRS will allow rapid access to the treatment allocation 
codes when relevant for site or CRO personnel. However, codes should only be broken if 
it is considered as 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. Site personnel should inform the Medical Monitor (SGS Life 
Science Services) immediately. If the Investigator accidentally breaks the code, the 
Medical Monitor 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 followed as appropriate. If the 


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code is broken by the Sponsor or designee for safety reporting purposes the subject may 
remain in the study. 
At the time of the interim analysis, which will be conducted on the primary endpoint, 
DEXA parameters and safety data once the first 16 subjects will have completed 
12 weeks of treatment and the follow-up visit (or have discontinued earlier), the interim 
analysis subjects’ treatment arm will be unblinded. All other subjects will remain 
blinded. 
5.7 
DOSE AND ADMINISTRATION 
A rationale for the dose of study drug selected in this study is provided in Section 3.2. 
Subjects will be randomly, sequentially, and in a blinded fashion assigned to one of 
2 treatments arms (i.e., ESN364 90 mg b.i.d. [total daily dose of 180 mg] or placebo) in a 
1:1 ratio according to the randomization schedule. An overview of the treatment in each 
of the treatment arms is provided in Table 2. 
Table 2: 
Treatment Overview 
Treatment Arm 
Number of 
Subjects 
Treatment 
ESN364 90 mg b.i.d. 
40 
oral dose of 90 mg ESN364 b.i.d. for 12 weeks 
Placebo 
40 
oral dose of placebo b.i.d. for 12 weeks 
 
All visits need to be planned in the morning, fasted (for unbiased glucose, insulin, and 
C-peptide determination). Visit 2 should be planned to allow for first intake of study 
drugs at the clinical site, between 7:00 and 10:00 AM. For each subject, all visits during 
the treatment period subsequent to Visit 2 should be planned at the same time of the day, 
in the morning. 
Study drugs will be dispensed to the subjects at Visits 2, 3, and 4 (one bottle containing 
68 capsules at every visit). 
The first intake of study drug (Day 1; Visit 2) will be done at the clinical site (between 
7:00 and 10:00 AM), under the supervision of the clinical staff. Study drug intake will be 
done with a glass of tap water at room temperature. Also on other days of visits, the 
morning dose of study drug will be taken at the clinical site, under the supervision of the 
clinical staff, after collection of predose blood samples. Subjects will be instructed not to 
consume food/fluids for at least 10 hours before their visit to the clinical site (except 
water intake until one hour before). On all other days throughout the treatment period, 
subjects will be asked to take their morning dose of study drug at home, around the same 
time of the day (preferably between 7:00 and 10:00 AM). Morning intake at home may 
be done together with a light meal. 
All evening doses of study drug will be taken at home (preferably between 7:00 and 
10:00 PM). 
Subjects need to record all home study drug intakes in the Electronic Patient Reported 
Outcome (ePRO) diary. 
In case a subject accidentally misses a scheduled dose of the study drug and this is 
noticed within 12 hours of the time of scheduled intake, the missed dose should be taken 


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as soon as possible, with or without food. The subject may then continue her usual 
dosing schedule. In case a subject accidentally misses a scheduled dose of the study drug 
and this is noticed more than 12 hours after the time of scheduled intake, the missed dose 
should be skipped and the subject should simply resume her usual dosing schedule. 
Any deviation from the treatment regimen defined in the protocol must be documented in 
the electronic Case Report Form (eCRF). 
5.8 
TREATMENT COMPLIANCE 
Study drugs will be dispensed to the subjects at Visits 2, 3, and 4 (one bottle containing 
68 capsules at every visit). 
On days of visits during the treatment period, the morning dose of study drug will be 
taken at the clinical site, under the supervision of the clinical staff. All other study drug 
intakes (evening dose and morning dose on all days without visits) will be done at home. 
When taking their 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 
drugs. 
Compliance towards study drug intake will be assessed by counting returned dosage units 
in addition to ePRO entries upon study drug intake. Any discrepancies between returned 
dosage units 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, despite educational 
efforts, the Investigator should contact the Sponsor to discuss withdrawal of the subject 
from the study. 


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6. 
PRIOR AND CONCOMITANT THERAPY 
The use of concomitant therapies should be kept at a minimum throughout the study. All 
therapies (prescriptions and over-the-counter medications) other than the study drug 
administered from informed consent until the last study visit 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 a protocol-related (S)AE. 
6.1 
PERMITTED CONCOMITANT THERAPIES 
Any medications, other than those excluded by the protocol (see Section 6.2), 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. 
The use of analgesics is permitted on an as-needed basis. Prophylactic use is not allowed 
due to potential impact on the efficacy endpoints of this study.  
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 is allowed on the condition that hypertension is under control. 
Occasional use (defined as less than 3 times per week) of benzodiazepine or Z-drugs can 
be allowed on an as-needed basis. 
6.2 
PROHIBITED CONCOMITANT THERAPIES 
Prophylactic use of analgesics is not allowed due to potential impact on the efficacy 
endpoints of this study. 
Current use of hormonal medications such as hormone therapy or hormonal 
contraception or any treatment for hot flashes (prescription, over-the-counter, or herbal) 
is not allowed during the study. These treatments must be discontinued at least 6 weeks 
prior to screening. 
Other medications that should be washed-out prior to screening and are not allowed 
during the study are:  
- 
12 weeks wash-out: 
 tricyclic antidepressants 
 selective noradrenaline reuptake inhibitors 
 selective serotonin reuptake inhibitors (SSRIs) 
 lithium 
 oral neuroleptics 
 all sedatives 
 all hypnotics 
Note that occasional use (defined as less than 3 times per week) of 
benzodiazepine or Z-drugs can be allowed on an as-needed basis. 


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- 
4 weeks wash-out: 
 fluoxetine 
 monoamine oxidase inhibitors (MAOIs) 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered. 
Any medication that is not explicitly covered by the permitted and non-permitted 
medication sections can only be allowed after discussion with the Medical Monitor. 


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7. 
ASSESSMENTS 
7.1 
TIMING OF ASSESSMENTS 
All visits need to be planned in the morning, fasted (for unbiased glucose, insulin, and C-
peptide determination). Visit 2 should be planned to allow for first intake of study drugs 
at the clinical site between 7:00 and 10:00 AM. For each subject, all visits during the 
treatment period subsequent to Visit 2 should be planned at the same time of the day, in 
the morning, fasted. A deviation of ± 1 day is allowed on the visits during the treatment 
period (Visits 3-5). 
At Visits 2 and 5, DEXA will be performed. For practical reasons, the timing of DEXA 
may vary from the actual time of the visit, depending on the DEXA availability (DEXA 
appointment): 
- 
The Visit 2 DEXA can be performed prior to Visit 2 during the screening period, 
as well as at Visit 2 but must be performed before randomization; 
- 
The Visit 5 DEXA can be performed ±4 days from the actual time of Visit 5. It is 
however to be performed before the last dose of the study drug; in case the 
DEXA appointment related to Visit 5 is scheduled later in time than Visit 5, study 
drug intake must be continued until DEXA has been performed (study drug intake 
at home and recorded in the ePRO diary). 
An overview of the timing of study drug intake and assessments is given in the Time and 
Events Schedule. 
All assessments will be done predose, except for 3 hours postdose blood sampling for PK 
and PD assessments at Visit 5 and administration of questionnaires, which can be done at 
any time during the visit. 
7.1.1 
Screening Period (Visit 1) 
Subjects will be given a full explanation of the nature of the study and written informed 
consent (approved by the local ethics committee) will be obtained according to local 
requirements before any study-related assessment will be carried out. 
Screening (Visit 1) will be performed within 4 weeks prior to the first intake of study 
drug (with a minimum of 7 days to allow for baseline data collection of Hot Flash Score 
and Hot Flash Frequency). The visit will consist of screening assessments for eligibility 
purposes (physical examination, thorough medical history, demographic data, vital signs, 
ECG, blood/urine samples for PD measurements, clinical laboratory tests, serology, urine 
drug screen, and urine pregnancy test). In addition, subjects will be trained in the use of 
the ePRO diary to record their hot flashes severity and frequency, to administer HFRDIS, 
and to register their study drug intake. 
Collection of hot flashes severity and frequency will be started on an ad hoc basis, but at 
a minimum twice-daily (morning and evening), via ePRO diary. Data on hot flash 
severity and frequency collected during the screening period will serve as baseline for 
Hot Flash Score and Hot Flash Frequency. 
An overview of the assessments to be performed at the screening visit is provided in the 
Time and Events Schedule. 


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Adverse events and concomitant therapies will be collected from signing of informed 
consent onwards (screening) through the follow-up visit. 
All results from the screening procedure that are needed to evaluate eligibility, including 
the clinical laboratory results, must be available prior to randomization (Visit 2). Any 
abnormal assessment at the screening visit will be assessed according to its clinical 
relevance, and if found relevant, the subject will not be included in the study. 
Unscheduled visits may be planned 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 urine drug screen. Results of this retest must be available prior to 
randomization. The result of the retest will be considered for subject eligibility. Findings 
made during unscheduled visits should be reported in the source documents and in the 
designated sections of the eCRF. 
For screening failures, demographic data, the date of screening and signature of the ICF, 
and the reason(s) for screening failure will be recorded on the eCRF. 
7.1.2 
Treatment Period (Visits 2-5; Weeks 1-12) 
Visit 2 should be scheduled in the morning between 7:00 and 10:00 AM, fasted. In- and 
exclusion criteria will be reassessed. Eligible subjects will be randomized in a 1:1 ratio to 
one of the 2 treatment arms (ESN364 90 mg b.i.d. or placebo). Predose assessments for 
efficacy (questionnaires), PK (ESN364 plasma concentrations), PD (hormone 
concentrations), and safety (clinical laboratory testing, bone density marker 
concentrations, vital signs, ECG, and physical examination) parameters will be made to 
serve as baseline (except for Hot Flash Score and Hot Flash Frequency, for which 
baseline will be data collected during the screening period). 
Baseline body composition will be assessed by means of DEXA. For practical reasons, 
the timing of DEXA may vary from the actual time of the visit, depending on the DEXA 
availability (DEXA appointment). Baseline DEXA can be performed prior to Visit 2 
during the screening period, as well as at Visit 2 but must be performed before 
randomization. 
Treatment will be dispensed (first of 3 bottles each containing 68 capsules) and the 
subjects will start taking their study drug in a q.d. regimen for 12 weeks. The first intake 
of study drug (Day 1; Visit 2) will be done at the clinical site (between 7:00 and 
10:00 AM), under the supervision of the clinical staff. Also on other days of visits, the 
morning dose of study drug will be taken at the clinical site, under the supervision of the 
clinical staff. All other study drug intakes (evening dose and morning dose on all days 
without visits) will be done at home. When taking their study drug at home, subjects will 
be asked to record their home study drug intake in the ePRO diary. Also see Section 5.7 
for dosing instructions. 
After the start of treatment, the subjects will be asked to return to the clinical site every 
4 weeks (Weeks 4, 8, 12; Visits 3, 4, 5) to follow-up on compliance, efficacy, PK, PD, 
and safety parameters. A second and third bottle of study drug will be dispensed at 
Visits 3 and 4, respectively. 
Hot flashes severity and frequency will be assessed on an ad hoc basis, but at a minimum 
twice-daily (morning and evening), via ePRO at home from screening (Visit 1) to follow-


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up (Visit 6). Other efficacy questionnaires will be administered at the clinical site on 
paper (LSEQ, SDS, and GCS) or in the ePRO diary (HFRDIS) at every visit from Visit 2 
onwards. The questionnaires can be administered at any time during the visit. 
Blood sampling for PK assessments (ESN364 plasma concentrations) will be taken at 
every visit during the treatment period, i.e., at Visits 2, 3, and 4 predose and at Visit 5, 
predose and 3 hours postdose. 
Blood sampling for PD assessment (LH, FSH, E2, SHBG, leptin, insulin, C-peptide, and 
HBA1c) will also be performed at every visit (at Visits 2, 3, and 4 predose and at Visit 5, 
predose and 3 hours postdose; HBA1c at Visits 2 and 5 only). Additional back-up 
samples will be collected at every visit and stored for future, exploratory use. 
Blood samples for clinical laboratory tests will be taken at every visit and should be 
taken in a fasted state (overnight fast for at least 10 hours) for unbiased glucose, insulin, 
and C-peptide determination. Physical examination and vital sign assessments will also 
be made at every visit. An ECG will be recorded at every visit except Visit 4. Levels of 
the bone density markers BALP and CTX will be assessed at Visits 2 and 5 only. 
DEXA will be repeated at Visit 5, before the last dose of the study drug. For practical 
reasons, the timing of DEXA may vary from the actual time of the visit, depending on 
the DEXA availability (DEXA appointment). The Visit 5 DEXA can be performed 
±4 days from the actual time of Visit 5. It is however to be performed before the last dose 
of the study drug; in case the DEXA appointment related to Visit 5 is scheduled later in 
time than Visit 5, study drug intake must be continued until DEXA has been performed 
(study drug intake at home and recorded in the ePRO diary). 
Adverse events and concomitant therapies will be collected from signing of informed 
consent onwards (screening) through the follow-up visit. 
Compliance towards study drug intake and ePRO completion will be checked at every 
visit during the treatment period. Compliance towards study drug intake will be assessed 
by counting returned dosage units in addition to ePRO entries. Any discrepancies 
between returned dosage units and dosing in the ePRO diary will be discussed with the 
subject for whom a discrepancy was seen. 
An overview of the assessments to be performed during the treatment period is also 
provided in the Time and Events Schedule. 
7.1.3 
Follow-up Period (Visit 6) 
Two to 3 weeks after the last intake of the study drug, subjects will be asked to come to 
the clinical site for a follow-up visit. 
An overview of the assessments to be performed at the follow-up visit is provided in the 
Time and Events Schedule. 
7.1.4 
Unscheduled Visits 
Unscheduled visits can be planned for instance: 
- 
to obtain additional information to ensure safety to the subject. Additional blood 
and urine samples may be taken at the discretion of the Investigator. 


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- 
to collect an additional blood sample for PK assessment if a subject discontinues 
the study drug due to an AE; 
- 
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. 
Findings made during unscheduled visits should be reported in the source documents and 
in the designated sections of the eCRF. 
7.2 
PHARMACOKINETIC EVALUATIONS 
7.2.1 
Blood Sample Collection and Handling 
Venous blood samples will be collected for analysis of ESN364 in plasma according to 
the time points defined in the Time and Events Schedule. The exact date and time of 
blood sampling must be recorded in the source documents and on the eCRF. 
Blood samples of approximately 2 mL will be collected by venipuncture or indwelling 
cannula in the forearm into vacuum tubes containing lithium heparin (Venoject green top 
or equivalent). Immediately after blood collection, the plasma will be separated in a 
refrigerated centrifuge (4°C) for 10 minutes at ca 1500 g and transferred with a sterile 
plastic pipette into 2 polypropylene tubes with at least 400 µL of plasma per tube. In case 
immediate centrifugation is not possible, the samples should be chilled in an ice bath for 
a maximum of 30 minutes after blood collection until centrifugation. 
After appropriate labeling, the plasma samples will be stored below -20°C at the clinical 
site. Thereafter, the frozen plasma samples will be transported/shipped on dry ice to the 
central laboratory (BARC, Gent, Belgium), where they will be collected and kept frozen 
below -20°C until shipment to the bioanalytical laboratory (SGS, Wavre, Belgium). 
Further procedures for sample collection, shipment, processing, and storage are described 
in the laboratory manual. 
7.2.2 
Bioanalysis 
Samples for determination of plasma ESN364 concentrations will be analyzed by a 
qualified vendor (SGS, Wavre, Belgium) under the responsibility of the Sponsor, using a 
validated analytical method (liquid chromatography with tandem mass spectrometric 
[LC-MS/MS]). 
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. No human deoxyribonucleic acid (DNA) or ribonucleic acid 
(RNA) analysis will be performed.  
7.2.3 
Pharmacokinetic Endpoints 
Assessment of plasma ESN364 concentrations will be exploratory. 


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7.3 
PHARMACODYNAMIC EVALUATIONS 
7.3.1 
Blood Sample Collection and Handling 
Blood samples for PD assessments will be drawn at the time points indicated in the Time 
and Events Schedule. The exact date and time of blood sampling must be recorded in the 
source documents and on the eCRF. 
Blood samples for the assessment of LH, FSH, E2, SHBG, insulin, and leptin, C-peptide, 
and HBA1c (HBA1c at Visits 2 and 5 only) in plasma will be collected and handled as 
specified in the central laboratory manual. 
Additional back-up samples will be collected at every visit and stored for future, 
exploratory use. 
After appropriate labeling, the plasma samples will be stored below -70°C at the clinical 
site. Thereafter, the frozen plasma samples will be transported/shipped on dry ice to the 
central laboratory (BARC, Gent, Belgium), where they will be collected and kept frozen 
below -70°C until analysis. 
Further procedures for sample collection, shipment, processing, and storage are described 
in the laboratory manual. 
7.3.2 
Bioanalysis 
Plasma samples for PD assessments will be analyzed by BARC (Gent, Belgium), using a 
validated analytical method. 
After completion of the analytical study, the study samples will be kept deep frozen until 
three months after issuing of the final Clinical Study Report, or six months after issuing 
of the draft Clinical Study Report, whichever comes first. Then, upon agreement with the 
Sponsor Representative, the study samples will either be transferred to the sponsor 
facilities, or kept deep frozen at BARC (Gent, Belgium) for a longer period of time (as to 
be agreed with the Sponsor) at -70°C ± 6°C, or destroyed at BARC (Gent, Belgium). 
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. No human DNA or RNA analysis will be performed.  
7.3.3 
Pharmacodynamic Endpoints 
Changes in plasma concentrations of LH, FSH, E2, SHBG, leptin, insulin, C-peptide, and 
HBA1c from baseline over time will be evaluated. 
7.4 
EFFICACY EVALUATIONS 
7.4.1 
Efficacy Variables 
Efficacy evaluation in this study will be based on hot flash severity and frequency as well 
as HFRDIS, assessed via ePRO diary, and the following paper-based questionnaires: 
LSEQ, SDS, and GCS, as described in the following sections. All questionnaires used in 
the study will be validated and available in the local language of the clinical sites. 


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7.4.1.1 
HOT FLASH FREQUENCY AND SEVERITY 
Hot flashes severity and frequency will be assessed on an ad hoc basis, but at a minimum 
twice-daily (morning and evening), via ePRO diary from screening (Visit 1) through the 
follow-up visit (Visit 6). Data on hot flash severity and frequency collected during the 
screening period will serve as baseline for Hot Flash Score and Hot Flash Frequency. 
Night sweats should be recorded no later than morning upon awakening to start a new 
day. 
The severity of hot flashes is defined clinically as follows (according to the FDA and 
EMA Guidance for Industry [19,20] and the National Institutes of Health (NIH) Hot 
Flash Workshop [21]): 
- 
Mild:  
Sensation of heat without sweating/dampness. If at night, patient doesn’t wake up 
but later notices damp sheets or clothing. 
- 
Moderate:  
Sensation of heat with sweating/dampness, but able to continue activity. If at 
night, patient 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, 
patient wakes up hot and is sweating and needs to take action (e.g., removing 
layers of clothes, open the window, or get out of bed). 
The Hot Flash Score (based on severity and frequency) is calculated as follows [22]: 
(number of mild hot flashes/day × 1) + (number of moderate hot flashes/day × 2) + 
(number of severe hot flashes/day × 3) 
Higher scores indicate worse symptoms. There is no maximum score since the score is 
patient-dependent for both number and severity. 
7.4.1.2 
HOT FLASH RELATED DAILY INTERFERENCE SCALE (HFRDIS) 
Perceived hot flash interference on daily activities will be evaluated every 4 weeks from 
the start of study drug intake (Visit 2) through the follow-up visit (Visit 6) using the 
HFRDIS. The HFRDIS will be completed at the clinical site in the ePRO diary, at any 
time during the visit. 
The HFRDIS is a 10-item scale which measures a woman’s perceptions of the degree to 
which hot flashes interfere with 9 daily life activities (work, social activities, leisure, sleep, 
mood, concentration, relations with others, sexuality, enjoying life); the 10th item measures 
interference with overall quality of life [23]. This scale was modeled after items on the 
Brief Pain Inventory [24] and Brief Fatigue Inventory [25] both of which assess the 
extent to which pain or fatigue interfere with daily life. Subjects will be asked to rate the 
extent to which hot flashes have interfered with each item during the previous 4-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) [26]. 
Scoring of each item of the HFRDIS is illustrated in Attachment 1. 


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7.4.1.3 
LEEDS SLEEP EVALUATION QUESTIONNAIRE (LSEQ) 
Subjects’ sleep quality will be evaluated every 4 weeks from the start of study drug 
intake (Visit 2) through the follow-up visit (Visit 6) using the LSEQ. The questionnaire 
will be paper-based, administered at the clinical site at any time during the visit. 
The LSEQ is a 10-item self-rated questionnaire which assesses subjects' aspects of sleep 
and early morning behavior. The questions are grouped into 4 chronological areas: the 
ease of getting to sleep, the perceived quality of sleep, the ease of awaking from sleep, 
and the integrity of early morning behavior following wakefulness [27]. The LSEQ is a 
visual analogue scale which requires respondents to place marks on a group of 10-cm 
lines representing the changes they have experienced in a variety of symptoms since the 
beginning of treatment. 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. 
A copy of the LSEQ is provided in Attachment 2. 
7.4.1.4 
GREENE CLIMACTERIC SCALE (GCS) 
Changes in climacteric symptoms will be evaluated every 4 weeks from the start of study 
drug intake (Visit 2) through the follow-up visit (Visit 6) using the GCS. The 
questionnaire will be paper-based, administered at the clinical site at any time during the 
visit. 
The GCS is a 21-item scale which provides a brief but comprehensive and valid measure 
of climacteric symptomatology [28]. Each item is rated by the subject according to its 
severity using a four-point rating scale from 0 (none) to 3 (severe). The first 20 items of 
the scale combine into three main independent symptom measures: 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), by summing up the 
individual item scores. Item 21 is a probe for sexual dysfunction. The total score can 
range from 0 to 63. Higher scores indicate worse symptoms. 
Scoring of each item of the GCS is illustrated in Attachment 3. 
7.4.1.5 
SHEEHAN DISABILITY SCALE (SDS) 
Subjects’ functional impairment of life will be evaluated every 4 weeks from the start of 
study drug intake (Visit 2) through the follow-up visit (Visit 6) using the SDS. The 
questionnaire will be paper-based, administered at the clinical site at any time during the 
visit. 
The SDS is a composite of 3 self-rated items designed to measure the extent to which 
3 major sectors in a patient’s life are impaired by panic, anxiety, phobic, or depressive 
symptoms [29]. The patient rates the extent to which his/her 1- work/school, 2- social 
life, and 3- family life are impaired by his/her symptoms on a 10-point visual analog 
scale. The 3 items may be summed into a single dimensional measure of global 
functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). It is 
recommended that clinicians pay attention to patients who score 5 or greater on any of 
the 3 scales, because such high scores are associated with significant functional 
impairment [30]. 


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A copy of the SDS is provided in Attachment 4. 
7.4.1.6 
BODY COMPOSITION 
Lean body mass, fat mass, muscle mass, bone mass/density will be assessed by DEXA at 
Visits 2 and 5. 
7.4.2 
Efficacy Endpoints 
7.4.2.1 
PRIMARY ENDPOINT 
- 
Change from baseline to Week 12 in weekly Hot Flash Score 
7.4.2.2 
SECONDARY ENDPOINTS 
- 
Changes from baseline over time in weekly Hot Flash Score and Hot Flash 
Frequency; 
- 
Change from baseline over time in HFRDIS score; 
- 
Changes from baseline over time in LSEQ, GCS, and SDS score. 
7.4.2.3 
EXPLORATORY ENDPOINT 
The change from baseline to Week 12 in body composition (lean mass, fat mass, bone 
mass/density) will be explored. 
7.5 
SAFETY EVALUATIONS 
Safety evaluation in this study will be based on AEs, clinical laboratory tests, plasma 
bone density marker concentrations, ECG, vital signs, and physical examination, as 
described in the following sections. 
7.5.1 
Safety Variables 
7.5.1.1 
ADVERSE EVENTS 
Adverse events will be monitored continuously from informed consent until the last 
study-related activity. At regular intervals during the study, subjects will be asked 
non-leading questions to determine the occurrence of any AEs. All AEs reported 
spontaneously during the course of the study will be recorded as well. 
For detailed definitions and reporting procedures of AEs, see Section 10. 
7.5.1.2 
CLINICAL LABORATORY TESTS 
Blood and urine samples will be collected at the time points indicated in the Time and 
Events Schedule. 
Blood samples will be collected and handled as specified in the central laboratory 
manual. Biochemistry and hematology testing will be performed on these samples, as 
well as coagulation and serology (HbsAg, anti-HCV and HIV antibodies) on the sample 
from screening. All blood samples for clinical laboratory tests should be taken in a fasted 
state (overnight fast for at least 10 hours; intake of water will be allowed until one hour 
before study drug intake) for unbiased glucose, insulin, and C-peptide determination. 


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Standard laboratory tests will be performed by the central laboratory BARC (Gent, 
Belgium). Further procedures for sample collection, shipment, processing, and storage 
are described in the laboratory manual provided by the central laboratory. 
The following clinical laboratory tests will be performed on the samples: 
- 
Biochemistry: sodium, potassium, uric acid, creatinine, calcium, AST, ALT, urea, 
alkaline phosphatase (ALP), gamma glutamylaminotransferase (GGT), albumin, 
glucose (fasted for at least 10 hours) total bilirubin (and direct bilirubin in case 
>1.3 x ULN), creatine kinase (CK), and total protein; 
- 
Coagulation: international normalized ratio (INR), activated partial 
thromboplastin time (aPTT) (at screening only); 
- 
Hematology: white blood cell (WBC) count with differential (neutrophils, 
lymphocytes, eosinophils, monocytes, basophils), hemoglobin, hematocrit, red 
blood cell (RBC) count, platelet count. 
Urinalysis will be performed on site using a commercial urine dipstick (dipstick will be 
provided by BARC to the clinical sites). In case the dipstick result is positive, a urine 
sample has to be shipped to BARC for urine sediment analysis. 
A urine pregnancy test will be performed at screening, as well as a urine drug screen for 
amphetamines, tricyclic antidepressants, cannabinoids, cocaine, tetrahydrocannabinol, or 
opiates. 
The Investigator must review the laboratory report, document this review, and record any 
change occurring during the study he/she considers to be clinically relevant in the source 
documents and in the AE 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. No human DNA or RNA analysis will be performed. 
7.5.1.3 
BONE DENSITY MARKERS 
Plasma concentrations of the bone density markers BALP and CTX will be assessed at 
Visits 2 and 6. 
Blood samples for the assessment of BALP 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 clinical 
site. Thereafter, the frozen plasma samples will be transported/shipped on dry ice to the 
central laboratory (BARC, Gent, Belgium), where they will be collected and kept frozen 
below -70°C until analysis. 
Further procedures for sample collection, shipment, processing, and storage are described 
in the laboratory manual. 


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7.5.1.4 
VITAL SIGNS 
Vital sign parameters will be assessed after 5 minutes in supine position at the time 
points indicated in the Time and Events Schedule. 
The vital sign parameters that will be assessed are body temperature (oral), supine 
systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse rate. 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 AE section of the 
eCRF. 
7.5.1.5 
ELECTROCARDIOGRAM 
Twelve-lead ECGs will be recorded after 5 minutes in supine position at the time points 
indicated in the Time and Events Schedule. 
The interpretations of the ECGs will be performed by the Investigator or his/her designee 
at the clinical site. Any change from baseline ECG occurring during the study that is 
considered to be clinically relevant by the Investigator should be recorded in the source 
documents and the AE section of the eCRF. 
A local ECG reader will be used. 
7.5.1.6 
PHYSICAL EXAMINATION 
Physical examination will be performed at the time points indicated in the Time and 
Events Schedule. 
Physical examination includes height, weight, and waist circumference (height at 
screening only). 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 guideline (see Attachment 5). 
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 AE section of the eCRF. 
7.5.2 
Safety Endpoints 
Safety endpoints are: 
- 
AE frequency and severity from first dose of study drug through the last visit; 
- 
Changes from baseline over time in hematology and biochemistry concentrations; 
- 
Changes from baseline over time in vital sign and ECG assessments; 
- 
Changes from baseline over time in BALP and CTX levels. 


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7.6 
APPROPRIATENESS OF MEASUREMENTS 
The assessments that will be made in this study are standard, and are generally 
recognized as reliable, accurate, and relevant. 


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8. 
STUDY TERMINATION/COMPLETION 
8.1 
STUDY COMPLETION 
A subject will be considered to have completed the study if she has completed the 
12-week treatment period. 
8.2 
REMOVAL OF SUBJECTS FROM THE STUDY OR TREATMENT 
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 eCRF. 
A subjects may be withdrawn from the study or treatment in the event of: 
- 
An AE, including clinically significant new or worsening existing conditions as 
judged by the Investigator (documented on the AE Form of the eCRF); 
- 
Subject request (subject moved, schedule conflicts, etc); 
- 
A major protocol violation which would confound interpretation of the results; 
- 
Other: this reason should only be used if the reason for withdrawal is not better 
accounted for by one of the other categories. 
A subjects must be withdrawn the study or treatment in the event of: 
- 
Withdrawal of informed consent; 
- 
Lost to follow-up; 
- 
For safety reasons, it being 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 6.2); 
- 
Breaking of the randomization code during administration of the study drug by 
the Investigator or by a member of his/her staff. If the code is broken by the 
Sponsor, for safety reporting purposes, the subject may remain in the study. 
- 
QT interval corrected according to Fridericia’s formula (QTcF) increases to 
>500 ms, as confirmed by 2 additional ECG recordings obtained within 
10 minutes of the initial recording; 
- 
Confirmed decrease in thrombocytes below 75.000, which does not normalize 
after 7 days; 
- 
ALT or AST >8x ULN; 
- 
ALT or AST >5x ULN for more than 2 weeks; 
- 
ALT or AST >3x ULN and total bilirubin >2x ULN; 
- 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
See Attachment 6 for the procedure to follow in case of suspected drug-induced 
liver injury (DILI). 


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In the event that a subject is withdrawn from the study, the monitor and Sponsor should 
be informed: in case of withdrawal due to an SAE (for details on AE reporting see 
Section 10), the Sponsor should be notified within 24 hours; in case of withdrawal for 
other reasons, the Sponsor should be notified within 2 days from the event. 
If there is a medical reason for withdrawal, the subject will remain under the supervision 
of the Investigator until satisfactory health has returned. 
Subjects who are withdrawn from the study prior to completion of the scheduled study 
procedures for any reason (AE, withdrawal of consent, etc.) should be invited to 
complete the assessments as much as possible: as long as the subject consents, all 
relevant assessments of the day on which the subject withdrew from the study should be 
completed, at least those related to safety, and the subject should come for a safety 
follow-up visit 2-3 weeks after the last intake of study drug. In case of an AE, the 
appropriate follow-up will be done. 
Subjects who are withdrawn from the study will not be replaced. 
Study drugs assigned to a withdrawn subject must not be assigned to another subject. 
8.3 
STOPPING RULES OR DISCONTINUATION CRITERIA 
The study may be stopped for any of the following reasons: 
- 
If 2 or more subjects on the study drug are withdrawn from the study due to QTcF 
interval increases >500 ms, as confirmed by 2 additional ECG recordings 
obtained within 10 minutes of the initial recording; 
- 
If 2 or more subjects on the study drug are withdrawn from the study due to a 
confirmed increase in ALT or AST >5x ULN for more than 2 weeks; 
- 
If 2 or more subjects on the study drug are withdrawn from the study due to a 
confirmed decrease in thrombocytes below 75.000, which does not normalize 
after 7 days. 


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9. 
STATISTICAL METHODS 
9.1 
STATISTICAL ANALYSIS 
All statistical analyses will be performed by SGS Life Science Services using SAS® 
(SAS Institute Inc., Cary, NC, USA; version 9.2 or higher) software for statistical 
computations. 
All statistical methods shall be detailed in a Statistical Analysis Plan (SAP) that will be 
finalized before database lock. 
All data collected in this study will be documented using summary tables, figures, and 
subject data listings. 
Descriptive statistics will include number of subjects, (arithmetic) mean, standard 
deviation (SD), median, minimum and maximum, and a 95% confidence interval (CI). 
Frequency tabulations will show counts and percentages. 
All statistical tests will be interpreted at the 5% significance level (2-tailed). 
An interim analysis on the primary endpoint, DEXA parameters and safety data will be 
performed once the first 16 subjects will have completed 12 weeks of treatment and the 
follow-up visit (or have discontinued earlier). The final analysis will be performed once 
all subjects will have completed 12 weeks of treatment and the follow-up visit (or have 
discontinued earlier). 
The following populations will be considered for analysis: 
- 
Safety population: defined as all subjects who are randomized into the study and 
received at least one dose of the study drug. All safety tables and listings will be 
based on the safety population. 
- 
Intent-to-treat (ITT) population: defined as all randomized subjects who received 
at least one dose of the study drug and who have post-baseline efficacy data. 
Unless specified otherwise, the ITT population will be used for efficacy analysis. 
- 
Per-protocol (PP) population: defined as a subset of the ITT population, 
excluding those subjects who have major protocol deviations and violations. All 
deviations and violations will be reviewed prior to database lock and classified as 
either minor or major. 
9.1.1 
Initial Characteristics of the Subject Sample 
Demographic data (age, race, body weight, height and Body Mass Index [BMI]) will be 
summarized. Demographic data will be presented for the safety population. In case the 
ITT and/or PP population(s) deviate by more than 5% from the safety population, 
demographic data will also be presented for the ITT and/or PP population(s). The 
evaluation consists of descriptive statistics and frequency tabulations, as appropriate. 
Subject disposition data such as study termination reasons, visit adherence, and 
compliance to ePRO completion will be tabulated. 
Demographic data and disposition data will be presented overall and per treatment arm. 
Findings for medical and surgical history and concomitant diseases will be tabulated per 
treatment arm. 


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The use of study drugs will be summarized by treatment arm. 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO)_DRUG dictionary and will be summarized. 
Protocol deviations will be tabulated. 
9.1.2 
Pharmacokinetic Data 
Individual plasma ESN364 concentration values and actual sampling times relative to 
study drug intake will be listed. Descriptive statistics will be summarized by assessment 
time point. 
9.1.3 
Pharmacodynamic Data 
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 time point and by treatment arm. 
9.1.4 
Efficacy Data 
For a list of efficacy endpoints, see Sections 7.4.2. 
Primary Endpoint 
Changes from baseline in Hot Flash Score will be analyzed using an Analysis of 
Covariance (ANCOVA) model with treatment as fixed effect and baseline as covariate. If 
a significant difference between the treatment arms is present, differences between each 
active treatment arm and placebo will be tested, correcting for multiplicity. 
Rules for defining valid diary days and imputing missing scores will be elaborated in the 
SAP. 
Secondary Endpoints 
Hot Flash Score and Hot Flash Frequency at all time points will be evaluated by means 
of descriptive statistics (actual values and changes from baseline) by treatment arm. 
The percentage of subjects with at least 70% reduction from baseline in Hot Flash Score 
will be compared across the treatment arms, using chi-square or Fisher exact test, as 
appropriate. 
The percentage of subjects with at least 50% reduction in the number of moderate and 
severe hot flashes will be compared across the treatment arms, using chi-square or Fisher 
exact test, as appropriate. 
Questionnaires will be evaluated by means of descriptive statistics (actual values and 
changes from baseline) by treatment arm. HFRDIS, GCS, SDS and LSEQ total scores 
and subscores (if applicable) are to be reported. 
Change in lean body mass, fat mass, and bone mass/density will be explored by means of 
descriptive statistics on the actual values, at each assessment time point and by treatment 
arm. Changes from baseline to Week 12 will be summarized by treatment arm. 


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9.1.5 
Safety Data 
Safety parameters will be tabulated and analyzed descriptively. 
Adverse Events 
The original terms used in the source documents and the designated sections of the 
eCRFs by the Investigator to identify AEs will be fully described and coded according to 
the Medical Dictionary for Regulatory Activities (MedDRA). 
The reported AEs will be allocated to phases based on their start date. All AEs will be 
listed. All AEs with onset during the treatment phase (i.e., TEAEs) will be summarized 
by treatment arm by System Organ Class (SOC) and Preferred Term (PT). 
Special attention will be paid to those subjects who died, discontinued the study drug due 
to an AE, or experienced a severe or serious AE. Summaries, listings, and narratives 
(also see Section 12.11) may be provided, as appropriate. 
Clinical Laboratory Tests 
Each continuous biochemistry and hematology laboratory test will be evaluated by 
means of descriptive statistics on the actual values, at each assessment time point and by 
treatment arm. Changes from baseline will be summarized by assessment time point and 
by treatment arm. 
Laboratory tests will be categorized according to the normal ranges of the clinical 
laboratory (below, within, or above normal). A shift table versus baseline will be created. 
The worst post-baseline value will be summarized as well. 
A listing of subjects with any clinical laboratory test result outside the normal range of 
the clinical laboratory will be provided. 
Vital Signs 
Body temperature, pulse rate, SBP, and DBP will be evaluated by means of descriptive 
statistics (actual values and changes from baseline) and shift tables according to the 
normal ranges (as defined in Attachment 7) at each assessment time point and by 
treatment arm. 
Electrocardiogram 
Electrocardiogram variables will be evaluated by means of descriptive statistics (actual 
values and changes from baseline) and shift tables according to the normal ranges (as 
defined in Attachment 7) at each assessment time point and by treatment arm. 
The ECG variables that will be analyzed are HR, PR interval, QRS interval, QT interval. 
Values for QTc will be derived. QTcF will be the primary correction parameter [31]. 
Categorical assessment will be performed on absolute QTcF interval prolongation (>450, 
>480, >500 ms) and on changes from baseline (increase >30 and >60 ms). 
Physical Examination 
Abnormal findings in physical examination will be listed. 


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9.1.6 
Interim Analysis 
In order to get a preliminary view on efficacy and safety results, an interim analysis is 
planned once the first 16 subjects will have completed 12 weeks of treatment and the 
follow-up visit (or have discontinued earlier). The interim analysis will be limited to the 
primary efficacy endpoint, DEXA parameters and safety data. At the time of the interim 
analysis, the interim analysis subjects’ treatment arm will be unblinded. All other 
subjects will remain blinded. 
9.2 
DETERMINATION OF SAMPLE SIZE 
As this study is only the first proof-of-concept Phase IIa study in this therapeutic area, no 
formal power calculations have been done. All the statistical analyses involving testing 
for significance will be exploratory in nature and will serve as a basis for designing and 
powering a subsequent (dose-ranging) Phase IIb study. 
One (and actually the main reason) for the absence of such power calculation is the fact 
that this study is unprecedented. There are no references available that can give an 
indication of observed effect size of NK3 antagonism on Hot Flash Score and Hot Flash 
Frequency. 
In a review article by Sloan et al. [22], the authors propose the following general 
guideline regarding set-up of studies using hot flash diary data (severity and frequency): 
- 
For Phase III placebo-controlled studies, 50 patients per treatment arm seem 
appropriate to provide sufficient power specifications to detect a clinically 
meaningful change in hot flash activity. 
- 
For Phase II trials, 25 patients per study seem to provide reasonable estimates of 
eventual hot flash efficacy to screen potential agents for more definitive testing. 
Since the review article typically considers paroxetine and hormones, we would, in our 
specific case, expect the effect size to be larger and would therefore propose to be 
sufficiently powered to conduct a successful Phase II proof-of-concept study, while 
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10. 
ADVERSE EVENT REPORTING 
10.1 
DEFINITIONS 
Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily 
have a causal relationship with the study drug. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non-investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal result of diagnostic procedures, including 
clinical laboratory test abnormalities. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
- 
results in death; 
- 
is life-threatening, i.e., the subject was at risk of death at the time of the event 
(e.g., ventricular fibrillation and anaphylaxis). The term does not refer to an event 
which hypothetically might have caused death if it were more severe. 
- 
requires inpatient hospitalization or prolongation of existing inpatient 
hospitalization: 
Hospitalization refers to an overnight admission into hospital for the purpose of 
investigating and/or treating the AE. Hospitalization for an elective procedure, or 
routinely scheduled treatment for a pre-existing condition that has not worsened, 
is not an SAE. 
- 
results in persistent or significant disability/incapacity, i.e., causing substantial 
disruption of the subject’s ability to conduct normal life; 
- 
is a congenital anomaly/birth defect; 
- 
is medically significant, i.e., may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject’s health or may require 
intervention to prevent one of the above outcomes. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that does not result in hospitalization or 
development of drug dependency or drug abuse. 
Unlisted (Unexpected) Adverse Event 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information (see Investigator’s Brochure [14]). 


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10.2 
INTENSITY OF ADVERSE EVENTS 
The severity of each AE must be rated as follows: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily life (preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.). 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated, disabling; limiting self-care activities of daily 
life (bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden). 
10.3 
CAUSALITY ASSESSMENT 
The causality of each AE must be assessed as follows: 
Not related/unlikely related: 
The AE is considered not related to the use of the study drug. 
Possibly related: 
The AE may be due to the use of the study drug. An alternative explanation e.g., 
concomitant drug(s), concomitant disease(s) is inconclusive. The relationship of the AE 
with study drug administration in time is reasonable, therefore, the causal relationship 
cannot be excluded. 
Very likely related/related: 
The AE is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The 
relationship of the event with study drug administration in time is very suggestive (e.g., it 
is confirmed by dechallenge and rechallenge). 
10.4 
ACTION TAKEN REGARDING THE STUDY DRUG 
The action taken towards the study drug of each AE must be described as follows: 
- 
Permanently discontinued; 
- 
Stopped temporarily; 
- 
No action taken; 
- 
Unknown; 
- 
Not applicable. 


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10.5 
OUTCOME 
The outcome of each AE must be rated as follows: 
- 
Recovered/resolved; 
- 
Recovered with sequelae/resolved with sequelae; 
- 
Recovering/resolving; 
- 
Not recovered/not resolved; 
- 
Fatal; 
- 
Unknown. 
10.6 
RECORDING OF ADVERSE EVENTS 
All (S)AEs occurring during the clinical investigation must be documented in the source 
documents and on the AE forms of the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as “upper respiratory infection”). Investigators must record their 
opinion concerning the relationship of the (S)AE to the study drug in the source 
documents and on the eCRF. All measures required for (S)AE management must be 
recorded in the source documents and reported according to Sponsor’s instructions. 
All AEs occurring at any time during the study (including the follow-up period) will be 
followed by the Investigator until satisfactory resolution (e.g., value back to baseline 
value) or stabilization or until final database lock. If necessary, in order to obtain 
additional information to ensure safety to the subject, additional blood and urine samples 
may be taken at the discretion of the Investigator. Certain long-term AEs related to 
therapy cannot be followed until resolution within the setting of this study. In these cases 
follow-up will be the responsibility of the treating physician. 
10.7 
REPORTING OF SERIOUS ADVERSE EVENTS TO SGS LIFE SCIENCE 
SERVICES MEDICAL AFFAIRS 
All SAEs, independent of the circumstances or suspected cause, must be reported on a 
Serious Adverse Event Form by the Investigator to the SGS Life Science Services 
Medical Affairs Department within 24 hours of their knowledge of the event, preferably 
by fax (+32 15 29 93 94) or by e-mail (be.life.saefax-ma@sgs.com). 
The SAE form should include a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae, in order to allow a complete medical assessment of the case and 
independent determination of the possible causality. 
Follow-up and outcomes should be reported for all subjects who experience an SAE. 
It is critical that the information provided on the Serious Adverse Event Form matches 
the information recorded in the source documents and on the eCRF, for the same event. 
Copies of additional laboratory tests, consultation reports, post-mortem reports, hospital 
case reports, autopsy reports, and other documents should be sent when requested and 
applicable. Follow-up reports relative to the subject’s subsequent course must be 


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submitted to SGS Life Science Services Medical Affairs Department until the event has 
subsided, or, in case of permanent impairment, until the condition stabilizes. 
10.8 
REPORTING OF SERIOUS ADVERSE EVENTS TO COMPETENT 
AUTHORITIES/ETHICS COMMITTEES 
The SGS Life Science Services Medical Affairs Department assumes responsibility for 
appropriate reporting of AEs to the regulatory authorities. The SGS Life Science 
Services Medical Affairs Department will also report to the Investigator all SAEs that are 
unlisted (unexpected) and associated with the use of the study drug. The Investigator (or 
the SGS Life Science Services Medical Affairs Department where required) must report 
these events to the appropriate Independent Ethics Committee/Institutional Review 
Board (IEC/IRB) that approved the protocol, unless otherwise required and documented 
by the IEC/IRB. 
Adverse events reporting, including suspected unexpected serious adverse reactions 
(SUSARs), will be carried out in accordance with applicable local regulations. 
After completion of the clinical study (determined as LPLV), any unexpected safety 
issue that changes the risks benefit analysis and is likely to have an impact on the 
subjects who have participated in the study, will be reported by the Sponsor or designee 
to the competent authority(ies) concerned as soon as possible. 


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11. 
ETHICAL ASPECTS 
11.1 
STUDY-SPECIFIC DESIGN CONSIDERATIONS 
Potential subjects will be fully informed of the nature of the study and of the risks and 
requirements of the study before any study-related assessment will be carried out. During 
the study, subjects will be given any new information that may affect their decision to 
continue participation. They will be informed that their participation in the study is 
voluntary and that they may withdraw from the study at any time with no reason given 
and without penalty or loss of benefits to which they would otherwise be entitled. Only 
subjects who are fully able to understand the risks, benefits, and potential AEs of the 
study, and who provide their consent voluntarily will be enrolled. 
11.2 
REGULATORY ETHICS COMPLIANCE 
11.2.1 
Investigator Responsibilities 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications 
specified by the applicable regulatory requirement(s), and should provide evidence of 
such qualifications through up-to-date curriculum vitae or other relevant documentation 
requested by the Sponsor, the IRB/IEC, or the regulatory authority(ies). 
The Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current International Conference on Harmonization (ICH) 
guidelines on GCP, and applicable regulatory and country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of study subjects are protected, consistent with the principles 
originating from the Declaration of Helsinki (1964 and revisions), and that the clinical 
study data are credible. 
11.2.2 
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) 
An IRB/IEC should safeguard the rights, safety, and well-being of all study subjects. 
Special attention should be paid to studies that may include vulnerable subjects. 
Before the start of the study, the Investigator (or Sponsor where required) will provide 
the IEC/IRB with current and complete copies of the following documents: 
- 
final protocol and, if applicable, amendments; 
- 
Sponsor-approved ICF (and any updates or any other written materials to be 
provided to the subjects); 
- 
Sponsor-approved subject recruiting materials; 
- 
Investigator’s Brochure (or equivalent information) and addenda; 
- 
available safety information; 


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- 
information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable; 
- 
Investigator’s current curriculum vitae or other documentation evidencing 
qualifications (unless not required, as documented by the IEC/IRB); 
- 
information regarding funding, name of the Sponsor, institutional affiliations, 
other potential conflicts of interest, and incentives for subjects; 
- 
any other documents that the IEC/IRB may require to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full written approval of 
the final protocol and amendments (if any), the ICF(s) and updates (if any), applicable 
recruiting materials, and any other written information to be provided to the subjects, and 
the Sponsor has received a copy of this approval. This approval letter must be dated and 
must clearly identify the IEC/IRB and the documents being approved. 
During the study, the Investigator (or Sponsor where required) will send the following 
documents and updates to the IEC/IRB for its review and approval, where appropriate:  
- 
protocol amendments; 
- 
revision(s) of the ICF and any other written materials to be provided to the 
subjects; 
- 
new or revised subject recruiting materials approved by the Sponsor, if 
applicable; 
- 
revisions of compensation for study-related injuries or payment to subjects for 
participation in the study; 
- 
Investigator’s Brochure addenda or new edition(s); 
- 
summaries of the status of the study at intervals stipulated in guidelines of the 
IEC/IRB (at least annually); 
- 
reports of AEs that are serious, unlisted, and associated with the IMP; 
- 
new information that may adversely affect the safety of the subjects or the 
conduct of the study; 
- 
deviations from or changes to the protocol to eliminate immediate hazard to the 
subjects; 
- 
report of death of any subjects under the Investigator’s care; 
- 
notification if a new Investigator is responsible for the study at the clinical site; 
- 
Development Safety Update Report, Short-Term Study Specific Safety Summary 
and Line Listings, where applicable; 
- 
any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s), except when necessary to eliminate immediate hazard 
to the study subjects. If a deviation from or a change to the protocol was implemented to 
eliminate an immediate hazard to study subjects, then the implemented deviation or 
change, the reasons for it, and, if appropriate, the protocol amendment should be 
submitted to the IEC/IRB as soon as possible. 


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The Investigator (or Sponsor where required) will notify the IEC/IRB about the study 
completion within 90 days after the end of the study (defined as LPLV). 
11.2.3 
Informed Consent 
Each subject must give written consent according to local requirements after the nature 
of the study has been fully explained. The consent form must be signed before 
performance of any study-related activity. The consent form that is used must be 
approved by both the Sponsor and the reviewing IEC/IRB. The informed consent should 
be in accordance with the principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and Sponsor 
policy. 
Before enrollment in the study, the Investigator or an authorized member of the clinical 
staff must explain to potential subjects the aims, methods, reasonably anticipated 
benefits, and potential hazards of the study, and any discomfort participation in the study 
may entail. Subjects will be informed that their participation is voluntary and that they 
may refuse to participate or withdraw consent to participate at any time, without penalty 
or loss of benefits to which the subject was entitled. Finally, they will be told that the 
Investigator will maintain a subject identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and 
authorized Sponsor staff without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF the subject is 
authorizing such access, and agrees to allow her study physician to recontact her for the 
purpose of obtaining consent for additional safety evaluations, if needed. 
The language about the study used in the oral and written information, including the ICF, 
should be non-technical and practical and should be understandable to the subject or the 
subject’s legal representative. The subject will be given sufficient time to read the ICF 
and the opportunity to ask questions. After this explanation and before entry into the 
study, consent should be appropriately recorded by means of the subject's personally 
dated signature. After having obtained consent, a copy of the ICF must be given to the 
subject. 
If a subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) 
and should personally date and sign the ICF after the oral consent of the subject is 
obtained, if permitted by local law. 
11.2.4 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in the study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
IMP used in the study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations. Appropriate technical and organizational measures to protect the personal 
data against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration must be put in place. Sponsor personnel whose 


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responsibilities require access to personal data need to agree to keep the identity of the 
study subjects confidential. 
The informed consent obtained from the subjects includes explicit consent for the 
processing of personal data and for the Investigator to allow direct access to subjects’ 
original medical records for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries. 


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12. 
ADMINISTRATIVE REQUIREMENTS 
12.1 
PROTOCOL AMENDMENTS 
Neither the Investigator nor the Sponsor will modify this protocol without a formal 
amendment. All protocol amendments must be issued by the Sponsor and signed and 
dated by the Investigator. Protocol amendments must not be implemented without prior 
IEC/IRB approval nor when the relevant competent authority has raised any grounds for 
non-acceptance, except when necessary to eliminate immediate hazard to the subjects, in 
which case an amendment must be promptly submitted to the IEC/IRB and relevant 
competent authority. Documentation of amendment approval by the Investigator and 
IEC/IRB must be provided to the Sponsor or his designee. When the change(s) involves 
only logistic or administrative aspects of the study, the IRB (and IEC where required) 
only needs to be notified. 
12.2 
SUBJECT IDENTIFICATION, ENROLLMENT, AND SCREENING LOGS 
The Investigator agrees to complete a subject identification and enrollment log to permit 
easy identification of each subject during and after the study. This document will be 
reviewed by the Sponsor site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be 
filed by the Investigator in the study file. To ensure subject confidentiality, no copies will 
be made. All reports and communications related to the study will identify subjects by 
initials and/or assigned number only. 
The Investigator must also complete a subject screening log which reports on all subjects 
who were seen to determine eligibility for inclusion in the study. 
12.3 
SOURCE DOCUMENTATION 
At a minimum, source documentation must be available for the following to confirm data 
collected on the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent, dates of visits, results of safety and efficacy 
parameters as required by the protocol, record of all AEs, follow-up of AEs, concomitant 
medication, study drug receipt/dispensing/return records, study drug administration 
information, laboratory and ECG printouts, date of study completion, and reason for 
early discontinuation of study drug or withdrawal from the study, if applicable. 
Direct access to source documentation must be allowed for the purpose of verifying that 
the data recorded on the eCRF are consistent with the original source data. 
It is recommended that the author of an entry in the source documents be identifiable. 
At a minimum, the type and level of detail of source data available for a study subject 
should be consistent with that commonly recorded at the clinical site as a basis for 
standard medical care. Specific details required as source data for the study will be 
reviewed with the Investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). The nature and location of all source 
documents will be identified in the Source Document Identification Form. Data that will 
be recorded directly on the eCRF are specified in the Source Document Identification 
Form. 


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12.4 
CASE REPORT FORM COMPLETION 
Electronic Data Capture will be used for this study. The study data will be transcribed by 
study personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the Sponsor. The electronic file will be considered to be the eCRF. 
All eCRF entries, corrections, and alterations must be made by the Investigator or other 
authorized study site personnel. 
Worksheets may be used for the capture of some data to facilitate completion of the 
eCRF. Any such worksheet will become part of the subject’s source documentation. Such 
worksheet should not resemble an eCRF. All data related to the study must be recorded 
on the eCRFs prepared by the Sponsor. Data must be entered on the eCRFs in English. 
Designated study site personnel must complete the eCRF as soon as possible after a 
subject visit, and the forms should be available for review at the next scheduled 
monitoring visit. 
The Investigator must verify that all data entries on the eCRFs are accurate and correct. 
12.5 
MONITORING 
The monitoring of the study will be done under the responsibility of the Sponsor by SGS 
Life Science Services. 
The monitor will perform on-site monitoring visits as frequently as necessary. The 
monitor will record the dates of the visits in a study site visit log that will be kept at the 
clinical site. The first post-initiation visit will be made as soon as possible after 
enrollment has begun. At these visits, the monitor will compare the data entered onto the 
eCRFs with the hospital or clinic records (source documents). The nature and location of 
all source documents will be identified to ensure that all sources of original data required 
to complete the eCRF are known to the Sponsor and study site staff and are accessible for 
verification by the Sponsor site contact. If electronic records are maintained at the 
clinical site, the method of verification must be discussed with the clinical staff. 
Direct access to source documentation must be allowed at all times for the purpose of 
verifying that the data recorded on the eCRF are consistent with the original source data. 
Findings from this review of eCRFs and source documents will be discussed with the 
clinical staff. During on-site monitoring visits (notified and agreed upfront with the 
clinical staff), the relevant clinical staff will be available, the source documentation will 
be accessible, and a suitable environment for review of study-related documents will be 
provided. The monitor will meet with the Investigator on a regular basis during the study 
to provide feedback on the study conduct. 
12.6 
DATA MANAGEMENT 
Data management of the study will be performed under the responsibility of the Sponsor 
by SGS Life Science Services. 
After the monitor has reviewed the data entered onto the eCRFs for completeness and 
accuracy and the data are released by the Investigator, data will be uploaded into the 
clinical database to perform cleaning activities. Computerized data cleaning checks will 
be used in addition to manual review, including listings review, to check for 
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If necessary, queries will be generated in the EDC tool. The Investigator or an authorized 
member of the clinical staff must adjust the eCRF (if applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be 
done in 3 different ways: 1- site personnel can make corrections in the EDC tool at their 
own initiative or as a response to an auto query (generated by the EDC tool), 2- the site 
manager can generate a query (field data correction form [DCF]) for resolution by the 
clinical staff, and 3- the clinical data manager can generate a query for resolution by the 
clinical staff. 
The clinical database will be locked as soon as it is considered clean. Only authorized 
and well-documented updates to the study data are possible after database lock. The 
locked database is used in the final statistical analysis for study reporting. Measures will 
be undertaken to protect subject data handed over by the Investigator to the data 
management department and during inspections against disclosure to unauthorized third 
parties. Subject confidentiality will be maintained at all times. 
An interim lock is planned once the first 16 subjects will have completed 12 weeks of 
treatment and the follow-up visit (or have discontinued earlier) to allow for an interim 
analysis on the primary endpoint, DEXA parameters and safety data. 
12.7 
DATA QUALITY ASSURANCE 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the 
Investigator and associated personnel prior to the study, and by periodic monitoring visits 
by the Sponsor or designate. 
Written instructions will be provided for the collection, preparation, and shipment of 
plasma samples. Instruction booklets for completion of eCRFs will be provided and 
reviewed with the study personnel prior to the start of the study. 
The Sponsor or his designee will review the eCRFs system for accuracy and 
completeness during (on-site) monitoring visits and after transmission to the Sponsor; 
any discrepancies will be resolved with the Investigator or designee, as appropriate. After 
upload of the data into the clinical study database, their accuracy is verified using 
appropriate validation programs. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, 
the Sponsor will be entitled to audit the facilities used in the clinical and laboratory parts 
of the study, as well as to access all the data files pertaining to the study. Similar 
procedures may also be conducted by agents of any regulatory body, either as part of a 
national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The Investigator should immediately notify the Sponsor if they 
have been contacted by a regulatory agency concerning an upcoming inspection. 
12.8 
ON-SITE AUDITS 
Representatives of the Sponsor’s clinical quality assurance department may visit the 
clinical site at any time during or after completion of the study to conduct an audit of the 
study in compliance with regulatory guidelines and company policy. These audits will 
require access to all study records, including source documents, for inspection and 
comparison with the eCRFs. Subject privacy must, however, be respected. The 


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Investigator and clinical staff are to be present and available for consultation during 
routinely scheduled site audit visits conducted by the Sponsor or his designees. 
Similar procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in 
support of a regulatory submission. The Investigator should immediately notify the 
Sponsor if they have been contacted by a regulatory agency concerning an upcoming 
inspection. 
12.9 
STUDY TERMINATION 
The Sponsor has the right to terminate the study at any time. In case of an early 
termination of the study for safety reasons, or temporary halt by the Sponsor, the 
IEC/IRB should be notified within 15 calendar days and should be provided with a 
detailed written explanation for the termination/halt. 
An end-of-study declaration will be submitted to the regulatory authorities and the 
IEC/IRB after the complete study has ended. This notification will be submitted within 
90 days after the end of the study. 
12.10 RECORD RETENTION 
In compliance with the ICH/GCP guidelines, the Investigator/Institution will maintain all 
eCRFs and all source documents that support the data collected from each subject, as 
well as all study documents as specified in ICH/GCP Section 8, Essential Documents for 
the Conduct of a Clinical Trial, and all study documents as specified by the applicable 
regulatory requirement(s). The Investigator/Institution will take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents will be 
retained for a longer period if required according to the applicable regulatory 
requirements or per agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the Investigator/Institution as to when these documents no longer need to be 
retained. 
If the responsible Investigator retires, relocates, or for any other reasons withdraws from 
his responsibility of keeping the study records, custody must be transferred to a person 
who will accept the responsibility. The Sponsor must be notified in writing of the name 
and address of the new custodian. Under no circumstance shall the Investigator relocate 
or dispose of any study documents without having obtained written approval from the 
Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review 
any documentation related to the study, the Investigator must permit access to such 
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12.11 USE OF INFORMATION AND PUBLICATION 
All information, including but not limited to, information regarding ESN364 or the 
Sponsor’s operations (e.g., patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the Sponsor to 
the Investigator and not previously published, and any data generated as a result of this 
study are considered confidential and remain the sole property of the Sponsor. The 
Investigator agrees to maintain this information in confidence, to use this information 
only to accomplish this study, and not to use it for other purposes without the Sponsor’s 
prior written consent. 
The Investigator understands that the information generated in this clinical study will be 
used by the Sponsor in connection with the continued development of the study drug, and 
thus may be disclosed as required to other clinical Investigators or regulatory agencies. 
To permit information derived from the clinical studies to be used, the Investigator is 
obliged to provide the Sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated under the 
responsibility of the Sponsor and will contain eCRF data from all clinical sites that 
participated in the study. Recruitment performance or specific expertise related to the 
nature and the key assessment parameters of the study will be used to determine a 
coordinating Investigator. 
Clinical narratives may be written for the following events: 
- 
All deaths (irrespective of drug relationship); 
- 
All other SAEs during treatment with the study drug; 
- 
All discontinuations of the study drug due to AEs (irrespective of drug 
relationship); 
- 
At the discretion of the team and after statistical analysis of the data, certain 
discontinuations not related to AEs or treatment failure, i.e., related to lost to 
follow-up or withdrawal of consent (irrespective of treatment arm); 
- 
Any events of special interest explicitly requested by the regulatory agencies. 
The coordinating Investigator will sign off the final version of the Clinical Study Report. 
A summary of this final version will be provided to the Investigators, the applicable 
regulatory authorities, and the IECs/IRB, if required by the applicable regulatory 
requirements, within one year after the end of the study (LPLV). 
The Sponsor shall have the right to publish study data and information without approval 
from the Investigator. If an Investigator wishes to publish information from the study, a 
copy of the manuscript must be provided to the Sponsor for review at least 60 days 
before submission for publication or presentation. Expedited reviews will be arranged for 
abstracts, poster presentations, or other materials. If requested by the Sponsor in writing, 
the Investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific 
integrity or regulatory compliance, the Sponsor will review these issues with the 
Investigator. The Sponsor will not mandate modifications to scientific content and does 
not have the right to suppress information. For multicenter study designs and substudy 
approaches, results may need to be published in a given sequence (e.g., substudies should 
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Similarly, Investigators will recognize the integrity of a multicenter study by not 
publishing data derived from an individual clinical site until the combined results from 
the completed study have been published in full, within 12 months after conclusion, 
abandonment, or termination of the study at all clinical sites, or the Sponsor confirms 
there will be no multicenter study publication. Authorship of publications resulting from 
this study will be based on the guidelines on authorship, such as those described in the 
Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which state 
that the named authors must have made a significant contribution to the design of the 
study or analysis and interpretation of the data, provided critical review of the paper, and 
given final approval of the final version. 
12.12 REGISTRATION OF CLINICAL STUDIES AND DISCLOSURE OF 
RESULTS 
The Sponsor will register the existence of a clinical study and disclose the results as 
required by law. 
12.13 INVESTIGATOR INDEMNITY 
The Sponsor holds and will maintain an adequate insurance policy covering damages 
arising out of Euroscreen-sponsored clinical research studies. 
The Sponsor will indemnify the Investigator and hold him/her harmless for claims related 
to damages arising from the investigation, provided that the study drug was administered 
under the Sponsor’s or deputy’s supervision and in strict accordance with accepted 
medical practice and the study protocol. 
The Investigator must notify the Sponsor immediately upon notice of any claims or 
lawsuits. 
12.14 CONFIDENTIALITY 
All study documents are provided by the Sponsor to the Investigator and appointed 
clinical staff in confidence. None of this material may be disclosed to any party not 
directly involved in the study without the Sponsor’s written permission. 
The Investigator must assure that subjects’ anonymity will be maintained. The 
Investigator will keep a separate list with at least the initials, the subjects’ study numbers, 
names, addresses, and telephone numbers. The Investigator will maintain this for the 
longest period of time allowed by his/her own institution and, in any case, until further 
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13. 
REFERENCES 
1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus 
progestin in healthy postmenopausal women: principal results from the Women's 
Health Initiative randomized controlled trial. JAMA. 2002; 288:321-333. 
2. Kronenberg F. Hot flashes: phenomenology, quality of life, and search for treatment 
options. Exp Gerontol. 1994; 29:319-336. 
3. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the 
treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003; 
289(21):2827-2834. 
4. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci.1990; 
592:52-86. 
5. US Census Bureau. Resident population estimates of the United States by age and 
sex: April 1, 1990 to July 1, 1999, with short-term projection to November 1, 2000. 
Washington, DC; January 2, 2001. Available at: 
http://www.census.gov/population/estimates/nation/intfile2-1.txt 
6. De Villiers TJ, Gass MLS, Haines CJ, et al. Global consensus statement on 
menopausal hormone therapy. Maturitas. 2013; 74:391-392. 
7. Loprinzi CL, Sloan JA, Perez EA et al. Phase III evaluation of fluoxetine for 
treatment of hot flashes. J Clin Oncol. 2002; 20:1578-1583. 
8. Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in management of hot flashes 
in survivors of breast cancer: a randomised controlled trial. Lancet. 2000; 356:2059-
2063. 
9. Stearns V, Isaacs C, Rowland J et al. A pilot trial assessing the efficacy of paroxetine 
hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann 
Oncol. 2000; 11:17-22. 
10. Topaloglu AK, Reinmann F, Guclu M, 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. 2009; 41(3):354-358. 
11. Francou B, Bouligand J, Voican A, et al. Normosmic Congenital Hypogonadotropic 
Hypogonadism Due to TAC3/TACR3 Mutations: Characterization of 
Neuroendocrine Phenotypes and Novel Mutations. PLoS One 2011; 6(10):e25614. 
12. Millar RP and Newton CL. The year in G protein-coupled receptor research. Mol 
Endocrinol. 2010; 24(1):261-74. 
13. Simpson TR et al. Discovery of AZD2624: a potent and selective NK3R antagonist 
to the NK3 hypothesis in schizophrenia. 2010. Oral Presentation, 239th ACS 
Meeting, (San Francisco, CA), paper ID: 17404. 
14. Investigator’s Brochure ESN364, version 3.0, in preparation. 
15. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, et al. Role for 
kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and 
the estrogen modulation of body temperature. Proc Natl Acad Sci USA. 2012; 
109(48):19846-51. 


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16. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, et al. Modulation of 
body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin 
B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. 
Front Neuroendocrinol. 2013; 34(3):211-27. 
17. Jayasena CN, Comninos AN, Stefanopoulou E, et al. Neurokinin B administration 
induces hot flushes in women. Scientific Reports. 2015; 5:8466. 
18. Krajewski SJ, Anderson MJ, Iles-Shih L, et al. Morphologic evidence that 
neurokinin B modulates gonadotropin-releasing hormone secretion via neurokinin 3 
receptors in the rat median eminence. J Comp Neurol. 2005; 489:372–386. 
19. U.S 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; 
JAN/2003. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm071643.pdf 
20. European Medicines Agency. Guideline of clinical investigation of medicinal 
products for hormone replacement therapy of oestrogen deficiency symptoms in 
menopausal women. Available at: 
http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2009
/09/WC500003348.pdf 
21. National Institute of Health. Assessing and improving measures of hot flashes: 
Summary of an NIH workshop; 1/20/2004; Available at: 
http://nccam.nih.gov/health/hotflashes/ 
22. Sloan JA, Loprinzi CL, Novotny PJ et al. Methodologic lessons learned from hot 
flash studies. J Clin Oncol. 2001; 19(23):4280-4290. 
23. Carpenter JS. 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. 2001; 22:979-989. 
24. Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin brief pain 
questionnaire to assess pain in cancer and other diseases. Pain. 1983; 17:197-210. 
25. Hann DM, Jacobsen PB, Azzarello LM, et al. Measurement of fatigue in cancer 
patients: Development and validation of the Fatigue Symptom Inventory. Qual Life 
Res. 1998; 7:301-310. 
26. Carpenter JS, Rand KL. Modeling the hot flash experience in breast cancer 
survivors. Journal of Clinical Oncology. Menopause. 2008; 15(3):469-75. 
27. Parrot AC and Hindmarch I. Factor analysis of a sleep evaluation questionnaire. 
Psychological Medicine. 1978; 8(2):325–329. 
28. Greene JG. A factor analytic study of climacteric symptoms. Journal of 
Psychosomatic Research. 1976; 20:425-430. 
29. Sheehan DV. The Sheehan Disability Scales. In: The Anxiety Disease and How to 
Overcome It. 1983. New York. Charles Scribner and Sons, p. 151. 


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30. Rush JA et al. Handbook of Psychiatric Measures. American Psychiatric 
Association. 2000; 113-115. 
31. Fridericia LS. The duration of systole in the electrocardiogram of normal subjects 
and of patients with heart disease. Acta Medica Scandinavica. 1920; 53:469–486..


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Hot Flash Related Daily Interference Scale (HFRDIS): 
Perceived hot flash interference will be evaluated at each of the assessment points using 
the HFRDIS. This 10-item scale measures a woman’s perceptions of the degree to which 
hot flashes interfere with nine daily life activities; the tenth item measures interference 
with overall quality of life1. This scale was modeled after items on the Brief Pain 
Inventory22 and Brief Fatigue Inventory3, which assess the degree pain or fatigue 
interfere with similar activities. Participants rate the degree to which hot flashes have 
interfered with each item during the previous week 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)4.4 As 
of March 2015, the original publication of this scale had been cited over 130 times by 
national and international colleagues, referenced in books on menopause, and translated 
into 12 different languages (Afrikaans, Danish, Farsi, Flemish, French, Italian, Mandarin, 
Norwegian, Portuguese, Spanish, Swedish, and Taiwanese). The HFRDIS is included as 
a psychometrically sound outcome measure for use in treatment trials within the National 
Cancer Institute’s Physician Data Query Cancer Information Summaries for Supportive 
and Palliative Care5,6. 
                                                 
1 Carpenter JS. 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. 2001; 22:979-89. 
2 Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin brief pain questionnaire to assess pain 
in cancer and other diseases. Pain. 1983; 17:197-210. 
3 Hann DM, Jacobsen PB, Azzarello LM, et al. Measurement of fatigue in cancer patients: Development 
and validation of the Fatigue Symptom Inventory. Qual Life Res. 1998; 7:301-310. 
4 Carpenter JS, Rand KL: Modeling the hot flash experience in breast cancer survivors. Journal of Clinical 
Oncology, Submitted. 
5 Carpenter JS, Storniolo AM, Johns S, et al. Randomized, double-blind, placebo-controlled crossover trials 
of venlafaxine for hot flashes after breast cancer. Oncologist. 2007; 12:124-135. 
6 Elkins G, Marcus J, Stearns V, et al. Pilot evaluation of hypnosis for the treatment of hot flashes in breast 
cancer survivors. Psychooncology. 2007; 16:487-492. 
CCI






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ATTACHMENT 4: SHEEHAN DISABILITY SCALE 
CCI


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ATTACHMENT 5: WAIST CIRCUMFERENCE MEASUREMENT 
The NIH provided a protocol for the Measurement of waist circumference. 
 
Adapted from the National Heart, Lung, and Blood Institute asa 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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ATTACHMENT 6: EVENTS OF CLINICAL INTEREST GUIDANCE FOR 
POTENTIAL DRUG-INDUCED LIVER INJURY 
 


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ATTACHMENT 7: NORMAL RANGES FOR VITAL SIGNS AND ECG 
 
Normal Ranges for Vital Sign Parameters 
Systolic blood pressure 
(mmHg) 
Diastolic blood pressure 
(mmHg) 
Pulse rate 
(bpm) 
Oral 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 ECG Parameters 
PR 
(ms) 
QRS 
(ms) 
QTcF 
(ms) 
Heart rate 
(bpm) 
120 ≤ PR ≤ 220 
QRS ≤ 120 
QTc ≤ 450 
40 ≤ HR ≤ 100