Conditions: Post-menopausal Vasomotor Symptoms
Keywords: Hot flashes Post-menopausal
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 76
Healthy volunteers: no

Brief summary:
This is a multi-center, double-blind, randomized, placebo-controlled multiple ascending dose study in post-menopausal women with vasomotor symptoms. Single ascending doses of NT-814 will be investigated in 4 cohorts. Each cohort will comprise of 20 subjects. Subjects will be dosed for 14 days.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: BAY3427080 intervention 2: Placebo (for BAY3427080)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
 
 
Document Type: 
Study Protocol 
Official Title: 
Evaluation of the Pharmacokinetics and Safety of NT-814 in Post-
Menopausal Women With Vasomotor Symptoms 
NCT Number: 
NCT02865538 
Document Date: 
13 DEC 2016 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: RELENT-1 
NT-814 
 
 
NeRRe Therapeutics Ltd 
 
Protocol Version: 4.0 
 FINAL 
Page 1 of 62 
13 December 2016 
 
CLINICAL STUDY PROTOCOL 
 
EVALUATION OF THE PHARMACOKINETICS AND SAFETY OF NT-814 IN 
POST-MENOPAUSAL WOMEN WITH VASOMOTOR SYMPTOMS  
IND No:  
129492 
Protocol No.: 
RELENT-1 
Version No: 
Final 4.0 
 
Date of Protocol: 
13 December 2016 
 
Sponsor:        
NeRRe Therapeutics Ltd,   
 
 
 
SBC, Incubator Building,  
 
 
 
Gunnels Wood Rd.,  
 
 
 
Stevenage, 
 
 
 
SG1 2FX 
 
 
 
UK 
Confidentiality Statement: 
 
This protocol contains information which is the property of NeRRe Therapeutics Ltd and therefore is 
provided to you in confidence for review by you, your staff, an applicable institutional review board 
and regulatory authorities. It is understood that this information will not be disclosed to others 
without the written approval from NeRRe Therapeutics Ltd. 
 
This study will be conducted in compliance with Good Clinical Practice (GCP), the Declaration 
of Helsinki (with amendments), and in accordance with local legal and regulatory 
requirements. 
 
 
 
 
 


Investigational product:  
CONFIDENTIAL  
 
 
Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 2 of 62 
13 December 2016 
 
1. 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
 
EVALUATION OF THE PHARMACOKINETICS AND 
SAFETY OF NT-814 IN POST-MENOPAUSAL WOMEN 
WITH VASOMOTOR SYMPTOMS  
PROTOCOL No. 
RELENT-1 
SPONSOR 
NeRRe Therapeutics Ltd   
INVESTIGATIONAL PRODUCT  
NT-814 
PHASE OF DEVELOPMENT 
Phase 1b 
INDICATION AND RATIONALE 
Not applicable. 
STUDY DESIGN 
A 
multi-center, 
double-blind, 
randomized, 
placebo-
controlled multiple ascending dose study in post-
menopausal women with vasomotor symptoms.  
 
Multiple ascending doses of NT-814 (50 mg, 100 mg, 150 
mg then two additional cohorts up to 400mg) will be 
investigated in up to 5 cohorts. Each cohort will comprise of 
20 subjects randomized 3:1 (15 NT-814: 5 Placebo). No 
subject will participate in more than one cohort. 
 
For each cohort, subjects will enter a 4-week screening 
period to determine eligibility. Eligible subjects will be 
admitted to a Phase 1 clinical unit on Day -1 and remain in 
residence to receive study treatment, complete 7 days’ study 
assessments and pharmacokinetic (PK) sampling. Subjects 
will be discharged on Day 8 to continue to take their 
allocated study treatment at home. A study visit will be 
performed on Day 14 at the Phase 1 clinical unit when the 
subjects will return for a 24 hour stay. During this visit 
subjects will take their final dose, complete study 
assessments and PK sampling, before discharge on Day 15. 
Single PK samples will be taken at outpatient visits on the 
mornings of Days 16 and 17. A safety follow-up call will 
take place by phone on Day 21. 
 
STUDY OBJECTIVES 
Primary 
 
x To evaluate the PK and safety profile of multiple 
ascending dose levels of NT-814 compared to 
placebo, by once daily administration of each dose 
for 14 days  


Investigational product:  
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Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 3 of 62 
13 December 2016 
 
 
Exploratory 
x To assess effects of multiple, single daily doses of 
NT-814 compared to placebo on hot flash frequency 
and severity using objective and subjective measures  
x To assess the relationship between PK exposure and 
hot flash measures, if data permit 
x To explore the relationship between plasma 
concentrations and placebo-corrected change from 
baseline QTcF and QTcB values using concentration 
effect modeling, depending on the results observed  
 
STUDY ENDPOINTS 
 
Pharmacokinetic parameters 
 
 
x AUC0-t, AUC0-τ, AUC0-∞, Cmax, Tmax, CL/F, and 
t½   
Safety 
 
x Physical Examinations 
x Analysis for arrhythmias by continuous Holter 
monitoring from Day -1 to Day 8 and Day 14 
(24 hours)  
x Abnormalities on 12-lead ECG  
x Change from Baseline in clinical laboratory 
assessments including lipids and coagulation profile 
x Change from Baseline in hormones including 
estradiol, testosterone, follicle stimulating hormone 
(FSH), 
adrenocorticotropic 
hormone 
(ACTH), 
cortisol, 
thyroid-stimulating 
hormone 
(TSH), 
triiodothyronine (T3) and thyroxine (T4) 
x Change from Baseline in vital signs including 
oxygen saturation, oral temperature and postural 
blood pressure (BP) changes  
x Adverse Events (AEs) of dehydration (supported by 
changes in serum urea and creatinine, urinary 
sediment and weight and vital signs) 
x Nature and severity of Adverse Events (AE) 
x Withdrawals due to an AE 
x Change from baseline in ECG variables (heart rate, 
RR, PR, QRS, QT, QTcF and QTcB) 
 
 


Investigational product:  
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Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 4 of 62 
13 December 2016 
 
Exploratory 
x Change in frequency of hot flashes from Pre-dose 
(Day -1) as assessed by skin conductance  
x Change from Baseline in frequency of moderate to 
severe hot flashes, hot flash average severity and hot 
flash severity score as measured by twice daily paper 
diary throughout study 
x Change from Baseline in frequency of hot flashes as 
measured by continuous day time diary from Day -1 
pre-dose to Day 7 and to Day 14 
x Change from Baseline in night time awakenings 
(NTA) secondary to hot flashes as measured by 
paper diary 
x Change in Luteinizing Hormone (LH) AUC0-8 hours 
on Day-1 versus Day 1 and Day 7 
x To explore the relationship between plasma 
concentrations and placebo-corrected, change from 
baseline QTcF and QTcB values using concentration 
effect modeling, depending on the results observed.  
 
PLANNED SAMPLE SIZE AND 
STATISTICAL CONSIDERATIONS 
The planned sample size is 20 subjects per cohort, with 15 
active and 5 placebo. This is deemed enough to provide 
sufficient separation of exposures between dose groups and 
to allow for an assessment of safety versus dose 
group/exposure. Assuming a standard deviation on the log 
scale of 0.413 for plasma AUC0-24 (based on Day 7 mean 
AUC0-24 data for 200 mg from study MNK111857), 15 
active subjects per cohort provides close to 80% power at a 
type I error rate of 0.1 to detect a difference from one in the 
ratio of geometric means between the two highest possible 
dose levels (and greater than 90% power for the middle two 
dose levels) given the previously seen slightly greater than 
dose proportionality increase in systematic exposure. The 
placebo subjects are included primarily to provide a 
reference group for comparison of safety in the target 
population. 
 
SUBJECT POPULATION 
 
Inclusion Criteria 
 
1. Post-menopausal female subjects 40-65 years of age 
Menopause will be defined as: 
a) 12 months of spontaneous amenorrhea; 


Investigational product:  
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Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 5 of 62 
13 December 2016 
 
b) OR at least 6 weeks’ post-surgical bilateral 
oophorectomy with or without hysterectomy. 
2. At Baseline women: 
a) With an average of ≥ 7 and ≤ 20 moderate to 
severe hot flashes/day during the last week’s 
diary during screening 
b) That have a change of < 50% in average 24-hour 
hot flash frequency between the first and second 
week of the screening period diary (Week -2 and 
Week -1 respectively). 
3. Able to understand and comply with the requirements of 
the study and sign Informed Consent forms 
 
Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
1. Any active comorbid disease deemed by the investigator 
to be clinically significant which could impact safety 
during study conduct including renal or hepatic 
impairment:  
 
  
a) Serum creatinine laboratory value greater than 1.2 
times upper limit of normal (ULN) reference range 
(after adjustment for age) at Screening or Day -1 or 
subjects with renal function glomerular filtration rate 
(GFR) 
<60mL/min/1.73m2 
based 
on 
the 
modification of diet in renal disease (MDRD) 
equation 
b) Total bilirubin greater than upper limit of normal 
reference range (with the exception of Gilbert's 
Syndrome) and/ or alanine transaminase (ALT) >2 
times ULN reference ranges and/ or aspartate amino 
transferase (AST) >2 times ULN reference ranges at 
Screening or Day -1. 
2. Subjects with a prior medical history of or an increased 
risk of seizures, or who have a history of recent (within 
6 months of Screening) head trauma that resulted in a 
loss of consciousness or concussion 
3. Any prior or ongoing history of arrhythmias  
4. Any ongoing cardiovascular disease including heart 
failure, 
coronary 
artery 
disease 
or 
uncontrolled 
hypertension or uncontrolled diabetes 
5. Any clinically relevant ECG abnormalities at Screening 


Investigational product: 
CONFIDENTIAL
Protocol No.: RELENT-1
NT-814
NeRRe Therapeutics Ltd
Protocol Version: 4.0
FINAL
Page 6 of 62
13 December 2016
6. Unwillingness to refrain from eating grapefruit, 
grapefruit juice, Seville oranges, and pomelos from 7 
days prior to admission on Day -1 until after their final 
follow-up visit
7. Use of any prohibited medications (see Section 9.13.2)
8. Any history of invasive malignancy in the past 2 years 
9. Any active ongoing condition that could cause difficulty 
in interpreting vasomotor symptoms such as:  infection 
that 
could 
cause 
pyrexia, 
pheochromocytoma, 
hyperthyroidism, carcinoid syndrome, alcohol abuse
10. Body mass index (BMI) > 35kg/m2
11. Inability to complete questionnaires for any reason 
including 
psychiatric 
disorders 
and 
inability 
or 
unwillingness to use electronic devices
12. History of hypothalamic dysfunction
13. Any clinically significant or unstable medical or 
psychiatric condition that would interfere with the 
subject's ability to participate in the study including 
anxiety syndromes 
14. Any clinically significant abnormal laboratory test 
result(s) measured at Screening or on Day -1
15. Participation in any clinical research study evaluating 
another investigational drug or therapy within 30 days or 
within 5 half-lives (whichever is longer), of the 
investigational drug prior to consenting to study entry.
If the subject is in an observational clinical study no 
washout is required
16. Subjects who, in the opinion of the Investigator, should 
not participate in the study for any other reason
17. Any known allergy or hypersensitivity to any of the 
ingredients in the study medication or to skin adhesives
IMP FORMULATION / DOSE
NT-814 50 mg capsules or matching placebo
Up to 5 different doses will be investigated, starting with 
50 mg
ROUTE OF ADMINISTRATION
Oral
DURATION/FREQUENCY OF 
TREATMENT
Once daily dosing for 14 days. IMP will be administered in 
the morning


Investigational product:  
CONFIDENTIAL  
 
 
Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 7 of 62 
13 December 2016 
 
PHARMACOKINETIC 
ASSESSMENTS 
Blood samples for PK analysis will be collected at the 
following time points on Day 1, and Day 7:  
Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 
24.0 hours 
On Day 14 blood samples will be taken for PK analysis at 
the following time points: 
Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 
24.0, 48.0, 72.0 hours 
The pre-dose sample will be collected within 30 minutes 
prior to dose administration. On Days 1 and 7 the 24 hour 
PK sample must be taken prior to the dose of study 
medication the following morning. 
 
SAFETY ASSESSMENTS 
Safety and tolerability will be assessed by the following: 
x Physical Examinations 
x Continuous Holter monitoring from Day -1 to Day 8 
and Day 14 (24 hours)   
x Abnormalities on 12-lead ECG from Day -1 to 
Day 8 and, Day 14 and Day15 
x Change in ECG variables (heart rate, RR, PR, QRS, 
QT, QTcF and QTcB) 
x Change from Baseline in Clinical laboratory 
assessments including lipids and coagulation profile 
x Change from Baseline in hormones including 
estradiol, testosterone, follicle stimulating hormone 
(FSH), 
adrenocorticotropic 
hormone 
(ACTH), 
cortisol, 
thyroid-stimulating 
hormone 
(TSH), 
triiodothyronine (T3) and thyroxine (T4) 
x Change from Baseline in vital signs including 
oxygen saturation, oral temperature and postural BP 
changes  
x Adverse events (AE) of dehydration (serum urea and 
creatinine, urinary sediment, weight and vitals) 
x Nature and severity of AEs 
x Withdrawals due to an AE 
 
 


Investigational product:  
CONFIDENTIAL  
 
 
Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 8 of 62 
13 December 2016 
 
EFFICACY ASSESSMENTS 
Subjects will be required to complete a paper diary twice 
daily (morning and evening) throughout the study to record 
subjective hot flash severity and frequency (number of mild, 
moderate 
and 
severe 
hot 
flashes) 
and 
night-time 
awakenings. On Days -1 through to Day 7) and on Day 14 
subjects will also be required to complete a paper diary on a 
real-time basis relating to their hot flashes. A sternal skin 
conductance monitor will also be fitted on Day -1 through 
Day 8 (24 hours post Day 7 dose) and through Day 14 to 15 
(24 hours post Day 14 dose) for an objective assessment of 
hot flash frequency.  
 
Blood samples for analysis of LH will be collected every 60 
minutes from time 0 (pre-dose) to 8 hours on Day -1, 1 and 
Day 7 
 
STATISTICAL METHODS 
PK, safety and efficacy data will be presented by means of 
descriptive statistics and figures, as appropriate, by 
treatment. Data for the placebo subjects will be combined 
across cohorts prior to any summaries.  
 
Plasma concentration versus time data for NT-814 will be 
evaluated by standard non-compartmental analysis using 
appropriate software. The following PK parameters for 
NT-814 will be log-transformed, where appropriate, prior to 
statistical analysis: AUC0-t, AUC0-τ, AUC0-∞, Cmax, CL/F, 
and t½. 
The safety and tolerability profile will be assessed versus 
baseline conditions and differences between treatment 
groups and descriptive statistics will be produced, where 
applicable. A concentration-effect model may be built 
investigating 
ECG 
assessments 
versus 
plasma 
concentrations. Exploratory dose response and PK-
Pharmacodynamic (PD) analyses may be conducted for the 
efficacy assessments. 
Any statistical hypothesis tests and/or confidence intervals 
will be two sided, using a type I error rate of 0.1. No 
adjustments will be made for multiplicity in this early phase 
study. Raw data will be listed.  


Investigational product:  
CONFIDENTIAL  
 
 
Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
FINAL 
Page 9 of 62 
13 December 2016 
 
 
PLANNED 
DATE 
OF 
FIRST 
SUBJECT ENROLLED 
01-Aug-2016 
PLANNED 
DATE 
OF 
LAST 
SUBJECT COMPLETED 
31-Mar-2017 
NUMBER OF STUDY CENTRES 
4 
 
 
 


Investigational product: 
CONFIDENTIAL
Protocol No.: RELENT-1
NT-814
NeRRe Therapeutics Ltd
Protocol Version: 4.0
FINAL
Page 10 of 62
13 December 2016
2.
TABLE OF CONTENTS
1. 
PROTOCOL SYNOPSIS........................................................................................................2 
2. 
TABLE OF CONTENTS......................................................................................................10 
3. 
LIST OF ABBREVIATIONS...............................................................................................15 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE..........................................18 
5. 
BACKGROUND INFORMATION .....................................................................................20 
5.1 
NT-814..................................................................................................................................20 
5.2 
Hot flashes in post-menopausal women................................................................................20 
5.3 
Pre-clinical research..............................................................................................................21 
5.4 
Clinical experience................................................................................................................22 
5.5 
Rationale for this study .........................................................................................................22 
6. 
STUDY OBJECTIVES AND PURPOSE.............................................................................23 
6.1 
Primary objectives.................................................................................................................23 
6.2 
Exploratory objectives ..........................................................................................................23 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................23 
7.1 
Subject numbers....................................................................................................................23 
7.2 
Inclusion criteria....................................................................................................................23 
7.3 
Exclusion criteria ..................................................................................................................24 
7.4 
Withdrawal criteria................................................................................................................25 
8. 
STUDY DESIGN..................................................................................................................26 
8.1 
Pharmacokinetic endpoints ...................................................................................................26 
8.2 
Safety endpoints....................................................................................................................26 
8.3 
Exploratory endpoints...........................................................................................................27 


Investigational product: 
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Protocol No.: RELENT-1
NT-814
NeRRe Therapeutics Ltd
Protocol Version: 4.0
FINAL
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13 December 2016
8.4 
Study design..........................................................................................................................27 
9. 
STUDY MEDICATION AND ADMISTRATION..............................................................31 
9.1 
Study medication...................................................................................................................31 
9.2 
Selection of doses in the study..............................................................................................31 
9.3 
Allocation to treatment..........................................................................................................33 
9.4 
Study treatment and administration ......................................................................................33 
9.5 
Packaging and labelling ........................................................................................................34 
9.6 
Handling and storage.............................................................................................................34 
9.7 
Duration of subject participation...........................................................................................34 
9.8 
Discontinuation criteria.........................................................................................................34 
9.9 
Cohort and dose escalation stopping criteria ........................................................................35 
9.10 
Premature termination of study.............................................................................................36 
9.11 
Treatment accountability and compliance checks.................................................................37 
9.12 
Treatment blinding code .......................................................................................................37 
9.13 
Study restrictions...................................................................................................................38 
9.13.1 
Permitted concomitant medications .....................................................................................38 
9.13.2 
Prohibited concomitant medication......................................................................................38 
9.13.3 
Dietary restrictions...............................................................................................................39 
9.13.4 
Other restrictions..................................................................................................................40 
10. 
STUDY SCHEDULE ...........................................................................................................41 
10.1 
Volume of blood sampling....................................................................................................43 
10.2 
Efficacy assessments.............................................................................................................43 
10.2.1 
Hot flash paper-diaries .........................................................................................................43 


Investigational product: 
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Protocol No.: RELENT-1
NT-814
NeRRe Therapeutics Ltd
Protocol Version: 4.0
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13 December 2016
10.2.2 
Day time continuous hot flash diary ....................................................................................43 
10.2.3 
Sternal skin conductance monitors.......................................................................................43 
10.2.4 
Luteinizing hormone ............................................................................................................44 
10.3 
Pharmacokinetics ..................................................................................................................44 
10.3.1 
Sample transfer and assay methodology..............................................................................44 
10.4 
Safety assessments ................................................................................................................45 
10.4.1 
Medical history and concomitant diseases...........................................................................45 
10.4.2 
Physical examinations..........................................................................................................45 
10.4.3 
24-hour Holter monitoring ...................................................................................................46 
10.4.4 
12-lead ECGs .......................................................................................................................46 
10.4.5 
Biochemistry ........................................................................................................................46 
10.4.6 
Hematology..........................................................................................................................46 
10.4.7 
Urinalysis .............................................................................................................................46 
10.4.8 
Hormone level assessments..................................................................................................47 
10.4.9 
Vital signs.............................................................................................................................47 
10.5 
Priority order of study assessments.......................................................................................47 
10.6 
Adverse events ......................................................................................................................47 
10.6.1 
Definitions............................................................................................................................47 
10.6.2 
Assessment of causality .......................................................................................................49 
10.6.3 
Serious Adverse Event reporting..........................................................................................49 
10.7 
Safety review committee.......................................................................................................50 
11. 
STATISTICAL CONSIDERATIONS..................................................................................51 
11.1 
Estimated sample size ...........................................................................................................51 


Investigational product: 
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Protocol No.: RELENT-1
NT-814
NeRRe Therapeutics Ltd
Protocol Version: 4.0
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13 December 2016
11.2 
Analysis sets..........................................................................................................................51 
11.3 
Data analysis .........................................................................................................................51 
11.3.1 
Baseline assessment .............................................................................................................52 
11.3.2 
Safety analysis methodology................................................................................................52 
11.3.3 
Pharmacokinetic analysis methodology...............................................................................52 
11.3.4 
Exploratory analyses ............................................................................................................53 
11.4 
Study specific data analysis ..................................................................................................53 
12. 
END OF THE STUDY .........................................................................................................53 
13. 
IRB REVIEW/INFORMED CONSENT..............................................................................53 
13.1 
Institutional Review Board (IRB) and relevant authorities...................................................53 
13.2 
Ethical conduct of the study..................................................................................................53 
13.3 
Informed consent...................................................................................................................53 
14. 
STUDY AND DATA MANAGEMENT..............................................................................54 
14.1 
Protocol amendments............................................................................................................54 
14.2 
Monitoring ............................................................................................................................54 
14.3 
Quality assurance ..................................................................................................................54 
14.4 
Data recording.......................................................................................................................55 
14.4.1 
Case report form...................................................................................................................55 
14.5 
Confidentiality ......................................................................................................................55 
14.6 
Retention of study data..........................................................................................................55 
14.7 
Communication and publication of results ...........................................................................56 
14.8 
Indemnification .....................................................................................................................57 
15. 
REFERENCES......................................................................................................................58 


Investigational product: 
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Protocol No.: RELENT-1
NT-814
NeRRe Therapeutics Ltd
Protocol Version: 4.0
FINAL
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13 December 2016
16. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ........................................61 


Investigational product:  
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Protocol No.: RELENT-1 
NT-814 
NeRRe Therapeutics Ltd 
Protocol Version: 4.0 
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13 December 2016 
 
3. 
LIST OF ABBREVIATIONS 
ACTH 
Adrenocorticotropic hormone 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate amino transferase 
AUC 
Area under the curve 
BCRP 
Breast Cancer Resistance Protein 
BMI 
Body mass index 
BP 
Blood pressure 
Cmax 
CL/F 
Maximum observed concentration 
Apparent clearance 
CMO 
Chief medical officer 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
Ctrough24h 
Trough concentration at 24 hours post-dosing 
ECG 
Electro cardiogram 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
FDA 
Food and drug administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate  
GGT 
Gamma-glutamyl transferase 
HDL 
High-density lipoprotein 
HDPE 
High-density polyethylene 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
IMP 
Investigational Medicinal Product 


Investigational product:  
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Protocol No.: RELENT-1 
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IRB 
Institutional Review Board 
IWRS 
Interactive Web Response Services 
KNDy 
Kisspeptin-Neurokinin B-Dynorphin 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LH 
Luteinizing hormone 
MAD 
Multiple ascending dose 
MCV 
Mean corpuscular volume 
MDRD 
Modification of diet in renal disease 
MnPO 
Medial preoptic nucleus 
NK 
Neurokinin 
NOAEL 
No-observed-adverse-effect-level 
NTA 
Night time awakening 
OD 
Once daily 
OTC 
Over the counter 
PD 
Pharmacodynamic 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
QoL 
Quality of Life 
RBC 
Red blood cell count 
RO 
Receptor occupancy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SOP 
Standard operating procedure 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine  
T4 
Thyroxine 
T 1/2 
Time to half observed concentration 
TBL 
Total bilirubin 


Investigational product:  
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Protocol No.: RELENT-1 
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Tmax 
Time of maximum observed concentration 
TMF 
Trial master file 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell count 


Investigational product:  
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Protocol No.: RELENT-1 
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13 December 2016 
 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE 
List of Investigators and Affiliations 
 
 
 
 
 USA 
Tel: 
 
 
 
 
 USA 
Tel: 
 ext 
 
 
 
 USA 
Tel: 
 
 
 
 
 
USA 
Tel: 
 
 
Medical Monitor (Sponsor) 
 
 
Artemida Pharma Limited,   
SBC, Incubator Building, Gunnels Wood Rd.,  
Stevenage,  
SG1 2FX 
UK 
UK Tel/fax: 
 
US Tel/fax:   
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Investigational product:  
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Protocol No.: RELENT-1 
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Contract Research Organization / Monitors 
 
ICON Early Phase Services, LLC 
8307 Gault Lane,  
San Antonio,  
TX 78209,  
USA 
Statistical Consultant 
 
 
CROS NT Ltd, 
Beechwood House, 
Grove Park, 
White Waltham, 
Berkshire, 
SL6 3LW, 
UK 
 
PK Bioanalytical Laboratory 
 
Aptuit Srl, Italy 
Center for Drug Discovery & Development  
Via Fleming 4 
37135 Verona,  
Italy 
 
PPD
PPD


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NT-814
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5.
BACKGROUND INFORMATION
5.1
NT-814
N.B. Prior to its acquisition by NeRRe Therapeutics, NT-814’s former laboratory code name was 
GSK1144814. The former GSK laboratory code is used in this document when referring to the 
studies conducted by GSK, but NT-814 is used for all development activities conducted by NeRRe 
Therapeutics.
In vitro binding and functional studies have demonstrated that NT-814 is a potent and selective 
antagonist of both human neurokinin-1 (NK1) and NK3 tachykinin receptors [Catalani.et al., 2011].  
NT-814 was active in pharmacodynamic (PD) models for the NK1 receptor (the gerbil foot tapping 
test) and NK3 receptor (wet dog shaking behavior in guinea pigs); both in a dose dependent manner.  
NT-814 also shows non-sedating anxiolytic-like properties in the human threat test in the marmoset.  
The brain penetrant properties of NT-814 have been confirmed in the gerbil in which receptor 
occupancy (RO) in the brain was demonstrated at both the NK1 and NK3 receptors in a dose- and 
concentration-dependent manner; the RO at both receptors was sustained for extended periods post-
dose. NT-814 also occupied guinea pig striatal NK1 receptors and cortical NK3 receptors in a dose-
and concentration-dependent manner. In a positron emission tomography (PET) study in baboons, 
NT-814 achieved high NK1 RO at modest plasma concentrations. These studies demonstrated that 
NT-814 is an orally active antagonist of brain NK1 and NK3 receptors in vivo. 
NT-814 was shown to be >100-fold selective for the human NK3 receptor and >300-fold for the 
human NK1 receptor, in comparison to a panel of 88 other non-tachykinin human receptors, enzymes 
and transporters.
5.2
Hot flashes in post-menopausal women
Over the next 25 years, more than 1 billion women worldwide will be older than 50 years, and up to 
75% of these women will experience adverse symptoms related to menopausal transition, 
particularly hot flash (also called flush) vasomotor symptoms, sleep disturbances and adverse mood 
that have such a negative impact upon patient daily activities and quality of life [Williams et al., 
2009; Joffe et al., 2010; Santoro et al., 2015]. 
Hot flashes are transient, but recurrent episodes of flushing, perspiration and intense sensation are 
one of the most common, bothersome and distressing symptoms felt by women during the transition 
to menopause (peri-menopause) and post-menopause periods [Pachman et al. 2010]. They are the 
leading cause for seeking medical attention during this particular phase of a woman’s life [Williams 
et al., 2007], particularly with those experiencing the severest symptoms [Whiteley et al., 2013].


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Current treatment options include hormone replacement therapies which are effective in reducing 
vasomotor symptoms in many women, but have a safety profile which include increased thrombotic 
and cardiovascular effects that precludes their use in many women. The only licensed non hormonal 
therapy is a low dose of paroxetine which has limited efficacy and also a number of unwanted safety 
and toleration issues limiting widespread usage.
Kisspeptin-Neurokinin B-Dynorphin (KNDy) neurons, expressing NK3 receptors, branch extensively 
within the arcuate nucleus and are also linked to the medial preoptic nucleus (MnPO) of the 
hypothalamus, which has been identified as the control centre for thermoregulation [Boulant, 2000] 
that is responsive to both estrogen and ambient temperature [Rance et al., 2013]. Support for the 
hypothesis that KNDy neurons have a thermoregulatory role and are involved in hot flash generation 
has been described in a number of animal studies [Deecher et al., 2007; Mittelman-Smith et al., 
2012; Rance et al., 2013]. Furthermore in humans in a randomised, double-blinded, placebo-
controlled, two-way cross-over study in healthy women it has been shown that intravenous infusion 
of NK-B (agonist that binds the NK3 receptor) acutely induces hot flashes in healthy women 
[Jayasena et al., 2015]. Modulation of the KNDy neurons by NK3 receptor antagonism could 
therefore be a viable approach to develop anti-hot flash medications
In addition, given NK1 receptor antagonism has proven to be effective in Phase 2 studies in mood 
[Kramer et al., 1998; Kramer et al., 2004; Ratti et al., 2011; Ratti et al., 2013a] and primary insomnia 
[Ratti et al., 2013b]; it is possible that the mood and sleep comorbidities associated with menopausal 
hot flashes could also be addressed.
Taken together, this evidence further supports the notion that the dual NK1,3 receptor antagonism that 
NT-814 offers could be an efficacious treatment for vasomotor symptoms in the menopausal patient 
population as well as addressing important comorbidities.
5.3
Pre-clinical research
Toxicology studies have been completed with NT-814 including single dose studies in marmoset and 
monkey (up to 1000 mg/kg) and repeat dose studies of up to 13-weeks in rat (up to 100 mg/kg/day) 
and cynomolgus monkey (up to 40 mg/kg/day). In general, the findings indicated an acceptable 
safety profile that did not preclude entry into clinical studies with appropriate monitoring.
Genotoxicity and reproductive toxicity studies have also been undertaken. There was no evidence of 
developmental toxicity in the rat at doses up to 100 mg/kg/day or in the rabbit at doses up to 
140 mg/kg/day. 
Further details can be found in the current Investigator’s Brochure (IB).


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5.4 
Clinical experience 
To date, four clinical studies have been completed in the European Union and Australia with single 
total daily doses up to 250 mg and repeat doses up to 200 mg total daily dose for 29 days. Studies 
comprise a single dose escalation safety study including PET (MNK111321), a repeat-dose safety 
study with a drug interaction assessment and PET (MNK111587), a single-dose study assessing the 
pharmacokinetics (PK) and effect of food on a tablet formulation (MNK112891), and a single dose 
study assessing whether the psychomotor and cognitive effects of alcohol are exacerbated by NT-814 
(tablet formulation) (MNK113476). NT-814 has been well tolerated and no safety signals of note 
have been identified in the 89 male and 1 female healthy volunteers exposed to date. In addition, PK 
parameters from the female dosed with single doses of 100 mg and 200 mg were within the range of 
those seen in the males. 
Further details can be found in the current IB. 
5.5 
Rationale for this study 
To date NT-814 has been tested in 90 volunteers in 4 phase 1 studies of which 15 subjects were 
dosed with 200 mg up to 29 days. To date only 1 female subject has been dosed. The aim of this 
study is to investigate the PK and safety of NT-814 in post-menopausal women with hot flashes to 
help inform design of subsequent studies in the target population. The target population of post-
menopausal women is required to have a minimum hot flash frequency and severity requirement for 
entry into this study. These characteristics have been selected as it is deemed to be important to 
define the safety profile of NT-814 in a controlled setting in a population with similar characteristics 
to that to be studied in further development due to the nature of the symptoms associated with the 
disease under study: hot flashes are often associated with symptoms such as palpitations, 
tachycardias and dizziness. To help in this assessment a careful pre-dose characterization of the 
subjects will be carried out on before dosing on Day -1, the study will be placebo controlled and 
involve 24-hour ECG monitoring through the first 7 days of dosing, when steady state plasma drug 
levels are predicted to be reached.  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), and in accordance with local legal and regulatory 
requirements. 
 
 
 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1 
Primary objectives 
x To evaluate the PK and safety profile of multiple dose levels of NT-814 compared to 
placebo, by once daily administration of each dose for 14 days.  
6.2 
Exploratory objectives 
x To assess effects of multiple, single daily doses of NT-814 compared to placebo on hot flash 
frequency and severity using objective and subjective measures. 
x To investigate the relationship between PK exposure and hot flash measures, if data permit. 
x To explore the relationship between plasma concentrations and placebo-corrected change 
from Baseline QTcF and QTcB values using concentration effect modeling, depending on the 
results observed.  
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Subject numbers 
Up to a total of up to 100 subjects randomized across 5 cohorts (20 subjects per cohort).  
7.2 
Inclusion criteria 
The following inclusion criteria will apply to all subjects: 
1. Post-menopausal female subjects 40-65 years of age 
Menopause will be defined as: 
a) 12 months of spontaneous amenorrhea; 
b) OR 6 weeks’ post-surgical bilateral oophorectomy with or without hysterectomy. 
2. At Baseline women: 
a) With an average of ≥ 7 and ≤ 20 moderate to severe hot flashes/day during the last 
week’s diary during screening  
b) That have a change of < 50% in average 24-hour hot flash frequency between the 
first and second week of the screening period diary (Week -2 and Week -1 
respectively). 
3. Able to understand and comply with the requirements of the study and sign Informed 
Consent forms 


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7.3
Exclusion criteria
The following exclusion criteria will apply to all subjects:
1. Any active comorbid disease deemed by the investigator to be clinically significant which 
could impact safety during study conduct including renal or hepatic impairment:
a) Serum creatinine laboratory value greater than 1.2 times upper limit of normal (ULN) 
reference range (after adjustment for age) at Screening or Day -1 or subjects with
renal function glomerular filtration rate (GFR) <60mL/min/1.73m2 based on the 
MDRD equation.
b) Total bilirubin greater than upper limit of normal reference range (with the exception 
of Gilbert's Syndrome) and/ or alanine transaminase (ALT) >2 times ULN reference 
ranges and/ or aspartate amino transferase (AST) >2 times ULN reference ranges, at 
Screening or Day -1.
2. Subjects with a prior medical history of or an increased risk of seizures, or who have a history 
of recent (within 6 months of Screening) head trauma that resulted in a loss of consciousness 
or concussion
3. Any prior or ongoing history of arrhythmias 
4. Any ongoing cardiovascular disease including heart failure, coronary artery disease or 
uncontrolled hypertension or uncontrolled diabetes 
5. Any clinically relevant ECG abnormalities at Screening 
6. Unwillingness to refrain from eating grapefruit, grapefruit juice, Seville oranges, and 
pomelos from 7 days prior to admission on Day -1 until after their final follow-up visit
7. Use of any prohibited medications (see Section 9.13.2)
8. Any history of invasive malignancy in the past 2 years 
9. Any active ongoing condition that could cause difficulty in interpreting vasomotor symptoms 
such as:  infection that could cause pyrexia, pheochromocytoma, hyperthyroidism, carcinoid 
syndrome, alcohol abuse
10. Body mass index (BMI) > 35kg/m2
11. Inability to complete questionnaires for any reason including psychiatric disorders and 
inability or unwillingness to use electronic devices
12. History of hypothalamic dysfunction.
13. Any clinically significant or unstable medical or psychiatric condition that would interfere 
with the subject's ability to participate in the study including anxiety syndromes 
14. Any clinically significant abnormal laboratory test result(s) at Screening or on Day -1.


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15. Participation in any clinical research study evaluating another investigational drug or therapy 
within 30 days or within 5 half-lives (whichever is longer), of the investigational drug prior to 
consenting to study entry.  If the subject is in an observational clinical study no washout is 
required.
16. Subjects who, in the opinion of the Investigator, should not participate in the study for any 
other reason.
17. Any known allergy or hypersensitivity to any of the ingredients in the study medication or to 
skin adhesives.
Any clinical or laboratory readings that narrowly miss the exclusion criteria such as BMI, serum 
creatinine and liver function tests can be considered on a case by case basis for inclusion after 
discussion with the medical monitor.
7.4
Withdrawal criteria
A subject should be withdrawn from treatment if they meet the discontinuation criteria in 
Section 9.8. If a subject is discontinued at any time after entering the study the investigator will make 
every effort to see the subject and complete the early termination visit assessments.
Subjects may withdraw from the study at any time without stating a reason and without prejudice to 
further treatment. The Investigator may withdraw a subject from the study and discontinue study 
treatment and assessments at any time.  
Early discontinuation of any subject who has given informed consent to participate will be recorded 
including the reason for discontinuation. The primary reason for a subject withdrawing prematurely 
will be selected from the following standard categories of early discontinuations:
x
Failed to meet randomization criteria
x
Adverse Event (Adverse Reaction): Clinical events occurred or laboratory results are reported 
that in the medical judgment of the investigator are grounds for discontinuation in the best 
interests of the subject.
x
Withdrawal of Consent: The subject desired to withdraw from further participation in the study. 
The subject is not obliged to provide any reason for withdrawal of consent, but where a reason is 
given this will be recorded on the eCRF.
x
Protocol Violation: The subject failed to adhere to the protocol requirements, at the 
investigator’s discretion e.g. the subject needs to start taking a medication from the prohibited 
medications list (Section 9.13.2).


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x Lost to Follow-Up: The subject stopped coming for visits and study personnel were unable to 
contact the subject. 
x Other: The subject was terminated for a reason other than those listed above, such as theft or 
loss of study drugs or electronic equipment or termination of study by Sponsor. 
All subjects who withdraw from the study may be replaced. 
8. 
STUDY DESIGN 
8.1 
Pharmacokinetic endpoints 
x Pharmacokinetics of NT-814: Peak concentration (Cmax), time of occurrence of Cmax (tmax), 
area under the curve (AUC) from time zero (pre-dose) to the time of the last quantifiable 
concentration (AUC0-t), AUC in the dosing interval at steady state AUC0-τ (AUC0-24) after single 
and repeat dosing, apparent terminal phase half-life (t½), AUC from time zero (pre-dose) 
extrapolated to infinity (AUC0-∞) after single dose, and apparent clearance (CL/F). 
8.2 
Safety endpoints 
Safety and tolerability will be assessed by the following: 
x Physical Examinations 
x Analysis for arrhythmias as assessed by continuous Holter monitoring from Day -1 to Day 8 
(24 hours post Day 7 dose) and Day 14 (24 hours) 
x Abnormalities on the 12-lead ECGs 
x Change in ECG variables (heart rate, RR, PR, QRS, QT, QTcF and QTcB) 
x Change from Baseline in clinical laboratory assessments including lipids and coagulation 
profile 
x Change from baseline in hormones including estradiol, testosterone, follicle stimulating 
hormone (FSH), adrenocorticotropic hormone (ACTH), cortisol, thyroid-stimulating hormone 
(TSH), triiodothyronine (T3) and thyroxine (T4) 
x Change from Baseline in vital signs including oxygen saturation, oral temperature and 
postural blood pressure (BP) changes  
x Adverse events (AEs) of dehydration (supported by changes in serum urea and creatinine, 
urinary sediment and weight and vital signs) 
x Nature and severity of Adverse Events (AE) 
x Withdrawals due to AEs 


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8.3
Exploratory endpoints
x
Change in frequency of hot flashes from Pre-dose (Day -1) as assessed by skin conductance 
x
Change from Baseline in frequency of moderate to severe hot flashes, hot flash average 
severity and hot flash severity score as measured by twice daily paper diary throughout study
x
Change in frequency of hot flashes as measured by continuous day time diary from Day -1
pre-dose to Day 7 and Day 14
x
Change from Baseline in night-time-awakenings (NTA) secondary to hot flashes as measured 
by paper diary
x
Change in LH AUC0-8 hours on Day-1 versus Day 1 and Day 7
x
To explore the relationship between plasma concentrations and placebo-corrected change
from baseline QTcF and QTcB values using concentration effect modeling, depending on the 
results observed
8.4
Study design
This is a multi-center, double-blind, randomized, placebo-controlled multiple ascending dose trial in
post-menopausal women with vasomotor symptoms.
Subjects will be recruited into a maximum of 5 sequentially dosed cohorts; Cohort 1 (50 mg 
NT-814), Cohort 2 (100 mg NT-814), Cohort 3 (150 mg NT-814) and, if needed, 2 further cohorts up 
to 400mg NT-814. See Figure 1 for study design schematic.
For each cohort, subjects will enter a 4 week screening period to determine eligibility. Twenty 
eligible subjects will be randomized per cohort (15 active and 5 placebo). 
During the screening period each subject will be required to complete twice daily paper diaries. 
Eligible subjects will demonstrate, at the Baseline visit, an average 24-hour moderate to severe hot 
flash frequency ≥ 7 and ≤ 20 based upon the average daily frequency of all available readings (at 
least 4 days) in the final week of screening (Week -1). If at the Baseline visit subjects have an 
average 24-hour hot flash frequency <7/ day or > 20/day they will be discontinued from the study.  
In addition, subjects that have a change of ≥50% in average 24-hour hot flash frequency between the 
first and second week of the screening period (Week -2 and Week -1 respectively) will be excluded.
Subjects will also be provided with the continuous daily diary during screening and instructed to start 
completing this on the morning of Day -1 after waking, prior to admission to the clinic, and to 
continue to complete this throughout Day -1.
It may be necessary to extend a patient’s screening period beyond 28 days (with the approval of the 
sponsor) when a subject is held over from one cohort to the next because the original cohort into 
which they would have been enrolled is complete. If this occurs, the following safety procedures 
must be repeated such that the most recent evaluation occurs within 28 days of the rescheduled 
randomization:


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x
Biochemistry and hematology
x
Vital signs
x
12-lead ECG
x
Physical examination
If the subject has completed (or partially completed) the screening twice daily Hot Flash Diary this 
must still be repeated and a new diary started on the new planned Day -15 and completed for the 2 
weeks up to Day -2. Eligibility will be assessed on the repeated diary, not the initial one. If the 
subject had not started completing their screening diary at the time screening was put on hold, they 
will start this screening diary on the re-scheduled Day -15.
Eligible subjects will be admitted to a Phase 1 Unit as an inpatient on the morning of Day -1 and will 
be fitted with and instructed on use of a sternal skin conductance monitor and Holter monitor which 
will be worn continuously until discharge from the clinic on Day 8; both the Holter monitor and 
sternal skin conductance monitor will be refitted on return to the Phase 1 Unit on Day 14. Routine 
safety monitoring will be carried out in a manner that will form the baseline for comparisons for the 
remainder of the study.
On Day 1, the subjects will be randomized in a 3:1 ratio to once daily (morning) doses of NT-814 or 
placebo, to be taken for a total of 14 days. Subjects will be monitored as an inpatient from Day -1 to 
Day 8 and will undergo blood draws for intensive PK sampling, safety monitoring and for impact on
blood hormonal profiling as well as 24-hour skin conductance measurements and continuous 
completion of hot flash diaries. 
Subjects will be discharged from the clinic on Day 8 without any monitoring devices, providing there 
are no safety concerns and will undergo dosing for a further 5 days as an outpatient. Subjects will be 
instructed to continue recording details of the hot flashes experienced, using the twice daily diary.
They will be provided with the continuous daily diary and instructed to start completing this upon 
waking on the morning of Day 14 prior to admission to the clinic. They will be re-admitted to clinic 
on the morning of Day 14 for the final dose and undergo the same assessments with the same devices
including Holter and skin conductance as Day 1. Subjects will be discharged following the 24-hour
post Day 14 assessments (Day 15). Subjects will return to the clinic, as outpatients, for a single PK 
sample on the mornings of Days 16 and 17 (48 hours and 72 hours after the Day 14 dose 
respectively).
Throughout the study, subjects will be closely monitored for safety including assessments of AEs, 
12-lead ECGs, atrial oxygen saturation using pulse oximetry, vital signs (sitting and standing BP, 
heart rate, oral body temperature, and respiration rate), clinical labs and physical examinations.
At the end of each Cohort a blinded review of PK and safety data from all subjects will be conducted 
by the Safety Review Committee (see Section 10.7) to confirm that it is safe to proceed to the next 


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dose. This review must comprise complete data up to Day 17 from a minimum of 14 subjects per 
cohort. 
In the case of any safety concern or any ambiguous data, from any one of the cohorts, either 
individual subjects or the entire cohort may be unblinded to enable decision making. In this 
eventuality a separate un-blinded Safety Review Committee will be used to maintain the integrity of 
following cohorts if needed. Details are outlined in the Safety Review Committee Charter.  
Subjects may not participate in more than one Cohort. 
A final Follow-up visit will be conducted by phone one week after completion of dosing for each 
Cohort, unless a clinic visit is deemed more appropriate by the Investigator in order to follow up any 
ongoing adverse events.  
 


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Figure 1: Study schematic  
 
 


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9.
STUDY MEDICATION AND ADMISTRATION
9.1
Study medication
The test product, NT-814A in the free base form, formulated as a 50 mg dose in opaque white / white 
hard gelatin capsules to be taken orally once-daily. The physical, chemical, pharmaceutical 
formulation properties and characteristics of NT-814 are described in the IB. 
The planned dosing schedule is as detailed in Table 1.
Table 1: Dosing schedule
Cohort 1
50 mg (1 x 50 mg capsule)
Cohort 2
100 mg (2 x 50 mg capsules)
Cohort 3
150 mg (3 x 50 mg capsules)
Cohort 4
TBD
Cohort 5
TBD
Matching placebo capsules will be used as the reference treatment in this study and will be 
administered as for the test product. 
Subjects will take capsule(s) once a day in the morning on an empty stomach and should not eat 
anything for 4 hours following administration. Subjects will be required to fast from midnight prior 
to dosing on Days 1,7 and 14, and for up to 4 hours after (see Section 9.13.3).
Subjects will receive doses on Days 1 to 8 whilst at clinic. On Day 8, subjects will be dispensed 5
days’ supply for self-administration at home on Days 9 to 13, along with an Investigational 
Medicinal Product (IMP) administration diary which they will be asked to complete. Subjects will be 
asked to return the remaining medication when they return to the clinic. The Day 14 dose will be 
administered in the clinic.
If subjects forget to take a dose when at home they will be instructed to miss that dose and take the 
next dose as scheduled.
9.2
Selection of doses in the study
To date 90 volunteers (including only 1 female) have been dosed with NT-814 with single doses up
to 250 mg once daily (OD) with 15 subjects being dosed with a total daily dose of 200 mg for up to
29 days in the repeat dose human safety study (MNK111587) where attained exposures up to a 


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maximum AUC 0-24 of 41900 ng.h/mL were considered safe and well tolerated. A PK/PD model was 
created using serum total testosterone levels as a marker of target engagement from data from the 
Phase 1 studies.  Based upon this model a mean AUC of 14040 ng.h/mL predicts near maximal 
target engagement at the NK3 receptor. This exposure was achieved in male subjects following doses 
of 200 mg for 28 days.
The objective of this study is to characterize the PK and safety of NT-814 in a controlled setting in
post-menopausal women with vasomotor symptoms to inform future development in this population 
using a target of maximum exposures of around 15000 ng.h/mL. To achieve the target PK AUC 
exposure objective, the study will be conducted in a controlled Phase 1 Unit setting with close safety 
monitoring and using predefined stopping criteria outlined in Section 9.9 as well as pre-defined PK 
stopping limits outlined below and will consist of a maximum of 4 sequentially dosed cohorts: 
Cohort 1, Cohort 2, Cohort 3 and if needed Cohorts 4 and 5. Planned dose escalation steps for the 
first 3 cohorts are in multiples of 50 mg NT-814 starting with an initial dose of 50 mg. Subsequent 
doses will be based on PK modelling of data from the first 3 cohorts increasing to a maximum dose 
of 400 mg if appropriate and needed. The predicted exposure increase between Cohorts 3 and 4 and 
between Cohorts 4 and 5 (if applicable) will be ≤ 2 fold. In the one-month monkey toxicity study, the 
effect level was considered as 60 mg/kg/day and this corresponded to a geometric mean AUC0-24 of 
35700 ng.h/mL. However, exposures up to a maximum AUC0-24 of 41900 ng.h/mL were safe and 
well tolerated in the repeat dose human safety study (MNK111587); and this maximum value is used 
as the basis of safety margin estimates.
As outlined in the IB, the non-clinical data for sex differences in PK measures are not clear and are 
contradictory. Allowing for a step wise dose escalation with adequate monitoring and PK based 
stopping limits is considered an appropriate means of conducting the study to allow for a comparison 
of PK across sexes and providing for the maximum chance of achieving full target engagement.  
The Cmax pharmacokinetic safety margin is based on the no-observed-adverse-effect-level 
(NOAEL) in the rat 3-month toxicity study. In this study GSK1144814A (vehicle, 5, 25 or 100 
mg/kg/day) was given orally to rats for 13 weeks. There were no adverse, test-article related 
changes; therefore, the NOAEL was considered to be 100 mg/kg/day and corresponded to a 
geometric mean AUC of 95900 ng.h/mL and a geometric mean Cmax of 6500 ng/mL. The use of rat 
data to determine Cmax stopping criteria is felt to be acceptable as dose limiting toxicology in the 
most sensitive species (monkey) was related to total exposure (AUC) and not related to Cmax, and 
there have been no adverse events (AEs) of concern related to Cmax in the four Phase 1 clinical 
studies conducted thus far.
The study starting dose of 50 mg is anticipated to provide safety margins of approximately 12- and 
14-fold respectively for AUC0-24 and Cmax. Subjects will be dosed and monitored in a controlled 
Phase 1 Unit clinic setting for the first 8 days of dosing and will only be escalated to the next cohort 
only when safety and PK data have been analyzed.


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The target exposure of 14040 ng.h/mL (geometric mean AUC0-24 achieved with 200 mg daily dose in 
males for 28 days) gives a safety margin of approximately 3-fold against the 41900 ng.h/mL
observed value while the predicted geometric mean Cmax of 1836 ng/mL (at the 200 mg daily dose 
and after 14 days’ administration) gives a safety margin of ~3.5 fold against the Cmax.
No dose will be given that is expected to exceed a geometric mean AUC0-24 of 20950 ng.h/mL (2-
fold safety margin). 
As detailed in Section 10.7, the Safety Review Committee will evaluate safety and tolerability data 
from each cohort prior to escalating to the subsequent dose. 
If study stopping criteria (see Section 9.9) have not been met and there are no concerning safety 
signals, the subsequent Cohort will proceed to the next dose.
If study stopping criteria are met, no further subjects will be dosed and the study will be terminated.
In the event that study stopping criteria have not been met, but the Safety Review Committee do not 
feel that it is appropriate to escalate to the next planned dose, the subsequent Cohort may be dosed at 
any of the previous dose levels, in order to confirm safety and PK data for this dose.
9.3
Allocation to treatment
The study will be conducted in a double-blind manner, with the subjects, Investigators and Sponsor 
all blinded to the treatment allocated. Both NT-814 and placebo will be presented as white capsules, 
identical in size and shape.
Following a 4-week screening period and confirmation of eligibility, subjects in each cohort will be 
randomized in a 3:1 ratio to receive either NT-814 or placebo. The IMP each subject will receive will 
be allocated by an Interactive Web Response Services (IWRS) tool provided by the Clinical 
Research Organization (CRO) on behalf of the Sponsor.
The dose will start at 50 mg for Cohort 1 and will increase in increments of 50 mg for the first 3 
cohorts and for subsequent cohorts, the dose will be set based on tolerability and PK as deemed 
appropriate by the Safety Review Committee, up to a maximum of 400 mg.
9.4
Study treatment and administration
Subjects will be administered study medication in the morning, according to the randomization 
schedule, at the clinic on Day 1, through Day 8. On Day 8, subjects will be dispensed study 
medication for self-administration on Days 9 to 13 (1-2 days’ overage should be included). On Day 
14 subjects will be administered study medication on the morning of admission to the Phase 1 Unit.
Subjects will be reminded to take the study medication at the same time each morning and to return 


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any unused medication when they return to clinic on Day 14. Subjects will be required to fast 
overnight prior to study drug administration on Day 1 through Day 14 (see Section 9.13.3).
9.5
Packaging and labelling
Investigational sites will be provided with bulk drug supplies (NT-814 50 mg capsules and matching 
placebo) in high-density polyethylene (HDPE) bottles packaged and labeled according to local 
regulatory requirements. Whilst in the clinic, doses will be prepared for the subjects each day. In-
clinic doses can also be prepared in advance for convenience and stored in the secure area for 
dispensing each day. Upon discharge on Day 8 subjects will be provided sufficient capsules for 
dosing at home on Days 9 through 13, in HDPE bottles packages and labelled according to local 
regulatory requirements. 
9.6
Handling and storage
Investigational product must be dispensed or administered according to procedures described in the 
Study Manual. Only subjects enrolled in the study may receive investigational product. Only 
authorized site staff may supply or administer investigational product. All investigational products 
must be stored in a secure area with access limited to the Investigator and authorized site staff. The 
investigational products must be kept in the original bottles and are to be stored at ambient room 
temperature up to maximum of 25°C. Maintenance of a temperature log (manual or automated) is 
required, whilst held at the study site.
9.7
Duration of subject participation
Subjects will be in the study for up to 7 weeks, from screening through to the final Follow-up phone-
call assessment. During the study subjects will be required to attend the clinic on a total of 5
occasions, at Screening and for 8 continuous 24-hour assessment periods, then again on Day 14 for a 
24-hour assessment, and as an outpatient for visits on the mornings of Days 16 and 17. A final 
Follow-up phone call will be conducted on Day 21. This will be replaced by a clinic visit if deemed 
more appropriate by the Investigator in order to follow up any ongoing AEs.
9.8
Discontinuation criteria
Subjects meeting any of the following criteria (regardless of treatment assignment) will be required 
to stop study medication and complete the early termination visit assessments:
x
Intolerable complaints of undesirable sexual side effects from the study medication
x
Oxygen saturation < 90% during a laboratory session that does not increase after 
administration of supplemental oxygen. 
x
If AST and ALT increase to ≥3 times the upper limit of normal
x
Clinically relevant cardiovascular AE such as ventricular tachycardia or atrial fibrillation


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x Signs of dehydration (e.g. orthostatic hypotension or decreasing urine outflow, impaired renal 
function or biochemistry profile change from the baseline, weight loss more than 10% from 
the baseline) 
Subjects that discontinue early may be replaced. 
9.9 
Cohort and dose escalation stopping criteria  
After each cohort a Safety Review Committee will review and assess all the available safety and PK 
study data from all of the cohorts to date in order to make a decision on the dose for the next cohort 
of subjects.  
Data from a minimum of 14 subjects from the previous cohort must be reviewed before a decision to 
escalate can be taken. 
The stopping criteria listed below apply to stopping during a cohort or at the end of a cohort during 
safety data review. Events that occur during the cohort will be passed onto the unblinded safety 
reviewers who will inform the study team of whether stopping criteria have been fulfilled and in such 
a case no other subjects will be enrolled. Subjects on treatment will be asked to stop dosing and if 
possible go through the early termination assessments.   
1. One subject who has received NT-814 reports a serious adverse event which is considered at 
least possibly related to the NT-814 
2. Two or more subjects, who have received NT-814, have QTc prolongation, defined as QTc 
> 500 ms for both Bazett and Fridericia corrections, or a prolongation from baseline of 
> 60 ms, confirmed (persistent for at least 5 min) during continuous ECG monitoring deemed 
to be at least possibly related to study drug (discovered at the end of the cohort during safety 
data review or on repeat ECGs taken during the study at the pre-determined time points or at 
the time of an AE) 
3. Two or more subjects, who have received NT-814, have tachycardia, defined as resting 
supine heart rate > 125 beats per minute persisting for at least 10 minutes deemed to be 
unrelated to a hot flash episode and at least possibly related to study drug during continuous 
ECG monitoring (discovered at the end of the cohort during safety data review or on a repeat 
ECGs taken during the study at the pre-determined time points or at the time of an AE) 
4.  Two or more subjects, who have received NT-814, have symptomatic bradycardia, defined 
as resting supine heart rate < 45 beats per minute or asymptomatic bradycardia defined as 
resting supine heart rate < 30 beats per minute while awake persisting for at least 10 minutes 
during continuous ECG monitoring deemed to be at least possibly related to study drug 
(discovered at the end of the cohort during safety data review  or on a repeat ECGs taken 
during the study at the pre-determined time points or at the time of an AE) 


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5. Two or more subjects, who have received NT-814, develop hypotension, defined as an 
asymptomatic fall in Systolic blood pressure (SBP) > 20 mmHg to below 70 mmHg 
persisting for at least 10 minutes, or a symptomatic fall in resting supine SBP > 20 mmHg 
(excluding vasovagal reaction or associated with hot flashes) deemed to be at least possibly 
related to study drug 
6. One or more subjects, who have received NT-814, fulfill Hy’s law, defined as “an increase in 
AST or ALT ≥ 3 x upper limit of normal (ULN) and total bilirubin (TBL) ≥ 2 x ULN, where 
no other reason can be found to explain the combination of increases, e.g., elevated serum 
alkaline phosphatase (ALP) indicating cholestasis, viral hepatitis, another drug.  The 
elevations do not have to be at the same time or within a specified time frame” 
7. Two or more subjects, who have received NT-814, have > 3 x ULN of either ALT or AST, or 
> 2 x ULN for bilirubin or ALP deemed to be at least possibly related to study drug 
8. Two or more subjects, who have received NT-814, have clinical and biochemical signs 
suggesting dehydration as assessed by the Investigator and Sponsor (weight loss > 10% from 
baseline, loss of skin turgor and biochemical signs such as increased serum urea and 
creatinine, high urinary osmolality and sediment) deemed to be at least possibly related to 
study drug 
9. Two or more subjects, who have received NT-814, have sustained oxygen saturations below 
90% that does not increase after administration of supplemental oxygen, deemed to be at least 
possibly related to study drug. 
10. Two or more subjects, who have received NT-814, with clinically relevant cardiovascular 
AEs such as ventricular tachycardia or atrial fibrillation deemed to be at least possibly related 
to study drug 
11. Dose escalation will not occur if the exposure of NT-814 is predicted to exceed a geometric 
mean AUC of 20950 ng.h/mL   
9.10 
Premature termination of study  
The study may be terminated prematurely if: 
x The Investigator and the Sponsor assess that the number and/or severity of AEs justify 
discontinuation of the study 
x The Sponsor considers the applied doses of the study drug to be no longer relevant 
x The Sponsor decides to discontinue the study 


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x Data not known before become available and raise concern about the safety of NT-814 so 
that continuation would pose potential risks to the subjects 
Premature termination of the study must be mutually agreed upon by the Investigator and the 
Sponsor and must be documented. However, study results will be reported according to the 
requirements outlined in this clinical study protocol as far as applicable. 
9.11 
Treatment accountability and compliance checks 
In accordance with regulatory requirements, the Investigator or designated site staff must document 
the amount of study medication dispensed and/or administered to study subjects, the amount returned 
by study subjects, and the amount received from and returned to the Sponsor (or representative) 
when applicable. Product accountability records must be maintained throughout the course of the 
study. 
The Investigator is responsible for investigational product accountability, reconciliation, and record 
maintenance. The Investigator or designated site staff (e.g., storage manager, where applicable) must 
maintain IMP accountability records throughout the course of the study. The responsible person(s) 
will document the amount of investigational product received and returned (on behalf of NeRRe) and 
the amount administered to subjects. The accountability unit for this study is a capsule. 
Discrepancies are to be reconciled or resolved. Procedures for final disposition of unused 
investigational product will be provided in the Pharmacy Manual. 
The Investigator has overall responsibility in ensuring that the study treatment is received and 
managed at the study site in accordance with GCP. 
Limited responsibility may be delegated to a nominated study site representative and this delegation 
must be documented. Study treatment will be dispensed by a nominated person at each study site. 
The Sponsor will be permitted upon request to audit supplies, storage and dispensing records and 
procedures. 
9.12 
Treatment blinding code 
Study investigators will be given access to the IWRS system for the purposes of emergency 
unblinding. Investigators are permitted to unblind treatment for a subject if it is deemed that the 
subject’s treatment will impact subject’s future medical care. If possible, the Sponsor should be 
notified prior to the blind being broken, if not possible, the Sponsor must be notified as soon as 
possible if a code break was performed.  
If a serious unexpected adverse reaction occurs requiring expedited reporting to the relevant 
regulatory agency / Institutional Review Board (IRB), then the blind will be broken for the relevant 
subject by the CRO safety group, in order to provide the regulators the knowledge of the event and 


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the causal agent. This is in agreement with ICH E2A and a blinded copy of the report will be 
provided to the investigators and the relevant IRB.
If unblinding occurs accidentally, this must be documented in the subject’s medical notes and in the 
trial master file (TMF), and the Sponsor must be informed.
As detailed in Section 10.7, in the case of any safety concern or any ambiguous data, an unblinded 
Safety Review Committee will be permitted to review unblinded data for either individual subjects or 
the entire cohort to enable decision making.  
9.13
Study restrictions
9.13.1
Permitted concomitant medications
All concomitant medications taken during the study will be recorded in the electronic case report 
form (eCRF) with indication, dose information, and dates of administration.
9.13.2
Prohibited concomitant medication
Subjects using the following medications will be excluded from the study:
x
Any antidepressants (e.g. SSRI, SNRIs) within 4 weeks of Screening Visit
x
NK receptor antagonists within 2 weeks of Screening visit
x
Women 
on 
tamoxifen 
(or 
other 
estrogen
modulating 
drugs) 
or 
receiving 
chemotherapy/radiation therapy within 4 weeks of Screening or planned antineoplastic 
chemotherapy/radiation therapy
x
Drugs or herbal medications that could be associated with hot flash like symptoms including 
nicotinic acid, calcium channel blockers, clonidine, opioid drugs, black cohosh within 2 
weeks of Screening Visit 
x
Drugs that are highly protein bound e.g. Warfarin and digoxin within 4 weeks of screening 
visit, use of non-steroidal anti-inflammatory drugs from the time of signing informed consent 
x
Use of any of the following hormonal treatment before Screening Visit:
o
1 week or longer for prior vaginal hormonal products (rings, creams, gels)
o
4 weeks or longer for prior transdermal estrogen alone or estrogen/progestin products
o
12 weeks or longer for prior oral estrogen and/or progestin therapy
o
3 months or longer for prior progestin implants and estrogen alone injectable drug 
therapy
o
6 months or longer for prior estrogen pellet therapy or progestin injectable drug 
therapy


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x Subjects using the following medications within 2 weeks prior to first dosing (or within 5 
times the half-life of that medication, whichever is longer) will be excluded from the study: 
o Inhibitors of CYP3A4 (including but not limited to macrolide antibiotics, HIV 
protease inhibitor, azole antifungal drugs, cyclosporine, calcium channel inhibitor, 
cimetidine), 
o Inducers of CYP3A4 (including but not limited to rifampicin, carbamazepine, 
efavirenz, bosentan, modafinil, St. John's Wort),  
o Known P-glycoprotein inhibitors (including but not limited to amiodarone, 
azithromycin, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir and 
ritonavir, quinidine, ranolazine, verapamil).  
x Known CYP3A4 substrates with narrow therapeutic range are not allowed from screening 
until up to 5 half-lives after last dose of NT-814 is administered (including but not limited to 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus).   
As the inhibition potential of NT-814 with Breast Cancer Resistance Protein (BCRP) transporter has 
not yet been evaluated in vitro, an interaction with statins cannot be ruled out. Subjects receiving 
statins can be allowed into the study, but should be monitored for signs and symptoms of 
rhabdomyolysis and will be withdrawn from the study if these are observed. 
Subjects will be required to inform the study investigator of any regularly taken medications 
(prescription or over the counter (OTC)), including hormone replacement therapy, natural and herbal 
products, vitamin, mineral or dietary supplement, taken within 2 weeks (or less than 5 times the half-
life of that medication, whichever is longer) prior to first dosing. Use of such medications should be 
reviewed with the medical monitor and permitted on a case by case basis. 
9.13.3 
Dietary restrictions 
Subjects must refrain from eating grapefruit, grapefruit juice, Seville oranges and pomelos within 7 
days prior to Day -1 until after their final follow-up visit. Other than this restriction subjects should 
maintain their usual diet during outpatient periods of the study. 
Subjects will be required to fast from midnight prior to dosing on Days 1, 7 and 14, for up to 4 hours 
after. Subjects are required to continue fasting until 4 hours post dose on these days. Water will be 
allowed ad libitum. On all other dosing days, the capsules must be taken on an empty stomach and 
no food is to be consumed for 4 hours following administration.    


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9.13.4 
Other restrictions 
If subjects experience somnolence or drowsiness at any time after discharge on Day 8 until they 
return to the clinic on Day 14 they should not drive or operate heavy machinery. 


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10. 
STUDY SCHEDULE 
Table 2: Schedule of Events 
Procedure 
Visit 1 
Screen 
Visit 2 
Visit 3 
Outpatient visits 
Early 
term 
visit12 
Follow-up 
Phone call11 
 
Day -28 
to -1 13 
Day -1 
Day 1 
Day 7 
Day 8 
Day 14 
Day 15 
Day 16 
Day 17 
Day 21 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Concomitant Diseases 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Inclusion/Exclusion criteria 
X 
X 
X2 
 
 
 
 
 
 
 
 
Outpatient visit 
X 
 
 
 
 
 
 
X 
X 
X 
 
Admission 
 
X 
 
 
 
X 
 
 
 
 
 
Inpatient stay 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
12-lead ECG 
X 
X4 
X4 
X 
X 
X4 
 
 
 
 
 
Hot flash paper diary5 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Day time continuous hot flash paper diary5 
 
X 
X 
X 
 
X 
 
 
 
 
 
Sternal Skin conductance monitor6 
 
X 
X 
X 
 
X 
 
 
 
 
 
Holter monitor6 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
AE/SAE recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose medication7 
 
 
 
 
 
 
 
 
 
 
 
Medication Dispensed7 
 
 
 
 
X 
 
 
 
 
 
 
Biochemistry/ Hematology 
X 
X 
 
 
X 
X 
 
 
 
X 
 
Urinalysis 
 
X 
 
 
X 
X 
 
 
 
X 
 
LH8, 10 
 
X 
X 
X 
 
 
 
 
 
 
 
estradiol, testosterone, FSH, ACTH, 
cortisol, TSH, T3 and T4 
 
X 
 
 
 
 
X 
 
 
 
 
PK9, 10 
 
 
X 
X 
 
X 
 
X 
X 
 
 


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Key: 
1 
Informed consent must be signed by the subject before the start of any study procedure 
2 
Baseline assessments to be conducted on Day 1, prior to dosing.  Key inclusion/exclusion criteria must be re-assessed before conducting any other 
baseline assessments 
3 
Vital signs include sitting and standing BP, heart rate, oral body temperature, pulse oximetry, respiration rate and weight will be performed daily during 
inpatient stays. Vital sign assessments will be performed on Day -1 at a similar time to the same assessments that are planned pre-dose on Day 1. The 
assessments will then be performed just prior to dosing (approx. 30 mins) for all other days in clinic and at a similar time on Day 15.  
4 
 
On Days 1 and 14, 12-lead ECG pre-dose and at 0.5, 1, 1.5, 2.0, 2.5, 3.0, 4.0, 8.0, 12.0 and 24.0 hours (all +/- 15 mins). The same assessments schedule 
is required on Day -1, starting at a similar time to that planned for Days 1 and 14. Once daily ECG recordings will be made just prior to dosing (approx. 
30 mins) on all other days (Days 3-8) during inpatient stays.  
5 
Subjects need to complete paper-diary for the 2 weeks prior to Baseline visit to ascertain eligibility. Subjects also to record number of times awoken 
during the night due to flashes (Night time awakening (NTA). On Days -1 to 7 and on Day 14 subjects to record the occurrence and severity of the flash 
(scale 1 to 3) in a continuous diary. Diary to be provided to subjects during screening and at discharge on Day 8 and subjects instructed to start 
completing it after waking on the mornings of Day -1 and 14 prior to admission and throughout the day and night. In the inpatient treatment part of the 
study, subjects also push a button on the skin conductance monitor when they sense a hot flash 
6 
Skin conductance and Holter monitors to be fitted on Day -1 (24 hours prior to the planned study drug administration on Day 1) and remain in place 
until after the 24 hour assessments are completed on Day 8 and then for 24-hours from pre-dose on Day 14 to discharge on Day 15. 
7 
Study drug will be administered in the morning from Day 1 to Day 14. Study medication will be dispensed to the subject on Day 8 for self-
administration at home (for Days 9 to 13). 
8 
LH sampling every 60 mins from time 0 (pre-dose on Day 1 and Day 7) to 8 hrs. The same sampling schedule is required on Day -1, starting at a similar 
time to that planned for Days 1 and 7. 
9 
PK Sampling at Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours; 48.0, 72.0 hours after Day 14 only. 
10 
Pre-dose samples for PK and LH to be taken within 30 minutes prior to dose administration 
11 
Telephone follow up visit, unless deemed by the investigator that a clinic visit is more appropriate to follow up an adverse event 
12 
Where possible, all subjects who are withdrawn or withdraw from the study early will undergo the Early Termination Visit assessments. 
13 
If the screening period is >28 days the following procedures must be repeated such that the most recent evaluation occurs within 28 days of the 
rescheduled randomization: biochemistry/hematology, vital signs, 12-lead ECG, physical examination. If the subject has completed (or partially 
completed) the screening twice daily Hot Flash Diary this must still be repeated and a new diary started on the new planned Day -15 and completed for 
the 2 weeks up to Day -2. Eligibility will be assessed on the repeated diary, not the initial one. If the subject had not started completing their screening 
diary at the time screening was put on hold, they will start this screening diary on the re-scheduled Day -15. 


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10.1
Volume of blood sampling 
Each individual blood sample volume is detailed below. The volumes for individual samples may 
vary accordingly to local laboratory requirements, however the total volume is not expected to 
exceed 500 mL per subject.
Biochemistry/ hematology
6 mL
LH
3.5 mL
FSH 
4 mL
PK
6 mL
Estradiol, testosterone, ACTH, cortisol, TSH, T3 and T4 
4 mL
10.2
Efficacy assessments
10.2.1
Hot flash paper-diaries 
Subjects will document the number of individual hot flashes experienced and rate the severity of 
each on a scale of 1 to 3 (mild, moderate or severe). The diaries are to be completed twice daily, 
in the morning and evening. The diaries are to be completed for the 2 weeks prior to Baseline 
visit to ascertain eligibility and from Screening until the morning of Day 15 (the last entry being 
the information from overnight). Subjects will also record the number of times that they were 
awake through the night (night time awakening [NTA]), secondary to hot flashing.
10.2.2
Day time continuous hot flash diary
Whilst in the clinic on Days -1, 1 through 7 and Day 14, subjects will record each hot flash and 
severity (scale of 1 to 3) in the hot flash paper-diary as they occur during the day and night.
Subjects will also be required to push a button on the skin conductance monitor (see Section 
10.2.3) when they sense a hot flash and then record the event in the diary. For Day -1 and Day 14 
subjects will be provided with the continuous diary at the previous visit and instructed to start 
completing it upon waking in the morning on Day -1 and Day 14 prior to admission to the unit.
10.2.3
Sternal skin conductance monitors 
Studies have shown that rather than over-reporting hot flashes when they do not occur, women 
tend to under report them when asked to complete hot flash diaries, thus leading to inaccuracy. 
Objective assessment is therefore useful and can be achieved using a sternal skin conductance 
monitor [Bahr et al., 2014]. Sternal skin conductance monitors will be fitted on Day -1 (24 hours
± 1 hour prior to the planned study drug administration on Day 1) and will remain in place until 
after the Day 7, 24 hour assessments are completed (Day 8).
The sternal skin conductance monitors will be refitted around 30 minutes prior to study drug 
administration on Day 14 and remain in place until after the 24 hour assessments are completed 
on Day 15.


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Subjects will be required to push a button on the skin conductance monitor when they sense a hot 
flash when fitted with the monitor and then provide details of the hot flash in the continuous hot 
flash diary.
10.2.4
Luteinizing hormone 
Blood samples for analysis of LH will be collected every 60 minutes from time 0 (pre-dose) to 8 
hours on Day 1 and Day 7. The same sampling schedule will also be followed on Day -1, starting 
at a similar time to that planned for Days 1 and 7.
LH samples will be collected as close to the nominal time point as possible. The allowable 
window for LH sample collection relative to dosing will be ± 5 minutes.
10.3
Pharmacokinetics
Blood samples for PK analysis will be collected at the following time points on Day 1 and Day 7:
Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours
On Day 14 blood samples will be taken for PK analysis at the following time points:
Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0, 48.0, 72.0 hours
The pre-dose sample will be collected within 30 minutes prior to dose administration. On Days 1 
and 7 the 24 hour PK sample must be taken prior to the dose of study medication the following 
morning.
Blood samples may be collected via a cannula or by direct venipuncture.
Pharmacokinetic samples will be collected as close to the nominal time point as possible. 
Allowable windows for PK sample collection relative to dosing (the dose at the start of the PK 
profile) will be as follows: ± 2 minutes up to and including 2 hours post-dose, ± 5 minutes up to 
and including 8 hours post-dose, ± 10 minutes up to and including 24 hours post-dose; ± 30 
minutes up to and including 72 hours post-dose.
The visits on Days 16 and 17 must be scheduled to enable the samples to be taken at 48 and 72 
hours, ± 30 minutes, relative to the final dose on Day 14.
10.3.1
Sample transfer and assay methodology
Plasma analysis will be performed under the management of Aptuit, SRL, Italy. Concentrations 
of NT-814 will be determined in plasma using the current Sponsor-approved analytical 
methodology.  Raw data will be stored in the Good Laboratory Practice Archive of Aptuit. Please 
refer to the laboratory manual for further details.


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Plasma concentration data will be transferred to Parexel International, USA, who will be 
responsible for generating the relevant tables and listings, and performing the PK analysis as 
described in Section 11.3.3.
10.4
Safety assessments
10.4.1
Medical history and concomitant diseases
The investigator must record all medically and clinical relevant information regardless of the time 
since the date of diagnosis.
History should include (but is not limited to):
x
All current and past medications taken during 3 months before the Screening Visit 
x
Relevant history of respiratory, cardiovascular, renal, gastro-intestinal, hepatic, endocrine, 
hematological, neurological, psychiatric and any other diseases
10.4.2
Physical examinations
A full physical examination will be conducted at the time points indicated in the Study Schedule 
in Table 2.  This will be completed by a physician or an appropriate qualified delegate.
A full physical examination is composed of a review of the following body systems:
-
General appearance
-
Skin
-
Head, eyes, ears, nose and throat
-
Respiratory
-
Cardiovascular
-
Abdomen (including liver and kidneys)
-
Musculoskeletal
-
Neurological
Any abnormalities that are identified at the Screening Visit will be documented on the medical 
history eCRF page. Any changes (including new and worsening findings) between the Screening 
Visit and final study visit should be captured as AEs on the AE eCRF page, as determined by the 
Investigator and documented in the subject’s notes.
If an improvement/resolution of a physical examination finding documented in the subject’s 
medical history occurs during the study, it should be recorded in the source document.  If there is 
resolution of a physical examination finding previously noted as an AE, then the event resolution 
and stop date should be recorded on the AE eCRF page and documented in the subject’s notes.


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10.4.3
24-hour Holter monitoring 
Subjects will be fitted with Holter monitors upon admission to the Phase 1 unit on Day -1. These 
will remain in place until after the 24-hour assessments are completed on Day 7 (Day 8). Subjects 
will be fitted with Holter monitors again upon admission to the clinic on Day 14. These will 
remain in place until after the 24-hour assessments are completed on Day 14 (Day 15).
10.4.4
12-lead ECGs
12-lead ECG data captured by the Holter monitors will be collected at the timepoints indicated in 
the Study Schedule in Table 2.
On Days 1 and 14, resting 12-lead ECG data will be collected at the following timepoints:  pre-
dose and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 8.0, 12.0 and 24.0 hours (all +/- 15 mins).
The same assessment schedule is also required on Day -1, starting at a similar time to that 
planned for Days 1 and 14. On Day 1 the 24 hour ECG must be performed prior to the dose of 
study medication the following morning.
Once daily ECG recordings will be made just prior to dosing (approx. 30 mins) on all other days 
during the inpatient stay (Days 3 to 8).
These specific 12-lead ECG recordings should be collected in accordance with the priority order 
of study assessments detailed in Section 10.5.
10.4.5
Biochemistry
Blood for biochemistry assessments will be collected as indicated in the Study Schedule (Table 
2). The following clinical chemistry/ biochemistry parameters will be assessed: sodium, 
potassium, glucose, urea, creatinine, creatine kinase, albumin, calcium, phosphate, bilirubin 
(total), alkaline phosphatase, AST, ALT, gamma-glutamyl transferase (GGT), bicarbonate, 
magnesium, chloride, total protein, total cholesterol, low-density lipoprotein (LDL), high-density 
lipoprotein (HDL), triglycerides.
10.4.6
Hematology
Blood for hematology assessments will be collected as indicated in the Study Schedule (Table 2). 
The following hematology parameters will be assessed: RBC, WBC, hematocrit, hemoglobin,
MCV, platelets, WBC differentials, prothrombin time, activated partial thromboplastin time 
(APTT).
10.4.7
Urinalysis
Urinalysis assessments will be conducted as indicated in the Study Schedules (Table 2). 
Urinalysis will include glucose, bilirubin, ketones, specific gravity, blood, pH, protein, 
urobilinogen, nitrites, leucocytes, sedimentation.


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10.4.8
Hormone level assessments
Blood samples will be collected to assess estradiol, testosterone, FSH, ACTH, cortisol, TSH, T3 
and T4 when the subjects are admitted to the unit on Day -1 and again prior to discharge on 
Day 15.
10.4.9
Vital signs
Vital signs will be measured at the time points indicated in the Study Schedule (Table 2) and will 
include sitting and standing BP, heart rate, pulse oximetry, oral body temperature, respiration rate
and weight.
10.5
Priority order of study assessments
At certain time points, several assessments will be required at the same time. In these cases, the 
following ‘priority order’ will be followed: 
x
Resting 12-lead ECG 
x
Vital signs
x
PK time-points (to be collected closest to the assigned time-point)
10.6
Adverse events
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, such as 
“How are you feeling?” It is also important to question the subject in a non-leading way about 
changes in their health or concomitant medication usage since their last visit. All AEs will be 
recorded from the time the informed consent is signed until study exit, and are recorded on the 
appropriate pages in the eCRF and in source documents. Appropriate follow-up will be required 
for any adverse events ongoing at study exit.
Serious Adverse Events (SAEs) occurring up to 30 days after the last dose of study medication 
should be reported.
10.6.1
Definitions
Adverse Event (AE)
Any untoward medical occurrence in a subject or clinical trial subject administered a medicinal
product and which does not necessarily have a causal relationship with this treatment.  An 
adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
Adverse Drug Reaction (ADR)
All events considered being untoward and unintended responses to a medicinal product related to 
any dose should be considered adverse drug reactions. The definition covers also medication 
errors and uses outside what is foreseen in the protocol, including misuse and abuse of the 
product. The phrase “responses to a medicinal product” means that a causal relationship between 


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a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.
Serious Adverse Event (SAE)
An adverse event that at any dose:
x
Results in death
x
Is life-threatening (i.e. the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe)
x
Requires inpatient hospitalization or prolongation of existing hospitalization (see 
explanation below)
x
Results in persistent or significant disability/incapacity
x
Is a congenital anomaly/birth defect
x
Is considered to be an important medical event
Based upon medical and scientific judgment, important medical events that may not be 
immediately life-threatening, or result in death or hospitalization, but may jeopardize the subject
or may require intervention to prevent one of the other outcomes listed in the definition above 
may be considered a serious adverse event.
Hospitalizations are defined as initial or prolonged admissions that include an overnight stay. 
Hospitalization or prolonged hospitalization for technical, practical or social reasons, in the 
absence of an adverse event is not an SAE.
An additional blood sample for the determination of NT-814 plasma levels should be taken in 
case of SAEs with reasonable possibility of relatedness to the study drug.  The analysis of such 
PK samples will be conducted as soon as possible after the occurrence of the SAE.
Pregnancy
Pregnancy itself is not considered an AE. However, any pregnancy complication, spontaneous or 
elective abortion (for medical reasons), still birth, neonatal death, or congenital anomaly will be 
recorded as an AE or SAE.
Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with applicable product 
information (e.g., IB for an unapproved investigational medicinal product).
Reports which add significant information on the specificity, increase of occurrence, or severity 
of a known, already documented serious adverse reaction constitute unexpected events.
Suspected Unexpected Serious Adverse Reaction (SUSAR)
A serious adverse event that is suspected to be related to the administered medicinal product and 
the nature or severity of which is not consistent with applicable product information.


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10.6.2
Assessment of causality
Severity
The severity (intensity) of each adverse event will be classified as:
x
Mild
Awareness of sign or symptom, but easily tolerated
x
Moderate
Sign or symptom causes discomfort, but does not interfere with normal             
activities
x
Severe
Sign or symptom of sufficient intensity to interfere with normal activities
Causality
An Investigator who is a qualified in medicine must make the determination of the relationship to 
study treatment for each AE.
The likely relationship of each adverse event to the medicinal product will be assessed according 
to the definitions below:
x
Unrelated
x
Possibly
x
Probably
x
Definitely
10.6.3
Serious Adverse Event reporting
Once the Investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to the Medical Monitor within 24 hours.  Any follow-up information on a 
previously reported SAE will also be reported to the Medical Monitor within 24 hours.
If the Investigator does not have all information regarding an SAE, he/ she will not wait to 
receive additional information before notifying the Medical Monitor of the event and completing 
the appropriate data collection form.  The Investigator will always provide a preliminary 
assessment of causality at the time of the initial report as described in Section 10.6.2.
The primary mechanism for reporting SAEs to the Medical Monitor will be a paper collection 
form.
The Medical Monitor contact details for SAE receipt can be found at the beginning of this 
protocol on the Sponsor/ Medical Monitor Contact Information page.
The contact details for reporting SAEs are as follows:
Fax transmission or ‘scan & email’ of the SAE form is the preferred method to transmit this 
information to the project contact for SAE receipt.  In rare circumstances and in the absence of 
fax equipment, notification by telephone is acceptable, with a copy of the SAE data collection 
form sent by overnight mail.  Initial notification via the telephone does not replace the need for 


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the Investigator to complete and sign the SAE data collection form within the designated 
reporting periods
All SUSARs, which occur with the investigational products within or outside the concerned 
clinical trial, if required, will be reported in compliance with the applicable regulatory authorities 
and Institutional Review Boards (IRBs). Fatal or life-threatening SUSARs must be reported 
within 7 calendar days and other SUSARs within 15 calendar days.
All investigators will receive a safety letter notifying them of relevant SUSAR reports. Each 
Investigator must then notify his or her Institutional Review Board (IRB) of the SAE as required 
by local regulatory authorities and in accordance with IRB policy. NeRRe will submit to the 
regulatory authorities all safety updates and periodic reports, as required by applicable regulatory 
requirements. 
10.7
Safety review committee
After each cohort, the Safety Review Committee will evaluate the safety, tolerability and PK up 
to 14 days of dosing with NT-814 to determine escalation to the next dose in Cohorts 2 and 3 and
the doses for Cohorts 4 and 5 (if applicable). Safety data to be reviewed will include, but is not 
limited to, AEs, vital signs, Holter monitoring data and available laboratory parameters. This 
review must comprise complete data up to Day 15 from a minimum of 14 subjects per cohort. 
The Safety Review Committee will be comprised of the Principal Investigator, Medical Monitor, 
appropriate Sponsor and CRO representatives.
Following review of data from a cohort of subjects, the timing of assessments and/or blood 
samples may be adjusted for subsequent cohorts. Additional assessment or sampling times may 
be added if indicated by the data; however, the maximum blood volume taken from each subject 
will not exceed 500 ml.
In the event that study stopping criteria have not been met, but the Safety Review Committee do 
not feel that it is appropriate to escalate to the next planned dose, the subsequent Cohort may be 
dosed at any of the previous dose levels, in order to confirm safety and PK data for this dose.
In the case of any safety concern or any ambiguous data, during any one of the cohorts, either 
individual subjects or the entire cohort may be unblinded to enable decision making. In this 
eventuality a separate un-blinded Safety Review Committee will be used to maintain the integrity 
of following cohorts. Details will be outlined in the Safety Review Committee Charter. 


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11.
STATISTICAL CONSIDERATIONS
The primary objective of the study is to evaluate the PK and safety profile of multiple doses of 
NT-814 compared to placebo by daily administration of each dose for 14 days. No primary 
hypothesis test is pre-specified for this Phase I study.
11.1
Estimated sample size
The planned sample size is 20 subjects per cohort, with 15 active and 5 placebo. This is deemed 
enough to provide sufficient separation of exposures between dose groups and to allow for an 
assessment of safety versus dose group/exposure. Assuming a standard deviation on the log scale 
of 0.413 for plasma AUC0-24 (based on Day 7 mean AUC0-24 data for 200 mg from study 
MNK111857), 15 active subjects per cohort provides close to 80% power at a type I error rate of 
0.1 to detect a difference from one in the ratio of geometric means between the two highest 
possible dose levels (and greater than 90% power for the middle two dose levels) given the 
previously seen slightly greater than dose proportionality increase in systematic exposure. The 
placebo subjects are included primarily to provide a reference group for comparison of safety in 
the target population.
11.2
Analysis sets
The following data sets will be used for the statistical analysis.
1. Safety Set: All subjects who receive at least one dose of double-blind study drug. 
Subjects will be analyzed according to treatment received.
2. Pharmacokinetic (PK) Set: all subjects who received at least one dose of active study 
drug and for whom the PK data are considered sufficient.
3. Full Analysis Set (FAS): All randomized subjects who received at least one dose of 
double-blind study drug and for whom the efficacy data are considered sufficient and 
interpretable. Subjects will be analyzed according to randomized treatment. 
Analysis Sets will be identified prior to the unblinding of the study data.
11.3
Data analysis
More details of the proposed statistical analysis will be documented in the statistical analysis plan 
(SAP), which will be written following finalization of the protocol and finalized prior to the 
breaking of the blind. PK, safety and efficacy data will be presented by means of descriptive 
statistics and figures, as appropriate, by treatment. Data for the placebo subjects will be combined 
across cohorts prior to any summaries. 
Summary statistics will be based primarily on non-missing values. 


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Full details on the handling of missing values, including rules applied to incomplete 
questionnaires (including incomplete diary entries) will be defined in the SAP. 
Raw data will be listed. 
11.3.1
Baseline assessment
Descriptive statistics will be performed on relevant screening and baseline data (i.e. data 
collected prior to the treatment administration) and on demographic characteristics for each 
treatment group. 
11.3.2
Safety analysis methodology
The safety and tolerability profile will be assessed versus baseline conditions and differences 
between treatment groups and descriptive statistics will be produced, where applicable. 
A treatment-emergent analysis will be done for AEs. AEs will be tabulated by MedDRA 
preferred term and system organ class. Tabulations by severity and drug-relatedness will also be 
made.
A concentration-effect model will be built investigating ECG assessments versus plasma 
concentrations.
Extent of exposure and compliance will be evaluated.
11.3.3
Pharmacokinetic analysis methodology
Plasma concentration versus time data for NT-814 will be evaluated by standard non-
compartmental analysis using appropriate software. Individual plasma concentration versus time 
profiles for each subject and mean and median plasma concentration versus time profiles by dose 
will be generated. The following PK parameters will be log-transformed prior to statistical 
analysis: AUC0-t, AUC0-τ, AUC0-∞, Cmax, CL/F, and t½.
For each of the parameters the following summary statistics will be calculated and tabulated by 
treatment: n, arithmetic mean, 95% CI (confidence interval) for the arithmetic mean, standard 
deviation, minimum, median, maximum, geometric mean, 95% CI for the geometric mean, and 
standard deviation of log-transformed data. Between-subject coefficient of variation (%CVb) will 
also be calculated.
For tmax, tlag, n, median, minimum, maximum, arithmetic mean, 95% CI for the arithmetic 
means and standard deviation will be calculated. 
Accumulation and time invariance will be evaluated by comparisons of Day 1 AUC0-24 versus 
Days 7 and 14 and Day 1 AUC0-∞versus AUC0-24 Days 7 and 14 respectively.
Dose proportionality will be assessed on Day 7 (AUC0-24 and Cmax).


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11.3.4
Exploratory analyses
Analysis of efficacy data will be primarily descriptive. Derivations of the efficacy endpoints will 
be provided in the SAP. Exploratory dose response and PK-PD analyses may be conducted. Any 
statistical hypothesis tests and/or confidence intervals will be two sided, using a type I error rate 
of 0.1. No adjustments will be made for multiplicity in this early phase study.
11.4
Study specific data analysis
At the end of each Cohort a blinded review of PK and safety data will be conducted by the 
Principal Investigator, Medical Monitor and Sponsor team to confirm whether it is considered 
safe to continue to the subsequent dose.  Dose escalation will not occur if the exposure of NT-814 
is predicted to exceed a geometric mean AUC of 20950 ng.h/mL (2-fold safety margin). 
In the case of an ambiguous decision, all data may be unblinded to help with the dose escalation 
decisions. 
12.
END OF THE STUDY
The end of the study will be defined as the last subject’s last visit.
13.
IRB REVIEW/INFORMED CONSENT
13.1
Institutional Review Board (IRB) and relevant authorities
The final study protocol and the subject information and consent form will be approved by an 
appropriately constituted independent Institutional Review Board (IRB).  Approval will be 
received in writing before initiation of the study.
Clinical Trial Authorization will be obtained prior to initiation of the study from the U.S. Food 
and Drug Administration (FDA).
13.2
Ethical conduct of the study
The study will be performed in accordance with the local regulations, the principals of Good 
Clinical Practice (GCP) as described by the International Council for Harmonization (ICH), and 
the ethical principles that have their origins in the Declaration of Helsinki.
13.3
Informed consent
For each study subject, written informed consent will be obtained prior to any protocol-related 
activities.  As part of this procedure, the principal investigator or one of his associates will 
explain orally and in writing the nature, duration, purpose of the study, and the action of the study 
drug in such a manner that the subject is aware of the potential risks, inconveniences, or adverse 
effects that may occur.  They will be informed that their medical records may be reviewed by 
appropriately qualified monitors of the Sponsor or Sponsor Representative, and by auditors or 
regulatory authorities to ensure the accuracy of the details recorded as part of the study.  They 
will be informed that they may withdraw from the study at any time without prejudice to further 


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treatment.  They will receive all information that is required by local regulations and ICH 
guidelines. 
14.
STUDY AND DATA MANAGEMENT
14.1
Protocol amendments
Once approved by the applicable Regulatory Authorities and IRBs, the protocol must not be 
amended without approval by NeRRe. Unless an amendment is required to be implemented 
urgently in the interests of safety, any amendments to the protocol must be authorized by the 
applicable Regulatory Authorities and IRB prior to implementation.
14.2
Monitoring
In accordance with applicable regulations including GCP and NeRRe or delegated CRO’s 
Standard Operating Procedures (SOP), approved clinical research monitors will contact the site 
prior to the start of the study to review with the site staff the protocol, study requirements, and 
their responsibilities to satisfy regulatory, ethical, and NeRRe requirements. When reviewing data 
collection procedures, the discussion will also include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document.  A list of 
what is to be classed as ‘source documentation’ will be documented in the Study Monitoring 
Manual.
NeRRe will monitor the study and sites to verify that the:
x
Data are authentic, accurate and complete.
x
Safety and right of the subjects are being protected
x
Investigational Product accountability
x
SAE reporting
x
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP and all applicable regulatory requirements.
The Investigator agrees to allow the monitor direct access to all relevant documents.
14.3
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, NeRRe may conduct 
a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this 
study. Such audits/ inspections can occur at any time during or after completion of the study. If 
an audit or inspection occurs, the Investigator and institution agree to allow the auditor/ inspector 
direct access to all relevant documents and to allocate his/ her time and the time of his/ her staff 
to the auditor/ inspector to discuss findings and any relevant issues.


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14.4
Data recording
14.4.1
Case report form
An eCRF will be used to capture subject data. Access to enter data in the eCRF will be limited to 
delegated and trained investigator site staff only.
100% of data in the eCRF will be source data verified by monitors.
14.5
Confidentiality
Study data will be handled with utmost discretion within the context of physician’s 
confidentiality. On the eCRFs and other study specific documents, subjects are not identified by 
their names, but by a unique subject number. Names of participating subjects and data generated 
as a result of this study will not be passed on to unauthorized persons.
The Investigator must assure that the subjects are properly anonymized throughout the study.  On 
all study documentation which is supposed to leave the site (i.e., to be transmitted to NeRRe, 
CRO or third parties), subjects will only be identified by their unique identification code and will 
not be referred to by name.
NeRRe may transfer some data collected during the study to a different company or regulatory 
authority outside of the US for the purpose of processing, review, analysis or storage. Whenever 
the subject’s personal data is transferred, it will be kept confidential and secure, and will used 
only for the purpose for which it was collected.
Safety analysis samples collected during the study will be analyzed at the local hospital facility 
per local procedures. As such samples will not be leaving the local hospital laboratory facility;
there will be no specific study requirements to make the samples anonymous. All safety samples
will be destroyed after the assays have been completed.
NT-814 PK samples will be shipped to Aptuit Srl, Italy for analysis. Analysis will be conducted 
after each cohort with the results included in the final study report. Following completion of the 
analysis, all samples will be destroyed.
14.6
Retention of study data
Following closure of the study, the Investigator must maintain all site study records, except for 
those required by local regulations to be maintained by someone else, in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff. Where permitted by 
local laws/ regulations or institutional policy, some or all of these records can be maintained in a 
format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The Investigator must assure that all reproductions are 
legible and are a true and accurate copy of the originals, and meet accessibility and retrieval 


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standards, including re-generating a hard copy, if required. Furthermore, the Investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.
NeRRe will inform the Investigator of the time period for retaining these records to comply with 
all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or local 
laws or regulations, or NeRRe, or delegated CRO’s SOPs; otherwise, the retention period will 
default to 15 years.
The Investigator must notify NeRRe of any changes in the archival arrangements, including, but 
not limited to, archival at an off-site facility or transfer of ownership of the records in the event 
the Investigator leaves the site. The Investigator may not dispose of any records without prior 
approval from NeRRe.
14.7
Communication and publication of results
Where required by applicable regulatory requirements, an Investigator signatory will be identified 
for the approval of the clinical study report (CSR). The Investigator will be provided appropriate 
access to statistical tables, figures, and relevant reports and will have the opportunity to review 
the complete study results at NeRRe or another mutually agreeable location.
The original eCRFs and all data generated during the study under this protocol will become the 
property of the Sponsor.
Upon completion of the CSR, NeRRe will ensure public disclosure of the clinical trial research 
results according to the NeRRe’s SOP and provide the Investigator with the full summary of the 
study results. The Investigator is encouraged to share the summary results with the study subjects, 
as appropriate. 
It is the intent of all parties that the results of the study be published in a timely manner consistent 
with academic standards and with due consideration given to the protection of intellectual 
property rights. The Principal Investigator and NeRRe will be responsible for assembling the 
proposed publication; this must happen with due diligence and with minimal delay. 
Any proposed publication or presentation (including a manuscript, abstract or poster) for 
submission to a journal or scientific meeting should be sent to the Sponsor for review at least one 
month prior to submission. The Sponsor's comments on the proposed publication shall be 
considered in good faith by the authors.  Sponsor may delay such submission by a maximum of 
ninety (90) days if it reasonably believes that publication of results may compromise its 
intellectual property rights or else insist that such information or data is removed from the 
proposed publication. Publication of the results will not include confidential information without
the permission of the Sponsor.


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14.8
Indemnification
In the event of study-related damage or injuries, the clinical trial insurance of the Sponsor 
provides compensation for claims that arise in accordance with the regulatory requirements of the 
countries involved, except for claims that arise from willful misconduct or gross negligence. A 
copy of the country-specific insurance certificates will be held in the TMF and in the Investigator 
site file.  


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Menopause-specific questionnaire assessment in US population-based study shows negative 
impact on health-related quality of life. 
Maturitas. 2009 Feb 20;62(2):153-9.


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SAP_001.pdf: 
 
 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
Evaluation of the Pharmacokinetics and Safety of NT-814 in Post-
Menopausal Women With Vasomotor Symptoms 
NCT Number: 
NCT02865538 
Document Date: 
Statistical Analysis Plan 27 February 2017 
Statistical Analysis Plan for Pharmacokinetics 05 May 2017 
 


NeRRe Therapeutics Ltd 
Protocol No: RELENT-1 
CONFIDENTIAL 
 
Final Report Version 1.0 dated 07 November 2017 
 
Appendix 16.1.9 
Documentation of Statistical Methods 
 
 
 
 
Statistical Analysis Plan (Final Version 2.0) 27 February 2017 
 
 
Statistical Analysis Plan for Pharmacokinetics (Final Version 1.0) 05 May 2017 
 
 


 
Confidential 
Page 1 of 52 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
EVALUATION OF THE PHARMACOKINETICS AND SAFETY OF 
NT-814 IN POST-MENOPAUSAL WOMEN WITH VASOMOTOR 
SYMPTOMS 
 
 
SAP Version 2.0 
FINAL 
Date: 27 February 2017 
 
for 
 
Protocol No. RELENT-1 
 
 
Submitted to: 
NeRRe Therapeutics Ltd, 
SBC, Incubator Building, 
Gunnels Wood Rd., 
Stevenage, 
SG1 2FX 
UK 
 
Prepared by: 
ICON Early Phase Services 
820 West Diamond Avenue, Suite 100 
Gaithersburg, Maryland 20878 USA  
Phone: 
 
Fax: 
 
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NeRRe Therapeutics Ltd. 
Protocol No. RELENT-I 
ICON Project No. 3651000 I 
Statistical Analysis Plan FINAL v2.0 
27Feb2017 
ICON CLINICAL RESEARCH LLC (ICON) SIGNATURE PAGE (all section except 
section 8.11.7) 
ICON Authors: 
 
06 Mar 2017 16:20:023+0000 
I approve this document. 
 
ICON Reviewers: 
o7Mar201703:39:024+oooo 
Date 
I have reviewed this document and have no comments that require addressing. 
 
o6 Mar 2011 20:2a:o17+oooo 
l approvetliisdocullleut. 
 
08Mar201715:08:014+0000 
lapprove thisdocument. 
ICON Approvals: 
 
06 Mar 2017 16:28:042+0000 
I approve tbjs document 
Confidential 
Date 
Date 
Date 
Date 
OocUUIO : 9f'96b4ca..f974-49e1-a41d .. 26a27b92b87 
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DocUUID : 9f96b4ca-f974-49e1-a41d-e26a27b92b87
:-.ieRRe Therapeutic · Ltd. 
Protocol t-:o. REL NT-I 
IC01 Pro' ect No. 
651000 I 
ICARDIAC 
PAGE (SECTION 8.1 1.7) 
Confidential 
Statistical Analysis Plan FINAL v2.0 
27 Feb 2017 
Date 
Date 
Page 3 of 52 
OocUUIO : 
... 26a27b92b87 
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DocUUID : 9f96b4ca-f974-49e1-a41d-e26a27b92b87
NeRRe Therapeutics Ltd. 
Protocol No. R.ELE T -I 
IC01 Project No. 3651000 I 
NERRE THERAPEUTICS SIGNATURE PAGE 
NeRRe Therapeutics Approvals: 
Confidential 
Statistical Analysis Plan FINAL v2.0 
27Feb2017 
OJ rv\A(<. l Oit 
Date 
l Mil( 
Date 
Page 4 of 52 
DocUUIO : 9f96b4ca-f974-49e1-a41d-e26a27b92b87 
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NeRRe Therapeutics Ltd. 
Protocol No.  RELENT-1 
ICON Project No.  36510001 
Statistical Analysis Plan FINAL v2.0 
27 Feb 2017 
 
 
 
Confidential 
Page 5 of 52 
 
TABLE OF CONTENTS 
ICON CLINICAL RESEARCH LLC (ICON) SIGNATURE PAGE (ALL 
SECTION EXCEPT SECTION 8.11.7) ....................................................... 2 
ICARDIAC SIGNATURE PAGE (SECTION 8.11.7)................................................. 3 
NERRE THERAPEUTICS SIGNATURE PAGE ....................................................... 4 
TABLE OF CONTENTS ............................................................................................... 5 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............. 8 
2 
INTRODUCTION ........................................................................................ 10 
3 
STUDY OBJECTIVES AND ENDPOINTS .............................................. 11 
3.1 
Primary Objective ................................................................................. 11 
3.2 
Exploratory Objectives ......................................................................... 11 
3.3 
Pharmacokinetic Endpoints ................................................................. 11 
3.4 
Safety Endpoints ................................................................................... 11 
3.5 
Exploratory Endpoints ......................................................................... 12 
4 
STUDY DESIGN .......................................................................................... 14 
4.1 
General ................................................................................................... 14 
4.2 
Study Population ................................................................................... 16 
4.3 
Evaluations at Screening and Check-in .............................................. 16 
4.3.1 
Screening................................................................................................. 16 
4.3.2 
Check-in .................................................................................................. 17 
4.4 
Randomization and Treatment Assignments ..................................... 17 
4.5 
Study Drug Administration ................................................................. 18 
4.6 
Concomitant Medications .................................................................... 18 
4.7 
Compliance ............................................................................................ 20 
4.8 
Evaluation of Efficacy........................................................................... 20 
4.8.1 
Hot Flash Diaries .................................................................................... 20 
4.8.1.1 
Twice Daily Diaries ................................................................................ 20 
4.8.1.2 
Continuous Diaries.................................................................................. 20 
4.8.2 
Sternal Skin Conductance Monitors ....................................................... 20 
4.8.3 
Luteinizing Hormone Analysis ............................................................... 21 
4.9 
Pharmacokinetic Sampling Schedule .................................................. 21 
4.10 
Evaluation of Treatment Safety ........................................................... 21 
4.10.1 
Adverse Events ....................................................................................... 21 
4.10.1.1 Definitions............................................................................................... 21 
4.10.1.2 Severity and Relatedness Assessment .................................................... 23 
4.10.2 
Clinical Laboratory Assessments ............................................................ 23 
4.10.3 
Vital Signs ............................................................................................... 24 


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4.10.4 
Twenty-four-hour Holter Monitoring ..................................................... 24 
4.10.5 
Electrocardiograms ................................................................................. 24 
4.10.6 
Physical Examinations ............................................................................ 24 
4.10.7 
Medical History and Concomitant Diseases ........................................... 25 
4.11 
Protocol Deviation Reporting .............................................................. 25 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS ................................................................................................... 26 
6 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS 
FOR DATA ANALYSIS .............................................................................. 27 
7 
PHARMACOKINETIC ASSESSMENTS ................................................. 28 
7.1 
Pharmacokinetic Assessments ............................................................. 28 
8 
STATISTICAL METHODS ....................................................................... 29 
8.1 
General ................................................................................................... 29 
8.2 
Handling of Dropouts or Missing Data ............................................... 29 
8.3 
Multicenter Studies ............................................................................... 30 
8.4 
Examination of Subgroups ................................................................... 31 
8.5 
Analysis Populations ............................................................................. 31 
8.6 
Subject Accountability.......................................................................... 31 
8.7 
Protocol Deviation Reporting .............................................................. 31 
8.8 
Subject Demographics and Baseline Characteristics ........................ 32 
8.9 
Study Drug Exposure and Compliance............................................... 32 
8.10 
Analysis of Efficacy Data...................................................................... 32 
8.10.1 
Twice Daily Hot Flash Paper Diaries ..................................................... 32 
8.10.1.1 Frequency of Hot Flashes ....................................................................... 32 
8.10.1.2 Hot Flashes Average Severity ................................................................. 33 
8.10.1.3 Hot Flashes Severity Score ..................................................................... 34 
8.10.1.4 Night Time Awakenings ......................................................................... 35 
8.10.2 
Continuous Hot Flash Diary ................................................................... 35 
8.10.2.1 Frequency of Hot Flashes ....................................................................... 35 
8.10.2.2 Night Time Awakenings ......................................................................... 36 
8.10.3 
Sternal Skin Conductance Monitors ....................................................... 37 
8.10.4 
Luteinizing Hormone .............................................................................. 38 
8.10.5 
Relationship Between PK Exposure and Responses .............................. 38 
8.11 
Analysis of Safety Data ......................................................................... 38 
8.11.1 
General .................................................................................................... 38 
8.11.2 
Adverse Events ....................................................................................... 39 
8.11.3 
Clinical Laboratory Assessments ............................................................ 40 
8.11.4 
Vital Signs ............................................................................................... 40 
8.11.5 
Safety Electrocardiograms ...................................................................... 40 
8.11.6 
24-hour Holter Monitoring ..................................................................... 41 
8.11.7 
Relationship Between Plasma Concentrations and Placebo-Corrected, 
Change from Baseline QTcF .................................................................. 41 


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8.11.8 
Physical Examinations ............................................................................ 43 
8.11.9 
Prior and Concomitant Medications and Procedures .............................. 43 
8.12 
Sample Size ............................................................................................ 44 
8.13 
General Conventions for Tables, Listings and Figures ..................... 44 
9 
TABLES, FIGURES, AND LISTINGS ...................................................... 45 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Explanation 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-24 
AUC from time 0 to 24 hours 
AUC0-8 
AUC from time 0 to 8 hours 
AUC0-∞ 
AUC from time 0 to infinity 
AUC0-t 
AUC from time 0 to the time of the last quantifiable concentration 
AUC0-τ 
AUC during a dosage interval 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CPU 
Clinical Pharmacology Unit 
CRF 
case report form 
CYP 
cytochrome P450 
DMP 
Data Management Plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FSH 
follicle stimulating hormone 
HR 
heart rate 
ICH 
international conference on harmonization 
IMP 
investigational medicinal product 
LH 
luteinizing hormone 
MedDRA 
medical dictionary for regulatory activities 
N.B. 
nota bene 
No. 
number 
NTA 
night time awakening 
PK 
pharmacokinetic 


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PR 
atrioventricular nodal delay 
PT 
preferred term 
QD 
once daily 
QRS 
ventricular depolarization 
QT 
electrical depolarization and repolarization of the ventricles 
QTcB 
corrected QT by Bazett's formula 
QTcF 
corrected QT by Fridericia’s formula 
RR interval 
time between heart beats used to calculate heart rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
T3 
triiodothyronine 
T4 
thyroxine 
t½ 
terminal elimination half-life 
Tmax 
the time that Cmax was observed 
TSH 
thyroid-stimulating hormone 
 


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2 
INTRODUCTION 
This statistical analysis plan (SAP) is consistent with the statistical methods section of the study 
protocol (version 4.0 dated 13 December 2016) and includes additional detail of safety and 
efficacy summaries to be included in the clinical study report. The bioanalyses will be performed 
by Aptuit Medicines Research Centre and the pharmacokinetic (PK) analyses will be done by 
Parexel and described in a separate document. 


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3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
The primary objective is to evaluate the PK and safety profile of multiple ascending dose levels 
of NT-814, compared to placebo, by once daily administration of each dose for 14 days. 
3.2 
Exploratory Objectives 
The exploratory objectives are as follows: 
• 
To assess effects of multiple, single daily doses of NT-814, compared to placebo, on hot 
flash frequency and severity using objective and subjective measures. 
• 
To investigate the relationship between PK exposure and hot flash measures, if data 
permit. 
• 
To explore the relationship between plasma concentrations and placebo-corrected change 
from baseline QTcF and QTcB values using concentration effect modeling, depending on 
the results observed. 
3.3 
Pharmacokinetic Endpoints 
The PK endpoints include:  
• peak concentration (Cmax) 
• time of occurrence of Cmax (Tmax) 
• area under the curve (AUC) from time zero to the time of the last quantifiable 
concentration (AUC0-t) 
• AUC in the dosing interval (AUC0-τ, synonymous with AUC0-24) 
• AUC from time zero extrapolated to infinity (AUC0-∞)  
• apparent terminal phase half-life (t½) 
• apparent clearance (CL/F) 
The PK parameters will be derived on Day 1, Day 7, and Day 14, as appropriate.     
3.4 
Safety Endpoints 
The safety endpoints are as follows: 
• 
Physical examinations 


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• 
Analysis for arrhythmias by continuous Holter monitoring from Day -1 to Day 8 and 
Day 14 (24 hours) 
• 
Abnormalities on 12-lead electrocardiograms (ECGs) 
• 
Change from baseline in ECG variables (heart rate [HR], RR, PR, QRS, QT, QTcF, and 
QTcB) 
• 
Change from baseline in clinical laboratory assessments, including lipids and coagulation 
profile 
• 
Change from baseline in hormones including estradiol, testosterone, follicle stimulating 
hormone (FSH), adrenocorticotropic hormone (ACTH), cortisol, thyroid-stimulating 
hormone (TSH), triiodothyronine (T3), and thyroxine (T4) 
• 
Change from baseline in vital signs including oxygen saturation, oral temperature, and 
postural blood pressure (BP) changes 
• 
Adverse events (AEs) of dehydration (supported by changes in serum urea and creatinine, 
urinary sediment and weight and vital signs) 
• 
Nature and severity of AEs 
• 
Withdrawals due to an AE 
3.5 
Exploratory Endpoints 
The exploratory endpoints are as follows: 
• 
Change in frequency of hot flashes from predose (Day -1) as assessed by skin 
conductance 
• 
Change from baseline in frequency of moderate to severe hot flashes, hot flash average 
severity, and hot flash severity score, as measured by twice daily diary throughout the 
study 
• 
Change from baseline in frequency of hot flashes as measured by continuous day time 
diary from Day -1 predose to Day 7 and to Day 14 
• 
Change from baseline in night time awakenings (NTA) secondary to hot flashes as 
measured by twice daily diary 
• 
Change in luteinizing hormone (LH) AUC0-8 hours on Day-1 versus Day 1 and Day 7 


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• 
To explore the relationship between plasma concentrations and placebo-corrected, change 
from baseline QTcF and QTcB values using concentration effect modeling, depending on 
the results observed. 


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4 
STUDY DESIGN 
4.1 
General 
This is a multicenter, double-blind, randomized, placebo-controlled multiple ascending dose trial 
in postmenopausal women with vasomotor symptoms. 
Subjects will be recruited into a maximum of 5 sequentially-dosed cohorts; Cohort 1 (50 mg 
NT-814), Cohort 2 (100 mg NT-814), Cohort 3 (150 mg NT-814), and, if needed, 2 further 
cohorts up to 400mg NT-814. Refer to Figure 1 for the study design schematic. 
For each cohort, subjects will enter a 4 week screening period to determine eligibility. 
Twenty eligible subjects will be randomized per cohort (15 active and 5 placebo). 
During screening, each subject will be required to complete twice-daily diaries. Eligible subjects 
will demonstrate, at the baseline visit, an average 24-hour moderate to severe hot flash frequency 
of ≥ 7 and ≤ 20, based upon the average daily frequency of all available readings (at least 4 days) 
in the final week of screening (Week -1). If, at the baseline visit, subjects have an average 24-
hour hot flash frequency < 7/ day or > 20/day, they will be discontinued from the study. In 
addition, subjects who have a change of  ≥ 50% in average 24-hour hot flash frequency between 
the first and second week of screening (i.e., Week -2 and Week -1) will also be discontinued. 
Subjects will also be provided with the continuous daily diary during screening and instructed to 
start completing this on the morning of Day -1 after waking, prior to admission to the clinic, and 
to continue to complete this throughout Day -1. 
It may be necessary to extend a patient’s screening period beyond 28 days (with the approval of 
the sponsor) when a subject is held over from one cohort to the next because the original cohort 
into which they would have been enrolled is complete. If this occurs, the following safety 
procedures must be repeated such that the most recent evaluation occurs within 28 days of the 
rescheduled randomization:  
• Biochemistry and hematology 
• Vital signs 
• 12-lead ECG 
• Physical examination 
 
If the subject has completed (or partially completed) the screening twice daily Hot Flash Diary 
this must still be repeated and a new diary started on the new planned Day -15 and completed for 
the 2 weeks up to Day -2. Eligibility will be assessed on the repeated diary, not the initial one. If 
the subject had not started completing their screening diary at the time screening was put on 
hold, they will start this screening diary on the re-scheduled Day -15. 


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Eligible subjects will be admitted to the Clinical Pharmacology Units (CPUs) as inpatients on the 
morning of Day -1 and will be fitted with and instructed on use of a sternal skin conductance 
monitor and Holter monitor, which will be worn continuously until discharge from the clinic on 
Day 8. Both the Holter monitor and sternal skin conductance monitor will be refitted on return to 
the CPU on Day 14. Routine safety monitoring will be carried out to form the baseline for 
comparisons for the remainder of the study. 
On Day 1, the subjects will be randomized in a 3:1 ratio to once daily (QD) morning doses of 
NT-814 or placebo, to be taken for a total of 14 days. Subjects will be monitored as inpatients 
from Day -1 to Day 8, and will undergo blood draws for intensive PK sampling, safety 
monitoring, blood hormonal profiling, 24-hour skin conductance measurements, and continuous 
completion of hot flash diaries. 
Subjects will be discharged from the clinic on Day 8 without any monitoring devices, providing 
there are no safety concerns and will undergo dosing for a further 5 days as an outpatient. 
Subjects will be instructed to continue recording details of the hot flashes experienced, using the 
twice daily diary. They will be provided with the continuous daily diary and instructed to start 
completing this upon waking on the morning of Day 14 prior to admission to the clinic. They 
will be re-admitted to clinic on the morning of Day 14 for the final dose and undergo the same 
assessments with the same devices, including Holter and skin conductance, as Day 1. Subjects 
will be discharged following the 24-hour post Day 14 assessments (Day 15). Subjects will return 
to the clinic, as outpatients, for a single PK sample on the mornings of Days 16 and 17 (48 hours 
and 72 hours after the Day 14 dose respectively). 
Throughout the study, subject safety will be closely monitored for safety including assessments 
of AEs, 12-lead ECGs, arterial oxygen saturation using pulse oximetry, vital signs (sitting and 
standing BP, HR, oral body temperature, and respiration rate), clinical labs and physical 
examinations. 
At the end of each cohort, a blinded review of PK and safety data from all subjects will be 
conducted by the Safety Review Committee to confirm it is safe to proceed to the next dose. This 
review must comprise complete data up to Day 17 from a minimum of 14 subjects per cohort. 
In the case of any safety concern or ambiguous data from any one of the cohorts, either 
individual subjects or the entire cohort may be unblinded to enable decision making. If this 
happens, a separate unblinded Safety Review Committee will be used to maintain the integrity of 
following cohorts if needed.  
Subjects may not participate in more than one cohort. 


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A final follow-up visit will be conducted by phone one week after completion of dosing for each 
cohort, unless a CPU visit is deemed more appropriate by the Investigator to follow-up on any 
ongoing AEs. 
Figure 1 
Study Schematic 
 
 
4.2 
Study Population 
The study population will include postmenopausal female subjects, 40 to 65 years of age. 
Subjects will have an average of ≥ 7 and ≤ 20 moderate to severe hot flashes/day during the last 
week’s twice daily diary during screening and have a change of < 50% in average 24-hour hot 
flash frequency between the first and second week of screening period  twice daily diary (Week -
2 and Week -1). 
4.3 
Evaluations at Screening and Check-in 
4.3.1 
Screening  
Screening procedures (Day -28 to Day -1) will include the following: 
• 
Informed consent 
• 
Medical history and concomitant disease evaluation 
• 
Physical examination 
• 
Evaluation of study entry criteria 
• 
Vital signs (sitting and standing BP, HR, oral body temperature, arterial oxygen 
saturation, respiration rate) 


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• 
Body weight 
• 
12-lead ECG 
• 
Hot flash twice daily diary:  Subjects will complete the twice daily diary for the 2 weeks 
prior to the baseline visit to ascertain eligibility. Subjects will record NTAs. The diary 
will be provided to subjects during screening. 
• 
Recording of AEs and serious adverse events (SAEs) 
• 
Clinical laboratory sampling (for chemistry and hematology) 
4.3.2 
Check-in  
Check-in procedures (Day -1) will include the following: 
• 
Medical history and concomitant disease evaluation 
• 
Evaluation of study entry criteria 
• 
Vital signs (sitting and standing BP, HR, oral body temperature, arterial oxygen 
saturation, respiration rate) 
• 
Body weight 
• 
12-lead ECG 
• 
Hot flash twice daily diary and day time continuous hot flash paper diary: Subjects will 
record the occurrence and severity of the flash (scale 1 to 3) in a continuous diary. 
Subjects will be instructed to start completing it after waking on the morning of Day -1 
prior to admission and throughout the day and night.  
• 
Sternal skin conductance monitor fitting 
• 
Holter monitor fitting 
• 
Recording of AEs and SAEs 
• 
Clinical laboratory sampling (for chemistry and hematology)  and urinalysis 
• 
Sampling for LH, estradiol, testosterone, FSH, ACTH, cortisol, TSH, T3, and T4 
4.4 
Randomization and Treatment Assignments 
Following screening and confirmation of eligibility, subjects in each cohort will be randomized 
on Day 1 in a 3:1 ratio to receive either NT-814 or placebo. The investigational medicinal 


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product (IMP) that each subject will receive will be allocated by an Interactive Web Response 
Services tool provided by the Clinical Research Organization on behalf of the Sponsor.  
4.5 
Study Drug Administration 
Subjects will be administered study medication in the morning, according to the randomization 
schedule, at the CPU on Day 1 through Day 8. On Day 8, subjects will be dispensed study 
medication to be self-administered on Days 9 to 13 (1-2 days’ overage should be included). On 
Day 14, subjects will be administered study medication on the morning of admission to the CPU. 
Subjects will be reminded to take the study medication at the same time each morning and to 
return any unused medication when they return to CPU on Day 14. Subjects will be required to 
fast overnight prior to study drug administration on Day 1 through Day 14.  
4.6 
Concomitant Medications 
All concomitant medications taken during the study will be recorded in the electronic case report 
form (eCRF) with indication, dose information, and dates of administration. Subjects using the 
following medications will be excluded from the study: 
• 
Any antidepressants (e.g., selective serotonin reuptake inhibitor, serotonin-
norepinephrine reuptake inhibitor) within 4 weeks of screening  
• 
Neurokinin receptor antagonists within 2 weeks of screening  
• 
Women on tamoxifen (or other estrogen modulating drugs) or receiving 
chemotherapy/radiation therapy within 4 weeks of screening or planned antineoplastic 
chemotherapy/radiation therapy 
• 
Drugs or herbal medications that could be associated with hot flash-like symptoms 
including nicotinic acid, calcium channel blockers, clonidine, opioid drugs, and black 
cohosh within 2 weeks of screening  
• 
Drugs that are highly protein bound (e.g., warfarin and digoxin) within 4 weeks of 
screening visit, use of non-steroidal anti-inflammatory drugs from the time of signing 
informed consent 
• 
Use of non-steroidal anti-inflammatory drugs from the time of signing the informed 
consent 
• 
Use of any of the following hormonal treatments within the washout period stated before 
screening: 
o Within 1 week for prior vaginal hormonal products (e.g., rings, creams, gels) 


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o Within 4 weeks for prior transdermal estrogen alone or estrogen/progestin 
products 
o Within 12 weeks for prior oral estrogen and/or progestin therapy 
o Within 3 months for prior progestin implants and estrogen alone injectable drug 
therapy 
o Within 6 months for prior estrogen pellet therapy or progestin injectable drug 
therapy  
• 
Subjects using the following medications within 2 weeks prior to first dosing (or within 
5 times the half-life of that medication, whichever is longer) will be excluded from the 
study: 
o Inhibitors of cytochrome P450 (CYP) 3A4 (including but not limited to macrolide 
antibiotics, human immunodeficiency virus protease inhibitors, azole antifungal 
drugs, cyclosporine, calcium channel inhibitors, and cimetidine) 
o Inducers of CYP3A4 (including but not limited to rifampicin, carbamazepine, 
efavirenz, bosentan, modafinil, and St. John's wort) 
o Known P-glycoprotein inhibitors (including but not limited to amiodarone, 
azithromycin, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir, 
ritonavir, quinidine, ranolazine, and verapamil) 
• 
Known CYP3A4 substrates with a narrow therapeutic range are not allowed from 
screening until up to 5 times the half-life after the last dose of NT-814 is administered 
(including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) 
As the inhibition potential of NT-814 with breast cancer resistance protein transporter has not yet 
been evaluated in vitro, an interaction with statins cannot be ruled out. Subjects receiving statins 
can be allowed into the study, but should be monitored for signs and symptoms of 
rhabdomyolysis and will be withdrawn from the study if these are observed. 
Subjects will be required to inform the study investigator of any regularly taken medications 
(prescription or over the counter), including hormone replacement therapy, natural and herbal 
products, vitamins, minerals, or dietary supplements taken within 2 weeks (or less than 5 times 
the half-life of that medication, whichever is longer) prior to the first dose. Use of such 
medications should be reviewed with the medical monitor and permitted on a case by case basis. 


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Subjects must refrain from eating grapefruit, grapefruit juice, Seville oranges, and pomelos 
within 7 days prior to Day -1 until after their final follow-up visit. Other than this restriction 
subjects should maintain their usual diet during outpatient periods of the study.  
4.7 
Compliance 
In accordance with regulatory requirements, the Investigator or designated site staff must 
document the amount of study medication dispensed and/or administered to study subjects, the 
amount returned by study subjects, and the amount received from and returned to the Sponsor (or 
representative), when applicable.  
4.8 
Evaluation of Efficacy 
4.8.1 
Hot Flash Diaries 
Subjects will complete two different diaries during the study to record the incidence and severity 
of hot flashes and NTAs. A twice daily diary will be completed throughout the study and a 
Continuous Diary will be completed on days subjects are resident in the clinical pharmacology 
unit.  
4.8.1.1 
Twice Daily Diaries 
Subjects will document the number of individual hot flashes experienced and rate the severity of 
each on a scale of mild, moderate or severe (1, 2, or 3). The diaries will be completed twice daily 
(evening and morning). The diaries will be completed for the 2 weeks prior to the baseline visit 
to ascertain eligibility, and from screening until the morning of Day 15 (the last entry will be the 
information from overnight). Subjects will also record the number of NTAs. 
4.8.1.2 
Continuous Diaries 
While in the clinic on Days -1, 1 through 7, and Day 14, subjects will record in the hot flash 
continuous diary each hot flash and its severity (3 point scale of mild, moderate, or severe), as 
they occur during the day and night. Subjects will also be required to push a button on the skin 
conductance monitor when they sense a hot flash, and then record the event in the continuous 
diary. For Days -1 and 14, subjects will be provided with the continuous diary at the previous 
visit and instructed to start completing it upon waking in the morning on Days -1 and 14. 
4.8.2 
Sternal Skin Conductance Monitors  
Studies have shown that rather than over-reporting hot flashes when they do not occur, women 
tend to under report them when asked to complete hot flash diaries, thus leading to inaccuracy. 
Objective assessment is therefore useful and can be achieved using a sternal skin conductance 
monitor. Sternal skin conductance monitors will be fitted on Day -1 (24 hours ± 1 hour prior to 


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the planned study drug administration on Day 1) and will remain in place until after the Day 7, 
24 hour assessments are completed (Day 8). 
The sternal skin conductance monitors will be refitted around 30 minutes prior to study drug 
administration on Day 14 and remain in place until after the 24 hour assessments are completed 
on Day 15. 
When fitted with the monitor, subjects will be required to push a button on the skin conductance 
monitor when they sense a hot flash, and then provide details of the hot flash in the continuous 
hot flash diary. 
4.8.3 
Luteinizing Hormone Analysis 
Blood samples for analysis of LH will be collected every 60 minutes from time 0 (predose) to 
8 hours on Days 1 and 7. The same sampling schedule will also be followed on Day -1, starting 
at a similar time to that planned for Days 1 and 7. 
Luteinizing hormone samples will be collected as close to the nominal time point as possible. 
The allowable window for LH sample collection relative to dosing will be ± 5 minutes. 
4.9 
Pharmacokinetic Sampling Schedule 
Blood samples for PK analysis will be collected at the following time points on Days 1, 7, and 
14: predose, and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, and 24.0 hours postdose. For 
Cohorts 3 onwards, additional samples will be collected at 48.0 and 72.0 hours after the Day 14 
dose.  
The predose sample will be collected within 30 minutes prior to dose administration.  
Pharmacokinetic samples will be collected as close to the nominal time point as possible. 
Allowable windows for PK sample collection relative to dosing will be as follows: ± 2 minutes 
through 2 hours postdose, ± 5 minutes through 8 hours postdose, ± 10 minutes through 24 hours 
postdose and ± 30 minutes for the 48 and 72 hour postdose samples. 
4.10 
Evaluation of Treatment Safety 
4.10.1 
Adverse Events 
All AEs will be recorded from the time the informed consent is signed until study exit, and SAEs 
occurring up to 30 days after the last dose of study medication should be reported. 
4.10.1.1 
Definitions 
An AE is any untoward medical occurrence in a subject or clinical trial subject administered a 
medicinal product, which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 


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finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
All events considered being untoward and unintended responses to a medicinal product related to 
any dose should be considered adverse drug reactions. The definition covers also medication 
errors and uses outside what is foreseen in the protocol, including misuse and abuse of the 
product. The phrase “responses to a medicinal product” means that a causal relationship between 
a medicinal product and an AE is at least a reasonable possibility (i.e., the relationship cannot be 
ruled out). 
An SAE is and AE that at any dose: 
• 
Results in death 
• 
Is life-threatening (i.e., the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalizations are defined as initial or prolonged admissions that include an overnight 
stay; hospitalization or prolonged hospitalization for technical, practical, or social 
reasons, in the absence of an AE, is not an SAE.) 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is considered to be an important medical event (based on medical and scientific 
judgment, important medical events that may not be immediately life-threatening, or 
result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed) 
An additional blood sample for the determination of NT-814 plasma levels should be taken in 
case of SAEs with reasonable possibility of relatedness to the study drug. The analysis of such 
PK samples will be conducted as soon as possible after the occurrence of the SAE. 
Pregnancy itself is not considered an AE. However, any pregnancy complication, spontaneous or 
elective abortion (for medical reasons), still birth, neonatal death, or congenital anomaly will be 
recorded as an AE or SAE. 
An unexpected adverse drug reaction is any adverse reaction, the nature or severity of which is 
not consistent with applicable product information (eg, Investigator’s Brochure for an 
unapproved IMP). Reports that add significant information on the specificity, increase of 
occurrence, or severity of a known, already documented serious adverse reaction constitute 
unexpected events. 


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A suspected unexpected serious adverse reaction is an SAE suspected to be related to the 
administered medicinal product; the nature or severity of the event is not consistent with 
applicable product information. 
4.10.1.2 
Severity and Relatedness Assessment 
Severity will be classified as follows: 
• 
Mild:  Awareness of sign or symptom, but easily tolerated 
• 
Moderate:  Sign or symptom causes discomfort, but does not interfere with normal 
activities 
• 
Severe:  Sign or symptom of sufficient intensity to interfere with normal activities 
The likely relationship of each AE to the medicinal product will be assessed according to the 
definitions below: 
• 
Unrelated 
• 
Possibly 
• 
Probably 
• 
Definitely 
4.10.2 
Clinical Laboratory Assessments 
Clinical chemistry/ biochemistry and hematology sampling will be performed at screening and 
on Days -1, 8, 14, and early termination. The following clinical chemistry/ biochemistry 
parameters will be assessed: sodium, potassium, glucose, urea, creatinine, creatine kinase, 
albumin, calcium, phosphate, bilirubin (total), alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, gamma-glutamyl transferase, bicarbonate, magnesium, chloride, total 
protein, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides. The 
following hematology parameters will be assessed: red blood cells, white blood cells, hematocrit, 
hemoglobin, mean corpuscular volume, platelets, white blood cell differentials, prothrombin 
time, and activated partial thromboplastin time. 
Urinalysis sampling will be performed on Days -1, 8, and 14. Urinalysis will include glucose, 
bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites, leucocytes, and 
sedimentation. 
Blood samples will be collected to assess estradiol, testosterone, FSH, ACTH, cortisol, TSH, T3, 
and T4 when the subjects are admitted to the unit on Day -1 and again prior to discharge on 
Day 15. 


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4.10.3 
Vital Signs 
Vital signs will include sitting and standing BP, HR, arterial oxygen saturation, oral body 
temperature, respiration rate, and weight. Vital sign assessments will be performed on Day -1 at 
a similar time to the same assessments that are planned predose on Day 1. The assessments will 
then be performed postdose for all other days in clinic and at a similar time on Day 15. 
4.10.4 
Twenty-four-hour Holter Monitoring 
Subjects will be fitted with Holter monitors upon admission to the CPU on Day -1. These will 
remain in place until after the Day 7, 24-hour assessments are completed (on Day 8). Subjects 
will be fitted with Holter monitors again upon admission to the CPU on Day 14. These will 
remain in place until after the Day 14, 24-hour assessments are completed (on Day 15). 
4.10.5 
Electrocardiograms 
On Days 1 and 14, resting 12-lead ECG data will be collected at the following timepoints:  
predose and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 8.0, 12.0 and 24.0 hours (all +/- 15 mins). 
The same assessment schedule is also required on Day -1, starting at a time similar to that 
planned for Days 1 and 14. The Day -1 and Day 1, 24 hour ECGs must be performed prior to the 
dose of study medication the following morning (on Days 1 and 2, respectively). 
Once-daily ECG recordings will be just prior to dosing (approx. 30 mins) on all other days 
during the inpatient stay (Days 3 to 8).  
4.10.6 
Physical Examinations 
A full physical examination will be performed at screening and Days 1, 8, and 15, and is 
composed of a review of the following body systems: 
• 
General appearance 
• 
Skin 
• 
Head, eyes, ears, nose and throat 
• 
Respiratory 
• 
Cardiovascular 
• 
Abdomen (including liver and kidneys) 
• 
Musculoskeletal 
• 
Neurological 


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Any abnormalities that are identified at screening will be documented on the medical history 
eCRF page. Any changes (including new and worsening findings) between screening and the 
final study visit should be captured as AEs on the AE eCRF page. 
If an improvement/resolution of a physical examination finding documented in the subject’s 
medical history occurs during the study, it should be recorded in the source document. If there is 
resolution of a physical examination finding previously noted as an AE, then the event resolution 
and stop date should be recorded on the AE eCRF page and documented in the subject’s notes.  
4.10.7 
Medical History and Concomitant Diseases 
The investigator must record all medically and clinical relevant information regardless of the 
time since the date of diagnosis. The history should include (but is not limited to): 
• 
All current and past medications taken during 3 months before screening  
• 
Relevant history of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and any other diseases  
4.11 
Protocol Deviation Reporting 
Procedural deviations found by the clinical research associate during monitoring visits and data 
deviations captured on the eCRF and found through programming and examining the database 
will be collected.  Examples of deviations are documented in the Protocol Deviation Criteria 
Form. 


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5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS 
The conduct of the study and planned analyses are consistent with the study protocol 
(Version 4.0, dated 13 December 2016). The exposure response analysis on QTcB will not 
perform since this correction method is not regarded as appropriate ; per the Q&A E14, question 
1.5 (available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_
As_R3__Step4.pdf). 


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6 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS 
Clinical source data will be entered into eCRFs, which will then be monitored by an independent 
Monitor designated by the Sponsor. All eCRF data will be processed according to the ICON 
Study Specific Procedure SSP DM-RELENT-1.01 Data Management Plan (DMP). The DMP 
describes eCRF data processing, edit checks, data query management, medical dictionary coding, 
SAE reconciliation, data transfers, and data quality review through database lock or any 
necessary reopening of the database. After database lock, the data will be retrieved from the 
database and analysed using SAS® 9.3 or higher. 


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7 
PHARMACOKINETIC ASSESSMENTS 
7.1 
Pharmacokinetic Assessments 
The bioanalyses for plasma NT-814 concentrations will be performed by Aptuit Medicines 
Research Centre and the PK analyses will be done by Parexel and described in a separate 
document. 


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8 
STATISTICAL METHODS 
8.1 
General 
The statistical analysis will be conducted following the principles specified in the International 
Council for Harmonization, formerly the International Conference on Harmonization, Topic E9 
Statistical Principles for Clinical Trials (CPMP/ICH/363/96). 
All statistical tabulations and analyses will be done using SAS®, Version 9.3 or higher. 
Unless otherwise noted, continuous variables will be summarized using number of non-missing 
observations, arithmetic mean, standard deviation (SD), median, minimum, and maximum; 
categorical variables will be summarized using the frequency count and the percentage of 
subjects in each category. 
In the data listings, study day relative to first dose of study drug may be presented. Study day 
relative to first dose will be calculated as: event date – first dose date (+ 1 if event date ≥ first 
dose date). That is, there is no Day 0. 
Baseline will be the latest available measurement prior to the first study drug administration in 
the study, unless otherwise specified. 
For safety summaries, the unscheduled and repeat assessments will not be summarized; however, 
all results will be included in the data listing. 
All subject level data, including those derived, will be presented in the individual subject data 
listings. 
Unless otherwise noted, the analyses will be done by treatment (50 mg NT-814, 100 mg NT-814, 
150 mg NT-814, etc… (XX mg NT-814), Total NT-814 (if applicable), placebo). Data for the 
placebo subjects will be combined across cohorts prior to any summaries. 
8.2 
Handling of Dropouts or Missing Data 
For the calculation of the luteinizing hormone AUC0-8 at any visit, 
• If more than one time point is missing, then the AUC won’t be calculated and will 
be considered as missing. 
• If one of the following time points is missing (T1, T2, T3, T4, T5, T6, T7) then 
the AUC will be calculated without the missing time point. 
• If one of the following time points is missing (T0 or T8), then the AUC won’t be 
calculated and will be considered as missing. 


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For the derivation of the daily scores in the efficacy section, the daily derivation will not be 
calculated and will be treated as missing if the results of the corresponding day are incomplete:  
Twice daily diary 
- The hot flash data are collected twice (day time and night time) and if either period is 
not complete, then the whole day will be considered incomplete and therefore missing for 
the corresponding daily variable derived. For each period of the diary to be considered 
incomplete, there must be no hot flashes of any severity recorded and the box indicating 
that there were no hot flashes must also not have been completed.  
Continuous diary 
- For the hot flash data, the diary will be considered incomplete if there are no hot flashes 
of any severity recorded and the box indicating that there were no hot flashes has also not 
been completed. 
- For NTA not associated with hot flashes, the diary will always be considered complete  
Skin Conductance 
- If the skin conductance device has not recorded the hot flashes for a continuous period 
(e.g. due to battery failure) on a given day, then the whole day is considered incomplete 
and therefore missing for the corresponding daily variable derived. 
For the calculation of the weekly scores, at least 4 complete days are needed for the derivations 
of the weekly values. The results from the complete days will then be averaged to give the 
weekly score. 
Summary statistics will be based primarily on non-missing values. For hypothesis tests, estimates 
and confidence intervals (CIs) of the exploratory efficacy endpoints, missing values for efficacy 
endpoints will not be directly imputed. Missing values for endpoints analyzed via likelihood 
methods (e.g. mixed models) are handled within the analysis itself, under the assumption that the 
model specification is correct and that the data is missing at random. Sensitivity analyses may be 
conducted to check the robustness of the analysis results under alternative assumptions with 
regards to missing data.  
8.3 
Multicenter Studies 
This is a multi-center study. 


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8.4 
Examination of Subgroups 
No pre-specified subgroup analysis is planned. 
8.5 
Analysis Populations 
The following data sets will be used for the statistical analysis. 
1. All Subjects Set: all subjects who signed the informed consent. 
2. All Randomized Set: all subjects who were randomized. 
3. Safety Set: all subjects who receive at least 1 dose of double-blind study drug (any dose 
of NT-814 or matching placebo). Subjects will be analyzed according to treatment 
received. 
4. Full Analysis Set: all randomized subjects who received at least 1 dose of double-blind 
study drug and for whom the efficacy data are considered sufficient and interpretable. 
Subjects will be analyzed according to randomized treatment. 
Analysis sets will be identified prior to the unblinding of the study data. 
8.6 
Subject Accountability 
Summaries of analysis populations and subject disposition will be presented by treatment based 
on the All Randomized Set and will contain the following information: 
• Number and percent of subjects who were dosed. 
• Number and percent of subjects who completed the study (completed the Day 21 follow-
up call) 
• Number and percent of subjects who discontinued early and reason for early 
discontinuation 
• Number and percent of subjects in the Safety and Full Analysis Set 
Subject disposition will be presented in listings. 
The screening outcomes will be listed and summarized based on the All Subjects Set. 
The randomization allocation and the reason for exclusion from each population will also be 
listed. 
8.7 
Protocol Deviation Reporting 
Protocol deviations determined to have significant or potential impact on the safety or integrity 
of the study data will be listed only. 


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8.8 
Subject Demographics and Baseline Characteristics 
Demographics (sex, age [in years, at time of signing informed consent], race, and ethnicity) and 
physical measurements (height, weight, and body mass index) will be listed and summarized by 
treatment based on the safety set. 
8.9 
Study Drug Exposure and Compliance 
Duration of study drug exposure (in days) will be calculated as: last dose date – first dose 
date + 1 day, regardless of study drug interruption. Exposure summaries will be based on the 
safety set. 
Dosing administration will be presented in an individual subject data listing. 
8.10 
Analysis of Efficacy Data 
All efficacy analyses will be performed using the Full Analysis Set and are considered as 
exploratory. Any statistical hypothesis tests and/or CIs will be two-sided, using a type I error rate 
of 0.1. No adjustments will be made for multiplicity in this early phase study. An unstructured 
covariance matrix is planned for the analyses that use linear mixed-effects models. However, 
alternative covariance matrices may be used if the unstructured matrix causes model 
convergence issues. 
8.10.1 
Twice Daily Hot Flash Paper Diaries 
8.10.1.1 
Frequency of Hot Flashes 
Frequency by day   
Daily (24-hour) frequency of hot flashes for Day Y will be equal to the number of hot flashes 
recorded on Day Y (day time hot flushes recorded in the evening + night time hot flushes 
recorded the following morning).   
The daily frequency of mild, moderate, severe, moderate/severe, and total hot flashes will be 
summarized for each day. The mean (+SE) frequency of mild, moderate, severe, moderate/severe 
(moderate and severe combined), and total hot flashes will be displayed graphically by day (Day 
-8 onwards). 
Average daily frequency by week 
The average daily frequency of hot flashes for each of Week -1, Week 1, and Week 2 will be 
equal to the average of the daily frequency of hot flashes from Day -8 to Day -2 inclusive, from 
Day 1 to Day 7 inclusive, and from Day 8 to Day 14 inclusive, respectively. 


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The average daily frequency by week and the change from Week -1 (for Week 1 and Week 2) of 
mild, moderate, severe, moderate/severe, and total hot flashes will be summarized descriptively 
by treatment.   
Statistical analysis 
The analysis will test the treatment difference of change in the average daily frequency of 
moderate/severe hot flashes from Week -1 to each of Week 1 and Week 2.  
The analysis will be based on a linear mixed-effects model with the change from Week -1 as a 
dependent variable, treatment, week, treatment-by-week interaction as fixed effects, subject as a 
random effect, and baseline (frequency of moderate/severe hot flashes at Week -1) and baseline-
by-week interaction as covariates. Subjects dosed with placebo will be analyzed as a pooled 
group. An unstructured covariance matrix will be specified for the repeated measures at postdose 
timepoints for each subject. From this analysis, the least-squares (LS) mean and 2-sided 90% CIs 
will be calculated for the contrast “NT-814 versus placebo” for each treatment and each postdose 
week, separately. 
Following is the SAS code for reference: 
proc mixed data=dataset ; 
class TRT <50 mg NT-814, 100 mg NT-814, 150 mg NT-814, etc… , placebo> WEEK <1,2> USUBJID; 
model CHG = TRT WEEK TRT*WEEK BSL BSL*WEEK / s ddfm=kr; 
random USUBJID; 
repeated WEEK / type=un subject=USUBJID; 
lsmeans TRT*WEEK / cl diff alpha=0.1; 
run; 
The analysis assumes a constant average treatment difference on the original scale. The 
possibility of a proportional treatment effect will also be explored as it is not certain whether the 
continuous endpoints will be normally or log-normally distributed, and/or whether an absolute or 
proportional change in endpoints will be observed. If deemed necessary, data will be log 
transformed prior to the analysis. The subsequent results (mean differences and corresponding 
CIs) will be back transformed and hence reported in terms of ratios of geometric means. 
8.10.1.2 
Hot Flashes Average Severity 
Severity by day 
Daily (24-hour) hot flashes average severity for Day Y will be equal to the (number of mild hot 
flashes recorded on Day Y + number of moderate hot flashes recorded on Day Y x 2 + number of 
severe hot flashes recorded on Day Y x 3) / total number of hot flashes recorded on Day Y. As 


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the hot flashes are recorded twice daily, the number of hot flashes recorded on Day Y is equal to 
the sum of the Day Y day time hot flushes recorded in the evening + night time hot flushes 
recorded following morning.   
The daily hot flashes average severity will be summarized and displayed graphically (Day -8 
onwards) for each day.  
Average daily severity by week 
The average daily hot flashes severity for each of Week -1, Week 1, and Week 2 will be equal to 
the average of the daily hot flashes average severity from Day -8 to Day -2 inclusive, from Day 1 
to Day 7 inclusive, and from Day 8 to Day 14 inclusive, respectively. The average hot flashes 
severity by week and the change from Week -1 (for Week 1 and Week 2) will be summarized by 
treatment.  
The same statistical analyses as described in Section 8.10.1.1 will be done for the average daily 
severity by week and change from Week -1 in hot flashes average severity. 
8.10.1.3 
Hot Flashes Severity Score 
Severity score by day 
The hot flashes severity score for Day Y will be equal to the number of mild hot flashes recorded 
on Day Y+ number of moderate hot flashes recorded on Day Y x 2 + number of severe hot 
flashes recorded on Day Y x 3. As the hot flashes are recorded twice daily, the number of hot 
flashes recorded on Day Y is equal to the sum of the Day Y (day time hot flushes recorded in the 
evening + night time hot flushes recorded following morning).   
The daily hot flashes severity score will be summarized and displayed graphically (Day -8 
onwards) for each day.  
Average daily severity score by week 
The average daily hot flashes severity score for each of Week -1, Week 1, and Week 2 will be 
equal to the average of the daily hot flashes average severity scores from Day -8 to Day -2 
inclusive, from Day 1 to Day 7 inclusive, and from Day 8 to Day 14 inclusive, respectively. The 
daily average hot flashes severity scores by week and the change from Week -1 (for Week 1 and 
Week 2) will be summarized descriptively by treatment.  
The same statistical analyses as described in Section 8.10.1.1 will be done for the average change 
in severity score from Week -1 hot flashes severity score. 


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8.10.1.4 
Night Time Awakenings  
8.10.1.4.1 Night Time Awakenings Secondary to Hot Flashes 
The number of NTA secondary to hot flashes will be the sum of the number of moderate and 
severe night time hot flashes recorded the following morning. 
The NTA secondary to hot flashes will be summarized for each day and displayed graphically by 
day. 
The average daily NTA secondary to hot flashes by week for each of Week -1, Week 1, and 
Week 2 will be equal to the average of the number of NTA secondary to hot flashes per day from 
Day -8 to Day -2 inclusive, from Day 1 to Day 7 inclusive, and from Day 8 to Day 14 inclusive, 
respectively. The weekly average number of NTA secondary to hot flashes per day and change 
from Week -1 will be summarized by treatment.  
The same statistical analyses as described in Section 8.10.1.1 will be done for the weekly 
average change from Week -1 NTA secondary to hot flashes. 
8.10.1.4.2 Night Time Awakenings – Total  
The total number of night time awakenings for Day Y will be equal to the number of NTA 
recorded the following morning.  
The total NTA will be summarized for each day and displayed graphically by day. 
The weekly average NTA per day for each of Week -1, Week 1, and Week 2 will be equal to the 
average of the number of NTA per day from Day -8 to Day -2 inclusive, from Day 1 to Day 7 
inclusive, and from Day 8 to Day 14 inclusive, respectively. The weekly average number of 
NTA per day and change from Week -1 will be summarized by treatment.  
The same statistical analyses as described in section 8.10.1.1 will be done for the weekly average 
change from Week -1 NTA. 
8.10.2 
Continuous Hot Flash Diary 
8.10.2.1 
Frequency of Hot Flashes 
Frequency by day 
Daily (24-hour) frequency of hot flashes for Day Y for the continuous hot flash diary will be 
equal to the number of hot flashes recorded on Day Y (day period + night period) 
The daily frequency of mild, moderate, severe, moderate/severe, and total hot flashes as 
measured by continuous day-time diary will be summarized for each day. The mean (+-SE) in 
frequency of mild, moderate, severe, moderate/severe, and total hot flashes will be displayed 
graphically by day. The change from Day -1 will also be summarized. 


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Average daily frequency by week 
The average daily frequency of hot flashes for Week 1 will be equal to the average of the daily 
frequency of hot flashes from Day 1 to Day 7, inclusive. 
The Week 1 average frequency of mild, moderate, severe, moderate to severe, and total hot 
flashes will be summarized by treatment.  
Statistical analysis 
The analysis will test the treatment difference of daily frequency of moderate/severe hot flashes 
from Day -1 to Day 7 and Day 14.  
The analysis will be based on a linear mixed-effects model with the change from Day -1 as a 
dependent variable, treatment, day and treatment-by-day interaction as fixed effects, subject as a 
random effect, and the number of moderate/severe hot flashes at Day -1 and the interaction with 
day as covariates. Subjects dosed with placebo will be analyzed as a pooled group. An 
unstructured covariance matrix will be specified for the repeated measures at postdose timepoints 
for each subject. From this analysis, the LS mean and 2-sided 90 % CIs will be calculated for the 
contrast “NT-814 versus placebo” at each treatment and each postdose day, separately. 
Following is the SAS code for reference: 
proc mixed data=dataset ; 
class TRT <50 mg NT-814, 100 mg NT-814, 150 mg NT-814, etc…, placebo> DAY <7,14> USUBJID; 
model CHG = TRT DAY TRT*DAY BSL BSL*DAY / s ddfm=kr; 
random USUBJID; 
repeated DAY / type=un subject=USUBJID; 
lsmeans TRT*DAY / cl diff alpha=0.1; 
run; 
8.10.2.2 
Night Time Awakenings 
8.10.2.2.1 
Night Time Awakenings Secondary to Hot Flashes 
Night time awakenings secondary to hot flashes for Day Y = the sum of the number of moderate 
and severe night time hot flashes recorded on the continuous diary (as these are defined as 
resulting in a night time awakening) .   
Frequency by day 
The NTA secondary to hot flashes will be summarized for each day and displayed graphically by 
day. The change from Day -1 will also be summarized. 
 
 


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Average daily frequency by week 
The average daily NTA secondary to hot flashes for Week 1 will be equal to the average of the 
NTA from Day 1 to Day 7. The average daily NTA secondary to hot flashes for Week 1 will be 
summarized by treatment.  
The same statistical analyses for the daily scores as described in section 8.10.2.1 will be done 
based on the change from Day -1 NTA. 
8.10.2.2.2 
Night Time Awakenings - Total  
The total NTA for Day Y = number of awakenings recorded on the continuous diary that are 
recorded as an awakening that is not accompanied by a hot flash + the number of night time 
moderate and severe hot flashes recorded.   
The total NTA will be summarized for each day and displayed graphically by day. The change 
from Day -1 will also be summarized. 
8.10.3 
Sternal Skin Conductance Monitors 
Frequency by day  
The Day -1 frequency of hot flashes will be the number of hot flashes detected by the device 
from 24 hours before dosing on Day 1 to the dosing on Day 1. If there is >24 hours of recorded 
data, then only the 24-hour prior to the time of dosing on Day 1 will be used. If there is <24 
hours of data recorded, then all the recorded data will be used and the actual recording duration 
will be used to derive a 24 hour value. 
Postbaseline values will be based on 24-hour periods from the dose time on Day 1. If the 
recording time on Day 7 (or an earlier day in the event of early withdrawal) is <24 hours, then all 
the recorded data will be used and the actual recording duration will be used to derive a 24-hour 
value.  
The number of algorithm-detected hot flashes (Bahr et al Physiol Meas. 2014 February ; 35(2): 
95–110. doi:10.1088/0967-3334/35/2/95; algorithm commercial property of SimplexScientific 
LLC) will be summarized and displayed graphically for each day by treatment. The change from 
Day -1 will also be summarized. 
Average daily frequency by week 
The average daily frequency of hot flashes detected by the device for Week 1 will be equal to the 
average of the daily frequency of hot flashes detected by the device from Day 1 to Day 7 
inclusive. 
The average daily frequency for Week 1 will be summarized by treatment.  
 
 


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Statistical analysis 
The same statistical analyses as described in Section 8.10.2.1 will be done for the change from 
Day -1 in the frequency of hot flashes detected by the device. 
8.10.4 
Luteinizing Hormone 
The observed values on Day -1, Day 1, and Day 7, and change from Day -1 (for Day 1 and Day 
7) data for continuous LH AUC0-8 values will be summarized by treatment at each visit. The 
AUC0-8 will be derived using the trapezoidal method and based on the actual times.  
An analysis will be based on a linear mixed-effects model with the change from Day -1 as a 
dependent variable, treatment, day and treatment-by-day interaction as fixed effects, subject as a 
random effect and the AUC0-8 value at Day -1 and the interaction with day as covariates. Subjects 
dosed with placebo will be analyzed as a pooled group. An unstructured covariance matrix will 
be specified for the repeated measures at postdose timepoints for each subject. From this 
analysis, the LS mean and 2-sided 90 % CIs will be calculated for the contrast “NT-814 versus 
placebo” at each treatment and each postdose day, separately. 
Following is the SAS code for reference: 
proc mixed data=dataset ; 
class TRT <50 mg NT-814, 100 mg NT-814, 150 mg NT-814, XX mg NT-814(2 further ascending doses up to 400mg), placebo> 
DAY <1,7 > USUBJID; 
model CHG = TRT DAY TRT*DAY BSL BSL*DAY / s ddfm=kr; 
random USUBJID; 
repeated DAY / type=un subject=USUBJID; 
lsmeans TRT*DAY / cl diff alpha=0.1; 
run; 
8.10.5 
Relationship Between PK Exposure and Responses 
The relationship between PK exposure and efficacy and pharmacodynamic responses will be 
investigated depending on what is seen in the response data. These analyses will be described in 
a separate document. 
8.11 
Analysis of Safety Data 
8.11.1 
General 
All analyses will be performed using the safety set. 


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8.11.2 
Adverse Events 
All AEs will be coded to system organ class (SOC) and preferred term (PT) using MedDRA, 
Version 19.0, and presented by subject in data listings. 
A treatment-emergent adverse event (TEAE) is defined as an AE that was not present prior to 
treatment with investigational product, but appeared following treatment or was present at 
treatment initiation but worsened during treatment. An AE that was present at treatment initiation 
but resolved and then reappeared while the subject was on treatment is a TEAE (regardless of the 
intensity of the AE when the treatment was initiated). Programmatically, an AE will be classified 
as a TEAE if the start date and time occurs on or after the start date and time of first 
investigational product dosing. Any change in severity will be recorded as a new AE in the 
eCRF. An AE with an incomplete start or end date will be considered a TEAE unless it is clear 
from the incomplete start and end date that the AE started before start of dosing. 
The overall incidence of TEAEs (number and percentage of subjects with one or more TEAEs) 
as well as the number of events will be summarized by treatment received. Separate summaries 
by treatment received will also be presented showing TEAE severity, causally related TEAE and 
SAEs, TEAEs leading to study or treatment discontinuation, all SAEs, life-threatening SAEs, 
SAEs resulting in death and TEAEs of dehydration (changes in serum urea and creatinine, 
urinary sediment and weight and vital signs that the PI classifies to be an AE). 
The TEAEs will be summarized and tabulated at both the subject (number [%] of subjects) and 
event (number of events) level: 
• By treatment, SOC, and PT 
• By treatment, SOC, PT, and reported severity 
• By treatment, SOC, PT, and relationship to study drug 
For the incidence at the subject level by SOC and PT, if a subject experiences more than one 
event within the same SOC and PT, the patient will only be included once in the incidence. 
For the incidence at the subject level by SOC, PT, and severity, if a subject experiences more 
than one event within the same SOC, PT, the patient will only be included once in the incidence 
and will be assigned the worst severity. 
For the incidence at the subject level by SOC, PT, and relationship to study drug; if a subject 
experiences more than one event within the same SOC, PT, to study drug, the patient will only 
be included once in the incidence and will be assigned the most conservative relationship. 


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Any SAEs, SAEs with outcome of death, AEs resulting in discontinuation of study or treatment, 
and TEAEs of dehydration will also be listed separately. 
8.11.3 
Clinical Laboratory Assessments 
Observed and change from baseline of continuous clinical laboratory values (chemistry, 
hematology, lipids, coagulation, and hormones including estradiol, testosterone, FSH, ACTH, 
cortisol, TSH, T3 and T4) for each parameter will be summarized by treatment at each time 
point. The number and percentage of subjects with shift changes from baseline based on the 
laboratory normal ranges will be tabulated. 
Laboratory data will be listed by subject at each time point. Clinical laboratory values that are 
out of normal ranges will be presented in a separate listing. 
Urinalysis laboratory tests will be presented in data listings only. 
8.11.4 
Vital Signs 
Vital signs data will be listed by subject at each time point. Observed and change from baseline 
vital signs values (pulse rate, respiration rate, arterial oxygen saturation, systolic and diastolic 
BP, oral temperature, and weight) will be summarized by treatment at each time point period. 
8.11.5 
Safety Electrocardiograms 
Observed values and change from baseline of 12-lead ECG parameters (HR, RR, PR, QRS, QT, 
QTcB and QTcF intervals) will be summarized descriptively by treatment at each scheduled time 
point collected. Individual ECG data will be listed. The baseline for the assessments done on 
Day 1 and 14 for each scheduled post-treatment timepoint will be the time-matched assessment 
on Day -1. The baseline for the assessments done on Day 3 to 8 will be the last assessment done 
before dosing on Day 1. 
12-lead ECGs that the investigator flags as being abnormal (both clinically significant and not 
clinically significant) will be summarized separately.  
In addition, the number and percentage of subjects by maximum baseline and post baseline value 
of QTcB and QTcF intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec 
and ≤500 msec, and >500 msec, as well as the daily maximum category, will be summarized. In 
addition, the same summaries (overall maximum and daily maximum) for change from baseline 
value of QTcB and QTcF intervals, categorized as ≤0 msec, >0 msec and ≤30 msec, >30 msec 
and ≤60 msec, and >60 msec will be tabulated based on 12-lead ECG measurements.  


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8.11.6 
24-hour Holter Monitoring 
The 24-hour Holter Monitoring data will be listed. The arrhythmias analysis by continuous 
Holter monitoring will be summarized. All findings will be summarized on the basis of incidence 
rates for the study overall (by baseline and post-baseline) and by day.  A subject will be counted 
only once for a particular morphological abnormality if the subject experiences more than one 
incidence of that event.  
8.11.7 
Relationship Between Plasma Concentrations and Placebo-Corrected, Change from 
Baseline QTcF  
The analyses described in this section may be conducted depending on the results observed. 
They will be based on the QT/QTc and PK/QTc Analysis Set. 
QT/QTc Analysis Set will include all subjects in the Safety Set with measurements at baseline as 
well as on-treatment with at least one postdose timepoint with a valid ΔQTcF value. The 
QT/QTc Analysis Set will be used for the analysis of ECG parameters. 
PK/QTc Analysis Set will include all subjects in both the QT/QTc and PK analysis sets with at 
least one pair of postdose PK and QTcF data from the same timepoint. The PK/QTc Analysis Set 
will be used for the exposure-response analysis.  
Baseline: For all ECG parameters, baseline is defined as the measured QTc intervals from the 
time-matched predose timepoint on Day 1.  
Exposure-Response Analysis 
The relationship between NT-814 plasma concentration and ∆QTcF (change-from-baseline 
QTcF) will be quantified using a linear mixed-effects model with ΔQTcF as the dependent 
variable, NT-814 plasma concentration as a continuous covariate (zero for placebo), treatment 
(active or placebo) and time since drug administration as categorical factors, and a random 
intercept per subject. The degrees of freedom for the model estimates will be determined by the 
Kenward-Rogers method. From the model, the slope (i.e., the regression parameter for the 
concentration) and the treatment effect (defined as the difference between active and placebo) 
will be estimated together with 2-sided 90% CI. The estimates for the time effect will be reported 
with degrees of freedom and standard error (SE).  
The geometric mean of the individual Cmax values for subjects in each of the NT-814 dose groups 
will be determined. The predicted effect and its 2-sided 90% CI for ΔΔQTcF (placebo-corrected 
change-from-baseline QTcF) (ie, the product with the slope estimate + treatment effect) at the 
geometric mean Cmax will be obtained for each NT-814 dose, separately. If the upper bound of 
the 90% confidence interval of the predicted effect at this plasma level is below 10 ms, it will be 


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concluded that NT-814 does not cause clinically relevant QTc prolongation. These analyses will 
be performed using the PK/QTc population.  
The plot of the observed median-quantile NT-814 concentrations and associated mean ΔΔQTcF 
(90% CI) adjusted for diurnal effects together with the regression line presenting the predicted 
ΔΔQTcF (90% CI) (as described in the publication by Tornoe et al1) will be used to evaluate the 
adequacy of the model fit to the assumption of linearity and the impact on quantifying the 
exposure response relationship. Additional exploratory analyses (via graphical displays and/or 
model fitting) will include accounting for a delayed effect (hysteresis) and the justification for 
the choice of pharmacodynamic model (linear versus nonlinear) as follows. 
Investigation of hysteresis 
If a QTc effect (∆∆QTcF) exceeding 10 msec cannot be excluded in the by-timepoint analysis, 
hysteresis, i.e., difference in peak QT response and Cmax, will be explored through visual 
inspection of overlaid NT-814 concentration and ΔΔQTc time curves and through so called 
hysteresis loops for each dose of NT-814.   
Appropriateness of a linear model 
To assess the appropriateness of a linear model, normal QQ-plots for the residuals and plots of 
weighted residuals versus concentration and vs. fitted values will be produced. The scatter plot of 
residuals versus concentration by Loess (i.e., locally weighted scatterplot smoothing as described 
in the publication by Cleveland2) fitting will be also produced with an optimal smoothing 
parameter selected by the Akaike information criterion with a correction (AICC3). In addition, a 
model with a quadratic term in concentration will be fitted and the quadratic term will be tested 
on the two-sided 5 % level. If there is an indication that a linear model is inappropriate, 
additional models will be fitted, in particular: 
• An E-max model; 
• A log-linear model where the plasma concentration (C) is replaced by log(C/C0), C0 is the 
limit of quantification of the assay used to determine C and all values below C0 are 
replaced by C0 (i.e., log[C0/C0] = 0). 
The Exposure-Response analysis will then be repeated for the model found to best accommodate 
the nonlinearity detected. 
By-Timepoint Analysis:  
                                                 
1  Tornoe C et al. J Clin Pharmacol 2011; 7: 1035-42 
2 Cleveland WS. J Amer Statist Assoc 1979; 74: 829-36 
3 Hurvich, CM, Simonoff, JS, and Tsai, CL 1998; J. Roy. Statist. Soc. Ser. B, 60: 271–93. 


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The analysis for QTcF will be based on a linear mixed-effects model with change-from-baseline 
QTcF (ΔQTcF) as the dependent variable, time (categorical), treatment (each NT-814 dose group 
and all placebo group), and time-by-treatment interaction as fixed effects, and baseline QTcF as 
a covariate. Baseline will be the derived QTc intervals from the ECG timepoint recorded predose 
on Day 1. Subjects dosed with placebo will be analyzed as a pooled group. An unstructured 
covariance matrix will be specified for the repeated measures at postdose timepoints for each 
subject. If the model with unstructured covariance matrix fails to converge, other covariance 
matrix such as autoregressive and compound symmetry will be considered. From this analysis, 
the LS mean and 2-sided 90 % CIs will be calculated for the contrast “NT-814 versus placebo” at 
each treatment and each postdose timepoint, separately. These analyses will be performed using 
the QT/QTc population.  
For HR, PR, QTcB, QT, RR, and QRS intervals, the analysis will be based on the change-from-
baseline post-dosing (ΔHR, ΔPR, ΔQTcB, ΔQT, ΔRR, and ΔQRS). The same model will be 
used as described for QTcF. The LS mean, SE and 2-sided 90% CI from the statistical modeling 
for both change-from-baseline and placebo-corrected change-from-baseline values will be listed 
in the tables and graphically displayed. 
Categorical Analyses 
The analyses results for categorical outliers, T-wave morphology and U-wave presence will be 
summarized in frequency tables with counts percentages for both number of subjects and number 
of timepoints. For categorical outliers, the number (percentage) of subjects as well as timepoints 
who had increases in absolute QTc (QTcF and QTcB) values >450, 480, and 500 msec, and 
changes from predose baseline of >30 or >60 msec; increase in PR from predose baseline >25% 
to a PR >200 msec; increase in QRS from predose baseline >25% to a QRS >120 msec; decrease 
in HR from predose baseline >25% to a HR <50 bpm; and increase in HR from predose baseline 
>25% to a HR >100 bpm will be determined. For T-wave morphology and U-wave presence, the 
analyses will be focused on change from baseline (i.e., treatment-emergent changes). These 
analyses will be performed using the QT/QTc population.  
8.11.8 
Physical Examinations 
Physical examination findings will be presented in a subject listing. 
8.11.9 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (Version March 2017) and classified according to ATC codes levels 2 (therapeutic 
sublevel) and 4 (chemical sublevel). Prior medications are defined as all medications with start 
date before first dose date. Concomitant medications are defined as all medications with start 


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date on or after the first dose date. Medications with an incomplete start or end date will be 
considered concomitant unless it is clear from the incomplete start and end date that the 
medication started before the first dose date. Prior and concomitant medication data will be 
listed. 
The concomitant procedures will also be listed. 
8.12 
Sample Size 
The planned sample size is 20 subjects per cohort, with 15 active and 5 placebo. This is deemed 
enough to provide sufficient separation of exposures between dose groups and to allow for an 
assessment of safety versus dose group/exposure. Assuming a SD on the log scale of 0.413 for 
plasma AUC0-24 (based on Day 7 mean AUC0-24 data for 200 mg from study MNK111857), 15 
active subjects per cohort provides close to 80% power at a type I error rate of 0.1 to detect a 
difference from one in the ratio of geometric means between the 2 highest possible dose levels 
(and greater than 90% power for the middle 2 dose levels) given the previously seen slightly 
greater than dose proportionality increase in systematic exposure. The placebo subjects are 
included primarily to provide a reference group for comparison of safety in the target population. 
8.13 
General Conventions for Tables, Listings and Figures  
For summary tables, unless otherwise specified, the number of decimal places provided in the 
SAS output will be based on the accuracy of the least accurate value in the raw data as follows: 
• 
n 
integer 
• 
Arithmetic mean 
1 decimal place more than the least accurate number in the raw 
data 
• 
SD 
2 decimal places more than the least accurate number in the raw 
data 
• 
Median 
1 decimal place more than the least accurate number in the raw 
data 
• 
Minimum 
same number of decimal places as raw data 
• 
Maximum 
same number of decimal places as raw data 


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9 
TABLES, FIGURES, AND LISTINGS 
Table/Figure Number 
Table/Figure Name 
Section 14.1 
Demographic and Subject Characteristics Data Summaries 
Table 14.1.1 
Summary of Screening Outcome (All Subjects Set) 
Table 14.1.2 
Summary of Subject Disposition (All Randomized Set) 
Table 14.1.3 
Summary of Analysis Populations (All Randomized Set) 
Table 14.1.4 
Summary of Demographic Data (Safety Set) 
Table 14.1.5 
Summary of Baseline Physical Measurements (Safety Set) 
Table 14.1.6 
Summary of Study Drug Exposure (Safety Set) 
Section 14.2 
Efficacy/Pharmacokinetic/Pharmacodynamic Data Summaries 
Section 14.2.1 
Efficacy Data Summaries 
Table 14.2.1.1.1 
Summary of Daily Frequency of Hot Flashes - Twice Daily Diary 
(Full Analysis Set) 
Table 14.2.1.1.2 
Summary of Average Daily Frequency of Hot Flashes By Week 
and Change from Week -1 - Twice Daily Diary (Full Analysis Set) 
Table 14.2.1.1.3 
Statistical Analysis of Change from Week -1 in Average Daily 
Frequency of Moderate/Severe Hot Flashes - Twice Daily Diary  
(Full Analysis Set) 
Table 14.2.1.2.1 
Summary of Hot Flashes Average Severity - Twice Daily Diary 
(Full Analysis Set) 
Table 14.2.1.2.2 
Summary of Average Daily Severity of Hot Flashes by Week and 
Change from Week -1 - Twice Daily Diary (Full Analysis Set) 
Table 14.2.1.2.3 
Statistical Analysis of Change from Week -1 in Hot Flashes 
Average Daily Severity - Twice Daily Diary (Full Analysis Set) 
Table 14.2.1.3.1 
Summary of Hot Flashes Severity Score - Twice Daily Diary (Full 
Analysis Set) 
Table 14.2.1.3.2 
Summary of Average Daily Severity Score of Hot Flashes by 
Week and Change from Week -1 - Twice Daily Diary(Full 
Analysis Set) 
Table 14.2.1.3.3 
Statistical Analysis of Change from Week -1 in Hot Flashes 


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Average Daily Severity Score - Twice Daily Diary (Full Analysis 
Set) 
Table 14.2.1.4.1 
Summary of Night Time Awakenings Secondary to Hot Flashes - 
Twice Daily Diary (Full Analysis Set) 
Table 14.2.1.4.2 
Summary of Average Daily Night Time Awakenings Secondary to 
Hot Flashes by Week and Change from Week -1 - Twice Daily 
Diary (Full Analysis Set) 
Table 14.2.1.4.3 
Statistical Analysis of Change from Week -1 in Average Daily 
Night Time Awakenings Secondary to Hot Flashes - Twice Daily 
Diary (Full Analysis Set) 
Table 14.2.1.5.1 
Summary of Total Number of Night Time Awakenings - Twice 
Daily Diary (Full Analysis Set) 
Table 14.2.1.5.2 
Summary of Average Daily Night Time Awakenings (Total) by 
Week and Change from Week -1 - Twice Daily Diary (Full 
Analysis Set) 
Table 14.2.1.5.3 
Statistical Analysis of Change from Week -1 in Average Daily 
Night Time Awakenings (Total) - Twice Daily Diary (Full 
Analysis Set) 
Table 14.2.2.1.1 
Summary of Daily Frequency of Hot Flashes - Continuous Hot 
Flash Diary (Full Analysis Set) 
Table 14.2.2.1.2 
Summary of Average Daily Frequency of Hot Flashes by Week - 
Continuous Hot Flash Diary (Full Analysis Set) 
Table 14.2.2.1.3 
Statistical Analysis of Change from Day -1 in Daily Frequency of 
Moderate/Severe Hot Flashes - Continuous Hot Flash Diary (Full 
Analysis Set) 
Table 14.2.2.2.1 
Summary of Night Time Awakenings Secondary to Hot Flashes - 
Continuous Hot Flash Diary (Full Analysis Set) 
Table 14.2.2.2.2 
Summary of Average Daily Night Time Awakenings Secondary to 
Hot Flashes by Week - Continuous Hot Flash Diary (Full Analysis 
Set) 
Table 14.2.2.2.3 
Statistical Analysis of Change from Day -1 in Daily Night Time 
Awakenings Secondary to Hot Flashes - Continuous Hot Flash 
Diary (Full Analysis Set) 


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Table 14.2.2.3.1 
Summary of Night Time Awakenings (Total) - Continuous Hot 
Flash Diary (Full Analysis Set) 
Table 14.2.2.3.2 
Summary of Average Daily Night Time Awakenings (Total) by 
Week - Continuous Hot Flash Diary (Full Analysis Set) 
Table 14.2.2.3.3 
Statistical Analysis of Change from Day -1 in Daily Night Time 
Awakenings (Total) - Continuous Hot Flash Diary (Full Analysis 
Set) 
Table 14.2.3.1 
Summary of Daily Frequency of Hot Flashes Detected by the 
Device - Sternal Skin Conductance (Full Analysis Set) 
Table 14.2.3.2 
Summary of Average Daily Frequency of Hot Flashes Detected by 
the Device by Week - Sternal Skin Conductance (Full Analysis 
Set) 
Table 14.2.3.3 
Statistical Analysis of Change from Day -1 in Daily Frequency of 
Hot Flashes Detected by the Device - Sternal Skin Conductance 
(Full Analysis Set) 
Table 14.2.4.1 
Summary of Luteinizing Hormone AUC0-8 and Change from Day 
-1 (Full Analysis Set) 
Table 14.2.4.2 
Statistical Analysis of Luteinizing Hormone AUC0-8 Change from 
Day -1 (Full Analysis Set) 
Figure 14.2.1.1.1 
Mean (+/- SE) Daily Frequency of Hot Flashes - Twice Daily 
Diary (Full Analysis Set) 
Figure 14.2.1.2.1 
Mean (+/- SE) Daily Hot Flashes Average Severity - Twice Daily 
Diary (Full Analysis Set) 
Figure 14.2.1.3.1 
Mean (+/- SE) Daily Hot Flashes Severity Score - Twice Daily 
Diary (Full Analysis Set) 
Figure 14.2.1.4.1 
Mean (+/- SE) Night Time Awakenings Secondary to Hot Flashes 
- Twice Daily Diary (Full Analysis Set) 
Figure 14.2.1.5.1 
Mean (+/- SE) Night Time Awakenings (Total) - Twice Daily 
Diary  (Full Analysis Set) 
Figure 14.2.2.1.1 
Mean (+/- SE) Daily Frequency of Hot Flashes - Continuous Hot 
Flash Diary  (Full Analysis Set) 
Figure 14.2.2.2.1 
Mean (+/- SE) Night Time Awakenings Secondary to Hot Flashes 


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- Continuous Hot Flash Diary (Full Analysis Set) 
Figure 14.2.2.3.1 
Mean (+/- SE) Night Time Awakenings (Total) - Continuous Hot 
Flash Diary (Full Analysis Set) 
Figure 14.2.3.1 
Mean (+/- SE) Daily Frequency of Hot Flashes Detected by the 
Device - Sternal Skin Conductance (Full Analysis Set) 
 
 
 
Section 14.3 
Safety Data Summaries 
Section 14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety 
Set) 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Set) 
Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by Reported 
Severity (Safety Set) 
Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by Relationship 
to Study Drug (Safety Set) 
Section 14.3.2 
Listings of Deaths, Other Serious and Certain Significant 
Adverse Events 
Table 14.3.2.1 
Listing of Adverse Events Leading to Death (Safety Set) 
Table 14.3.2.2 
Listing of Serious Adverse Events (Safety Set) 
Table 14.3.2.3 
Listing of Adverse Events Resulting in Discontinuation of Study or 
Treatment (Safety Set) 
Table 14.3.2.4 
Listing of Treatment-Emergent Adverse Events of Dehydration 
(Safety Set) 
Section 14.3.4 
Abnormal Laboratory Value Listing 
Table 14.3.4.1 
Listing of Abnormal Laboratory Results (Safety Set) 
Section 14.3.5 
Additional Safety Data Summaries 
Table 14.3.5.1 
Absolute and Change from Baseline for Clinical Laboratory 
Parameters (Chemistry, Hematology, Lipids and Coagulation) 


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Page 49 of 52 
 
(Safety Set) 
Table 14.3.5.2 
Absolute and Change from Baseline for Laboratory Hormones 
Results (Safety Set) 
Table 14.3.5.3 
Laboratory Shift in Normal Range Indicator by Category 
(Chemistry, Hematology, Lipids and Coagulation) (Safety Set) 
Table 14.3.5.4 
Laboratory Shift in Normal Range Indicator of Hormones Results 
(Safety Set) 
Table 14.3.5.5 
Absolute and Change from Baseline Vital Signs (Safety Set) 
Table 14.3.5.6 
Summary Statistics of 12-Lead ECG Values and Change from 
Baseline (Safety Set) 
Table 14.3.5.7.1.1 
Summary of Daily Maximum QTcB and QTcF Interval Results 
(Safety Set) 
Table 14.3.5.7.1.2 
Summary of Overall Maximum Post-Baseline QTcB and QTcF 
Interval Results (Safety Set) 
Table 14.3.5.7.1.3 
Summary of Overall Maximum Predose QTcB and QTcF Interval 
Results (Safety Set) 
Table 14.3.5.7.2.1 
Summary of Daily Maximum Change From Baseline QTcB and 
QTcF Interval Results (Safety Set) 
Table 14.3.5.7.2.2 
Summary of Overall Maximum Change From Baseline QTcB and 
QTcF Interval Results (Safety Set) 
Table 14.3.5.7.3 
Abnormal Interpretation for 12-Lead ECG (Safety Set) 
Table 14.3.5.8.1 
Analysis for Arrhythmias by Continuous Holter Monitoring  by 
Day (Safety Set) 
Table 14.3.5.8.2 
Analysis for Post-Baseline Arrhythmias by Continuous Holter 
Monitoring (Safety Set) 
 
 
Listing Number 
Listing Name 
Section 16.1.7 
Randomization 
Listing 16.1.7 
Randomization Allocation (All Randomized Set) 


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Section 16.2.1 
Discontinued Subjects 
Listing 16.2.1.1 
Screening Outcome (All Subjects Set) 
Listing 16.2.1.2 
Subject Disposition (Safety Set) 
Section 16.2.2 
Protocol Deviations 
Listing 16.2.2 
Protocol Deviations (All Randomized Set) 
Section 16.2.3 
Subjects Excluded from Analysis 
Listing 16.2.3 
Exclusions from Analysis Populations (All Randomized Set) 
Section 16.2.4 
Demographic Data 
Listing 16.2.4.1 
Demographics Data (Safety Set) 
Listing 16.2.4.2 
Physical Measurements (Safety Set) 
Listing 16.2.4.3 
Inclusion/Exclusion Criteria (Safety Set) 
Listing 16.2.4.4 
Consent Information (Safety Set) 
Listing 16.2.4.5 
Medical and Surgical History (Safety Set) 
Listing 16.2.4.6 
Prior and Concomitant Medications (Safety Set) 
Listing 16.2.4.7 
Concomitant Procedures (Safety Set) 
Listing 16.2.4.8 
Visit Dates (Safety Set) 
Section 16.2.5 
Compliance and/or Drug Concentration Data 
Listing 16.2.5.1 
Study Drug Dosing (Safety Set) 
Section 16.2.6 
Individual Efficacy Data 
Section 16.2.6.1 
Individual Efficacy Response Data 
Listing 16.2.6.1.1.1 
Hot Flash Twice Daily Diaries Data (Full Analysis Set) 
Listing 16.2.6.1.1.2 
Hot Flash Twice Daily Diaries Data - Daily Derivation (Full Analysis 
Set) 
Listing 16.2.6.1.1.3 
Hot Flash Twice Daily Diaries Data - Weekly Derivation (Full 
Analysis Set) 
Listing 16.2.6.1.2.1 
Continuous Hot Flash Diary Data (Full Analysis Set) 
Listing 16.2.6.1.2.2 
Continuous Hot Flash Diary Data - Daily Derivation (Full Analysis 
Set) 


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Listing 16.2.6.1.2.3 
Continuous Hot Flash Diary Data - Weekly Derivation (Full Analysis 
Set) 
Listing 16.2.6.1.3.1 
Data Collection of the Skin Conductance Monitor (Full Analysis Set) 
Listing 16.2.6.1.3.2 
Skin Conductance Monitor Hot Flashes (Full Analysis Set) 
Listing 16.2.6.1.3.3 
Skin Conductance Monitor Hot Flashes Detected by the Device - 
Derivation  (Full Analysis Set) 
Listing 16.2.6.1.4 
Luteinizing Hormone Data (Full Analysis Set) 
Section 16.2.7 
Adverse Event Listings 
Listing 16.2.7.1 
All Adverse Events (Safety Set) 
Listing 16.2.7.2 
Verbatim to Preferred Term Mapping of All Adverse Events 
Section 16.2.8 
Individual Laboratory Measurements by Subject 
Listing 16.2.8.1 
Normal Ranges for Laboratory Data 
Listing 16.2.8.2 
Clinical Laboratory Data by Category (Chemistry, Hematology, 
Lipids and Coagulation) (Safety Set) 
Listing 16.2.8.3 
Hormones Results (Safety Set) 
Listing 16.2.8.4 
Urinalysis Results (Safety Set) 
Listing 16.2.8.5 
Vital Signs (Safety Set) 
Listing 16.2.8.6 
12-Lead Electrocardiogram Results (Safety Set) 
Listing 16.2.8.7 
Holter Electrocardiogram Monitoring (Safety Set) 
Listing 16.2.8.8 
Physical Examination (Safety Set) 
Listing 16.2.8.9 
Investigator Comments (Safety Set) 
 
 
 
 


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VERSION HISTORY 
Version 
Date 
List principal changes from previous version 
2.0 
27FEB2017 
- Section 4.1 and 4.10.5 has been changed to take into account the 
changes in the protocol version 4.0 dated 13DEC2016. 
- The night time awakenings analyses are now separated in 2 
groups: NTA secondary to hot flashes and NTA, Total 
- The baseline for ECG is now defined as the time matched  
assessment done at Day -1 
- The maximum QTcB and QTcF values are analysed daily and 
overall. 
1.0 
01DEC2016 
NA. Initial Version 
 


STATISTICAL ANALYSIS PLAN FOR 
PHARMACOKINETICS 
Protocol RELENT -1 
EVALUATION OF THE PHARMACOKINETICS AND SAFETY OF NT-814 IN POST-
MENOPAUSAL WOMEN WITH VASOMOTOR SYMPTOMS 
REVISION HISTORY 
Version 
Version Date 
Draft 1.0 
April 10, 2017 
Final 1.0 
May 5, 2017 
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Author 
Summary of Changes Made 
 
New Document 
 
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PPD
PPD


SIGNATURE PAGE- NERRE THERAPEUTICS LTD. 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this clinical study, as 
p1·cscntcd in this document. 
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.Dntc (DD 1\'T:mm YY1'Y) 
Date (DD M mm Y"r'YY) 
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PPD


SIGNATURE PAGE- NERRE THERAPEUTICS LTD. 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this clinical study, as 
presented in this document. 
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t '1 \'\1 f\ 'f 
ll....l.T __ 
_ 
Date (DD Mm m YYYY) 
.. (:)D Mmm YYYY) 
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PPD


SIGNATURE PAGE- PAREXEL 
Declaration 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
If this document has been signed electronically, signature(s) and date(s) are present at the end of the document: 
Document prepared and approved by: 
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Date (DD Mmm YYYY) 
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PPD


TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 1 
SIGNATURE PAGE- NERRE THERAPEUTICS LTD ............................................................... 2 
SIGNATURE PAGE - P AREXEL ................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 4 
ABBREVIATION AND ACRONYM LIST .................................................................................. 5 
STATISTICAL ANALYSIS PLAN ............................................................................................... 7 
1. 
PRIMARY OBJECTIVE ................................................................................................... 7 
2. 
PRIMARY PHARMACOKINETIC ENDPOINTS .......................................................... 7 
3. 
STUDY DESIGN .............................................................................................................. 8 
4. 
STUDY POPULATION .................................................................................................... 8 
5. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................... 9 
6. 
RANDOMIZATION ......................................................................................................... 9 
7. 
ANALYSIS POPULATIONS ........................................................................................... 9 
8. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 10 
8.1 
Pharmacokinetic Variables ................................................................................. 10 
8.1.1 
Handling of Values Below the Limit of Quantification ................................. 1 0 
8.1.2 
Pharmacokinetic Parameter Calculation Methods .......................................... 11 
8.2 
Statistical Analysis Methods .............................................................................. 13 
8.2.1 
Software .......................................................................................................... 13 
8.2.2 
Missing Data ................................................................................................... 13 
8.2.3 
Pharmacokinetic Concentrations and Variables ............................................. 13 
8.2.4 
Presentation ofPK Data, Descriptive Statistics and PK Assessment.. ........... 14 
9. 
REFERENCES ................................................................................................................ 14 
10. 
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT ........................ 15 
11. 
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT ...................... 15 
12. 
LISTINGS TO BE INCLUDED IN THE CLINICAL STUDY REPORT ..................... 15 
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ABBREVIATION AND ACRONYM LIST 
<. Abbrev,ia'tjoniAcr()tiyrit 
,. __ ,.;.:.·.--
'' 
'--+··"···.::, '"'"'';;··.;<-•\ ;_, 
%AUCex 
AUCo.24 
AUCo.oo 
AUCo.1 
AUCo-r 
BLQ 
CL!F 
Clast 
CRF 
CSP 
c, 
CV% 
GCV% 
GM 
LLOQ 
PD 
PK 
PKAS 
PTF 
QCD 
Rac(AUC) 
Rac(Cmax) 
R2 adjusted 
SAP 
so 
tlast 
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Percentage of AUCo-inf obtained by extrapolation 
Area under the concentration-time curve from time zero to 24 hours 
postdose 
AUC from time zero extrapolated to infinity 
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration postdose 
AUC over the dosing interval 
Below the limit of quantification 
Apparent total systemic clearance 
Last quantifiable concentration at t1ast 
Peak concentration 
Minimum observed concentration at steady state 
Case rep01i form 
Clinical study protocol 
Trough concentration observed predose during multiple dosing 
Coefficient of variation 
Geometric coefficient of variation 
Geometric mean 
Lower limit of quantification 
Pharmacodynamic 
Pharmacokinetic 
Pharmacokinetic analysis set 
Peak to trough fluctuation 
Quantitative Clinical Development 
Accumulation ratio calculated using AUC 
Accumulation ratio calculated using Cmax 
Adjusted correlation coefficient 
Statistical Analysis Plan 
Standard deviation 
Apparent terminal phase half-life 
Time of last quantifiable concentration 
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> 
·. 
,_ " 
if-- -.;',"" 
'·""""'. 
TLFs 
WNL 
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Tables, listings and figures 
Time of occurrence of Cmax 
WinNonlin 
Tenninal elimination rate constant 
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STATISTICAL ANALYSIS PLAN 
This Statistical Analysis Plan (SAP) details the methodology to be used in analyzing the pharmacokinetic (PK) 
data and outlines the PK Tables, Listings and Figures (TLFs). It describes the variables and populations, 
anticipated data transfotmations and manipulations and other details of the analyses not provided in the Clinical 
Study Protocol (CSP). 
The PK analyses described are based on the final CSP Version 4.0, dated 13 December 2016. The SAP will be 
finalized prior to database lock and describes the pharmacokinetic analysis as it is foreseen when the study is 
being planned. If circumstances should arise during the study rendering this analysis inappropriate, or if 
improved methods of analysis should arise, updates to the analyses may be made. Any deviations from the SAP 
after database lock, reasons for such deviations and all alternative or additional statistical analyses that may be 
performed, will be described in a SAP Addendum. 
1. 
PRIMARY OBJECTIVE 
To evaluate the PK and safety profile of multiple ascending dose levels ofNT-814 compared to placebo, by once 
daily administration of each dose for 14 days 
2. 
PRIMARY PHARMACOKINETIC ENDPOINTS 
The PK endpoints are: 
• 
peak concentration (Cmax) 
• 
time of occurrence of Cmax (T max) 
• 
area under the curve (AUC) from time zero to the time of the last quantifiable concentration 
(AUCo_t) 
• 
AUC in the dosing interval (AUCo-r, synonymous with AUCo-24) 
• 
AUC from time zero extrapolated to infinity (AUCo-oo) 
• 
apparent terminal phase half-life (tlh) 
• 
apparent clearance (CL/F) 
The PK parameters will be derived on Day 1, Day 7, and Day 14, as appropriate. 
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3. 
STUDY DESIGN 
This is a multi-center, double-blind, randomized, placebo-controlled multiple ascending dose trial in post-
menopausal women with vasomotor symptoms. Subjects will be recruited into sequentially dosed cohorts; 
Cohort 1 (50 mg NT -814 or placebo), Cohort 2 ( 1 00 mg NT -814 or placebo), Cohort 3 (150 mg NT -814 or 
placebo) and Cohort 4 (300 mg NT-814 or placebo). For each cohort, subjects will enter a 4-week screening 
period to determine eligibility. Twenty eligible subjects will be randomized per cohort (15 active and 5 placebo). 
On Day 1, the subjects will be randomized in a 3:1 ratio to once daily (morning) doses ofNT-814 or placebo, to 
be taken for a total of 14 days. Subjects will be monitored as an inpatient from Day -1 to Day 8 and will undergo 
blood draws for intensive PK sampling, safety monitoring and for impact on blood hormonal profiling as well as 
24-hour skin conductance measurements and continuous completion of hot flash diaries. 
Subjects will be discharged from the clinic on Day 8 without any monitoring devices, providing there are no 
safety concerns and will undergo dosing for a fllliher 5 days as an outpatient. Subjects will be instructed to 
continue recording details of the hot flashes experienced, using the twice daily diary. They will be provided 
with the continuous daily diary and instructed to start completing this upon waking on the morning of Day 14 
prior to admission to the clinic. They will be re-admitted to clinic on the morning of Day 14 for the final dose 
and undergo the same assessments with the same devices including Halter and skin conductance as Day 1. 
Subjects will be discharged following the 24-hour post Day 14 assessments (Day 15). Subjects will return to 
the clinic, as outpatients, for a single PK sample on the mornings of Days 16 and 17 ( 48 hours and 72 hours 
after the Day 14 dose respectively). 
Throughout the study, subjects will be closely monitored for safety including assessments of AEs, 12-lead 
ECGs, atierial oxygen saturation using pulse oximetry, vital signs (sitting and standing BP, heart rate, oral body 
temperature, and respiration rate), clinical labs and physical examinations. 
Blood samples for PK analysis will be collected at the following time points on Day 1, Day 7 and Day 14: Pre-
dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 24.0 hours. Additional sampling times of 48 and 72 
hours will be collected following the Day 14 dose. The pre-dose sample will be collected within 30 minutes 
prior to dose administration. 
4. 
STUDY POPULATION 
Post-menopausal female subjects 40-65 years of age 
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5. 
STATISTICAL BASIS FOR SAMPLE SIZE 
The planned sample size is 20 subjects per cohmi, with 15 active and 5 placebo. This is deemed enough 
provide sufficient separation of exposures between dose groups and to allow for an assessment of safety versus 
dose group/exposure. Assuming a standard deviation on the log scale of 0.413 for plasma AUC0•24 (based on 
Day 7 mean AUC0•24 data for 200 mg from study MNK111857), 15 active subjects per cohort provides close to 
80% power at a type I error rate of 0.1 to detect a difference from one in the ratio of geometric means between 
the two highest possible dose levels (and greater than 90% power for the middle two dose levels) given the 
previously seen slightly greater than dose proportionality increase in systemic exposure. The placebo subjects 
are included primarily to provide a reference group for comparison of safety in the target population. 
6. 
RANDOMIZATION 
On Day 1, the subjects will be randomized in a 3:1 ratio to once daily (morning) doses ofNT-814 or placebo, to 
be taken for a total of 14 days. 
7. 
ANALYSIS POPULATIONS 
The following data sets will be used for the analysis: 
• Safety Analysis Set: All subjects who receive at least one dose of double-blind study drug. Subjects will 
be analyzed according to treatment received. 
• Pharmacokinetic Analysis Set (PKAS): All subjects who received at least one dose of active study 
drug and for whom the PK data are considered sufficient. Subjects or data may be excluded from the 
PKAS at the discretion of the PK Scientist, including, but not limited to the following: 
Concomitant medication which could render the plasma concentration-time profile unreliable 
Any data excluded will be discussed in the CSR. Any excluded subject will have their concentration and PK 
parameter data listed only. Subjects who receive placebo will not be part of the PKAS. 
Analysis Sets will be identified prior to the unblinding of the study data. 
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8. 
STATISTICAL ANALYSIS CONVENTIONS 
8.1 
Pharmacokinetic Variables 
Derivation of PK parameters will be the responsibility of Quantitative Clinical Development (QCD), P AREXEL 
International. The PK parameters will be determined for NT -814 in plasma following single and multiple dose 
administration. 
8.1.1 
Handling of Values Below the Limit of Quantification 
All plasma concentrations below the lower limit of quantification (LLOQ) or missing data will be labeled as 
below the limit of quantification (BLQ) or missing, respectively, in the concentration data listings. 
Considerations in the handling of BLQ data for the generation of plasma PK Parameters 
BLQ values will be imputed in the PK concentration dataset used for the derivation of PK parameters. The 
following rules will be applied: 
• 
BLQs at the beginning of a subject profile (i.e. before the first incidence of a measurable concentration) will 
be assigned to zero. 
• 
BLQs at the end of a subject profile (i.e. after the last incidence of a measurable concentration) will be set to 
missing. 
• 
Single BLQs which fall between two measurable concentrations will be set to missing. 
• 
Consecutive BLQs which fall between measureable concentrations will be set to missing. Measurable 
concentrations after consecutive BLQs will also be set to missing. 
Considerations in the handling of BLQ data for plotting of individual plasma PK concentration 
data 
BLQ values will be imputed for individual concentration-time plots according to the following rules: 
• 
BLQs at the beginning of a subject profile (i.e. before the first incidence of a measurable concentration) will 
be assigned to zero. 
• 
BLQs at the end of a subject profile (i.e. after the last incidence of a measurable concentration) will be set to 
missing. 
• 
Single BLQs which fall between two measurable concentrations will be set to missing. 
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• 
Consecutive BLQs which fall between measureable concentrations will be set to zero. Measurable 
concentrations after consecutive BLQs will be retained. 
For linear plots, zero concentration value(s) will be included in the plot. 
For log-linear plots, zero concentration value(s) will be assigned a missing value. 
A reference line indicating LLOQ may be included on plots. 
Considerations in the handling of BLQ data for summarizing plasma PK concentration data 
BLQ values will be imputed for mean/median concentration-time plots and tabular summaries according to the 
following rules: 
• 
All BLQ values will be set to zero, except when an individual BLQ falls between two measurable values, in 
which case it will be set to missing. 
• 
All BLQ values will be substituted with the LLOQ for calculation of geometric means and geometric CVs 
• 
Measurable concentrations after consecutive BLQs will be set to missing. 
Zero mean or median values will be included in tabular summaries. 
A high proportion of BLQ values may affect derivation of standard deviation; if more than 30% of values at a 
time-point are imputed, then standard deviation (SD) will not be displayed. 
Tabular summaries for concentration-time data will report N (number of subjects who received treatment) and n 
(number of subjects with non-missing values. 
8.1.2 
Pharmacokinetic Parameter Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the concentration-time data 
using Phoenix® WinNonlin® (WNL) Professional (Version 6.3 or higher) following these guidelines: 
• 
Actual sampling times relative to dosing rather than nominal times will be used in the calculation of all 
derived PK parameters. 
• 
There will be no imputation of missing data. 
• 
Any subjects with missing concentration data will be included in the PK analysis set provided that at 
least Cmax and AUCo.t can be reliably calculated. 
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PK parameters will be estimated according to the following guidelines: 
• 
Cmax will be obtained directly from the concentration-time data. 
• 
T max is the time at which Cmax is observed. 
• 
Az will be estimated at terminal phase by linear regression after log-transformation of the concentrations: 
Only those data points that are judged to describe the tenninal log-linear decline will be used in the 
regression. 
A minimum number of three data points in the terminal phase will be used in calculating Az with the line 
of regression starting at any post-Cmax data point (Cmax should not be pmi of the regression slope). The 
adjusted correlation coefficient (R2 adjusted) in general should be greater than 0.90. Any value< 0.90 but 
0.80 will be flagged but may be used at the PK Scientist's best knowledge and judgment; any value< 
0.80 will be excluded from the analysis. 
The interval used to determine "Az should be equal or greater than 1.5-fold the estimated half-life or 
otherwise flagged and excluded from the analysis. 
• 
t•;, will be calculated as ln2/"Az. 
• 
AUC is calculated by the linear up/log down method (linear method will be employed for all incremental 
trapezoids arising from increasing concentrations and the logarithmic method will be used for those arising 
from decreasing concentrations. 
rt c(t)dt 
AUCo-t=Jo 
AUCo-inr =fat C(t)dt + ft'' C ( t)dt = AUCo-t + C/"Az. 
AUC0 r,ss will be calculated at steady state during the time interval between consecutive doses 
• 
C1 is last observed quantifiable concentration. 
• 
o/oAUCex will be calculated as (1 - [AUC0•1/AUC0•1nr])xlOO. The o/oAUCex should not exceed 20% for each 
individual profile. If the o/oAUCex is more than 20%, the individual result should be flagged and mentioned 
in the report as well as all parameters depending on AUCo-inf· If the o/oAUCex is greater than 30% the value 
and all dependent parameters should be flagged and excluded from the analysis. 
• 
CLIF will be calculated as dose/AUC0•1nr, parent drug only. 
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The following PK parameters may also be derived. 
• 
Rac(AUC) Accumulation ratio is calculated as: AUC0_, (last dose interval)/ AUC0_, (first dose interval). 
• 
Rac(Cmax) 
Accumulation ratio is calculated as: Cmax (last dose interval)/ Cmax (first dose interval). 
8.2 
Statistical Analysis Methods 
8.2.1 
Software 
Statistical analysis of PK parameters will be performed using Phoenix® WinNonlin® (WNL) Professional 
(Version 6.3 or higher) and will be based on the PK analysis set (PKAS). 
8.2.2 
Missing Data 
There will be no imputation of missing data. The details on handling PK data below the lower level of 
quantification (LLOQ) are given in Section 8.1.2. 
8.2.3 
Pharmacokinetic Concentrations and Variables 
Phannacokinetic plasma concentration data will be listed by cohort and subject including actual sampling times 
relative to dosing. Plasma concentrations will be summarized by cohort, day and nominal time point. The 
following descriptive statistics will be presented for plasma concentrations obtained at each nominal time point: 
n, arithmetic mean, SD, coefficient of variation (CV%), geometric mean (GM), geometric coefficient of 
variation (GCV%), median, minimum and maximum values. 
Plasma pharmacokinetic parameters will be listed by cohmi, subject and day, and summarized by cohmi and 
day. Descriptive statistics for calculated PK parameters will include: n, arithmetic mean, SO, CV%, GM, 
GCV%, median, minimum and maximum values. For Tmax, only median, minimum and maximum values will 
be presented. No descriptive statistics will be determined when fewer than three individual PK parameters are 
available. 
Individual plasma concentration versus actual times will be plotted by cohoti and day in linear and semi-
logarithmic scale. Combined individual plasma concentrations versus actual times will be plotted by cohort and 
day. 
Arithmetic mean plasma concentrations versus nominal times will be presented by day on a linear scale and 
semi-logarithmic scale. All treatments will be overlaid on the same plot. 
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8.2.4 
Presentation of PK Data, Descriptive Statistics and PK Assessment 
The following rules will be followed with regards to the number of decimal places and presentation of data in 
the tables and listings of concentration data: 
• 
The individual concentrations will be reported to the same precision as the source data (for example, if the 
source data is presented to five significant digits, the individual values will be presented to five significant 
digits). 
• 
The mean, standard deviation (SD), geometric mean and median will be tabulated to one more significant 
digit compared to the source data, but with a maximum of four significant digits. 
• 
Minimum and maximum values will be tabulated to the same precision as the source data, but with a 
maximum of four significant digits. 
• 
Coefficient of variation (CV%) and geometric coefficient of variation (GCV)% will be presented to one 
decimal place. 
The following rules will be followed with regards to the number of decimal places and presentation of data in 
the tables and listings of PK parameters: 
• 
Individual PK parameters will be presented to four significant digits, with the exception ofT max, which will 
be presented to two decimal places. In addition, parameters directly derived from source data (e.g. Cmax) 
shall be repmied with the same precision as the source data (if this is not four significant digits). 
• 
The mean, geometric mean, median and SD values will be reported to four significant digits, all other 
descriptive statistics will be reported to three significant digits except for CV% and GCV%, which will be 
presented to one decimal place. For Tmax, the minimum and maximum will be presented to two decimals 
places and the rest of the descriptive statistics to three decimal places. 
• 
P-values will be presented to four decimal places. 
• 
Estimates and confidence intervals in the form of percentages will be presented to two decimal places. 
Source data shall be used in all derived PK parameter calculations without prior rounding. 
9. 
REFERENCES 
1. 
WinNonlin Professional Software Version 6.3. http://www.pharsight.com 
NeRRe Therapeutics Ltd. 
RELENT-! 
TP-EP.BS-WW-001-05 
Effective date: 29 Jul 15 
Related to: SOP-EP.BS-WW-002 
Final 1.0 
5 May 2017 
Page 14 of 15 


10. 
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Pharmacokinetic Data 
Table 1.1 
Table 1.2 
Table 1.3 
Individual and Summary of Plasma Concentrations of NT -814 versus Nominal 
Sampling Times by Cohort and Day (Pharmacokinetic Population) 
Individual and Summary of Plasma Pharmacokinetic Parameters ofNT-814 by Cohort 
and Day (Phmmacokinetic Population) 
Power Model for Dose Proportionality (Pharmacokinetic Population) 
11. 
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Figure 1.1 
Figure 1.2 
Figure 1.3 
Individual Profiles for NT-814 Plasma Concentration Time Data (Linear and Semi-
logarithmic Scale) (Pharmacokinetic Population) 
Mean Profiles for NT -814 Plasma Concentration Time Data Overlaid by Cohort and 
Day (Linear and Semi-logarithmic Scale) (Pharmacokinetic Population) 
Assessment ofNT -814 Dose PropOttionality (Pharmacokinetic Population) 
12. 
LISTINGS TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Listing 1.1 
Listing 1.2 
NeRRe Therapeutics Ltd. 
RELENT-I 
TP-EP.BS-WW-001-05 
Effective date: 29 Jul 15 
Individual Blood Sampling Times and Concentrations ofNT-814 
Individual Pharmacokinetic Parameters ofNT -814 in Plasma 
Related to: SOP-EP.BS-WW-002 
Final 1.0 
5 May 2017 
Page 15 of 15