Clinical trial NCT03596762
Conditions: Menopause Hot Flashes Night Waking
Sponsor: Bayer
Start date: 2018-11-20; Completion date: 2019-11-21
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the effectiveness of BAY3427080 (NT-814), taken once a day, in the treatment of troublesome post-menopausal symptoms.

Detailed description:
This is a multi-centre, multi-country, double-blind, randomised, placebo-controlled Phase 2b study. The study will have a single-blind run-in period and will be adaptive with respect to the number of subjects recruited into each dose group. Four doses of BAY3427080 (40 mg once a day, 80 mg once a day, 120 mg once a day and 160 mg once a day) will be investigated and compared to placebo, in five parallel groups. Subjects will participate in the study for a total of approximately 19 weeks, comprising a screening period of 1 week, a 14 week treatment period, and then a final follow up visit 4 weeks after the end of the treatment period. There will be a total of 8 visits whilst participating in the study. Subjects will record their hot flashes in an electronic diary during the screening period to establish eligibility and throughout the study after randomisation.

Arms: arm 1: Participants received 4x40 mg elinzanetant capsules. arm 2: Participants received 3x40 mg elinzanetant capsules and 1 placebo capsule. arm 3: Participants received 2x40 mg elinzanetant capsules and 2 placebo capsules. arm 4: Participants received one 40 mg elinzanetant capsule and 3 placebo capsules. arm 5: Participants received four placebo capsules orally once daily in the evening before bedtime.
Interventions: intervention 1: Elinzanetant (BAY3427080) intervention 2: Placebo
Intervention descriptions: intervention 1: BAY3427080 capsules intervention 2: Placebo capsules

Protocol documents:
Prot_000.pdf: 
 
 
 
Document Type: 
Study Protocol 
Official Title: 
A Double-Blind, Randomised, Placebo Controlled, Adaptive 
Design Study of the Efficacy, Safety and Pharmacokinetics of NT-
814 in Female Subjects With Moderate to Severe Vasomotor 
Symptoms Associated With the Menopause 
NCT Number: 
NCT03596762 
Document Date: 
21 MAY 2019 
 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 1 of 100 
21 May2019 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A DOUBLE-BLIND, RANDOMISED, PLACEBO CONTROLLED, ADAPTIVE DESIGN 
STUDY OF THE EFFICACY, SAFETY AND PHARMACOKINETICS OF NT-814 IN 
FEMALE SUBJECTS WITH MODERATE TO SEVERE VASOMOTOR SYMPTOMS 
ASSOCIATED WITH THE MENOPAUSE 
 
The “SWITCH-1” Study 
 
 
 
 
IND No:  
EudraCT No: 
ClinicalTrials.gov No: 
129492 
2018-002763-26 
NCT03596762 
Protocol No.: 
814-PM-02 
Version No:  
Final 2.1 (US) 
Date of Protocol:  
21 May 2019 
 
 
Sponsor:            
 
NeRRe Therapeutics Ltd,  
 
 
 
 
SBC, Incubator Building,  
 
 
 
 
Gunnels Wood Rd.,  
 
 
 
 
Stevenage, 
 
 
 
 
SG1 2FX 
 
 
 
 
United Kingdom  
 
SAE Reporting: 
Emas Pharma Pharmacovigilance 
Tel.: 
 
Fax: 
 
Email: 
  
 
 
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 ethics 
committee/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 General 
Principles of the Declaration of Helsinki (with amendments), and in accordance with local 
legal and regulatory requirements. 
 
 
 
PPD
PPD
PPD


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 2 of 100 
21 May 2019 
 
 
 
 
1. 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
A double-blind, randomised, placebo-controlled, 
adaptive-design study of the efficacy, safety and 
pharmacokinetics of NT-814 in female subjects with 
moderate to severe vasomotor symptoms associated 
with the menopause 
 
PROTOCOL  
NUMBER 
 
814-PM-02 
CHIEF 
INVESTIGATOR 
 
 
 
 
 
 United States 
 
SPONSOR 
 
NeRRe Therapeutics Ltd 
INVESTIGATIONAL 
MEDICINAL PRODUCT  
  
NT-814 
PHASE OF 
DEVELOPMENT 
 
2b 
INDICATION  
 
Post-menopausal vasomotor symptoms 
STUDY DESIGN 
This is a multi-centre, multi-country, double-blind, 
randomised, placebo-controlled Phase 2b study. The 
study will have a single-blind placebo run-in period and 
will be adaptive with respect to the number of subjects 
recruited into each dose group.  
Four doses of NT-814 (40 mg once a day, 80 mg once a 
day, 120 mg once a day and 160 mg once a day) will be 
investigated and compared to placebo, in five parallel 
groups. All subjects will receive placebo for the last 2 
weeks of the screening/baseline period, after which 
subjects who meet the eligibility criteria will be 
randomised into the study.  Subjects will initially be 
randomised 1:1:1:1:1 to each of the treatment groups, 
with the randomisation ratio subject to change in 
response to emerging efficacy and safety data. 
Regardless of any changes to the randomisation ratio,  
subjects will continue to receive the dose regimen they 
were randomised to for the full 12-week treatment 
period.  
Subjects will participate in the study for a total of 
PPD
PPD
PPD
PPD
PPD


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 3 of 100 
21 May 2019 
 
 
 
 
approximately 19 weeks, comprising a screening & 
baseline period (3 weeks), 12 weeks of double-blind 
treatment and then a final follow up visit, 4 weeks after 
the end of the treatment period. There will be a total of 
8 visits whilst participating in the study.  
Subjects who provide informed consent will be 
screened for participation in the study. After giving 
informed consent, but before Screening Visit 2 (i.e. 
before starting the placebo run-in period), subjects will 
be 
withdrawn 
from 
prohibited 
concomitant 
medications. 
At the first visit (Screening Visit 1), they will be 
provided with a paper diary, which they will be asked 
to complete once daily (prior to retiring to bed) for 7 
days, recording their recall of the total number of hot 
flushes (also known as hot flashes) over the previous 24 
hours, and the severity of each of those hot flushes. At 
the second visit (Screening Visit 2), the investigator or 
designee will review the paper diary to determine if the 
subject can continue in the study. To continue, subjects 
must have completed the paper diary for at least 6 days 
and recorded an average of at least 8 moderate or severe 
hot flushes per day over the last 5 days that the paper 
diary was completed. 
Subjects who continue to satisfy all the initial selection 
criteria at Screening Visit 2 will commence placebo 
treatment on a single-blind (subject only) basis and be 
provided with an electronic diary (eDiary) which they 
will be asked to complete twice a day for 14 (+2) days 
during the remaining screening/baseline period. The 
eDiary will record the subject’s recall of the number of 
hot flushes during the day (recorded just prior to 
retiring to bed) and overnight (recorded on wakening). 
The severity of each hot flush will also be recorded. To 
proceed to randomisation, the subject will be required 
to have completed the eDiary for at least 9 days and to 
have recorded an average of at least 7 moderate or 
severe hot flushes per day over the last 7 days that the 
eDiary was completed. 
At the baseline visit (Day 1), subjects who comply with 
all selection criteria will be enrolled into the 12-week 
double-blind portion of the study and be randomised to 
one of the NT-814 doses or placebo. Subjects who do 
not meet the eDiary criteria will not continue into the 
study (they will be screen failures). 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 4 of 100 
21 May 2019 
 
 
 
 
Randomised subjects will undergo further clinic visits 
at Week 2, Week 4, Week 8, Week 12 (end of treatment 
visit) and Week 16 (end of study) with regular 
assessments of compliance with study medication, 
compliance with the eDiary completion as well as 
assessments of concomitant medications, mental well-
being, quality of life (QoL), sleep, and safety.  
A treatment kit will be dispensed at Screening Visit 2 
(for the placebo run-in), the Baseline Visit, Week 4 and 
Week 8. A final follow-up safety assessment will be 
performed at Week 16, 4-weeks after stopping study 
medication. 
Blood samples will be collected for pharmacokinetic 
(PK) analysis for all subjects at Weeks 2, 4, 8, and 12. 
STUDY OBJECTIVES 
Primary 
 
x To evaluate the efficacy of once daily doses of 
40 mg, 80 mg, 120 mg and 160 mg NT-814, 
compared with placebo, in reducing the 
frequency and severity of hot flushes. 
x To assess the safety and tolerability of once 
daily doses of 40 mg, 80 mg, 120 mg and 160 
mg NT-814, compared with placebo, in subjects 
with post-menopausal symptoms. 
Secondary 
 
x To evaluate the effect of once daily doses of 40 
mg, 80 mg, 120 mg and 160 mg NT-814, 
compared with placebo, on mental well-being, 
quality of life and measures of sleep in subjects 
with post-menopausal symptoms.  
x To evaluate the dose-response relationship of 40 
mg, 80 mg, 120 mg and 160 mg NT-814 in 
reducing hot flush frequency and severity. 
Pharmacokinetics 
 
 
 
x To evaluate the exposure-response relationship 
of NT-814 using population pharmacokinetics 
(PK) with sparse sampling. 
Pharmacodynamics 
 
x Not applicable 
EFFICACY ASSESSMENTS AND ENDPOINTS 
EFFICACY 
ASSESSMENTS 
EFFICACY ENDPOINTS 
x Number of hot 
flushes recorded in 
the eDiary 
 
Co-Primary Efficacy Endpoints: 
x Mean change from baseline in frequency of 
moderate and severe hot flushes from baseline 
to Week 4 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 5 of 100 
21 May 2019 
 
 
 
 
x Severity of each hot 
flush recorded on a 
3-point scale (mild, 
moderate or severe) 
 
 
x Mean change from baseline in frequency of 
moderate and severe hot flushes from baseline 
to Week 12 
x Mean change from baseline in severity of 
moderate and severe hot flushes from baseline 
to Week 4 
x Mean change from baseline in severity of 
moderate and severe hot flushes from baseline 
to Week 12 
 
Secondary Efficacy Endpoints: 
x Mean change from baseline in frequency of 
moderate and severe hot flushes from baseline 
to Weeks 1, 2, 8 and 16 
x Mean change from baseline in severity of 
moderate and severe hot flushes from baseline 
to Weeks 1, 2, 8 and 16 
x Mean change from baseline in frequency of all 
hot flushes from baseline to Weeks 1, 2, 4, 8, 12 
and 16 
x Mean change from baseline in severity of all hot 
flushes from baseline to Weeks 1, 2, 4, 8, 12 and 
16 
x Mean change from baseline in the Hot Flush 
Score (frequency x severity) at Weeks 1, 2, 4, 8, 
12 and 16 
x Responder analyses (proportion of subjects with 
>50% and >80% reductions from baseline in hot 
flush frequency at Week 12) 
x Number of night time 
awakenings in the 
diary either due to a 
hot flush or unrelated 
to flushing 
x Mean change from baseline in number of night 
time awakenings secondary to hot flush at 
Weeks 1, 2, 4, 8, 12 and 16 
x Mean change from baseline in number of all 
night time awakenings at Weeks 1, 2, 4, 8, 12 
and 16 
x Pittsburgh Sleep 
Quality Index, 
completed at 
Baseline and Weeks 
4, 8, 12 and 16 
x Change from baseline in the Global and 
individual domain scores at Weeks 4, 8, 12 and 
16  
x Insomnia Severity 
Index completed at 
Baseline and Weeks 
x Change from baseline in the Insomnia Severity 
Index score at Weeks 4, 8, 12 and 16 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 6 of 100 
21 May 2019 
 
 
 
 
4, 8, 12 and 16 
x Hot Flush Related 
Daily Interference 
Scale (HFRDIS) 
completed at all visits 
except Screening 
x Change from baseline in the HFRDIS scores at 
Weeks 2, 4, 8, 12 and 16 
x Menopause-Specific 
Quality of Life 
Intervention Version 
(MenQoL-I) 
completed at 
Baseline and Weeks 
4, 8, 12 and 16 
x Change from baseline in the MenQoL-I scores 
at Weeks 4, 8, 12 and 16 
x Beck Depression 
Inventory (Version 
II) completed at all 
visits except 
Screening 
x Change from baseline in the Beck Depression 
Inventory II scores at Weeks 2, 4, 8, 12 and 16 
SAFETY ASSESSMENTS 
SAFETY ENDPOINTS 
x Adverse events 
recorded throughout 
the study (from 
Screening Visit 2 to 
Week 16) 
x Number of treatment emergent adverse events 
x Number of treatment emergent serious adverse 
events 
x Number of treatment emergent adverse events 
resulting in treatment discontinuation 
x Severity of treatment emergent adverse events 
x Number of treatment emergent related adverse 
events 
x Physical Examination 
recorded at Screening 
Visit 2, Baseline and 
Week 16  
x Treatment emergent changes in physical 
examination will be recorded as adverse events 
x Weight recorded at 
each visit (except 
Screening Visit 1) 
and height at 
Screening Visit 2 
x Waist circumference 
recorded at each visit 
(except Screening 
visits 1 and 2) 
x Change from baseline in weight at Weeks 2, 4, 
8, 12 and 16 
x Change from baseline in body mass index at 
Weeks 2, 4, 8, 12 and 16 
x Change from baseline in waist circumference at 
Weeks 2, 4, 8, 12 and 16 
x Electronic Columbia 
Suicide Severity 
Rating Scale (eC-
SSRS) recorded at 
x Change from baseline in eC-SSRS at Weeks 4, 
12 and 16 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 7 of 100 
21 May 2019 
 
 
 
 
Baseline and Weeks 
4, 12 and 16 
x Vital Signs (pulse 
rate, systolic and 
diastolic blood 
pressure, 
temperature) 
recorded at each visit 
(except Screening 
Visit 1) 
x Change from baseline at Weeks 2, 4, 8, 12 and 
16 in each vital sign: 
- 
Systolic blood pressure 
- 
Diastolic blood pressure 
- 
Pulse rate 
- 
Temperature 
x Haematology, 
clinical chemistry 
(including HbA1c) 
and urinalysis 
parameters, collected 
at each visit (except 
Screening Visit 1 and 
also Week 8 for 
haematology and 
urinalysis) 
x Change from baseline at Weeks 2, 4, 12 and 16 
in each haematology and urinalysis parameter 
x Change from baseline at Weeks 2, 4, 8, 12 and 
16 for each clinical chemistry parameter 
x 12-lead ECG, 
recorded at each visit 
(except Screening 
Visit 1) 
x Proportion of subjects with clinically significant 
abnormal ECG findings at each visit 
x Proportion of subjects with non-significant 
abnormal findings at each visit 
x Change from baseline at Weeks 2, 4, 8, 12 and 
16 in ECG intervals: 
- 
PR 
- 
QT, QTc and QTcF 
- 
RR 
x Proportion of subjects with maximum absolute 
QTcF values by category at each visit 
- 
<450, >450 to <480, >480 to <500, >500 
msec 
x Proportion of subjects with maximum change 
from baseline in QTcF values by category at 
Weeks 2, 4, 8, 12 and 16 
- 
<0, >0 to <30, >30 to <60, >60 msec 
x Plasma bone turnover 
markers measured at 
Baseline and Weeks 
12 and 16 
x Change from baseline to Weeks 12 and 16 in:  
- 
Serum concentration of bone-specific 
alkaline phosphatase (BALP)  
- 
Serum concentration of procollagen type 1 
N-terminal pro-peptide (P1NP) 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 8 of 100 
21 May 2019 
 
 
 
 
Baseline and week 12 and 16 visits should be 
conducted at similar times of day to reduce 
diurnal variation in these markers. 
 
PHARMACOKINETIC 
ASSESSMENTS 
PHARMACOKINETIC ENDPOINTS 
x 
Single samples for 
NT-814 plasma 
concentration 
determination at 
Weeks 2, 4, 8 and 12 
x Exposure-response modelling will be 
undertaken on a number of efficacy and safety 
endpoints on an exploratory basis.  
ELIGIBILITY CRITERIA 
INCLUSION CRITERIA 
1. Females aged 40 to 65 years, inclusive, at Screening 
Visit 1 
2. Able to understand and comply with the 
requirements of the study and give informed consent 
3. Postmenopausal, defined as: (i) at least 12 months 
of spontaneous amenorrhea, or (ii) at least 6 months 
of spontaneous amenorrhea with serum FSH levels 
> 40 mIU/ml and a serum oestradiol concentration 
of < 30 pg/mL, or (iii) at least 6 weeks postsurgical 
bilateral oophorectomy with or without 
hysterectomy1,2 
4. Body mass index between 18 and 38 kg/m2, 
inclusive, at Screening Visit 2 
5. Negative urinary pregnancy test at Screening Visit 2 
6. In good general health, in the opinion of the 
investigator, based on the medical history, physical 
examination, 12-lead ECG, vital signs and clinical 
laboratory tests assessed at Screening Visit 2 
7. Subject has completed the paper diary for at least 6 
days between Screening Visits 1 and 2 and has 
recorded an average of at least 8 moderate or severe 
hot flushes per day (including night-time) over the 
last 5 days that the paper diary was completed  
(assessed at Screening Visit 2) 
8. Subject has completed the eDiary for at least 9 days 
between Screening Visit 2 and Day 1 and has 
recorded an average of at least 7 moderate or severe 
hot flushes per day (including night-time) over the 
last 7 days  that the eDiary was completed  
(assessed at the Baseline Visit) 
                                                 
1 Durations are relative to screening visit 1 
2 Subjects who do not clearly fall into 1 of the 3 defined categories, but who are hormonally post-menopausal (serum 
FSH levels > 40 mIU/ml and a serum oestradiol concentration of < 30 pg/mL) and of an appropriate age, may also be 
considered for inclusion. 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 9 of 100 
21 May 2019 
 
 
 
 
EXCLUSION CRITERIA 
1. Have used or unwilling to wash-out use of any of 
the following hormonal therapies for the periods 
stated prior to Screening Visit 2: 
- 
>1 week for vaginal hormonal products 
(rings, creams, gels and including DHEA or 
analogues thereof) 
- 
>4 weeks for transdermal oestrogen alone or 
oestrogen/progestin products  
- 
>8 weeks for oral oestrogen (including 
selective oestrogen receptor modulators) 
and/or progestin therapy 
- 
>8 weeks for intrauterine progestin therapy 
- 
>3 months for progestin implants and
oestrogen alone injectable drug therapy 
- 
>6 months for oestrogen pellet therapy or 
progestin injectable drug therapy  
2. The use of non-hormonal prescription (eg 
paroxetine, other anti-depressants, alpha agonists 
[eg clonidine], methyldopa, gabapentin, pregabalin, 
medicinal cannabis) or over the counter/herbal 
treatments for treatment of menopausal symptoms is 
not allowed throughout the study. Subjects must 
have discontinued these drugs at least 28 days prior 
to Screening Visit 2. Subjects may, however, be 
permitted to continue to use these drugs if the dose 
has been stable for at least 4 weeks and they have 
been prescribed solely for the management of 
another disorder (e.g. neuropathic pain, depression). 
3. Inability to comply with the use of prohibited 
medications as described below (See Appendix A 
for more details): 
i. Use of digoxin is not allowed from 
Screening Visit 2 until 1 week after the last 
dose of IMP 
ii. Use of known CYP3A4 substrates with a 
narrow therapeutic range is not allowed from 
Screening Visit 2 until 1 week after the last 
dose of IMP  
iii. Use of strong or moderate inhibitors of 
CYP3A4 is not allowed from Screening 
Visit 2 until 1 week after the last dose of 
IMP  
iv. Use of moderate or strong inducers of 
CYP3A4 is not allowed from Screening 
Visit 2 until Week 12  
v. Use of known P-glycoprotein inhibitors is 
not allowed from Screening Visit 2 until 1 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 10 of 100 
21 May 2019 
 
 
 
 
week after the last dose of IMP  
4. Any prior or ongoing history of clinically relevant 
drug or alcohol abuse within 12 months of 
Screening Visit 13 
5. Any clinically significant prior or ongoing history 
of arrhythmias, either determined through clinical 
history or on ECG evaluation.  
6. Any clinically significant abnormal laboratory test 
result(s), measured at Screening Visit 2. 
Specifically, severe hepatic impairment is excluded. 
7. Any active ongoing condition that could have 
caused difficulty in interpreting vasomotor 
symptoms such as: infection that could have caused 
pyrexia, pheochromocytoma, hyperthyroidism, 
carcinoid syndrome, alcohol abuse. 
8. Current history or previous (within the past 5 years) 
history of any malignancy (except basal and 
squamous cell skin tumours). 
9. Uncontrolled hypertension4  
10. A history of hyperthyroidism or hypothyroidism. 
Treated hypothyroidism with normal thyroid 
function test results at Screening Visit 2 and a stable 
(for >3 months before Screening Visit 2) dose of 
replacement therapy is acceptable. 
11. Known hypersensitivity to NT-814 or any of the 
excipients in the formulation. 
12. Concurrent (or within the 2 months prior to 
Screening Visit 1) participation in a clinical study 
with an investigational medicinal product. 
13. Concurrent (or within the 1 month prior to 
Screening Visit 1) participation in an interventional 
clinical study. 
14. Previous participation in a clinical study with NT-
814. 
15. Dependent on the investigator, the contract research 
organisation(s) or Sponsor for education or 
employment. 
16. Any unexplained post-menopausal bleeding. 
17. Abnormal findings on mammogram or subject has 
not undergone a mammogram within the guidelines 
recommended by applicable national authorities (eg 
United Kingdom National Health Service, United 
                                                 
3 Significant alcohol or drug abuse is behaviour that meets the DSM-5 criteria59 for substance use disorder. 
4 Uncontrolled hypertension is defined as blood pressure of >130 mmHg (systolic) or >80 mmHg (diastolic), based 
on the average of two to three readings on at least two different occasions.  Subjects with known hypertension should 
be reviewed to ensure their blood pressure is adequately controlled prior to study participation. 


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 11 of 100 
21 May 2019 
 
 
 
 
States Preventative Services Taskforce, Canadian 
Task Force on Preventative Healthcare)5  
 
NT-814 
FORMULATION/DOSE 
 
NT-814 40 mg soft gel capsules  
 
Dose           IMP Supply 
40 mg       1 x NT-814 capsule, 3 x placebo capsules 
80 mg       2 x NT-814 capsules, 2 x placebo capsules 
120 mg     3 x NT-814 capsules, 1 x placebo capsule 
160 mg     4 x NT-814 capsules  
 
REFERENCE 
FORMULATION/DOSE 
 
Matching placebo soft gel capsules 
4 capsules 
ROUTE OF 
ADMINISTRATION 
 
Oral 
DURATION/FREQUENCY 
OF TREATMENT 
 
Once daily dosing in the evening for 12 weeks. 
 
All subjects will also receive placebo capsules for the 
last 2 weeks of the screening/baseline period. 
 
PLANNED SAMPLE SIZE 
For the efficacy objectives of the study, assuming a 
common standard deviation (SD) of 4.4, N=27 per 
treatment group has ~95% power (alpha=0.05 2-sided) 
via trend test across all doses including placebo if the 
true underlying dose response is non-decreasing from a 
reduction of 4 hot flushes on placebo up to 8 on the 
highest dose of NT-814.   N=33 per treatment group is 
required for 95% power for pairwise comparison of the 
highest dose to placebo under these same assumptions. 
Hence, a total of 150 completed subjects (30 x 5) was 
used for the simulations of adaptive design.  The actual 
sample size will be determined by the adaptive dose-
finding design algorithm outcomes. In addition, the 
initial actual sample size is increased by 10% to allow 
for subjects who withdraw prematurely and so the 
initial sample size will be 165 subjects. 
 
The sample size allows for 95% power since each of the 
four co-primary endpoints are required to demonstrate 
statistical significance to yield a firm conclusion of 
beneficial 
treatment 
effect 
on 
hot 
flushes.  
Conservatively, assuming independence among the four 
endpoints, this would yield approximately 81% power 
overall for achieving statistical significance for each of 
                                                 
5 Subjects who have not had a mammogram within the guidelines may have one performed as part of the screening 
process 


Product:  
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Protocol No.: 814-PM-02 
NT-814 
 
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Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 12 of 100 
21 May 2019 
 
 
 
 
the four endpoints.  Thus, overall power for the trial is 
estimated to be at least 81%; the actual power depends 
on the unknown magnitudes of correlations among the 
co-primary endpoints. 
 
 
STATISTICAL METHODS 
The Safety Analysis Set consists of all subjects who 
receive at least one dose of double-blind study drug 
irrespective of treatment received. Subjects will be 
analysed according to treatment received. The Full 
Analysis Set (FAS) consists of all randomised subjects 
who received at least one dose of double-blind study 
drug, irrespective of treatment received, and have a at 
least 7 days’ worth of post-treatment assessments (i.e. 
requirement for the primary efficacy endpoint). 
Subjects will be analysed according to randomised 
treatment. This is the primary efficacy analysis set for 
the study. The Per Protocol analysis set consists of all 
subjects in the FAS excluding those identified as having 
relevant protocol deviations. The Exposure-Response 
Set consists of all subjects who received at least one 
dose of double-blind study drug and for whom the PK 
data are considered sufficient. 
 
All statistical hypothesis tests and confidence intervals 
will be two sided, using a type I error rate of 0.05. No 
adjustment for multiple comparisons will be used for 
this Phase 2 study.  
 
The co-primary endpoints are the change from baseline 
in the mean daily frequencies of moderate and severe 
hot flushes in the 7 days before the Week 4 and Week 
12 visits, and the mean severity of moderate and severe 
hot flushes in the 7 days before the Week 4 and Week 
12 visits. The baseline assessment will be the last 7 
days of the baseline eDiary completion period. 
Absolute and changes from baseline in the mean daily 
frequencies and average hot flush severity will be 
summarised by treatment group. The change from 
baseline endpoint will be analysed by mixed model 
repeated measures.  Pairwise statistical comparisons are 
planned for each NT-814 dose group (40 mg, 80 mg, 
120 mg and 160 mg) versus placebo, presenting the 
adjusted 
mean 
treatment 
difference 
with 
its 
corresponding 95% confidence interval. Secondary 
efficacy endpoints will be analysed in a similar fashion, 
except that the proportion of responders, defined as a 
reduction of >=50% points and >=80% points on the 
weekly average frequency of hot flushes will be 
analysed by logistic regression.  


Product:  
CONFIDENTIAL 
Protocol No.: 814-PM-02 
NT-814 
 
NeRRe Therapeutics Ltd 
 
Protocol No.: 814-PM-02 
FINAL 2.1 (US) 
Page 13 of 100 
21 May 2019 
 
 
 
 
 
The safety analysis set will be used for all presentations 
of safety endpoints. No statistical testing will be used to 
compare 
treatment 
groups 
for 
different 
safety 
endpoints. Safety data will be summarised descriptively 
for each treatment group.  
 
All adverse events will be coded using the current 
version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment-emergent adverse 
events (TEAE) will be presented within summary 
presentations, by MedDRA system organ class (SOC), 
preferred term and treatment group.  
 
Blood 
samples 
for 
assay 
of 
NT-814 
plasma 
concentrations are collected periodically. The plasma 
NT-814 concentrations will be listed by visit. Further 
details of the analysis of PK data will be described in an 
Exposure-Response Data Analysis Plan and exposure-
response data will be reported in a separate report. 


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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ........................................................................................................ 2 
2. 
TABLE OF CONTENTS ...................................................................................................... 14 
3. 
LIST OF ABBREVIATIONS ............................................................................................... 17 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE .......................................... 19 
5. 
BACKGROUND INFORMATION ..................................................................................... 20 
5.1 
NT-814 .................................................................................................................................. 20 
5.1.1 
Pharmacology ....................................................................................................................... 20 
5.1.2 
Pre-clinical Safety ................................................................................................................ 20 
5.1.3 
Clinical Experience .............................................................................................................. 21 
5.2 
Hot flushes in post-menopausal women and rationale for this study.................................... 22 
5.3 
Rationale for endpoints ......................................................................................................... 24 
6. 
STUDY OBJECTIVE AND PURPOSE ............................................................................... 25 
6.1 
Primary objectives ................................................................................................................. 25 
6.2 
Secondary objectives ............................................................................................................. 25 
6.3 
Pharmacokinetic objectives ................................................................................................... 25 
6.4 
Pharmacodynamic objectives ................................................................................................ 26 
7. 
SELECTION AND WITHRAWAL OF SUBJECTS ........................................................... 26 
7.1 
Subject numbers .................................................................................................................... 26 
7.2 
Inclusion Criteria ................................................................................................................... 26 
7.3 
Exclusion Criteria.................................................................................................................. 27 
7.4 
Withdrawal Criteria ............................................................................................................... 28 
7.5 
Criteria for Stopping the Study ............................................................................................. 29 
8. 
STUDY DESIGN .................................................................................................................. 30 
8.1 
Co- Primary Efficacy Endpoints ........................................................................................... 30 
8.2 
Secondary efficacy endpoints ............................................................................................... 30 
8.3 
Pharmacokinetic endpoints ................................................................................................... 31 
8.4 
Pharmacodynamic endpoints ................................................................................................ 31 
8.5 
Safety endpoints .................................................................................................................... 31 
8.6 
Study design .......................................................................................................................... 32 
8.6.1 
Justification for Study Design .............................................................................................. 33 
8.6.2 
Duration of Subject Participation ......................................................................................... 33 
8.6.3 
Screening Visit 1 .................................................................................................................. 34 
8.6.4 
Screening Visit 2 .................................................................................................................. 34 
8.6.5 
Baseline (Day 1) ................................................................................................................... 35 
8.6.6 
Interim visits (Weeks 2, 4, 8, and 12) .................................................................................. 36 
8.6.7 
Final Follow-up / Early Termination visit ........................................................................... 37 
9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION ......................................... 37 
9.1 
Selection of doses in the study .............................................................................................. 37 
9.2 
Investigational medicinal product ......................................................................................... 39 
9.3 
Allocation to Treatment ........................................................................................................ 40 
9.4 
Study Treatment and Administration .................................................................................... 41 
9.4.1 
Dose Interruption.................................................................................................................. 41 
9.5 
Treatment Accountability and Compliance Checks .............................................................. 42 
9.6 
Treatment Blinding Code ...................................................................................................... 42 
9.7 
Permitted Concomitant Medications ..................................................................................... 43 
9.8 
Prohibited Concomitant Medication ..................................................................................... 43 
9.9 
Other Study Restrictions ....................................................................................................... 43 
10. 
STUDY SCHEDULE ........................................................................................................... 44 


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10.1 
Volume of Blood Sampling .................................................................................................. 46 
10.2 
Efficacy assessments ............................................................................................................. 46 
10.2.1 
Hot Flush Electronic Diary .................................................................................................. 46 
10.2.2 
MenQoL-I (1 month recall version) ..................................................................................... 46 
10.2.3 
Hot Flash Related Daily Interference Scale (HFRDIS) ....................................................... 47 
10.2.4 
Pittsburgh Sleep Quality Index ............................................................................................ 47 
10.2.5 
Insomnia Severity Index....................................................................................................... 47 
10.2.6 
Beck Depression Inventory II .............................................................................................. 47 
10.3 
Safety Assessments ............................................................................................................... 48 
10.3.1 
Medical history and concomitant diseases ........................................................................... 48 
10.3.2 
Physical examinations .......................................................................................................... 48 
10.3.3 
12-Lead ECGs ...................................................................................................................... 49 
10.3.4 
Electronic Columbia Suicide Severity Rating Scale ............................................................ 49 
10.3.5 
Clinical chemistry ................................................................................................................ 49 
10.3.6 
Haematology ........................................................................................................................ 50 
10.3.7 
Urinalysis ............................................................................................................................. 50 
10.3.8 
Vital signs ............................................................................................................................. 50 
10.3.9 
Bone Turnover Markers ....................................................................................................... 51 
10.3.10 
Pregnancy Testing, Contraception and Pregnancy ............................................................... 51 
10.4 
Pharmacokinetics .................................................................................................................. 51 
10.5 
Adverse events ...................................................................................................................... 51 
10.5.1 
Definitions ............................................................................................................................ 51 
10.5.2 
Assessment of Severity ........................................................................................................ 53 
10.5.3 
Assessment of Causality....................................................................................................... 53 
10.5.4 
Adverse Event Reporting ..................................................................................................... 53 
11. 
STATISTICAL CONSIDERATIONS .................................................................................. 55 
11.1 
Estimated Sample Size .......................................................................................................... 55 
11.3 
Analysis Sets ......................................................................................................................... 57 
11.4 
Data Analysis ........................................................................................................................ 57 
11.5 
Interim Analysis .................................................................................................................... 57 
11.6 
Protocol Deviations ............................................................................................................... 58 
11.7 
Subject Disposition ............................................................................................................... 58 
11.8 
Demographics and Baseline Characteristics ......................................................................... 58 
11.9 
Statistical Methods for Efficacy Parameters ......................................................................... 58 
11.9.1 
Primary Efficacy Analysis ................................................................................................... 58 
11.9.2 
Secondary Efficacy Analysis ............................................................................................... 59 
11.10 
Statistical Methods for Safety Parameters ............................................................................ 60 
11.10.1 
Adverse Events ..................................................................................................................... 60 
11.10.2 
Laboratory Parameters ......................................................................................................... 60 
11.10.3 
Vital Signs ............................................................................................................................ 61 
11.10.4 
ECG ...................................................................................................................................... 61 
11.10.5 
C-SSRS ................................................................................................................................ 61 
11.10.6 
Concomitant Medications .................................................................................................... 61 
11.11 
Pharmacokinetics Analysis ................................................................................................... 61 
11.12 
Missing Data ......................................................................................................................... 61 
12. 
END OF THE STUDY ......................................................................................................... 62 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT .............................................. 62 
13.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and Relevant 
Authorities ............................................................................................................................. 62 
13.2 
Ethical Conduct of the Study ................................................................................................ 62 


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13.3 
Informed Consent .................................................................................................................. 62 
13.4 
Protocol Amendments ........................................................................................................... 62 
14. 
STUDY AND DATA MANAGEMENT .............................................................................. 63 
14.1 
Monitoring ............................................................................................................................ 63 
14.2 
Quality Assurance ................................................................................................................. 63 
14.3 
Data Recording...................................................................................................................... 63 
14.3.1 
Data to be Considered as Source Data ................................................................................. 63 
14.4 
Confidentiality ...................................................................................................................... 64 
14.5 
Retention of Study Data ........................................................................................................ 64 
14.6 
Communication and Publication of Results .......................................................................... 65 
14.7 
Indemnification ..................................................................................................................... 65 
15. 
REFERENCES ...................................................................................................................... 66 
16. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ........................................ 69 
17. 
APPENDICES ...................................................................................................................... 70 
 


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3. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ALT 
Alanine amino transferase / alanine transaminase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate amino transferase / aspartate transaminase 
BALP 
Bone-specific alkaline phosphatase 
BDI-II 
Beck Depression Inventory – Version II 
BDRM 
Blinded Data Review Meeting 
BP 
Blood Pressure 
CHMP 
Committee for Medicinal Products for Human Use 
eCRF 
Electronic Case Report Form 
Cmax 
Maximum plasma concentration 
CSR 
Clinical Study Report 
eC-SSRS 
Electronic Columbia Suicide Severity Rating Scale 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CV% 
Coefficients of variation 
CYP3A4 
Cytochrome P450 3A4 
DHEA 
Dehydroepiandrosterone 
DR 
Dose Response 
DRC 
Data Review Committee 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
Electrocardiogram 
eDiary 
Electronic Diary 
ER 
Exposure-Response 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
GnRH 
Gonadotropin Releasing Hormone 
H0 
Null Hypothesis 
H1 
Alternative Hypothesis 
HbA1c 
Haemoglobin A1c 
HFRDIS 
Hot Flash Related Daily Interference Scale 
hERG 
Human ether-a-go-go 
HF 
Hot Flush / Hot Flash 
HRT 
Hormone Replacement Therapy 
IA 
Interim Analysis 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference for Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IM 
Intramuscular 
ISI 
Insomnia Severity Index 


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IVR 
Interactive Voice Response 
IWRS 
Interactive Web Response Services 
KaNDy 
KaNDy Therapeutics Ltd 
LH 
Luteinising hormone 
MCV 
Mean Corpuscular Volume 
MeDRA 
Medical Dictionary for Regulatory Activities 
MenQoL-I 
Menopause-specific Quality-of-Life Questionnaire Intervention Version 
NeRRe 
NeRRe Therapeutics Ltd 
NK 
Neurokinin 
NTA 
Night-time awakening 
PET 
Positron Emission Tomography 
P1NP 
Procollagen type 1 N-terminal pro-peptide  
PIS 
Participant Information Sheet 
PK 
Pharmacokinetic 
PM 
Post-menopausal 
Pop PK 
Population PK 
PP 
Per-Protocol 
PSQI 
Pittsburgh Sleep Quality Index 
QD 
One a day 
QoL 
Quality of Life 
RBA 
Relative bioavailability 
RBC 
Red Blood Cell 
RO 
Receptor occupancy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SP 
Substance P 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
VMS 
Vasomotor Symptoms 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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4.
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE
Chief Investigator 
Medical Expert (Sponsor) 
Contract Research Organization / 
Monitors 
Statistical Contract Research 
Organization 
Pharmacokinetic Laboratory 
Pharmacovigilance Provider 
 
 
 
  
 
 United States 
Email: 
 
 
NeRRe Therapeutics Ltd 
SBC, Incubator Building,  
Gunnels Wood Rd.,  
Stevenage, SG1 2FX, UK 
Phone: 
 
Email: 
 
Pharm Olam  
1st Floor, One Station Square, 
Bracknell, Berkshire RG12 1QB 
UNITED KINGDOM 
T: 
 
F: 
 
Cytel Inc., 
675 Massachusetts Avenue 
Cambridge  
Massachusetts 02139 
United States 
Aptuit Center for Drug Discovery and 
Development  
Via A. Fleming, 4 
37135 Verona, Italy 
Emas Pharma  
  
63-56 Knowl Piece, Wilbury Way,
Hitchin, SG4 0TY,
United Kingdom
Tel: 
Fax: 
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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5. 
BACKGROUND INFORMATION 
5.1 
NT-814 
Prior to its acquisition, initially by NeRRe Therapeutics Ltd (NeRRe), and then subsequently by 
KaNDy Therapeutics Ltd (KaNDy), NT-814’s laboratory code name was GSK1144814. The 
GSK laboratory code may be used in this and other trial related document when referring to the 
studies conducted by GSK, but NT-814 is used for all development activities conducted by 
NeRRe as Sponsor. NT-814 is being developed in a number of indications in women’s health, 
including the treatment of post-menopausal symptoms. 
KaNDy has delegated all regulatory and quality Sponsor responsibilities to NeRRe.  
5.1.1 
Pharmacology 
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.  NT-814 was active 
in pharmacodynamic models for the NK1 receptor (the gerbil foot tapping test) and NK3 receptor 
(wet dog shaking behaviour 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 were confirmed in the gerbil and guinea pig 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. 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 53 other non-tachykinin receptors, ion channels, enzymes 
and transporters. 
There were no clinically relevant findings in respiratory or neurobehavioral safety pharmacology 
studies at doses up to 100 mg/kg or in a cardiovascular study in cynomolgus monkeys at doses up 
to 60 mg/kg. NT-814 did not inhibit the human ether-a-go-go (hERG) tail current. 
5.1.2 
Pre-clinical Safety 
A full package of pre-clinical safety studies appropriate to the stage of development has been 
completed with NT-814.  This includes 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). The safety profile was acceptable and supported 
clinical evaluation with appropriate monitoring.  
Genotoxicity and reproductive toxicity studies have also been undertaken. NT-814 was not 
genotoxic and there was no evidence of embryofetal toxicity in the rat at doses up to 


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100 mg/kg/day or in the rabbit at doses up to 140 mg/kg/day. A signal with respect to potential 
phototoxicity warrants monitoring of subjects for skin reactions to sunlight.  
5.1.3 
Clinical Experience 
To date, five clinical studies in healthy volunteers have been completed with single total daily 
doses up to 250 mg and repeat doses up to 200 mg total daily dose for 28 days. These studies 
comprise a single dose escalation pharmacokinetic (PK) and safety study incorporating an 
assessment of NK1 RO using PET imaging (Study MNK111321), a repeat-dose PK and safety 
study with a drug interaction assessment and NK1 RO evaluation (MNK111587), a single-dose 
study assessing the PK and effect of food on a tablet formulation (MNK112891), a single dose 
study assessing whether the psychomotor and cognitive effects of alcohol are exacerbated by NT-
814 (MNK113476) and a relative bioavailability and food effect study (814-1-01).  
Thirty-seven female and 89 male healthy volunteers received NT-814 in these studies. NT-814 
was found to have a good pharmacokinetic profile after both single and repeat doses. The PK was 
characterized by rapid absorption, modest accumulation ratios and approximately linear increases 
in exposure with increasing dose. The terminal elimination half-life was estimated to be in the 
range ~15-20 hours and steady state was achieved within 7 days. NT-814 was well tolerated 
throughout the dose range. The only potential safety signal identified was a possible effect on 
cardiac rhythm, although review of the individual arrhythmias reported suggested that they were 
likely to be coincidental. Non-serious AEs considered possibly related to treatment with NT-814 
are headache, diarrhoea and somnolence. 
Seventy-six post-menopausal female subjects experiencing troublesome hot flushes participated 
in a 14 day repeat dose study which assessed the safety, efficacy and PK of NT-814 in this 
indication (Study RELENT-1). Eighteen subjects received placebo and 56 received NT-814 at 
doses ranging from 50 mg to 300 mg once daily. All doses were well tolerated, and no safety 
concerns were identified. Extensive Holter monitoring did not identify any treatment effect on 
cardiac rhythm. There was clear evidence of a beneficial effect on post-menopausal symptoms, 
with clinically relevant and statistically significant improvements on both daytime hot flush 
frequency and severity and night-time awakening at the higher doses (150 and 300 mg) compared 
to placebo.  
The PK profile in post-menopausal females was very similar to that observed in younger male 
volunteers. However, the hard gel capsule formulation used in the study resulted a high degree of 
within and between subject variability in exposure. The variability was generally greater at the 
higher doses, with the coefficients of variation (CV%) approaching 150% for some parameters.  
In addition to the high variability, the mean exposures observed at doses up to 150 mg were not 
as great as those expected based on previous studies.  Consequently, a new formulation was 
developed in which NT-814 was dissolved in a liquid lipid vehicle and encapsulated in a soft gel 
capsule. The kinetics of this soft gel formulation were evaluated in a relative bioavailability study 
and it was found to have acceptable variability (CV% <45%) and good exposures.  
Administration of the soft-gel capsule with food was found in this study to reduce the maximum 


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plasma concentration (Cmax) of NT-814 quite significantly (by around 70%) but with only a 
modest reduction (~9%) on overall exposure. This blunting of the Cmax dose not result in lower 
concentrations at later time points and the overall exposure is anticipated to be sufficient for 
efficacy in both the fed and fasted states. 
This soft gel formulation is the current development form of NT-814 and will be used in this 
study.  
Further information on the pre-clinical and clinical studies undertaken with NT-814 can be found 
in the current version of the Investigators Brochure (IB). 
5.2 
Hot flushes in post-menopausal women and rationale for this study 
Over the coming decades, it is estimated that more than 1 billion women worldwide will be older 
than 50 years. Up to 75% of these women will experience adverse symptoms related to 
menopausal transition, particularly hot flushes (also called flashes) vasomotor symptoms, sleep 
disturbances and adverse mood effects that have such a negative impact upon patient daily 
activities and quality of life1,2,3. Hot flushes are transient but recurrent episodes of flushing, 
perspiration and intense heat sensation that are one of the most common, bothersome and 
distressing symptoms felt by women during the transition to menopause (peri-menopause) and 
post-menopause periods4. They are the leading cause for seeking medical attention during this 
particular phase of a woman’s life, particularly amongst those experiencing the severest 
symptoms5,6.  The hot flushes may also be associated with difficulty in sleeping7, 8 worsen 
depressive symptoms and signal the onset or relapse of a major depressive episode9,10. When hot 
flushes occur at night they are known as night sweats and can cause insomnia and fatigue11,12. 
Hot flushes can vary in frequency, with some women experiencing episodes many times a day, 
and can last up to 10 years after the last menses13,14. Current treatment options are limited and 
include hormone replacement therapy (HRT) which is effective in many women but associated 
with an increased risk of hormone-dependent cancers, thrombotic risk and cardiovascular adverse 
effects15. HRT can also take several months to improve hot flush symptoms, especially when 
used at lower doses, and has limited effects on sleep disturbance16,17. These and other limitations 
preclude its use in many women. A low dose of the anti-depressant paroxetine is licensed for use 
in some countries but has limited efficacy and a range of safety and tolerability concerns that 
prevent its widespread usage especially in the breast cancer survivor population. 
Emerging data show that hot flushes may be treated by targeting the neuroendocrine factors that 
trigger the symptoms18. The menopause is characterized by decreased oestradiol levels due to 
ovarian failure, and a resultant increase in gonadotropin releasing hormone (GnRH) secretion 
from the hypothalamus leading to high gonadotropin (luteinising hormone [LH] and follicle 
stimulating hormone) concentrations.  A link between initiation of the LH pulse and hot flushes 
has been reported19. However, a number of studies involving oestrogen administration and 
withdrawal in patients who do not have elevated LH have shown they still experience hot 
flushes20,21,22, as do patients with Kallman’s syndrome who lack hypothalamic GnRH neurons, 
and in whom oestrogen withdrawal will trigger hot flushes23. These findings show that hot 


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flushes can occur even in the absence of pulsatile GnRH or LH release, implicating the 
involvement of upstream processes responsible for GnRH synthesis. The hypothalamic 
infundibular (arcuate) nucleus is a group of sex steroid-responsive neurons that co-express 
kisspeptin, dynorphin as well as NKB; the so-called ‘KNDy’ neurons24. Morphologic studies 
have shown that KNDy neurons from postmenopausal women are hypertrophied25 and this 
hypertrophy is accompanied by elevated NKB, kisspeptin and Substance P gene expression; but 
not dynorphin25-27.  These expression changes are a consequence of oestrogen withdrawal as they 
can be induced by oophorectomy and reversed by estrogen replacement in cynomolgus 
monkeys28-30.    
KNDy neurons, expressing NK3 receptors, branch extensively within the arcuate nucleus and are 
also linked to the medial preoptic nucleus of the hypothalamus which has been identified as the 
control center for thermoregulation and which is responsive to both oestrogen and ambient 
temperature31. Support for the hypothesis that KNDy neurons have a thermoregulatory role and 
are involved in hot flush generation has been described in animal studies32.  
It is hypothesised that in the menopausal state the KNDy neurons are in a state of hyperactivation 
(consistent with the observed hypertrophy) which could disrupt baseline thermoregulation and 
trigger hot flushes31. Therefore, modulation of the KNDy neurons could be a viable therapeutic 
approach to controlling hot flushes. Clinical evidence supporting the hypothesis comes from a 
study in healthy women in which it was shown that intravenous infusion of NKB (endogenous 
ligand that binds the NK3 receptor) acutely induces hot flushes in healthy women33. Furthermore, 
two recently completed proof of concept studies with NK3 receptor antagonists have provided 
direct evidence that NK3 receptor blockade can reduce the number and severity of hot flushes34,35. 
In a 12-week study in post-menopausal women, twice daily dosing with the NK3 antagonist 
fezolinetant resulted in a sustained reduction in the frequency (-93% vs -54% for placebo) and 
severity (-70% vs -23%) of hot flushes (HF). The maximum improvements were apparent within 
2 weeks of the start of treatment. In a 4-week study with the NK3 antagonist MLE4901, the 
reduction in HF frequency was 78.4% compared to a reduction of 45.6% with placebo.  
A role for SP and NK1 receptors in the control of post-menopausal and other reproductive system 
disorders is supported by a body of evidence that indicates that the SP/NK1 receptor system 
modulates KNDy neurons in unison with the NKB/NK3 system. In adult male and/or 
ovariectomised female rodents, central infusion of specific NK1 receptor agonists induces 
gonadotropin release36,37. In the mouse this response can be shown to be modulated by kisspeptin 
as knockout mice (Kiss1r-/-) fail to respond to the NK1 agonist36. Expression of the gene 
encoding for SP (Tacr1) can be inhibited by circulating estradiol in mice and ~50% of 
Kiss1 positive neurons also expressed the Tacr1 gene. In goats, however, although data suggests 
that SP (along with NKA and NKB) has a stimulatory effect on the GnRH pulse-generator 
and LH release, it only does so at high doses indicating that NKB in this species is the pivotal 
effector molecule38. Although there is evidence suggesting that SP does not play a key role in 
the non-human primate GnRH pulse generator39, SP immunoreactivity frequently co-localises 
with kisspeptin and NKB in the human infundibular region40. Further, hypertrophy and 
increased gene expression of 
neurons containing SP messenger ribonucleic acid and SP+ immunoreactive nerves has been 


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demonstrated in humans in the hypothalami of postmenopausal women, with significantly more 
SP+ immunoreactive neurons than in age-matched men41.  
In addition to a central role in flushing, NK1 receptors have been shown to be located in nerves 
associated with blood vessels in human skin and infusion of SP results in vasodilatation42 and the 
same remote flushing of the face and neck characteristic of post-menopausal hot flushes 42,43. 
As well as a role in improving vasomotor symptoms, NK1 receptor antagonists have proven to be 
effective in Phase 2 studies in mood and primary insomnia44,45,46,47 it is possible that the mood 
and sleep comorbidities associated with menopausal hot flushes could also be addressed with a 
molecule that has NK1 receptor antagonist properties. 
Taken together this evidence supports the hypothesis that the dual NK1,3 receptor antagonism that 
NT-814 offers could be an effective treatment for vasomotor symptoms in the menopausal patient 
population as well as addressing important comorbidities. 
5.3 
Rationale for endpoints 
There is no uniform clinical profile of hot flushes and variations are observed in terms of 
frequency, severity, duration, and course. Patients’ perception of a hot flush and their impact on 
quality of life (QoL), sleep and psychosomatic reactions differ, and each is vulnerable to 
confounders, such as current mood, environmental factors or stress. It is, therefore, important to 
use a variety of assessment tools in clinical studies of hot flushes.  
The primary efficacy assessment in this study will be based on subject reported assessments of 
hot flush frequency and severity. These will be recorded daily in an electronic diary (eDiary) 
throughout the study. Hot flush is a subjective experience for the subject and so its occurrence 
and intensity can only be assessed by the subject.  The assessment will be based on the subject’s 
recollection of the number and severity of hot flushes experienced twice daily; once in the 
evening on retiring to bed and once in the morning on waking. The morning assessment also 
enables the number of times the subject awoke at night to be recorded. These assessments are 
routinely employed in clinical studies in hot flush and their use is supported by recommendations 
from experts in the field48 and regulatory authorities49.  
The impact on sleep will be measured using the Pittsburgh Sleep Quality index which is a 
validated questionnaire that evaluates a number of dimensions of sleep50. Insomnia, a common 
symptom of the menopause, will be assessed using the specific Insomnia Severity Index 
assessment. The broader impact of menopausal symptoms on subjects’ health and well-being will 
be evaluated using the Menopause Specific Quality of Life Scale (MenQOL) which is a quality of 
life instrument designed specifically for use in the menopause and is used frequently in 
menopause clinical research51. In addition, the Hot Flash Related Daily Interference Scale 
(HFRDIS) will be used to evaluate interference with daily functioning. This is a validated 
instrument that has been shown to be sensitive to the effects of pharmacological interventions on 
menopause symptoms52,53.The effect of NT-814 on symptoms of depression will be assessed 


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using version II of the Beck Depression Inventory. This is a widely used and validated self-
reported tool for assessing both the psychological and physical symptoms of depression54. 
The PK exposure-response relationship will be established through the correlation of plasma NT-
814 concentrations derived from sparse sampling, with appropriate clinical efficacy endpoints. 
Sparse sampling is a well-established method of collecting PK data that avoids the need for 
multiple blood draws and extended clinic visits.  
The safety of NT-814 will be assessed using standard measures of safety appropriate for the stage 
of development (adverse events, routine safety laboratory tests, vital signs, electrocardiogram 
(ECG)). Although the effect is expected to be modest in the post-menopausal population, NK3 
receptor blockade may result in a reduction in circulating oestrogen concentrations and so safety 
assessments will, additionally, include an assessment of bone turnover. No adverse effects are 
anticipated but because NT-814 acts centrally in the nervous system its safety related to suicidal 
ideation will, in accordance with regulatory expectations, be assessed using the electronic version 
of the Columbia Suicide Severity Rating Score.   
The assessment of safety for hormonal menopause therapies typically includes evaluation of the 
endometrium by trans-vaginal ultrasound (TVU) and, if indicated, endometrial biopsy. Since NK 
receptor blockade will, if anything, reduce hormonal drive to the endometrium these invasive 
evaluations are not warranted routinely for all subjects. However, any subject experiencing 
uterine bleeding (including spotting) during the study will undergo TVU and biopsy if indicated. 
6. 
STUDY OBJECTIVE AND PURPOSE 
6.1 
Primary objectives 
x To evaluate the efficacy of once daily doses of 40 mg, 80 mg, 120 mg and 160 mg NT-
814, compared with placebo, in reducing the frequency and severity of hot flushes. 
x To assess the safety and tolerability of once daily doses of 40 mg, 80 mg, 120 mg and 160 
mg NT-814, compared with placebo, in subjects with post-menopausal symptoms.  
6.2 
Secondary objectives 
x To evaluate the effect of once daily doses of 40 mg, 80 mg, 120 mg and 160 mg NT-814, 
compared with placebo, on mental well-being, quality of life and measures of sleep in 
subjects with post-menopausal symptoms.  
x To evaluate the dose-response relationship of 40 mg, 80 mg, 120 mg and 160 mg NT-814 
in reducing hot flush frequency and severity. 
6.3 
Pharmacokinetic objectives  
x To evaluate the exposure-response relationship of NT-814 using population 
pharmacokinetics (PK) with sparse sampling. 


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6.4 
Pharmacodynamic objectives  
x Not applicable 
7. 
SELECTION AND WITHRAWAL OF SUBJECTS 
7.1 
Subject numbers 
Participants in the clinical investigation are referred to as “subjects”.  
The initial estimated sample size for the study is 165 subjects. However, the total number of 
subjects may be higher or lower according to the outcome of the interim analyses (see Section 
11).  
The maximum number of subjects randomised into the study will be 300.  
7.2 
Inclusion Criteria  
Subjects must meet all the inclusion criteria listed below.  
 
1. Females aged 40 to 65 years, inclusive, at Screening Visit 1. 
2. Able to understand and comply with the requirements of the study and give informed 
consent. 
3. Postmenopausal, defined as: (i) at least 12 months of spontaneous amenorrhea, or (ii) at 
least 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml and a 
serum oestradiol concentration of < 30 pg/mL, or (iii) at least 6 weeks postsurgical 
bilateral oophorectomy with or without hysterectomy6,7. 
4. Body mass index between 18 and 38 kg/m2, inclusive, at Screening Visit 2. 
5. Negative urinary pregnancy test at Screening Visit 2. 
6. In good general health, in the opinion of the investigator, based on the medical history, 
physical examination, 12-lead ECG, vital signs and clinical laboratory tests assessed at 
Screening Visit 2. 
7. Subject has completed the paper diary for at least 6 days between Screening Visits 1 and 2 
and has recorded an average of at least 8 moderate or severe hot flushes per day 
(including night-time) over the last 5 days that the paper diary was completed  (assessed 
at Screening Visit 2). 
                                                 
6 Durations are relative to screening visit 1 
7 Subjects who do not clearly fall into 1 of the 3 defined categories, but who are hormonally post-menopausal (serum 
FSH levels > 40 mIU/ml and a serum oestradiol concentration of < 30 pg/mL) and of an appropriate age, may also be 
considered for inclusion. 


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8.  Subject has completed the electronic diary for at least 9 days between Screening Visit 2 
and Day 1 and has recorded an average of at least 7 moderate or severe hot flushes per 
day (including night-time) over the last 7 days that the eDiary was completed (assessed at 
the Baseline Visit). 
7.3 
Exclusion Criteria  
Subjects who meet one or more of the following exclusion criteria will not be enrolled. 
1. Have used or unwilling to wash-out use of any of the following hormonal therapies for the 
periods stated prior to Screening visit 2: 
x >1 week for vaginal hormonal products (rings, creams, gels and including 
DHEA or analogues thereof) 
x >4 weeks for transdermal oestrogen alone or oestrogen/progestin products  
x >8 weeks for oral oestrogen (including selective oestrogen receptor 
modulators) and/or progestin therapy 
x >8 weeks for intrauterine progestin therapy 
x >3 months for progestin implants and oestrogen alone injectable drug therapy 
x >6 months for oestrogen pellet therapy or progestin injectable drug therapy 
 
2. The use of non-hormonal prescription (eg paroxetine, other anti-depressants, alpha 
agonists [eg clonidine], methyldopa, gabapentin, pregabalin, medicinal cannabis) or over 
the counter/herbal treatments for treatment of menopausal symptoms is not allowed 
throughout the study. Subjects must have discontinued these drugs at least 28 days prior 
to Screening Visit 2. Subjects may, however, be permitted to continue to use these drugs 
if the dose has been stable for at least 4 weeks and they have been prescribed solely for 
the management of another disorder (e.g. neuropathic pain, depression). 
 
3. Inability to comply with the use of prohibited medications as described below (See 
Appendix A for more details): 
i. 
Use of digoxin is not allowed from Screening Visit 2 until 1 week after the last 
dose of investigational medicinal product (IMP) 
ii. 
Use of known CYP3A4 substrates with a narrow therapeutic range is not allowed 
from Screening Visit 2 until 1 week after the last dose of IMP  
iii. 
Use of strong or moderate inhibitors of CYP3A4 is not allowed from Screening 
Visit 2 until 1 week after the last dose of IMP  
iv. 
Use of moderate or strong inducers of CYP3A4 is not allowed from Screening 
Visit 2 until Week 12  
v. 
Use of known P-glycoprotein inhibitors is not allowed from Screening Visit 2 
until 1 week after the last dose of IMP  
 


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4. Any prior or ongoing history of clinically relevant drug or alcohol abuse within 12 months 
of Screening Visit 1.8 
5. Any clinically significant prior or ongoing history of arrhythmias, either determined 
through clinical history or on ECG evaluation.  
6. Any clinically significant abnormal laboratory test result(s) measured at Screening Visit 2. 
Specifically, severe hepatic impairment is excluded.  
7. Any active ongoing condition that could have caused difficulty in interpreting vasomotor 
symptoms such as: infection that could have caused pyrexia, pheochromocytoma, 
hyperthyroidism, carcinoid syndrome, alcohol abuse. 
8. Current history or previous (within the past 5 years) history of any malignancy (except 
basal and squamous cell skin tumours). 
9. Uncontrolled hypertension9.   
10. A history of hyperthyroidism or hypothyroidism. Treated hypothyroidism with normal 
thyroid function test results at Screening Visit 2 and a stable (for >3 months before 
Screening Visit 2) dose of replacement therapy is acceptable. 
11. Known hypersensitivity to NT-814 or any of the excipients in the formulation. 
12. Concurrent (or within the 2 months prior to Screening Visit 1) participation in a clinical 
study with an investigational medicinal product. 
13. Concurrent (or within the 1 month prior to Screening Visit 1) participation in an 
interventional clinical study. 
14. Previous participation in a clinical study with NT-814. 
15. Dependent on the investigator, the contract research organisation(s) or Sponsor for 
education or employment. 
16. Any unexplained post-menopausal bleeding. 
17. Abnormal findings on mammogram or subject has not undergone a mammogram within 
the guidelines recommended by applicable national authorities (eg United Kingdom 
National Health Service, United States Preventative Services Taskforce, Canadian Task 
Force on Preventative Healthcare)10. 
7.4 
Withdrawal Criteria  
Subjects will be informed that they have the right to withdraw from the study at any time without 
stating a reason and without prejudice to further treatment.  
                                                 
8 Significant alcohol or drug abuse is behaviour that meets the DSM-5 criteria59 for substance use disorder. 
9 Uncontrolled hypertension is defined as blood pressure of >130 mmHg (systolic) or >80 mmHg (diastolic), based 
on the average of two to three readings on at least two different occasions. Subjects with known hypertension should 
be reviewed to ensure their blood pressure is adequately controlled prior to study participation. 
10 Subjects who have not had a mammogram within the guidelines may have one performed as part of the screening 
process 


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The Investigator may withdraw subjects from the study or may discontinue study treatment at any 
time. 
Early withdrawal or early discontinuation from the IMP of any subject who has given informed 
consent to participate will be recorded including the reason for withdrawal. The primary reason 
will be selected from the following standard categories of early discontinuations or withdrawals: 
x Failed to meet randomisation criteria  
x Adverse Event (AE): Clinical events occurred, or laboratory results are reported, that in 
the medical judgment of the investigator are grounds for discontinuation from 
participation 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 electronic Case Report Form (eCRF) 
x Protocol Violation: The subject failed to adhere to the protocol requirements, and, in the 
opinion of the investigator, this failure to comply increased the risk to the subject to an 
unacceptable level 
x Lost to Follow-Up: The subject stopped coming for visits and study personnel were 
unable to contact the subject. 
x Pregnancy: Any subject becoming pregnant during the study will be withdrawn from 
dosing.  
x Other: The subject was terminated for a reason other than those listed above 
Subjects who withdraw or are withdrawn from participation in the study should attend an Early 
Termination visit at which the procedures scheduled for the final Follow Up visit will be 
undertaken. If the subject withdraws due to an AE, the event should be followed until resolution 
or care is transferred to the subject’s usual physician. 
Subjects who are withdrawn after randomisation will not be replaced.  
In some circumstances, the Investigator may discontinue study treatment without the need to 
withdraw the subject from participation in the study. When subjects permanently discontinue 
IMP, effort should be made to continue following the subject through to the end of scheduled 
visits for safety and to obtain efficacy assessments that can be assigned to the originally 
randomised treatment. 
7.5 
Criteria for Stopping the Study 
The Sponsor may terminate the study for safety or administrative reasons at any time.  


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The safety of NT-814 and the risk-benefit profile of individual doses and the study overall will be 
monitored by the study Data Review Committee (DRC). Full details, including specific criteria 
that may lead to study suspension or termination are described in the SWITCH-1 DRC Charter.  
8. 
STUDY DESIGN 
8.1 
Co- Primary Efficacy Endpoints 
There are four co-primary efficacy endpoints: 
x Mean change from baseline in frequency of moderate and severe hot flushes from 
baseline to Week 4 
x Mean change from baseline in frequency of moderate and severe hot flushes from 
baseline to Week 12 
x Mean change from baseline in severity of moderate and severe hot flushes from baseline 
to Week 4 
x Mean change from baseline in severity of moderate and severe hot flushes from baseline 
to Week 12 
8.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints include: 
x Mean change from baseline in frequency of moderate and severe hot flushes from 
baseline to Weeks 1, 2, 8 and 16 
x Mean change from baseline in severity of moderate and severe hot flushes from baseline 
to Weeks 1, 2, 8 and 16 
x Mean change from baseline in frequency of all hot flushes from baseline to Weeks 1, 2, 4, 
8, 12 and 16 
x Mean change from baseline in severity of all hot flushes from baseline to Weeks 1, 2, 4, 8, 
12 and 16 
x Mean change from baseline in the Hot Flush Score (frequency x severity) at Weeks 1, 2, 
4, 8, 12 and 16 
x Responder analyses: proportion of subjects with >50% and >80% reduction from baseline 
in hot flush frequency at Week 12 
x Mean change from baseline in number of night time awakenings secondary to hot flush at 
Weeks 1, 2, 4, 8, 12 and 16 
x Mean change from baseline in number of all night time awakenings at Weeks 1, 2, 4, 8, 
12 and 16 
x Change from baseline in the Global and individual domain scores of the Pittsburgh Sleep 
Quality Index at Weeks 4, 8, 12 and 16  
x Change from baseline in the Insomnia Severity Index score at Weeks 4, 8, 12 and 16 
x Change from baseline in the HFRDIS scores at Weeks 2, 4, 8, 12 and 16 


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x Change from baseline in the MenQoL-I scores at Weeks 4, 8, 12 and 16 
x Change from baseline in the Beck Depression Inventory II scores at Weeks 2, 4, 8, 12 and 
16 
8.3 
Pharmacokinetic endpoints 
x Exposure-response modelling will be undertaken on a number of efficacy and safety 
endpoints on an exploratory basis. 
8.4 
Pharmacodynamic endpoints 
x Not applicable 
8.5 
Safety endpoints 
x Change from baseline in clinical laboratory assessments  
- 
At Weeks 2, 4, 12 and 16 for haematology and urinalysis  
- 
At Weeks 2, 4, 8, 12 and 16 for clinical chemistry 
x Change from baseline in vital signs (blood pressure, pulse rate, temperature) at Weeks 2, 
4, 8, 12 and 16 
x Change from baseline in weight, waist circumference and body mass index at Weeks 2, 4, 
8, 12 and 16 
x Proportion of subjects with clinically significant abnormal ECG findings at each visit 
x Proportion of subjects with non-significant abnormal ECG findings at each visit 
x Change from baseline at Weeks 2, 4, 8, 12 and 16 in ECG intervals (RR, PR, QT, QTc 
and QTcF) 
x Proportion of subjects with maximum absolute QTcF values by category at each visit 
- 
<450, >450 to <480, >480 to <500, >500 msec 
x Proportion of subjects with maximum change from baseline in ECG QTcF values by 
category at Weeks 2, 4, 8, 12 and 16 
- 
<0, >0 to <30, >30 to <60, >60 msec 
x Change from baseline in the electronic Columbia Suicide Severity Rating Scale (eC-
SSRS) at Weeks 4, 12 and 16 
x Change from baseline to Weeks 12 and 16 in:  
- 
Serum concentration of bone-specific alkaline phosphatase (BALP)  
- 
Serum concentration of procollagen type 1 N-terminal propeptide (P1NP) 
x Nature and severity of AEs 
x Withdrawals due to an AE 
x Use of concomitant medications 


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8.6 
Study design 
This is a multi-centre, multi-country, double-blind, randomised, placebo-controlled Phase 2b 
study. The study will have a single-blind (subjects only) placebo run-in period and will be 
adaptive with respect to the number of subjects recruited into each dose group. 
Subjects will be provided the Participant Information Sheet (PIS) and Informed Consent Form 
(ICF) for their prior review. Informed consent to participation in the study will be obtained for all 
subjects before any study related procedures are performed. 
Figure 1: Study schematic 
 
-3
-2
-1
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Paper Diary
eDIARY COMPLETION
HF and NTA ANALYSES
RANDOMISATION
Initial 
Randomisation
First Interim Analyses when 30 subjects complete Week 4
N=30
Review Week 4 efficacy & all available safety data
1:1:1:1:1
Decisions:
1. Increase number of subjects per treatment group or keep at 30
2. Continue randomisation to all groups or discontinue one or more
Further interim analyses when 60/90/120 subjects complete Week 4
Review all available efficacy & safety data
Decisions:
1. Increase number of subjects per treatment group or keep at [30]
2. Continue randomisation to all groups or discontinue one or more
Placebo
Baseline
Placebo run-in
80 mg
40 mg
120 mg
160 mg
Follow
up
 
Subjects will be recruited initially into five parallel groups: 40 mg once per day NT-814, 80 mg 
once per day NT-814, 120 mg once per day NT-814, 160 mg once per day NT-814 and placebo 
once per day. See Figure 1 for study design schematic. After 30 subjects have been randomised 
and completed all assessments through the Week 4 visit the emerging efficacy and safety data 
will be reviewed by the DRC and the first determination made as to whether randomization to all 
dose groups should be continued. Further interim reviews may be conducted after 60, 90, 120 and 
150 subjects have completed the Week-4 assessments. Once a subject has been allocated to a 
dose/treatment group they will continue to receive the same dose/treatment throughout the study. 
Subjects will continue to be allocated to placebo treatment throughout the study. Further details 
of the DRC reviews are provided in Section 11.2 and in the DRC Charter. 


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8.6.1 
Justification for Study Design 
The study is a dose-range finding study, with assessment of dose-response based on both efficacy 
and safety. A four-fold range of doses will be evaluated which broadly encompasses the 
equivalent exposures to those evaluated in the RELENT-1 study that were associated with 
efficacy (See Section 5.1.3).  
The study will have an adaptive design component in which the number of subjects randomised 
to each treatment group is modified on the basis of emerging safety and efficacy data. This design 
enables a broad range of doses to be evaluated in the first instance, but with the ability to reduce 
the number of doses of NT-814 being evaluated if this emerging data shows that there is no 
advantage in continuing to evaluate them. The interim reviews also enable the sample size (per 
treatment group) to be assessed on an ongoing basis and to be increased if the estimates of 
treatment effect and variability used to derive the sample size originally prove to be incorrect. 
These adaptive features ensure that the study has the greatest probability of success while making 
efficient use of the trial population.  
The study will be placebo controlled to minimise assessment bias. Placebo is considered an 
acceptable reference group for studies in PM VMS as the disorder, whilst uncomfortable and 
disruptive to the affected individual, is not life-threatening or limiting, and studies are typically of 
limited duration. Experience from multiple studies in women with VMS has shown that a placebo 
response of up to 60% can be expected48 and so even subjects allocated to placebo should expect 
to receive some benefit from study participation. The use of placebo is also recommended by 
both the United States FDA and EU CHMP disease-specific guidelines49,55.   
Although the interim analyses used to make the adaptive randomisation decisions will be 
reviewed by an unblinded Data Review Committee (DRC), the Sponsor and CRO study 
operational team will remain fully blinded throughout the study. The subjects and investigative 
site staff will also be blinded throughout the randomised phase of the trial and thus the study will 
be triple blind to reduce assessment bias. All subjects will receive placebo on a single blind basis 
during the last 2-weeks of the baseline period to enable baseline assessments to be recorded under 
similar conditions to those used during the randomised phase of the study. This run-in period, 
which has been used in similar trials previously56, also allows participants to familiarise 
themselves with the requirements and systems used in the study before the start of the 
randomised treatment phase. 
The study will comprise a 2-week baseline period followed by a 12-week treatment period. The 
2-week baseline period allows subjects one week to become familiar with eDiary completion 
before the baseline efficacy assessments are made during the second week. Studies with other NK 
antagonists have demonstrated that maximum efficacy is achieved within a matter of weeks34,35, 
and, in the case of fezolinetant, is sustained for at least 12-weeks. The disease-specific guidelines 
from both the FDA and CHMP recommend studies of 12-weeks duration to demonstrate 
maintenance of effect49,55.  
8.6.2 
Duration of Subject Participation 
Subjects will participate in the study for a total of approximately 19 weeks, comprising a formal 
screening and baseline period (3 weeks), 12 weeks of double-blind treatment and then a final 


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follow-up visit 4 weeks after the end of the treatment period. There will be a total of 8 visits 
whilst participating in the study. 
8.6.3 
Screening Visit 1 
Informed consent will be obtained prior to any screening procedures being performed. Consent 
can be obtained prior to Screening Visit 1 or at the actual visit.  
The visit will include the following assessments to determine the subject’s initial eligibility for 
inclusion into the study: 
x Recording of the subject’s medical history, and prior and concomitant medication use, in 
particular, hormonal therapies and drugs used to manage menopausal symptoms  
Subjects will be provided with, and trained on the use of, a paper diary to be completed once a 
day for 7 days. Each evening (before retiring to bed), subjects will record in the diary their recall 
of the total number of hot flushes of each severity experienced over the previous 24 hours.  
The minimum time between Screening Visits 1 and 2 is 6 days, to enable at least 6 days of paper 
diary data to be completed. If necessary, the time period between Screening Visits 1 and 2 can be 
extended to enable prohibited concomitant medications to be washed-out. 
8.6.4 
Screening Visit 2 
Subjects will return to the clinic for Screening Visit 2, during which the investigator or designee 
will review the paper diary to determine if the subject can continue in the study. To continue, 
subjects must have completed the paper diary for at least 6 days and have recorded an average of 
at least 8 moderate or severe hot flushes per day over the last 5 days that the paper diary was 
completed.  
Subjects who do not record an average of at least 8 moderate or severe hot flushes per day 
(including night-time) over the last 5 days that the paper diary was completed, or who are not 
compliant with diary completion will be Screen Failures and will not be able to continue into the 
study. Limited data will be collected for subjects who withdraw from the study after providing 
informed consent but prior to randomisation onto the study (Screen Failures). 
If the diary compliance and hot flush criteria are satisfied, the following assessments will be 
performed to further determine the subject’s eligibility for inclusion into the study: 
x Review of other inclusion/exclusion criteria 
x Full physical examination, 12-lead ECG, vital signs 
x Blood sampling for haematology and clinical chemistry, and urine sample collection for 
urinalysis and urine pregnancy test  
x Review for adverse events and changes in concomitant medications 


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Subjects who continue to satisfy selection criteria will be provided with, and trained on the use 
of, an eDiary to be completed twice a day, starting the evening of Screening Visit 2 and 
continuing until they return to the site for the Baseline visit. Each evening, subjects will record in 
the diary the total number of hot flushes of each severity experienced that day since waking. Each 
morning upon waking, subjects will record the number of times they woke up in the night and the 
total number of hot flushes of each severity experienced during the night. 
At Screening Visit 2, subjects will commence placebo treatment. Their first dose of placebo will 
be taken in the clinic and all subsequent doses at home once a day in the evening (starting the 
following day) up until the day before the Baseline visit. Subjects will be provided with a 
medication kit containing sufficient placebo capsules for a 2-week period (plus 2 days overage).  
This placebo-run in period will be single-blind in design, in that whilst the investigator and clinic 
staff will know that placebo is being provided, subjects must remain blinded, and should be 
merely be informed that they are being given study medication. 
8.6.5 
Baseline (Day 1) 
Subjects will return to the clinic for the Baseline visit at which compliance with eDiary 
completion and hot flush data will be reviewed. Subjects who comply with all other selection 
criteria, who have completed the diary for at least 9 days, and who have recorded an average of at 
least 7 moderate or severe hot flushes per day (including night-time) over the last 7 days that the 
eDiary was completed may enter the 12-week double-blind portion of the study and be 
randomised to one of 40 mg, 80 mg, 120 mg or 160 mg NT-814 or placebo treatments. The mean 
number of hot flushes will be calculated programmatically by the eDiary vendor and the outcome 
made available to the site.  
Subjects who do not record an average of at least 7 moderate or severe hot flushes per day 
(including night-time) over the last 7 days that the eDiary was completed, or who are not 
compliant with eDiary completion will be deemed Screen Failures and will not be able to 
continue into the study. Limited data will be collected for subjects who withdraw from the study 
after providing informed consent but prior to randomisation onto the study (Screen Failures). 
The Baseline visit will be Day 1. Prior to dosing on Day 1, the following assessments will be 
completed:  
x Review of inclusion/exclusion criteria, including eDiary data 
x Symptom directed physical examination 
x Vital signs (after resting for ≥ 5 mins, see Section 10.3.8) 
x 12-lead ECG  
x Blood samples for clinical chemistry, haematology and plasma bone turnover markers 
x Urine sample for urinalysis  


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x Subjects will be asked to complete the MenQoL-I, HFRDIS, Pittsburg Sleep Quality 
Index, Insomnia Severity Index, electronic Columbia Suicide Severity Rating Scale (eC-
SSRS) and the Beck Depression Inventory II. 
x Review for adverse events and changes in concomitant medications 
Eligible subjects will be randomised on Day 1 to NT-814 or placebo. Randomisation will be 
performed centrally via an interactive web response system (IWRS). 
Subjects will be given their first dose of IMP in the clinic and take all subsequent doses at home 
once a day in the evening (starting the following day) for a total of 12 weeks. At the baseline 
visit, subjects will be provided with IMP sufficient for the next 4 weeks. 
Subjects will continue to complete the eDiary twice a day throughout the study until the Final 
Follow-up visit at Week 16. 
8.6.6 
Interim visits (Weeks 2, 4, 8, and 12) 
During the double-blind treatment phase, subjects will return to the clinic for interim assessments 
at Weeks 2, 4, 8 and 12. Weeks 2 and 4 should be scheduled within ±3 days of the target visit day 
and Weeks 8 and 12 within ±4 days of the target visit day. The visit at Week 12 should be 
conducted at a similar time of day to the baseline visit to reduce diurnal variation in the plasma 
bone turnover markers. 
At the start of each visit a blood sample will be taken for determination of plasma levels of NT-
814. At the same time, if required per the Study Schedule, blood samples for safety laboratory 
assessments and plasma bone turnover markers will be taken. Subjects will be asked to provide 
the time they took their dose of study medication on the previous day and this will be recorded on 
the eCRF.  
Study medication compliance will be reviewed at all visits and a new supply of study medication 
(sufficient for the next 4 weeks) will be provided at Weeks 4 and 8. Diary completion compliance 
will also be reviewed, and training/re-training provided as necessary.  
At each visit the following assessments will be completed: 
x Vital signs (after resting for ≥ 5 mins, see Section 10.3.8) 
x 12-lead ECG  
x Blood samples for hematology (Weeks 2, 4 and 12), clinical chemistry (Weeks 2, 4, 8 and 
12), pharmacokinetic analysis (Weeks 2, 4, 8 and 12) and plasma bone turnover markers 
(Week 12 only) 
x Urine samples for urinalysis (weeks 2, 4 and 12)  


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x Subjects will be asked to complete the MenQoL-I, Pittsburgh Sleep Quality Index and 
Insomnia Severity Index (Weeks 4, 8 and 12), the HFRDIS and Beck Depression 
Inventory II Weeks 2, 4, 8 and 12) and eC-SSRS (Weeks 4 and 12) 
x Review of eDiary compliance 
x Review for adverse events and changes in concomitant medications 
At Week 12, subjects may be re-started on any prohibited medications that are permitted after 
the end of treatment (see Appendix A). 
8.6.7 
Final Follow-up / Early Termination visit 
Subjects will return to the clinic for the final study visit 4-weeks (+5 days) after the end of 
treatment. The visit should be conducted at a similar time of day to the baseline visit to reduce 
diurnal variation in the plasma bone turnover markers. 
The same procedures will also be undertaken if a subject withdraws from the study early.  
The eDiary will be collected and the following assessments completed:  
x Symptom directed physical examination 
x Vital signs (after resting for ≥ 5 mins per Section 10.3.8) 
x 12-lead ECG 
x Blood samples for clinical chemistry and hematology and plasma bone turnover markers  
x Urine sample for urinalysis  
x Subjects will be asked to complete the MenQoL, HFRDIS, Pittsburg Sleep Quality Index, 
Insomnia Severity Index, eC-SSRS and the Beck Depression Inventory II 
x Review for adverse events and changes in concomitant medications 
Subjects may be re-started on any prohibited medications and menopausal symptom management 
medications at this time. 
9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION 
9.1 
Selection of doses in the study 
Subjects will initially be randomised to one of four NT-814 dose regimens and placebo. The use 
of four active doses and placebo will enable an adequate range of doses and exposures and 
several dose-response scenarios to be evaluated. 


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An adaptive design will be used to maximise the efficiency of the study through discontinuation 
or reduction in the number of subjects randomised to doses that are found, on the basis of 
emerging data, to be either insufficiently effective or no more effective than an adjacent lower 
dose. Doses may also be discontinued for safety reasons and the randomisation ratio may be 
adjusted in favour of one or more doses without necessarily discontinuing other doses.  
Two reference points have been used to set the doses in the current study. The first is the efficacy 
findings in the RELENT-1 proof of concept study. Ideally, the pattern of response with respect to 
dose will be replicated in the current study but the treatment groups in RELENT-1 were small 
and interpretation of the findings was complicated by the variable pharmacokinetics of the hard 
gel capsule formulation used in that study. A 150 mg dose of NT-814 was found to be maximally 
effective with no greater efficacy observed at the higher dose of 300 mg. A dose of 100 mg was 
effective in some endpoints but was clearly sub-optimal in comparison to the 150 mg dose. A 
dose of 50 mg was ineffective. The RELENT-1 study sets the target exposures for future studies. 
Table 9-1  
Summary of doses and exposures in the RELENT-1 Proof of Concept Study 
Dose 
Mean AUC0-last,ss 
(ng*hr/mL) 
Mean AUC0-24,ss 
(ng*hr/mL) 
Effectiveness 
50 mg 
2,341 
2,341 
Ineffective 
100 mg 
3,503 
3,542 
Sub-optimal 
150 mg 
9,021 
5,165 
Highly effective 
300 mg 
25,874 
14,822 
No additional benefit over 150 mg 
AUC0-last,ss = Area under the plasma concentration-time curve from 0 to last measurable time-point at steady state 
Since the hard gel capsule formulation used in RELENT-1 had unacceptable variability in 
kinetics, an optimised soft-gel capsule formulation has been developed for use in this and future 
studies. A relative bioavailability (RBA) study has been conducted which confirmed an 
acceptable level of variability and showed that, compared to the exposures seen in RELENT-1 
with the hard gel capsule formulation, the soft-gel results in approximately twice the exposure on 
a “per mg” basis (Table 9-2). These data are the second reference point for setting the doses in 
the current study. 
Table 9-2 
Comparison of Exposures with single doses of the soft and hard gel capsule 
formulations of NT-814 
Geometric mean 
Cmax 
ng/ml 
AUC0-last 
ng*hr/ml 
AUC0-24 
ng*hr/ml 
25 mg soft gel (RBA Study) 
332 
1,010 
786 
150 mg hard gel (RELENT-1 Study) 
911 
3,012 
3,013 
AUC0-24 = Area under the plasma concentration-time curve from 0 to 24 hours, AUC0-last = Area under the plasma 
concentration-time curve from time 0 to the last measurable concentration, Cmax = maximum plasms concentration 
A 40 mg soft-gel capsule has been developed and so all doses in the current study will be a 
multiple of 40 mg. The exposure after a single 150 mg dose in RELENT-1 is approximately 3-
fold higher than the exposure after a single 25 mg dose of the soft gel capsule. Thus, an 
equivalent dose in the soft gel capsule is ~80 mg. In all previous clinical evaluations the kinetics 
of NT-814 have been found to be either linear or very close to linear with respect to dose and so 


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linearity is also assumed when setting the doses for the current study. Assuming a ‘pivot’ dose of 
80 mg, dose-linearity across the dose range and an accumulation ratio of 1.7 (to convert single 
dose data to steady state conditions), the estimated median AUCs at steady state at the four doses 
planned will be as shown in Table 9-3. 
Table 9-3 
Estimated NT-814 exposures at steady state  
Dose 
AUC0-last at Steady State 
Lower bound 95% CI 
Geometric Mean 
Upper Bound 95% CI 
40 mg 
2,390 
2,740 
3,150 
80 mg 
4,780 
5,500 
6,310 
120 mg 
6,760 
8,240 
9,460 
160 mg 
9,580 
10,990 
13,350 
AUC0-24 = Area under the plasma concentration-time curve from 0 to 24 hours, CI = confidence interval 
These four doses enable a range of exposures to be evaluated that encompass the full range of 
effectiveness responses observed in RELENT-1. The mean values at the mid doses (80 and 120 
mg) are around the point that exposure-response modelling predicts maximum efficacy and the 
low and high doses are, respectively, expected to enable the rising and plateau parts of the dose-
response curve to be demonstrated.   
The upper bound of the confidence interval for predicted exposure at the high dose is below the 
mean exposure for the high dose in the RELENT-1 study (~15,000 ng*hr/ml) and is substantially 
below the individual highest exposures (up to ~80,000 ng*hr/ml) that were well tolerated in that 
study. It is also below the mean (~14,000 ng*hr/ml) and maximum (~42,000 ng*h/mL) values 
observed in healthy males after repeat dosing for 4 weeks that were also well tolerated with no 
safety concerns.  
Thus, the administration of these four dose levels together with sparse PK sampling in this study 
will allow a robust evaluation of both the dose-response and PK exposure-response, from which 
it will be possible to select an appropriate dose to progress into the pivotal Phase 3 registration 
studies. 
9.2 
Investigational medicinal product 
The IMP will consist of NT-814 40 mg capsules or matching placebo. The capsules are oblong, 
soft-gelatin capsules and each subject will take 4 capsules orally once-daily. The number of 
active and placebo capsules that each subject will take will be dependent on the dose to which 
they have randomized: 
Dose            
 
IMP Supply 
Placebo  
 
4 x placebo capsules 
40 mg NT-814       
1 x NT-814 capsule, 3 x placebo capsules 
80 mg NT-814            2 x NT-814 capsules, 2 x placebo capsules 
120 mg NT-814          3 x NT-814 capsules, 1 x placebo capsule 
160 mg NT-814          4 x NT-814 capsules  
 


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Inactive ingredients in both the NT-814 capsules and the placebo capsules are Capmul MCM EP, 
Labrasol ALF, Tween 80, Peceol and Vitamin E. 
 
The physical, chemical, pharmaceutical formulation properties and characteristics of the IMP are 
described in the IB.  
All capsules will be blistered and packaged into weekly cards, with each weekly card containing 
capsules for a 7-day week plus an additional day for overage. These weekly cards will be further 
packaged into cardboard cartons: 
- 
For the single-blind placebo run-in period, a carton will be dispensed containing 2 weekly 
placebo cards thereby providing sufficient capsules for the 2-week period between 
Screening Visit 2 and the Baseline visit (plus 2 days overage to allow for delays in clinic 
visit scheduling). 
- 
For the post-randomisation double-blind treatment phase, each carton will contain 4 
weekly cards thereby providing sufficient capsules for a 4-week dosing period (plus 4 
days overage to allow for delays in clinic visit scheduling). 
The IMP cards and cartons will be labelled in accordance all applicable local regulatory 
requirements. Multi-language labels may be applied to the IMP. 
All IMP must be stored in a secure area with access limited to the Investigator and authorized site 
staff. The IMP is to be shipped and stored at controlled room temperature and be protected from 
light. 
Only authorized investigational site study staff members are to dispense the IMP. 
9.3 
Allocation to Treatment 
The 2-week placebo-run in period will be conducted in a single-blind manner, with the subjects 
blinded to the treatment allocated. 
The post-randomisation 12-week treatment phase of 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 soft-gel capsules, identical in size and shape. 
On successful completion of screening and confirmation of eligibility, subjects will initially be 
randomised in a 1:1:1:1:1 ratio to receive either NT-814 40 mg/day, 80 mg/day, 120 mg/day, 160 
mg/day or placebo. Randomisation will be stratified by region (North America or Europe). After 
completion of the first interim review the randomisation may be changed (see Section 11.2). 
Regardless of any changes to the randomisation ratio, subjects will continue to receive the dose 
regimen they were randomised to for the full 12-week treatment period. 
The IMP each subject will receive will be allocated by an IWRS tool provided by Pharm Olam on 
behalf of the Sponsor. 


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9.4 
Study Treatment and Administration 
IMP will be taken once daily both during the 2-week placebo run-in phase and the 12-week 
double-blind treatment phase.  
For the placebo run-in, the first dose will be taken in the clinic at Screening Visit 2 and the last 
dose will be taken the evening before the Baseline visit.  
For the double-blind treatment phase, the first dose will be taken in the clinic at the Baseline visit 
(Day 1) and the last dose will be taken the evening before the Week 12 visit. IMP doses are fixed 
and will not be adjusted for individual subjects during the study. 
Subjects will be required to take 4 capsules of IMP once-daily in the evening before bedtime. 
At Screening Visit 2, Baseline, Week 4 and Week 8 subjects will be dispensed sufficient IMP for 
daily dosing at home until the next visit, with overage included to allow for visit windows.  
At Screening Visit 2, subjects will be dispensed sufficient supply to cover the period to the 
Baseline visit. 
At the Baseline visit subjects will be dispensed sufficient supply to cover the period to Week 4. 
An interim check of compliance will be made at the Week 2 visit (subjects will be instructed to 
bring their IMP carton with them to this visit). 
At the Week 4 visit subjects will be dispensed sufficient supply of IMP to cover the period from 
Week 4 to Week 8. 
At the Week 8 subjects will be dispensed sufficient supply of IMP to cover the period from Week 
8 to Week 12. 
On the days of clinic visits (Baseline, Weeks 2, 4, 8, and 12) subjects will be asked to provide the 
time that they took their dose the previous evening and this will be documented in the eCRF. 
All doses are to be taken at approximately the same time each evening. If a subject forgets to take 
a dose in the evening then the dose can be taken at any time up until 9 a.m. the following day. 
After this time, the dose should not be taken and will be considered a missed dose.   
Subjects will return any unused medication at each clinic visit.  
9.4.1 
Dose Interruption 
In the event that a subject experiences an AE which the investigator believes is treatment related 
and which the subject finds intolerable, a break in dosing of up to one week is permitted. If, on 
reintroduction of the study medication, the adverse event recurs and remains intolerable the study 
drug will be withdrawn altogether. A break in dosing will not result in extension of the overall 
dosing period.  


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9.5 
Treatment Accountability and Compliance Checks 
In accordance with regulatory requirements, the Investigator or designated site staff must 
document the amount of IMP 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. IMP accountability records must be maintained throughout the 
course of the study. The accountability unit for this study is a capsule. Discrepancies are to be 
reconciled or resolved. Procedures for final disposition of unused IMP will be provided in the 
appropriate Study Manual. 
The Investigator has overall responsibility in ensuring that the study treatment is received and 
managed at the study site in accordance with Good Clinical Practice (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. 
Every effort should be made to encourage subject compliance with the dosage regimen as per the 
protocol. All subjects will be instructed to return their medication carton with any unused 
capsules at each visit. A record of the capsules dispensed, taken, and returned will be recorded at 
each visit and compliance calculated.   
9.6 
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 
knowledge of the subject’s treatment will impact subject’s future medical care. If possible, the 
CRO medical monitor or Sponsor medical expert should be consulted prior to the blind being 
broken. If this is not possible, the CRO medical monitor or Sponsor medical expert must be 
notified as soon as possible after a code break was performed.  
If a suspected unexpected serious adverse reaction (SUSAR) occurs that requires expedited 
reporting to the relevant regulatory agency/Institutional Review Board (IRB) /Independent Ethics 
Committee (IEC), then the blind will be broken for the relevant subject by Emas safety group, in 
order to provide the Regulators the knowledge of the event and the causal agent. A blinded copy 
of the report will be provided to the investigators and the relevant IRB/IEC. 
If unblinding occurs accidentally this will be considered a protocol deviation which must be 
documented in the subject’s medical notes and in the trial master file (TMF), and the Sponsor 
must be informed. 


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9.7 
Permitted Concomitant Medications 
All concomitant medications taken during the study will be recorded in the eCRF with indication, 
dose information, and dates of administration. 
Any medication that is not specifically prohibited is allowed.  
9.8 
Prohibited Concomitant Medication 
A list of prohibited medications is provided in Appendix A.  
The use of hormonal therapies is prohibited prior to Screening Visit 2 for the periods stated in 
exclusion criterion 1, and throughout out the study.  
The use of non-hormonal prescription (eg paroxetine, other anti-depressants, alpha agonists [eg 
clonidine], methyldopa, gabapentin, pregabalin, medicinal cannabis) or over the counter/herbal 
treatments for treatment of menopausal symptoms is not allowed throughout the study. Subjects 
must have discontinued these drugs at least 28 days prior to Screening Visit 2. Subjects may, 
however, be permitted to continue to use these drugs if the dose has been stable for at least 4 
weeks and they have been prescribed solely for the management of another disorder (e.g. 
neuropathic pain, depression). 
The following medications are also excluded from Screening Visit 2 until the last dose of IMP 
(unless stated otherwise).  
x
Known CYP3A4 substrates with a narrow therapeutic range
x
Strong or moderate inhibitors of CYP3A4
x
Strong or moderate inducers of CYP3A4 (until Week 12 only)
x
Known P-glycoprotein inhibitors
x
Digoxin
9.9 
Other Study Restrictions
Mild somnolence has been identified as a possible adverse reaction to NT-814. Subjects will be 
instructed neither to drive nor operate machinery if they experience somnolence. 


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10.
STUDY SCHEDULE
 Table 10-1: Schedule of Events 
Procedure 
Screening 
Visit 1 
(Visit 1) 
Screening 
Visit 2 
(Visit 2) 
Baseline 
(Visit 3) 
Week 2 
(Visit 4) 
Week 4 
(Visit 5) 
Week 8 
(Visit 6) 
Week 12 
(Visit 7) 
Week 16 
Follow-up/Early 
Termination visitb 
(Visit 8) 
Visit Day 
-21a
-14
1 
15 
29 
57 
85 
113 
Allowable window 
a 
±2 days 
0 
±3 days 
±3 days 
±4 days 
±4 days 
±5 days 
Informed Consentc 
X 
Medical History/Concomitant Diseases 
X 
X 
Demography 
X 
Physical Exam 
X 
Xd 
Xd 
Inclusion/Exclusion Criteria 
X 
Xe 
Xf 
Review of Concomitant Medications 
       X --------------------------------------------------------------------------------------------------------------------X 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
X 
X 
X 
X 
X 
AE and SAE Recording 
  X --------------------------------------------------------------------------------------------------- X 
Issue Paper Diary / Training 
X 
Paper Diary Completion (once daily) 
X-------Xh 
Issue eDiary / Training / Compliance check 
X 
X 
X 
X 
X 
X 
eDiary Completion (twice daily) 
       X---------------------------------------------------------------------------------------------------Xi 
Study Drug Dispensing/Training 
X 
X 
X 
X 
Placebo Treatment 
X-------Xj 
Study Drug Collection/Compliance 
X 
X 
X 
X 
X 
Randomisation 
X 
Daily Dosing (evening before bedtime) 
       X ------------------------------------------------------------- X 
MenQoL-I 
X 
X 
X 
X 
X 
HFRDIS 
X 
X 
X 
X 
X 
X 
Pittsburgh Sleep Quality Index 
X 
X 
X 
X 
X 
Insomnia Severity Index 
X 
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale 
X 
X 
X 
X 
Beck Depression Inventory II 
X 
X 
X 
X 
X 
X 
Clinical Chemistry and Haematology 
X 
X 
X 
X 
Xk 
X 
X 
Blood sample for NT-814 concentration 
X 
X 
X 
X 
Blood sample for bone turnover markers 
X 
X 
X 
Urine pregnancy Test 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 


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a 
Screening visit 1 must be at least 6 days before Screening Visit 2 to allow at least 6 days of paper diary data to be completed. It can be earlier than Day -21 
if needed to enable prohibited concomitant medications to be washed-out. 
b 
An Early Withdrawal/Safety Follow-up visit will be performed if the subject withdraws after the Baseline visit.  This visit will consist of the same 
assessments as the Week 16 Follow-up visit and should be scheduled within 14 days of the early termination date or discontinuation of investigational 
product. 
c 
Informed consent will be obtained prior to any screening procedures being performed. Consent can be obtained prior to Screening Visit 1 or at the actual 
visit.  
d 
Symptom directed examination, if required. 
e 
The paper diary Hot Flush requirements, as well as the other inclusion/exclusion criteria, will be assessed at Screening Visit 2.  
f 
The eDiary Hot Flush requirements will be assessed and other inclusion/exclusion criteria will be reviewed at the Baseline visit.  
g 
Systolic and diastolic blood pressure, pulse rate, temperature and weight will be recorded at all visits except Screening Visit 1. Waist circumference will be 
recorded at all visits except Screening Visits 1 and 2. Height will be measured at Screening Visit 2 only. 
h 
Subjects will complete a paper diary once a day for 7 days in between Screening Visit 1 and Screening Visit 2 (a minimum of 6 days of diary data is 
required to confirm eligibility).  
i 
Subjects will complete the eDiary twice a day, from the evening of Screening Visit 2 until they exit the study.  
j 
At Screening Visit 2, subjects will the commence placebo treatment (the placebo run-in period). Their first dose of placebo will be taken in the clinic and 
all subsequent doses at home once a day in the evening (starting the following day) up until the day before the Baseline visit. 
k 
At Week 8, this blood sample is for clinical chemistry only  


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10.1 
Volume of Blood Sampling 
Approximate blood sample volumes are detailed below. The volumes for individual samples may 
vary accordingly to laboratory requirements and the number of samples taken may increase due 
to unscheduled visits, lost or damaged samples where additional blood draws are needed, 
however, the total volume is not expected to exceed 150 mL per subject. 
Clinical chemistry  
5 mL 
Hematology  
3 mL 
PK  
6 mL 
Plasma bone turn-over markers  
10 mL 
 
10.2 
Efficacy assessments 
10.2.1 Hot Flush Electronic Diary 
Subjects will be provided with an eDiary to document the number of hot flushes experienced, the 
severity of each hot flush using a scale of 1 to 3 (mild, moderate or severe) and the number of 
night-time awakenings (Appendix C). Subjects will complete the eDiary twice a day, starting the 
evening of Screening Visit 2 and continuing throughout the study until the final Follow up visit. 
Each evening, subjects will record the total number of hot flushes of each severity experienced 
that day since waking. Each morning upon waking, subjects will record the number of times they 
woke up in the night and the total number of hot flushes of each severity experienced during the 
night. The severity of each hot flush will be graded by the subject as follows: 
Mild:  
Sensation of heat without sweating 
Moderate:  
Sensation of heat with sweating, but able to continue activity.  
Severe:  
Sensation of heat with sweating, causing cessation (stopping) of activity 
A hot flush at night which awakens the subject should be classed as severe. Once awake, subjects 
should record any further hot flush episodes according to their severity. 
10.2.2 MenQoL-I (1 month recall version) 
The MenQoL-I (Menopause-specific Quality-of-Life Questionnaire Intervention Version, 
Appendix C) is a validated questionnaire used to measure condition-specific quality of life in 
menopausal women. It is composed of 32 items across 4 domains (physical, vasomotor, 
psychosocial and sexual). For each item, subjects record whether they have experienced the 
problem in the past month, and if so, they rate how bothered they were by the problem on a scale 
of 0 (not at all bothered) to 6 (extremely bothered). The item responses can then be converted into 
analysis scores and an overall questionnaire score.  


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Subjects will complete the MenQoL-I questionnaire at each clinic visit except the two Screening 
visits and Week 2. 
10.2.3 Hot Flash Related Daily Interference Scale (HFRDIS) 
The HFRDIS (Appendix C) is a 10-item, self-report questionnaire assessing the impact of hot 
flushes on a woman’s life during the past week. For each of the 10 items, subjects rate how much 
hot flushes have interfered with that aspect of their life on a scale of 0 (not at all) to 10 (very 
much so). 
Subjects will complete the HFRDIS at each clinic visit except the two Screening visits. 
10.2.4 Pittsburgh Sleep Quality Index 
The Pittsburgh Sleep Quality Index (PSQI, Appendix C) is a self-rated questionnaire which 
assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items 
generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, 
habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime 
dysfunction. The sum of scores for these seven components yields one global score. 
Subjects will complete the PSQI at each clinic visit except the two Screening visits and Week 2. 
10.2.5 Insomnia Severity Index 
The Insomnia Severity Index (ISI, Appendix C) is a brief self-report questionnaire assessing the 
nature, severity, and impact of insomnia. The ISI comprises 7 items assessing the perceived 
severity of difficulties initiating sleep, staying asleep, and early morning awakenings, satisfaction 
with current sleep pattern, interference with daily functioning, noticeability of impairment 
attributed to the sleep problem, and degree of distress or concern caused by the sleep problem. 
Subjects rate each item on a scale of 0 to 4, yielding a total score ranging from 0 to 28. 
Subjects will complete the ISI at each clinic visit except the two Screening visits and Week 2.  
10.2.6 Beck Depression Inventory II 
The Beck Depression Inventory II (BDI-II, Appendix C) is a 21-item questionnaire assessing the 
intensity of depressive symptoms over the past 2 weeks. It is composed of items relating to 
symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings 
of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest 
in sex. Subjects rate each item on a scale of 0 to 3, with the total score ranging from 0 to 63, with 
a higher score suggesting more severe depressive symptoms. 
Subjects will complete the BDI-II at each clinic visit except the two Screening visits. 


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10.3 
Safety Assessments 
10.3.1 Medical history and concomitant diseases 
A review of medical and medication history will be performed at the Screening visits to confirm 
subject eligibility. This must be confirmed by medically qualified investigator or sub-
investigator. All medically and clinical relevant information must be recorded, 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 the six months before the Screening Visit  
x Relevant history of menopausal, respiratory, cardiovascular, renal, gastro-intestinal, 
hepatic, endocrine, hematological, neurological, psychiatric and any other diseases 
The menopausal symptom history does not need to be recorded on the general medical history 
page of the eCRF. However, surgeries related to menopause (e.g. bilateral oophorectomy, 
hysterectomy) do need to be recorded on the medical history page. 
10.3.2 Physical examinations 
A full physical examination will be conducted at Screening Visit 2 and a symptom directed 
physical examination at the Baseline and Week 16 visits. This will be completed by a physician 
or an appropriately qualified delegate. 
A full physical examination includes a review of the following body systems: 
x General appearance 
x Skin 
x Head, eyes, ears, nose and throat 
x Respiratory 
x Cardiovascular 
x Abdomen (including liver and kidneys) 
x Musculoskeletal 
x Neurological 
Any abnormalities that are identified at Screening Visit 2 will be documented on the medical 
history eCRF page. Any change (including new and worsening findings) between Screening Visit 
2 and the final study visit should be recorded as an AE on the AE eCRF page and in the subject’s 
medical record. 


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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. 
10.3.3 12-Lead ECGs 
Resting 12-lead ECG data will be captured at all study visits except Screening Visit 1. 
All ECGs will be performed after the patient has rested for five minutes in a semi-recumbent 
position. The same model of ECG recorder should be used throughout the study for any given 
subject wherever possible. 
All ECG reports must be reviewed, signed and dated by the Investigator or delegated physician. 
Reports will then be filed with the subject’s medical record. The Investigator will comment on all 
abnormal findings and determine whether they are clinically significant. These assessments will 
be recorded in the eCRF and clinically significant findings must also be reported as AEs in the 
eCRF. 
10.3.4 Electronic Columbia Suicide Severity Rating Scale 
The Columbia Suicide Severity Rating Scale, or C-SSRS (Appendix C), is a rating scale created 
to evaluate suicidality in adults and children over the age of 12. It rates an individual's degree of 
suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with 
specific plan and intent." The version used will be the electronic C-SSRS (eC-SSRS), which is a 
subject-reported version of the scale. The C-SSRS has been found to be reliable and valid in the 
identification of suicide risk in several research studies and is a standard tool used in clinical 
development studies with centrally acting investigational drugs, regardless of indication. 
Subjects will complete the eC-SSRS at Baseline, Weeks 4, 12, and 16. 
10.3.5 Clinical chemistry 
Blood for clinical chemistry assessments will be collected as indicated in the Study Schedule 
(Table 10-1) and sent to the central laboratory for analysis.  The following clinical chemistry 
parameters will be assessed: sodium, potassium, glucose, urea (blood urea nitrogen), creatinine, 
creatine kinase, albumin, calcium, phosphate, bilirubin (total), alkaline phosphatase, aspartate 
transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase (GGT), 
bicarbonate, magnesium, chloride, total protein and haemoglobin A1c (HbA1c). Subjects do not 
need to fast before clinical chemistry samples are taken. 
All clinical chemistry test reports must be reviewed, signed and dated by the Investigator or 
delegated physician. Reports will then be filed with the subject’s medical record. The Investigator 
will comment on all abnormal results and determine whether they are clinically significant. 
Clinically significant findings must also be reported as AEs in the eCRF. 


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10.3.6 Haematology 
Blood for haematology assessments will be collected as indicated in in the Study Schedule (Table 
10-1) and sent to the central laboratory for analysis. The following haematology parameters will 
be assessed: red blood cell (RBC) count, white blood cell (WBC) count, haematocrit, 
haemoglobin, MCV, platelet count and WBC differentials. 
All haematology test reports must be reviewed, signed and dated by the Investigator or delegated 
physician. Reports will then be filed with the subject’s medical record. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as AEs in the eCRF. 
10.3.7 Urinalysis 
Urine for urinalysis assessments will be collected as indicated in the Study Schedule in (Table 
10-1) and sent to the central laboratory for analysis. Urinalysis will include glucose, bilirubin, 
ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites, leucocyte esterase, 
sedimentation.  
All urinalysis test reports must be reviewed, signed and dated by the Investigator or delegated 
physician. Reports will then be filed with the subject’s medical record. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as AEs in the eCRF.  
10.3.8 Vital signs 
Vital signs will be measured at all visits except Screening Visit 1: 
x Systolic and diastolic blood pressure, pulse rate, temperature and weight will be recorded 
at all visits except Screening Visit 1 
x Waist circumference will be recorded at all visits except Screening Visits 1 and 2 
x Height will be measured at Screening Visit 2 only. 
At Screening Visit 2 only, blood pressure measurements may be repeated a maximum of twice 
(three measurements in total) if the first values are high and suggestive of uncontrolled 
hypertension. The repeat measurements should be taken after at least 5 minutes of rest in a quiet 
environment.  
All measurements are to be recorded on the Vital Signs eCRF. 
All vital signs must be reviewed by the Investigator or delegated physician. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. These 
assessments will be recorded in the eCRF and clinically significant findings must also be reported 
as AEs in the eCRF. 


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10.3.9 Bone Turnover Markers 
Blood for assessment of bone turnover markers will be collected at Baseline, Week 12 and Week 
16 and sent to the central laboratory for analysis. The serum concentration of the following 
markers will be assessed: bone-specific alkaline phosphatase (BALP) and procollagen type 1 N-
terminal pro-peptide (P1NP). 
 
Baseline and Week 12 and 16 visits should be conducted at similar times of day to reduce diurnal 
variation in these markers. 
 
10.3.10 Pregnancy Testing, Contraception and Pregnancy  
Pregnancy Testing 
A dipstick urine pregnancy test will be performed for all subjects at Screening Visit 2 and must 
be negative for the subject to remain eligible.  
Contraception 
There are no contraception requirements given that all subjects will be post-menopausal.  
Pregnancy 
Not applicable for this study.  
10.4 
Pharmacokinetics 
Blood samples for analysis of plasma NT-814 concentrations will be collected at Weeks 2, 4, 8, 
and 12. The actual date and time of each blood sample collection will be recorded, together with 
the date and time of the most recent dose of IMP.  
Approximately 6 mL of blood will be collected at each time point. Details of PK blood sample 
collection (including volume to be collected), processing, storage and shipping procedures will be 
provided in the Study Manual. 
10.5 
Adverse events 
10.5.1 Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a subject or clinical trial subject administered an IMP and 
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 finding, for example), 
symptom, or disease temporally associated with the use of an IMP, whether or not considered 
related to the IMP. 


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As the full medical history and physical evaluation does not take place until Screening Visit 2, 
the adverse event reporting period starts after this visit is complete.  
Adverse Drug Reaction (ADR) 
All AEs considered to be untoward and unintended responses to an IMP related to any dose 
should be considered ADRs. 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 
an IMP” means that a causal relationship between an IMP and an AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
Serious Adverse Event (SAE) 
An adverse event that: 
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 in-patient 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 
and/or11 may require intervention to prevent one of the other outcomes listed in the definition 
above may be considered a SAE. 
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 and neither is attendance at an Emergency Room / 
Accident and Emergency Department that takes place in the evening or night and does not result 
in formal admission to the hospital. 
Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with applicable product 
reference safety information (Section 6.5 of the Investigator Brochure). 
                                                 
11 The definition varies between regulatory jurisdictions 


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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 the reference safety information. 
Adverse Events of Special Interest 
NT-814 is a non-hormonal therapy and so is not expected to have any adverse effect on the 
endometrium. However, post-menopausal bleeding will be monitored as an AE of special interest 
and investigators should report any such events to the Sponsor in an expedited manner. This 
should be done by completing an AE of Special Interest form within 5 working days of awareness 
of the event and submitting the form to the medical monitor by email. Note, the AESI form 
should NOT be sent to Emas. 
Additionally, any subjects experiencing post-menopausal bleeding after randomisation should 
undergo a transvaginal ultrasound with subsequent investigation and management (including 
endometrial biopsy, if indicated) according to the investigator’s clinical judgement and usual 
practice (unexplained post-menopausal bleeding prior to randomisation will exclude the subject 
from the study). 
10.5.2 Assessment of 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 
10.5.3 Assessment of Causality 
A determination will be made of the relationship (if any) between an AE and the study drug. A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the AE may have been caused by the drug or study procedure. AEs will be classified as either 
related or unrelated.  
10.5.4 Adverse Event Reporting 
Adverse events may be volunteered spontaneously by the subject, or discovered as a result of 
general, non-leading questioning. As the full medical history and physical evaluation does not 
take place until Screening Visit 2, the adverse event reporting period starts after this visit is 


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complete. Adverse events occurring from the time of Screening Visit 2 up to the final study visit 
will be recorded. All AEs should be recorded in the eCRF and in the subjects’ source notes. 
Any SAE occurring from Screening Visit 2 until 28 days after the last dose of IMP must be 
reported immediately (within 24 hours of the investigator becoming aware of it) and recorded on 
the SAE Form. Detailed instructions for the reporting of SAEs can be found in the Study Manual. 
All subjects with a SAE must be followed up and the outcomes reported. The investigator must 
supply the Sponsor and the relevant agency/IRB/IEC with any additional requested information 
(e.g., autopsy reports and terminal medical reports). Any follow-up information on a previously 
reported SAE will also be reported within 24 hours of awareness. 
If the Investigator does not have all information regarding an SAE, he/ she will not wait to 
receive additional information before reporting the event and completing the appropriate data 
collection form. The Investigator should always provide a preliminary assessment of causality at 
the time of the initial report as described in Section 10.5.3. 
The primary mechanism for reporting SAEs will be a paper collection form. 
Scan & email of the SAE form is the preferred method to transmit this information to the project 
contact for SAE receipt although fax transmission is also acceptable. In rare circumstances and in 
the absence of email facilities or 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 the Investigator to complete and sign the SAE data collection form 
within the designated reporting periods. 
If required according to local regulatory authorities and IRB/IEC policy, each Investigator must 
then notify his or her relevant agency/IRB/IEC of the SAE. 
NeRRe is required to expedite to worldwide regulatory authorities reports of SUSARs in line 
with the relevant legislation. Fatal or life-threatening SUSARs must be reported within 7 calendar 
days and other SUSARs within 15 calendar days. 
In accordance with the European Commission Directive 2001/20/EC, NeRRe will notify the 
relevant Ethics Committees in concerned Member states of applicable SUSARs as individual 
notifications or through a periodic line listing. SUSARs will be reported to IRB/EC in non-EU 
countries according to local regulations and IRB/EC policy. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 
NeRRe (or their designee) will submit to the regulatory authorities all safety updates and periodic 
reports, as required by applicable regulatory requirements. 


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11. 
STATISTICAL CONSIDERATIONS 
11.1 
Estimated Sample Size 
11.1.1 Efficacy 
The total sample size for the trial yields high power for the expected large difference from 
placebo in hot flush reduction from baseline and adequate power for moderate difference.   
Assuming a common standard deviation (SD) of 4.4, N=27 per treatment group has ~95% power 
(alpha=0.05 2-sided) via trend test across all doses including placebo if the true underlying dose 
response is non-decreasing from a reduction of 4 hot flushes on placebo up to 8 on the highest 
dose of NT-814.   N=33 per treatment group is required for 95% power for pairwise comparison 
of the highest dose to placebo under these same assumptions. Hence, a total of 150 completed 
subjects (30 x 5) was used for the simulations of adaptive design.  [Note, the actual performance / 
power for the adaptive designs may be higher than the values cited in this report since additional 
subjects will be added to selected dose groups to better inform on safety.]  The actual sample size 
will be determined by the adaptive dose-finding design algorithm (See Appendix B). In addition, 
the actual sample size is increased by 10% to allow for subjects who withdraw prematurely and 
so the initial sample size will be 165 subjects. 
The sample size allows for 95% power since each of the four co-primary endpoints are required 
to demonstrate statistical significance in order to yield a firm conclusion of beneficial treatment 
effect on hot flushes.  Conservatively, assuming independence among the four endpoints, this 
would yield approximately 81% power overall for achieving statistical significance for each of 
the four endpoints.  Thus, overall power for the trial is estimated to be at least 81%; the actual 
power depends on the unknown magnitudes of correlations among the co-primary endpoints.   
11.1.2 Safety 
In addition to assessing efficacy, the study objectives also include further evaluation of the safety 
of a range of doses of NT-814 in women with menopausal symptoms. Regarding estimation of 
differences in AE rates from placebo for a given dose group, Table 11-1 (computed via normal 
approximation to the binomial distribution) shows the half-width of 95% confidence intervals for 
difference between a pair of treatment groups.  This indicates the precision for such estimation 
for several example cases.  The DRC will use these confidence intervals to assist in their 
consideration of increasing the sample size of those doses which achieve target levels of HF 
frequency and severity reduction in order to better assess safety.  Criteria for such considerations 
will be described more fully in the DRC Charter. 


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Table 11-1 
Estimates of 95% confidence interval half-widths for a representative range 
of treatment group differences in incidence of adverse events and sample sizes 
OBSERVED between-
group difference in 
percentage 
95% confidence interval half-width for indicated N/group and 
OBSERVED percentage point difference from placebo 
N=30 
N=40 
N=50 
15 - 5 = 10 
15 
13 
12 
25 – 5 = 20 
17 
15 
13 
35 – 5 = 30 
19 
16 
15 
20 – 10 =10 
18 
15 
14 
30 – 10 = 20 
20 
17 
15 
40 – 20 = 20 
21 
18 
16 
30 – 20 = 10 
22 
19 
17 
40 – 20 = 20 
23 
20 
18 
50 – 20 = 30 
23 
20 
18 
11.2 
Interim Reviews 
A number of interim analyses (IA) are planned to enable the following two questions to be 
addressed as the trial progresses: 
1) Do the emerging efficacy and safety data support the continued evaluation of all four
NT-814 doses?
2) Do the assumptions used in the original sample size estimate remain valid?
The first IA will be conducted after efficacy data for the frequency and severity of hot flushes is 
collected through Week 4 from 30 patients randomized in equal proportions to the four NT-814 
doses and placebo. The DRC will review the HF frequency and severity results, together with all 
available safety data, and will determine the randomisation ratios for subjects subsequent enrolled 
into the study. The ratio may be changed to optimise the adaptive design to estimate doses with 
target levels of weekly average daily HF reduction from baseline of between 6 and 8.  The 
adaptive design algorithm will be based on Bayesian Emax dose-response modeling57 and / or T-
statistic adaptive dose-finding design58.  The DRC will have dose assignment recommendations 
by each of those adaptive dose-finding algorithms and assign the randomization ratio that best 
integrates the safety and efficacy objectives of the trial and the adaptive design results.  
Additional details regarding the adaptive algorithms and their performance characteristics are in 
the adaptive dose-finding design simulation report (Appendix B).  Subsequent IA's will be 
conducted similarly, after Week 4 data from each cohort of ~30 additional subjects become 
available.  The DRC will evaluate stopping criteria according to the IA algorithms as described in 
Appendix B and decide on stopping assignment of subjects to specific doses or stopping the trial 
for an efficacy or safety conclusion, and dose choice for subsequent study or futility. 
The DRC will be unblinded to treatment allocation. Subjects will continue to be recruited and 
randomised while the interim analyses are being undertaken.  


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11.3 
Analysis Sets 
The following data sets will be used for the statistical analysis. 
1. Safety Analysis Set: All subjects who receive at least one dose of double-blind study drug 
irrespective of treatment received. Subjects will be analyzed according to treatment received 
2. Full Analysis Set (FAS): All randomised subjects who received at least one dose of double-
blind study drug, irrespective of treatment received, and have hot flush data for at least 7 
days’ worth of post-treatment assessments (i.e. requirement for the primary efficacy 
endpoint). Subjects will be analyzed according to randomised treatment. This is the primary 
efficacy analysis set for the study. 
3. Per Protocol (PP) Set: All subjects in the FAS excluding those identified as having relevant 
protocol deviations. 
4. Exposure-Response (ER) Set: all subjects who received at least one dose of double-blind 
study drug and for whom the PK data are considered sufficient. 
Analysis Sets will be identified prior to the unblinding of the study data. 
11.4 
Data Analysis 
A Statistical Analysis Plan (SAP) will be written and finalised prior to database lock and 
treatment unblinding. The SAP will give a more detailed description of the summaries and 
analyses that will be performed, expanding on the protocol specified analysis. Any deviation 
from the protocol specified analysis will be documented within a protocol amendment or in the 
SAP, as appropriate, and described within the CSR.  
Data will be analysed using SAS® version 9.4 or a later version. 
Continuous variables will be summarised using number of non-missing observations, mean, 
standard deviation, median, first and third quartiles, minimum and maximum values. Categorical 
variables will be summarised using counts and percentages. All statistical hypothesis tests and 
confidence intervals will be two sided, using a type I error rate of 0.05. No adjustment for 
multiple comparisons will be used for this Phase 2 study. For the analysis of each efficacy 
endpoint pairwise statistical comparisons are planned for each NT-814 dose group (40mg, 80mg, 
120 mg and 160 mg) versus placebo, with the understanding that this increases the overall type I 
error rate of the study. All collected subject data will be listed. 
No subgroup analyses are planned to be performed. 
11.5 
Interim Analysis 
The first interim analysis (IA) will be conducted after efficacy data from frequency and severity 
of hot flushes (HF) is collected through Week 4 from 30 patients randomized in equal proportions 
to the 4 doses and placebo.  Based on DRC review of the IA results, randomization ratios for 


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subsequent enrolled patients may be changed to optimize the adaptive design to estimate doses 
with target levels of weekly average daily HF reduction from baseline 6 and 8.  Adaptive design 
algorithm will be based on Bayesian Emax dose-response modeling57  and / or T-statistic adaptive 
dose-finding design58.  The DRC will have dose assignment recommendations by each of those 
adaptive dose-finding algorithms and assign the randomization ratio that best integrates the 
objectives of the trial and the adaptive design results.  Additional details regarding the adaptive 
algorithms and their performance characteristics are in the adaptive dose-finding design 
simulation report (Appendix B).  Subsequent IA's will be conducted similarly, after Week 4 data 
from each cohort of ~30 additional patients become available.  The DRC will evaluate stopping 
criteria per the IA algorithms as described in Appendix B, and decide on stopping assignment of 
subjects to specific doses or stopping the trial for an efficacy conclusion and dose choice for 
subsequent study or futility.  
11.6 
Protocol Deviations 
Protocol deviations will be listed by subject and treatment group. Relevant protocol deviations 
will be identified from review of the subject data, prior to database lock, at a blinded data review 
meeting (BDRM). Subjects with any relevant deviations that are judged to impact on the 
statistical analysis will be excluded from the PP analysis set. 
11.7 
Subject Disposition 
The number of subjects enrolled, randomised and within each subject analysis set will be 
summarised by treatment group and overall. Any screen failure subjects will be separately 
described in the CSR. In addition, the number of subjects completing / not completing the study 
will be summarised along with the primary reason for withdrawal from the study. 
11.8 
Demographics and Baseline Characteristics 
Relevant Screening and Baseline data (i.e. data collected prior to the study treatment 
administration initiation) and demographic characteristics will be summarised descriptively for 
each treatment group. The FAS will be used in summaries of demographic and baseline data. No 
statistical testing will be used to compare treatment groups for different baseline characteristics. 
11.9 
Statistical Methods for Efficacy Parameters 
All efficacy analyses will be performed on the FAS analysis sets which is the primary analysis set 
for all statistical comparisons of efficacy endpoints. The primary efficacy endpoint will, 
additionally, be analysed in the PP set.  
11.9.1 Primary Efficacy Analysis 
The co-primary endpoints are the change from baseline in the mean daily frequencies of moderate 
and severe hot flushes in the 7 days before the week 4 and Week 12 visits, and the mean severity 
of moderate and severe hot flushes in the 7 days before the week 4 and Week 12 visits. The 
baseline assessment will be the last 7 days of the baseline diary completion period. Absolute and 


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changes from baseline in the mean daily frequencies and average hot flush severity will be 
summarised by treatment group. The change from baseline endpoint will be analysed using a 
mixed model repeated measures analysis. Pairwise statistical comparisons are planned for each 
NT-814 dose group (40 mg, 80 mg, 120 mg and 160 mg) versus placebo, presenting the adjusted 
mean treatment difference with its corresponding 95% confidence interval.  In addition, treatment 
mean comparisons to placebo may be made via estimated means from a 4-parameter Emax model 
fit and trend test for increasing response with increasing dose based on isotonic regression 
modelling [details will be in the Statistical Analysis Plan]. 
The primary objective will be assessed by testing the following hypotheses for each NT-814 
group versus placebo separately: 
Null hypothesis (H0): There is no difference in the mean change from baseline in hot flush 
frequency [or severity] at Week 12 [or Week 4] compared to Baseline for the NT-814 treatment 
group compared to placebo. 
H0: μ (active) = μ (placebo) 
Alternative hypothesis (H1): There is a difference in the mean change from baseline in hot flush 
frequency [or severity] at Week 12 [or Week 4] compared to Baseline for the NT-814 treatment 
group compared to placebo. 
H1: μ (active) ≠ μ (placebo) 
Absolute and changes from baseline in the in the mean frequency and severity will be 
summarised by treatment group.  
11.9.2 Secondary Efficacy Analysis 
11.9.2.1 
Other hot flush frequency and severity secondary endpoints 
Each of the hot flush frequency and severity secondary endpoints, including night time 
awakening (Section 8.2), will be summarised by treatment group and scheduled visit (as 
applicable) and will be analysed, following the same approach as for the primary endpoint. 
The proportion of responders, defined as a reduction of >=50% points and >=80% points on the 
weekly average frequency of hot flushes will be summarised at each scheduled visit. The Week 4 
and Week 12 response will be analysed by logistic regression, including the same terms in the 
model as for the primary efficacy endpoint analysis. Pairwise statistical comparisons are planned 
for each NT-814 dose group versus placebo, presenting the adjusted odds ratio for the treatment 
difference with its corresponding 95% Wald confidence interval. 


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11.9.2.2 
Other Secondary endpoints  
The analyses of the following endpoints will use the same approach as for the primary endpoint: 
Pittsburgh Sleep Quality Index scores, Insomnia Severity Index Scores, Beck Depression 
Inventory Scores, MenQoL and HFRDIS (total score and domain/sub-scores, as applicable).  
For each of these secondary endpoints the appropriate analysis method to be used to assess the 
observed data will be reviewed, and any changes documented in the SAP. Only the Week 4 and 
Week 12 time points will be analysed, other visits summarised only, by treatment group. 
11.10 
Statistical Methods for Safety Parameters 
The safety analysis set will be used for all presentations of safety endpoints. No statistical testing 
will be used to compare treatment groups for different safety endpoints. Safety data will be 
summarised descriptively for each treatment group.  
11.10.1 Adverse Events 
All adverse events will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAE) will be presented 
within summary presentations, by MedDRA system organ class (SOC), preferred term and 
treatment group.  
An adverse event will be defined as treatment emergent if the onset date is on or after the date of 
first dosing with study treatment. Any adverse event with an onset date earlier than the first 
dosing with study treatment will be considered as a pre-treatment adverse event. If a subject 
experiences more than one AE with the same preferred term, that preferred term will be counted 
only once within summaries. It will be assigned the highest observed severity and the strongest 
relationship to study treatment among those events for the tables in which those characteristics 
are summarised. Pre-treatment AEs will be identified in a subject listing.  
Summaries presentations for the number and percentage of subjects reporting TEAEs, severity of 
TEAEs, TEAEs by relationship to study treatment, and treatment emergent serious adverse events 
(SAE) will be presented by treatment group and overall. In addition, SAEs and adverse events 
directly resulting in withdrawal from study will be listed. 
11.10.2 Laboratory Parameters 
Laboratory parameters (haematology, biochemistry, bone turnover markers and urinalysis) will 
be summarised over the scheduled visits by treatment group. Absolute values and changes from 
baseline will be summarised for the haematology, biochemistry and bone turn-over parameters. In 
addition, for haematology and biochemistry parameters, shift tables will be presented for changes 
in category (below, within or above normal range) from baseline to the subjects’ worst post-
baseline value (‘worst’ separately identified as either lowest or highest value observed on a 
subject for specific parameter being presented). Laboratory values outside the reference range 
will be identified in the subject listings.  


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A summary of abnormal clinically significant laboratory values will also be produced. 
11.10.3 Vital Signs 
Vital sign parameters (heart rate, systolic and diastolic blood pressure, temperature, weight, BMI, 
waist circumference) will be summarised (absolute values and changes from baseline) by 
treatment group and scheduled protocol visit.  
11.10.4 ECG 
ECGs will be assessed by the Investigator for abnormal findings. These will be categorised and 
summarised as normal, abnormal-not clinically significant or abnormal-clinically significant. A 
summary of abnormal clinically significant ECG findings will be produced.  
ECG intervals will be recorded and summarised as absolute values and changes from baseline. 
Other ECG findings will be listed. 
11.10.5 C-SSRS 
Absolute values and changes from baseline will be summarised by treatment group and scheduled 
protocol visit. 
11.10.6 Concomitant Medications 
Concomitant therapies will be coded to their generic name and Drug Class using the current 
version of the WHO Drugs Dictionary. Medications will be assigned as being prior to study 
treatment or concomitant with study treatment, based on the start and stop dates of the medication 
and the study treatment. If the medication stop date is before the study treatment start date, the 
medication will be assigned as being prior to study treatment. In all other situations, the 
medication will be assigned as being concomitant with study treatment. Concomitant medications 
will be summarised by WHO Drug Class, generic name and treatment group.  
11.11 
Pharmacokinetics Analysis 
Blood samples for assay of NT-814 plasma concentrations are collected at each of Weeks 2, 4, 8, 
and 12. The plasma NT-814 concentrations will be listed by scheduled visit. Further details of the 
analysis of PK data will be described in an Exposure-Response Data Analysis Plan and exposure-
response data will be reported in a separate report.  
11.12 
Missing Data 
Summary statistics and statistical analysis will be based primarily on non-missing values. 
Sensitivity analyses may be conducted to check the robustness of the analysis results under 
alternative assumptions with regards to missing data. Further details on the handling of missing 
values, including rules applied to incomplete questionnaires and any planned sensitivity analyses 
will be defined in the SAP. 


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12. 
END OF THE STUDY 
The end of the study will be defined as the last subject’s last visit. 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT 
13.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and 
Relevant Authorities 
The final study protocol, the subject information and consent form and any other subject facing 
materials (e.g. questionnaires, advertisements) will be approved by an appropriately constituted 
IRB/IEC. Approval will be received in writing before initiation of the study. 
Clinical study authorisation will be obtained prior to initiation of the study from the relevant 
Regulatory Authority. 
13.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the local regulations, 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, informed consent will be obtained prior to any protocol-related activities 
being undertaken. As part of this procedure, the principal investigator or one of his/her 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 a 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 
treatment. They will receive all information that is required by local regulations and ICH 
guidelines.  
13.4 
Protocol Amendments 
Once approved by the applicable Regulatory Authorities and IRBs/IECs, the protocol must not be 
amended without approval by NeRRe. Unless an amendment is required to be implemented 
urgently in the interests of safety, or is deemed administrative by NeRRe, any amendments to the 
protocol must be authorised by the applicable Regulatory Authorities and IRB/IEC prior to 
implementation. 


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14. 
STUDY AND DATA MANAGEMENT 
14.1 
Monitoring 
In accordance with applicable regulations, including GCP, and NeRRe or delegated CRO’s 
Standard Operating Procedures (SOP), clinical research monitors will, prior to the start of the 
study, review with the site staff the protocol, study requirements, and the sites’s responsibilities 
to satisfy regulatory, ethical, and NeRRe requirements. This review will also include a review of 
source documentation. A list of what is to be classed as ‘source documentation’ will be 
documented in the Study Monitoring Manual. 
During the study the clinical monitor will periodically visit the site to verify: 
x Data are authentic, accurate and complete 
x Safety and right of the subjects are being protected 
x IMP accountability 
x AE and SAE reporting 
x Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP and all applicable regulatory requirements 
14.2 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the 
investigator[s]/institution[s] will permit study-related audits, IRB/IEC review, and regulatory 
inspection[s], providing direct access to source data/documents. 
14.3 
Data Recording 
An eCRF will be used to capture subject data into a secure, validated database. Access to enter 
data in the eCRF will be limited to delegated and trained investigator site staff only.  
Primary efficacy endpoint data and some secondary efficacy endpoint data will be recorded 
directly by subjects into the eDiary. In addition, eC-SSRS data will be recorded directly by 
subjects into an interactive voice response (IVR) system. Subject-entered diary and IVR data will 
not be subjected to source data verification. 
14.3.1 Data to be Considered as Source Data 
Source data may be defined as information from an original record or certified copy of the 
original record containing patient information for use in the trial.  The information may include, 
but is not limited, to clinical findings, observations, or other activities necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source documents 


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(original records or certified copies) (ICH E2A Guideline). Examples of source data include 
subject identification and randomisation identification.  
14.4 
Confidentiality 
The Investigator must assure that the subjects’ anonymity is maintained. On all study 
documentation, with the exception of the consent form and subject ID logs, subjects will only be 
identified by their unique identification code and will not be referred to by name. 
Study data will be handled with utmost discretion within the context of physician’s 
confidentiality. Names of participating subjects and data generated as a result of this study will 
not be passed on to unauthorized persons. If original documents are to be sent outside of the 
research site they must be redacted to remove information which might potentially identify the 
subject.  
NeRRe may transfer some data collected during the study to a different company or regulatory 
authority outside of the US or EU 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 analysed at a central laboratory. 
Samples will be identified by the subjects’ unique identification code only. All safety samples 
will be destroyed after the assays have been completed. 
Blood samples for analysis of NT-814 concentrations will be shipped to Aptuit Srl, Italy for 
analysis. Samples will be identified by the subjects’ unique identification code only. Following 
completion of the analysis, all samples will be destroyed. 
14.5 
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). The Investigator must, 
however, ensure that all reproductions are legible and are a true and accurate copy of the 
originals, and meet accessibility and retrieval 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 be either 15 years or, if 


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a longer period if required by local institutional requirements or local laws or regulations, then 
the minimum will become that longer period.  
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 must not dispose of any records without prior 
approval from NeRRe. 
14.6 
Communication and Publication of Results 
Where required by applicable regulatory requirements, an Investigator signatory will be identified 
for the approval of the 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 each 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 writing the 
proposed publication; this must happen with due diligence and with minimal delay.  
Any proposed publication or presentation (including a manuscript, abstract or poster) originated 
by an Investigator for submission to a journal or scientific meeting should be sent to the Sponsor 
for review at least sixty days 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 six months 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. 
14.7 
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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15. 
REFERENCES 
 
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4. Pachman DR, Jones JM, Loprinzi CL. Management of menopause-associated vasomotor symptoms: 
Current treatment options, challenges and future directions. Int J Womens Health. 2010;2:123-35. 
5. Whiteley J, Wagner JS, Bushmakin A, et al. Impact of the severity of vasomotor symptoms on health 
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7. Reed SD, Ludman EJ, Newton KM, et al. Depressive symptoms and menopausal burden in the 
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8. Woods NF, Hohensee C, Carpenter JS, et al. Symptom clusters among MsFLASH clinical trial 
participants. Menopause. 2016; 23(2): 158-65 
9. Stahl SM. Vasomotor symptoms and depression in women, part I. Role of vasomotor symptoms in 
signaling the onset or relapse of a major depressive episode. J Clin Psychiatry. 2009;70(1):11-2. 
10. Worsley R, Bell RJ, Gartoulla P, et al. Moderate-severe vasomotor symptoms are associated with 
moderate-severe depressive symptoms. J of Womeens health 2017. DOI:1089/jwh.2016.6142 
11. Ratner S, Ofri D. Menopause and hormone replacement. Part 1. Evaluation and treatment. West J 
Med. 2001; 174(6): 400–404. 
12. Thurston RC, and Joffe H. Vasomotor Symptoms and Menopause: Findings from the Study of 
Women’s Health Across the Nation. Obstet Gynecol Clin North Am. 2011 Sep; 38(3): 489–501. 
13. Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: 
evidence from the Penn Ovarian Aging Study cohort. Menopause. 2014;21(9):924-32. 
14. Avis NE, Crawford SL, Greendale G, et al. Study of Women’s Health Across the Nation. Duration of 
menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175(4):531-
9. 
15. MHRA/CHM (Drug Safety Update 2007; 1 (2): 2–6) available at www.gov.uk/drug-safety-update 
16. Pinkerton JV, Pan K, Abraham L, et al. Sleep parameters and health-related quality of life with 
bazedoxifene/conjugated estrogens: a randomized trial. Menopause 2014 Mar;21(3):252-9 
17. Santoro N, Allshouse A, Neal-Perry G, et al. Longitudinal changes in menopausal symptoms 
comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus 
micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 
2017 Mar;24(3):238-246. 
18. Rance NE, Dacks PA, Mittelman-Smith MA, et al.  Modulation of body temperature and LH secretion 
by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the 
mechanism of hot flushes. Front Neuroendocrinol. 2013;34(3):211-27. 
19. Casper RF, Yen SSC & Wilkes MM. Menopausal flushes. A neuroendocrine link with pulsatile 
luteinising hormone secretion. Science 1979; 205: 823-825. 
20. Casper RF, Yen SS. Menopausal flushes: effect of pituitary gonadotropin desensitization by a potent 
luteinizing hormone-releasing factor agonist. J Clin Endocrinol Metab. 1981;53(5):1056-8 
21. Casper RF, Yen SS.  Neuroendocrinology of menopausal flushes: an hypothesis of flush mechanism. 
Clin Endocrinol (Oxf). 1985; 22: 293-312. 
22. DeFazio J, Meldrum DR, Laufer L, et al. Induction of hot flashes in premenopausal women treated 
with a long-acting GnRH agonist. J Clin Endocrinol Metab. 1983;56:445-8 
23. Gambone J, Meldrum DR, Laufer L, et al. Further delineation of hypothalamic dysfunction 
responsible for menopausal hot flashes. J Clin Endocrinol Metab. 1984;59(6):1097-102. 


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24. Lehman MN, Coolen LM, Goodman RL. Minireview: Kisspeptin/Neurokinin B/Dynorphin (KNDy) 
Cells of the Arcuate Nucleus: A Central Node in the Control of Gonadotropin-Releasing Hormone 
Secretion. Endocrinology. 2010;151(8):3479–3489. 
25. Rance NE, McMullen NT, Smialek JE, et al. Postmenopausal hypertrophy of neurons expressing the 
estrogen receptor gene in the human hypothalamus. J Clin Endocrinol Metab. 1990;71:79-85 
26. Rance NE, Young WS., III Hypertrophy and increased gene expression of neurons containing 
neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal 
women. Endocrinology. 1991;128(5):2239–2247 
27. Rometo AM, Rance NE. Changes in prodynorphin gene expression and neuronal morphology in the 
hypothalamus of postmenopausal women. J Neuroendocrinol. 2008;20(12):1376-81 
28. Abel TW, Voytko ML, Rance NE. The effects of hormone replacement therapy on hypothalamic 
neuropeptide gene expression in a primate model of menopause. J Clin Endocrinol Metab. 
1999;84(6):2111-8 
29. Sandoval-Guzmán T, Stalcup ST, Krajewski SJ, et al. Effects of ovariectomy on the neuroendocrine 
axes regulating reproduction and energy balance in young cynomolgus macaques. J Neuroendocrinol. 
2004;16(2):146-53 
30. Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene 
expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized 
monkeys. J Clin Endocrinol Metab. 2007;92(7):2744-50.Boulant 2000 
31. Rance NE, Dacks PA, Mittelman-Smith MA, et al.  Modulation of body temperature and LH secretion 
by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the 
mechanism of hot flushes. Front Neuroendocrinol. 2013;34(3):211-27 
32. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, et al. Role for kisspeptin/neurokinin 
B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body 
temperature. Proc Natl Acad Sci U S A. 2012;109(48):19846-51. 
33. Jayasena CN, Comninos AN, Stefanopoulou E, et al. Neurokinin B administration induces hot flashes 
in women. Sci Rep. 2015;5:8466 
34. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment 
for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 
2017;389:1809-1820. 
35. Fraser GL, Depypere H, Timmerman D, et al.  Clinical Evaluation of the NK3 Receptor Antagonist 
Fezolinetant (a.k.a. ESN364) for the Treatment of Menopausal Hot Flashes. Abstract OR16-5, 
Presented at ENDO 2017 
36. Navarro VM, Bosch MA, León S, et al. The Integrated Hypothalamic Tachykinin-Kisspeptin System 
as a Central Coordinator for Reproduction. Endocrinology. 2015;156::627-637. doi:10.1210/en.2014-
1651. 
37. Arisawa M, De Palatis L, Ho R, et al. Stimulatory role of substance P on gonadotropin release in 
ovariectomized rats. Neuroendocrinology. 1990;51(5):523–529. 
38. Yamamura T, Wakabayashi Y, Ohkura S, et al. Effects of intravenous administration of neurokinin 
receptor subtype-selective agonists on gonadotropin-releasing hormone pulse generator activity and 
luteinizing hormone secretion in goats. The Journal of Reproduction and Development. 
2015;61(1):20-29. doi:10.1262/jrd.2014-109. 
39. Kalil B, Ramaswamy S, Plant TM. The distribution of substance P and kisspeptin in the mediobasal 
hypothalamus of the male rhesus monkey and a comparison of intravenous administration of these 
peptides to release GnRH as reflected by LH secretion. Neuroendocrinology. 2016;103(6):711-723. 
doi:10.1159/000442420. 
40. Hrabovszky E, Borsay BÁ, Rácz K, et al. Substance P Immunoreactivity Exhibits Frequent 
Colocalization with Kisspeptin and Neurokinin B in the Human Infundibular Region. Wolfe A, ed. 
PLoS ONE. 2013;8(8):e72369.  
41. Borsay B, Skrapits K, Herczeg L, et al. Hypophysiotropic gonadotropin-releasing hormone projections 
are exposed to dense plexuses of kisspeptin, neurokinin B and substance p immunoreactive fibers in 
the human: a study on tissues from postmenopausal women. Neuroendocrinology 2014;100(2-3):141-
52 


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42. Wong BJ, Minson CT. Neurokinin-1 receptor desensitization attenuates cutaneous active 
vasodilatation in humans. J Physiol 2006; 577:1043-51 
43. Schaffalitzky De Muckadell OB, Aggestrup S, Stentoft P. Flushing and plasma substance P 
concentration during infusion of synthetic substance P in normal man. Scand J Gastroenterol. 1986 
May;21(4):498-502. 
44. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of 
central substance P receptors. Science. 1998;281(5383):1640-1645.  
45. Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance 
P (NK1) receptor antagonist in major depression. Neuropsychopharmacology. 2004;29(2):385-392.  
46. Ratti E, Bellew K, Bettica P, et al. Results from 2 randomized, double-blind, placebo-controlled 
studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder. J 
Clin Psychopharmacol. 2011;31(6):727-733  
47. Ratti E, Bettica P, Alexander R, et al. Full central neurokinin-1 receptor blockade is required for 
efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013;27(5):424-
434. 
48. Newton KM, Carpenter JS, Guthrie KA, et al. Methods for he design of vasomotor symptoms trials; 
the MsFLASH Network. Menopause 2014 21(1) doi:10.1097/GME.0b013e31829337a4.  
49. FDA guidance for industry: oestrogen and oestrogen/progestin drug products to treat vasomotor 
symptoms and vulvar and vaginal atrophy symptoms – recommendations for clinical evaluation. 
January 2003. 
50. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: 
a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. 
51. Hilditch JR, Lewis J, Peter A, et al. A menopause-specific quality of life questionnaire: development 
and psychometric properties. Maturitas. 1996; 24:161–175. 
52. Carpenter JS. The Hot Flash Related Daily Interference Scale: a tool for assessing the impact of hot 
flashes on quality of life following breast cancer. J Pain Symptom Manage. 2001; 22:979–989. 
53. Carpenter JS, Storniolo AM, Johns S, et al. Randomized, double-blind, placebo-controlled crossover 
trials of venlafaxine for hot flashes after breast cancer. Oncologist. 2007; 12:124–135. 
54. Beck AT, Steer RA and Brown GK (1996) "Manual for the Beck Depression Inventory-II". San 
Antonio, TX: Psychological Corporation 
55. CHMP Guideline on clinical investigation of medicinal products for hormone replacement therapy of 
oestrogen deficiency symptoms in postmenopausal women. May 2006. 
56. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor 
symptoms: two randomized controlled trials. Menopause 2013;20:1027-1035. 
57. COMPASS 1.1 (E) User Manual (2012), Cytel Inc., Cambridge, MA, USA. 
58. Ivanova, A., Bolognese, J. A., Perevozskaya I. Adaptive dose finding based on t-statistic for dose-
response trial. Statistics in Medicine 2008, 27:1581-1592. 
59. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th edition. 
Arlington: American Psychiatric Association; 2013. 
 
 


PPD
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17. 
APPENDICES 
 
APPENDIX A: 
 
LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
 
 
 
The following is a comprehensive (but not exhaustive list*) of prohibited concomitant 
medications.  
* Recently approved drugs may not be included in the list and should be checked on a case-by-case basis. 
 
Prohibited from the time shown until 1 week after the last dose of study medication 
Medications potentially 
confounding efficacy  
Hormonal therapies 
x 
Vaginal hormonal products (rings, creams, gels and including 
DHEA or analogues thereof) – from 1 week prior to Screening 
Visit 2 
x 
Transdermal oestrogen alone or or oestrogen/progestin products - 
from 4 weeks prior to Screening Visit 2 
x 
Oral 
oestrogen 
(including 
selective 
oestrogen 
receptor 
modulators) and/or progestin therapy - – from 8 weeks prior to 
Screening Visit 2 
x 
Intrauterine progestin therapy – from 8 weeks prior to Screening 
Visit 2 
x 
Progestin implants and oestrogen alone injectable drug therapy – 
from 3 months prior to Screening Visit 2 
x 
Oestrogen pellet therapy or progestin injectable drug therapy - – 
from 6 months prior to Screening Visit 2 
 
Non-hormonal therapies 
Non-hormonal prescription (eg paroxetine, other anti-depressants 
including 
selective 
serotonin 
reuptake 
inhibitors, 
serotonin 
norepinephrine reuptake inhibitors and tri-cyclic antidepressants, alpha 
agonists [clonidine], methyldopa, gabapentin, pregabalin, medicinal 
cannabis or derivatives) or over the counter/herbal treatments for 
treatment of menopausal symptoms is not allowed throughout the 
study. Subjects must have discontinued these drugs at least 28 days 
prior to Screening Visit 2. Subjects may, however, be permitted to 
continue to use these drugs if the dose has been stable for at least 4 
weeks and they have been prescribed solely for the management of 
another disorder (e.g. neuropathic pain, depression). 
Prohibited from Screening Visit 2 until 1 week after the last dose of study medication 
CYP3A4 substrates 
with a narrow 
therapeutic range 
alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, 
terfenadine 
Strong or moderate 
clarithromycin, 
atazanavir, 
idelalisib, 
nefazodone, 
nelfinavir, 


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inhibitors of CYP3A4 
boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir and 
ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and 
ritonavir, 
telaprevir, 
tipranavir 
and 
ritonavir, 
troleandomycin, 
voriconazole 
aprepitant, 
cimetidine, 
ciprofloxacin, 
clotrimazole, 
crizotinib, 
cyclosporine, 
dronedarone, 
fluconazole, 
fluvoxamine, 
imatinib, 
tofisopam, verapamil, troleandomycin, ciprofloxacin 
P-glycoprotein 
inhibitors 
azithromycin, conivaptan, cyclosporine, diltiazem, erythromycin, 
felodipine, ketoconazole, quinidine, ranolazine,  
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, propafenone, quinidine,   
P-glycoprotein 
substrates with a 
narrow therapeutic 
range 
Digoxin 
Prohibited from Screening Visit 2 until Week 12 
Strong or moderate 
inducers of CYP3A4 
rifampicin, carbamazepine, efavirenz, bosentan, modafinil, St. John's 
Wort, enzalutamide, mitotane, phenytoin, etravirine 
 


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APPENDIX B: 
PHASE 2B ADAPTIVE DOSE-FINDING DESIGN FOR NT-814 
EFFECT ON REDUCTION OF HOT FLUSHES 
 
 
J.Bolognese 
18 July 2018 
 
INTRODUCTION AND PURPOSE 
 
A Phase 2b dose-finding placebo-controlled trial of NT-814 treatment with four different doses 
for 12 weeks aimed at reduction of hot flushes is being planned.  Adaptive design options are 
being considered to modify randomization ratios to the NT-814 doses based on accumulating 
data.  This report summarizes several example adaptive design options along with their 
performance characteristics for an initial assumed example set of potential TRUE underlying 
dose-response curves.  The primary endpoints for the trial are hot flush frequency and severity; 
however, the adaptive design simulation software cannot handle multiple endpoints.  Hence, the 
scenarios evaluated focus on reduction of hot flush frequency. 
 
METHODS 
 
First, in order to arrive at some example TRUE underlying dose-response scenarios, prior data on 
hot flush reduction was examined.  NT-814 has shown efficacy in reduction of hot flushes over a 
2-week period in a Phase 1/2a trial.  Mean reductions in hot flush frequency of up to 9 per day 
from a baseline frequency ~10-12 were observed (with an observed SD of change from baseline 
ranged between ~3.4 to ~4.9; SD back-calculated from SE's from the analysis model yielded SD's 
of change ~3.7).  In order to obtain longer term prior data to inform on expected variability, the 
Duavee label was also examined.  It yielded SD's of change ~4.4 after 4 weeks' treatment and 
~3.6 after 12 weeks' treatment.  Based on these prior data, an SD=4.4 and somewhat conservative 
magnitudes of treatment effect were used to simulate adaptive design outcomes and performance 
characteristics.  The following TRUE underlying dose-response curves were examined: 
 
label 
Assumed TRUE underlying mean hot flush 
frequency reduction from baseline (SD=4)  
placebo 
(dose0) 
dose1 
dose2 
dose3 
dose4 
DRCID_1 
4 
4 
5 
6 
7 
DRCID_2 
4 
5 
6 
7 
8 
DRCID_3 
4 
5 
6 
8 
8 
DRCID_4 
4 
6 
8 
8 
8 
 


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The total sample size for the trial yields high power for the expected large difference from 
placebo in hot flush reduction from baseline and adequate power for moderate difference.   
 
Assuming a common standard deviation (SD) of 4.4, N=27 per treatment group has ~95% power 
(alpha=0.05 2-sided) via trend test across all doses including placebo if the true underlying dose 
response is non-decreasing from a reduction of 4 hot flushes on placebo up to 8 on the highest 
dose of NT-814.   N=33 per treatment group is required for 95% power for pairwise comparison 
of the highest dose to placebo under these same assumptions. Hence, a total of 150 completed 
subjects (30 x 5) was used for the simulations of adaptive design.  [Note, the actual performance / 
power for the adaptive designs may be higher than the values cited in this report since additional 
subjects will be added to selected dose groups to better inform on safety.]  The actual sample size 
will be determined by the adaptive dose-finding design algorithm. 
 
The sample size allows for 95% power since each of the four co-primary endpoints are required 
to demonstrate statistical significance in order to yield a firm conclusion of beneficial treatment 
effect on hot flushes.  Conservatively, assuming independence among the four endpoints, this 
would yield approximately 81% power overall for achieving statistical significance for each of 
the four endpoints.  Thus, overall power for the trial is estimated to be at least 81%; the actual 
power depends on the unknown magnitudes of correlations among the co-primary endpoints. 
 
Adaptive dose-finding design algorithms use results from interim analysis (IA) of accumulating 
data from the trial to modify dose-choices and / or randomization ratios for subsequent subjects 
entering the trial.  Three numbers of IA and two adaptive dose-finding algorithms were evaluated 
for each of the four potential TRUE underlying dose-response curves (total 24 scenarios = 4 DR 
curves X 3 cohort sizes X 2 design algorithms).  The three IA sizes evaluated are (i) no IA's (i.e., 
N=15 per dose group to compare to a non-adaptive design), (ii) two IAs, and (iii) five IAs.  Both 
the 2-IA and 5-IA designs randomize the initial 25 patients 1:1:1:1:1 to the 5 dose groups (note, 
placebo is the zero dose group) to obtain a reasonable amount of seeding data upon which to 
begin the adaptation.  Note, the actual planned size of the first cohort is N=30, which would yield 
results between those of the two sample size scenarios simulated for the adaptive designs.  Hence, 
the actual performance characteristics of the trial fall between the those two sample size 
scenarios.   Since the timing of the actual IA's may vary due to logistical / enrolment constraints, 
these two scenarios are representative of the those expected during the trial. Then the 2-IA design 
carries out a second IA after N=50 total patients are observed, and then the final analysis is 


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carried out after the 75 patients are completed.  After the initial IA at N=25, the 5-IA design 
carries out an IA after results of each 10 patients are added to the accumulating data. 
 
The two adaptive algorithms are (i) a Bayesian adaptive Emax (S-shaped) dose-response model 
fit at each IA (COMPASS User Manual), and (ii) a model based on classical T-statistics at each 
IA (Ivanova, 2008).  The Emax design uses a "vague" Bayesian prior distribution on each of the 
four parameters of the S-shaped Emax model in combination with the observed data to estimate 
the posterior distribution of the Emax model parameters from which estimates of mean response 
at each dose are obtained, along with their SE's.  Then randomization ratios are chosen for the 
next cohort to minimize the variances of the resulting Emax model estimates at two target levels 
of response, namely hot flush reductions of 6 per day and of 8 per day.  The Emax algorithm was 
set up to recommend stopping randomization to a given dose if (a) the probability is > 90% that 
the mean hot flush reduction at least 8 at that dose, or (b) the probability is <20% that the mean 
hot flush reduction is at least 5 (i.e., >80% probability that the mean hot flush reduction is <5). 
 
The T-statistic design relies on isotonic regression (i.e., best-fit non-decreasing dose-response 
curve) derived estimated means for each dose and then computes the resultant T-statistic for 
estimated mean difference from each target level of response (hot flush reduction of 6 and of 8) 
for each dose.  Then the subjects in the next cohort are split among the two doses with T-statistics 
pointing closest to each target level of response and placebo.  The sample sizes of each cohort are 
always 10 on placebo for the 2 IA design, and always 5 on placebo for the 5 IA design, to yield 
N=30 on placebo for the final analysis.  For the simulations, the subjects assigned to the active 
doses are randomized according to the randomization ratio indicated by the adaptive design 
algorithm for each cohort after the first.  The only stopping criteria recommendation available for 
the T-statistic in the simulation software (Cytel's COMPASS V1.1) is futility stopping; hence, if 
probability of a significant difference from placebo is <5% for a given dose based on the IA 
results, then the algorithm recommends that dose is dropped from any further randomization to it. 
 
The 24 scenarios (4 DR curves X 3 cohort sizes X 2 design algorithms) were each simulated 500 
times, and the following performance characteristics, averaged across the 500 simulations, were 
summarized in Tables 1a and 1b 
x Average total sample size 
x Power to reject a flat dose-response curve (alpha=0.05 2-sided), and conclude statistically 
significant NT-814 effect 
x Average sample size assigned to each dose 
x Average estimated dose level (among doses 1,2,3,4) closest to the target hot flush reduction 
from baseline of 6 
x Percent of simulations choosing the correct dose with TRUE underlying hot flush reduction 
from baseline of 6 
x Percent of simulations choosing the correct dose or adjacent to the correct dose with TRUE 
underlying hot flush reduction from baseline of 6 
x Average estimated dose level (among doses 1,2,3,4) closest to the target hot flush reduction 
from baseline of 8 
x Percent of simulations choosing the correct dose with TRUE underlying hot flush reduction 
from baseline of 8 
x Percent of simulations choosing the correct dose or adjacent to the correct dose with TRUE 
underlying hot flush reduction from baseline of 8 
 


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In order to account for recruitment rate and lag of data collection and analysis as patients 
continually enter the trial, the simulations were run assuming a 6-week lag for each patient 
entering and their 4 week hot flash frequency data entering the interim analysis.  An average 
recruitment rate of 5 patients per week was assumed, since the software cannot accommodate 
varying recruitment. 
 
It should be noted that the analysis models for the actual trial data will be longitudinal mixed 
effects models to model the correlation structure of all hot flash frequency data at each week from 
baseline to week 12.  Due to software limitations, the simulations only assume available data of 
Week 4, so the performance characteristics in this report are likely conservative. 
 
SIMULATION RESULTS 
 
For dose-response curve 1 (DRCID_1), power is approximately 90% for both the adaptive and 
the non-adaptive designs - highest for the (Emax 90 & 93%; Tstat 85 & 89%; non-adaptive 
design (88 & 89%).  The adaptive designs achieve this power with slightly smaller overall sample 
sizes (~148 for Emax, ~145 for Tstat), since they have potential for early stopping for futility.  
Note that all of the adaptive designs, except the Emax 3-cohort design, assign fewer subjects to 
the lower 2 doses that have TRUE underlying mean hot flash values less than the lower target 
value 6, and assign the majority of subjects to doses 3 and 4, the former having TRUE response 
equal to the lower target value 6.  The Emax 3-cohort design assigns more subjects to Dose1 
(which has TRUE underlying response 4) than to doses 2 and 3 in order to best fit the lower 
portion of the Emax model.  All of the adaptive designs assign most subjects to Dose 4.  The 
subtle distinction between the Emax and Tstat adaptive designs (more spread of subjects across 
the dose range via Emax design than via Tstat design) arises since the Emax design estimates 
target doses via optimally fitting the Emax model, whereas the Tstat design seeks to assign most 
subjects to the two doses closest to the target levels of response.  The average estimated target 
doses for both designs are very close to the TRUE target values (>4 for the upper target and 
approximately dos e3 for the lower target.  However, only approximately 2/3 of the simulations 
actually estimate the target dose exactly at Dose3 for the lower target, but nearly all simulations 
estimate the lower target dose at Dose3, or Dose4 (i.e., at or adjacent to the correct / TRUE target 
dose). 
 
For dose response curves 2,3 and 4 (DRCID_2, DRCID_3, DRCID_4) power is at least 94% for 
the adaptive designs, and generally similar to  that for the non-adaptive 1-cohort designs.  The 
Emax design achieves this power with somewhat smaller average sample sizes (N=133-146) than 
the Tstat and non-adaptive designs. The Tstat design sample sizes are N=146-149 because in a 
small portion of trials the design incorrectly stops early for futility - note the software does not 
permit inclusion of early stopping for an efficacy conclusion [NOTE: in the actual trial, the same 
early stopping criteria can be employed with the Tstat design as with the Emax design; it is just 
that the simulation software does not have that feature for the Tstat design].  Note also that the 
Emax design assigns more subjects to dose 4 (the highest dose) in order to fit the plateau 
response level, whereas the Tstat design focuses the dose assignments more at the doses with 
TRUE target levels of response 6 and 8.  The Tstat design seems slightly better than the Emax 
model in estimating the target doses on average; Tstat design average estimated target doses are 
generally closer to TRUE target doses or mid-point of TRUE target doses when multiple doses 
have same TRUE target level of response.  The percentage of correct target dose estimates are 
generally higher for the Tstat design than for the Emax design, except for the DRCID_2 lower 
target dose, for which they are generally similar, but the percentages are generally similar for the 
Emax adaptive designs compared to the non-adaptive designs, but higher for the Tstat design than 


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for the Emax and non-adaptive designs.  For the Emax design, this is could be at least partially 
due to the early stoppages of the Emax design indicated by lower average sample sizes. 
 
Type 1 error (false positive, i.e., rejecting the null hypothesis of flat dose-response curve when 
the TRUE underlying dose-response curve is flat) was estimated via simulation in the same 
manner as performance characteristics were simulated and summarized for the above four non-
flat dose-response curves (performance characteristics are summarized in Table 2). Type 1 error 
is estimated to be approximately 5% for both adaptive designs and the non-adaptive designs 
analyzed by the same methods as the adaptive designs.  Hence, the adaptive designs adequately 
preserve type 1 error.  Note the much lower average sample sizes associated with the adaptive 
designs; they result from the high proportion of adaptive designs that stop early for a futility 
conclusion (66-78%).  Finally, note the adaptive designs assign the largest number of subjects to 
dose 4, and minimize assignment to the lower doses. 
 
 
RECOMMENDATIONS for consideration 
 
Simulation software limitations to a single endpoint at a single time point make the performance 
characteristics summarized conservative.  The actual analysis model can incorporate all time 
points of observation and multiple endpoints (frequency and severity); hence, actual statistical 
precision and performance characteristics will likely improve during the actual study beyond 
those levels reported in this simulation report.  An adaptive dose-finding design is preferable to 
the fixed randomization design since it will allocate more subjects to doses with target levels of 
response and/or minimize randomization to doses below or above those with target levels of 
response.  In addition, both the Emax and Tstat algorithms can be run at each IA and the 
suggested dose-assignments can be compared by the Data Review Committee (DRC), which can 
recommend the best dose ratio assignments in the context of the overall accumulated data 
available at the IA.  Alternatively, depending on the performance characteristic(s) of most 
interest, the better performing adaptive design on that(those) performance characteristic(s) can be 
chosen. 
 
 
REFERENCES 
 
COMPASS 1.1 (E) User Manual (2012), Cytel Inc., Cambridge, MA, USA. 
 
Ivanova, A., Bolognese, J. A., Perevozskaya I (2008) Adaptive dose finding based on t-statistic 
for dose-response trial. Statistics in Medicine, 27:1581-1592.


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TABLE 1a - Performance Characteristics (sample sizes, power, early stopping probability) 
TRUE 
underlying 
Dose-
Response 
Curve 
Design Number 
of 
Cohorts 
Average 
Total 
Sample 
Size 
Power 
(%)* 
Average Sample Size Assigned 
Per Dose 
Proportion 
stopped 
early 
D0 
(pbo) 
D1 
D2 
D3 
D4 
D0=4, 
D1=4, 
D2=5, 
D3=6, 
D4=7 
Emax 
1 
150 
88 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
147 
90 
29.5 
25.1 18.4 20.5 53.9 
0.028 
6 
148 
93 
29.6 
21.6 19.1 22.2 55.3 
0.026 
Tstat 
1 
150 
89 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
144 
85 
28.8 
13.9 23.2 33.3 44.8 
0.074 
6 
145 
89 
29.0 
15.2 24.4 32.4 44.2 
0.066 
D0=4, 
D1=5, 
D2=6, 
D3=7, 
D4=8 
Emax 
1 
150 
98 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
146 
99 
29.1 
30.2 22.3 20.8 43.1 
0.056 
6 
145 
99 
29.0 
28.1 23.7 21.9 42.4 
0.078 
Tstat 
1 
150 
97 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
146 
94 
29.3 
21.1 30.8 34.0 31.2 
0.038 
6 
148 
96 
29.6 
24.3 31.7 32.3 30.1 
0.026 
D0=4, 
D1=5, 
D2=6, 
D3=8, 
D4=8 
Emax 
1 
150 
99 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
142 
98 
28.4 
31.5 22.9 20.6 38.6 
0.112 
6 
141 
100 
28.2 
29.7 24.2 21.5 37.2 
0.150 
Tstat 
1 
150 
99 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
148 
97 
29.6 
23.0 35.1 33.4 26.9 
0.020 
6 
149 
98 
29.7 
25.8 36.4 30.8 25.9 
0.016 
D0=4, 
D1=6, 
D2=8, 
D3=8, 
D4=8 
Emax 
1 
150 
96 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
136 
95 
27.1 
39.2 20.1 16.6 32.5 
0.186 
6 
133 
96 
26.7 
38.1 20.3 17.6 30.6 
0.242 
Tstat 
1 
150 
97 
30.0 
30.0 30.0 30.0 30.0 
0.000 
3 
146 
94 
29.2 
38.7 34.4 23.6 20.1 
0.044 
6 
149 
97 
29.8 
42.7 34.4 23.4 18.7 
0.010 
*Power to yield statistically significantly increasing trend across doses (i.e., not flat) at alpha=0.025 
1-sided 


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Table 1b - Performance Characteristics (accuracy of target dose estimation) 
TRUE 
underlying 
Dose-
Response 
Curve 
Design 
# of 
Cohorts 
Dose with Target Response 8 
Dose with Target Response 6 
TRUE 
Target 
Dose 
Average 
Estima-
ted 
Target 
Dose 
% correct 
Target 
Dose 
Estimates 
% correct 
or nearly 
correct 
Target 
Dose 
Estimates 
TRUE 
Target 
Dose 
Average 
Estim-ated 
Target 
Dose 
% correct 
Target 
Dose 
Estimates 
% correct or 
nearly correct 
Target Dose 
Estimates 
D0=4, D1=4, 
D2=5, D3=6, 
D4=7 
Emax 
1 
>4 
4.7 
86 
100 
3 
3.2 
58 
97 
3 
>4 
4.7 
89 
99 
3 
3.1 
59 
97 
6 
>4 
4.6 
89 
99 
3 
3.0 
62 
96 
Tstat 
1 
>4 
4.5 
73 
100 
3 
3.0 
71 
99 
3 
>4 
4.5 
74 
98 
3 
3.0 
66 
97 
6 
>4 
4.6 
76 
99 
3 
3.0 
68 
98 
D0=4, D1=5, 
D2=6, D3=7, 
D4=8 
Emax 
1 
4 
4.2 
54 
100 
2 
1.9 
66 
99 
3 
4 
4.1 
55 
96 
2 
1.9 
67 
99 
6 
4 
4.0 
55 
98 
2 
1.9 
71 
99 
Tstat 
1 
4 
4.0 
57 
100 
2 
2.0 
68 
100 
3 
4 
3.9 
54 
100 
2 
2.0 
65 
99 
6 
4 
3.9 
57 
100 
2 
2.0 
64 
99 
D0=4, D1=5, 
D2=6, D3=8, 
D4=8 
Emax 
1 
3(,4) 
3.8 
33 
81 
2 
1.7 
66 
100 
3 
3(,4) 
3.8 
26 
78 
2 
1.7 
65 
98 
6 
3(,4) 
3.8 
26 
81 
2 
1.7 
67 
98 
Tstat 
1 
3(,4) 
3.6 
47 
86 
2 
1.8 
76 
100 
3 
3(,4) 
3.5 
54 
88 
2 
1.9 
76 
99 
6 
3(,4) 
3.5 
50 
88 
2 
1.9 
78 
99 


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D0=4, D1=6, 
D2=8, D3=8, 
D4=8 
Emax 
1 
2(,3,4) 
3.4 
22 
51 
1 
0.8 
93 
100 
3 
2(,3,4) 
3.3 
18 
52 
1 
0.9 
85 
100 
6 
2(,3,4) 
3.2 
21 
54 
1 
0.9 
88 
100 
Tstat 
1 
2(,3,4) 
3.0 
39 
63 
1 
1.0 
91 
100 
3 
2(,3,4) 
2.9 
42 
66 
1 
1.0 
88 
100 
6 
2(,3,4) 
2.9 
43 
68 
1 
1.0 
93 
100 


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TABLE 2 - Performance Characteristics for TRUE underlying FLAT dose-response curve 
(sample sizes, power, early stopping probability); i.e., Hot Flash reduction 4 for all doses 
and placebo. 
TRUE 
underlying 
Dose-
Response 
Curve 
Design Number 
of 
Cohorts 
Average 
Total 
Sample 
Size 
Power 
(%)* 
Average Sample Size Assigned Per 
Dose 
Proportion 
stopped 
early 
D0 (pbo) 
D1 
D2 
D3 
D4 
D0=4, 
D1=4, 
D2=4, 
D3=4, 
D4=4 
Emax 
1 
150 
5.00 
30.0 
30.0 
30.0 
30.0 
30.0 
0.000 
3 
101 
4.60 
20.2 
22.8 
11.1 
11.5 
35.6 
0.674 
6 
97 
5.40 
19.3 
20.3 
12.3 
12.7 
32.1 
0.784 
Tstat 
1 
150 
4.20 
30.0 
30.0 
30.0 
30.0 
30.0 
0.000 
3 
103 
4.60 
20.6 
10.3 
13.2 
18.8 
40.0 
0.664 
6 
107 
5.00 
21.5 
12.3 
16.7 
18.9 
38.0 
0.682 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: 
 
ASSESSMENT PROFORMAS 
 
Note: The versions of the assessments provided in this Appendix are for reference only and may 
differ slightly from the actual versions used on the study. Where appropriate, permission and 
licenses to use the assessments will be obtained.  
 
 
Hot Flush Screening Diary (Paper Diary) 
 
 


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Hot Flush Electronic Diary 
 
The design of the electronic diary will be based around the following instructions and questions: 
 
 
 


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Menopause-specific Quality-of-Life Questionnaire Intervention Version 
 
 
 
 
 
 


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Hot Flash Related Daily Interference Scale (HFRDIS) 
 
Author: Janet S. Carpenter, PhD, RN, Indiana University School of Nursing, Indiana, USA 
 
 
 
 


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Pittsburgh Sleep Quality Index (PSQI)  
Authors: Buysse DJ; Berman SR; Kupfer DJ; Monk TH; Reynolds CF  
University of Pittsburgh School of Medicine, USA. 
 
 
 


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Insomnia Severity Index (ISI) 
 
Author: Charles M. Morin, Ph.D., Professor of Psychology, Université Laval, Quebec, Canada 
 
 
 


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Beck Depression Inventory II 
 
Authors: Aaron T. Beck, Robert A. Steer, Gregory K. Brown 
 
 
 
 


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Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) 
 
Below is an example of the C-SSRS. In this study, an electronic version of the C-SSRS will be 
used in which subjects self-report using an IVR system. 
 
 


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SAP_001.pdf: 
 
 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
A Double-Blind, Randomised, Placebo Controlled, Adaptive 
Design Study of the Efficacy, Safety and Pharmacokinetics of NT-
814 in Female Subjects With Moderate to Severe Vasomotor 
Symptoms Associated With the Menopause 
NCT Number: 
NCT03596762 
Document Date: 
11 DEC 2019 
 


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STATISTICAL ANALYSIS PLAN 
Protocol 814-PM-02
A double-blind, randomized, placebo controlled, adaptive design study of the 
efficacy, safety and pharmacokinetics of NT-814 in female subjects with 
moderate to severe vasomotor symptoms associated with the menopause 
Protocol Number:
(Version Date)
30
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Name of Test Drug:
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Phase:
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Methodology:
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Sponsor:
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Document Date:
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Document Version:
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SIGNATURE PAGE 
Protocol Title:
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Sponsor:
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Protocol Number:
30
Document Date/Version:
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Cytel, Inc. Author:
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Sponsor Approval
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Electronically signed by
Reason: Approve
Date: 2019-12-11 09:07:55-05:00
11-Dec-2019
Electronically signed by
Reason: Approve
Date: 2019-12-11 16:29:09Z
11-Dec-2019
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
3
TABLE OF CONTENTS 
Section
Page
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS......................8 
1.1. 
Introduction....................................................................................8 
1.2. 
Objectives of Statistical Analysis..................................................8 
1.3. 
Team involved in the study ...........................................................8 
2. 
STUDY DESIGN........................................................................................9 
2.1. 
Synopsis of Study Design...............................................................9 
2.2. 
Randomization Methodology........................................................9 
2.3. 
Stopping Rules and Unblinding....................................................9 
2.4. 
Study Procedures .........................................................................10 
2.5. 
Efficacy, Pharmacokinetic, and Safety Variables.....................13 
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3. 
SUBJECT POPULATIONS....................................................................15 
3.1. 
Population Definitions .................................................................15 
3.2. 
Protocol Deviations ......................................................................16 
4. 
STATISTICAL METHODS ...................................................................18 
4.1. 
Sample Size Justification.............................................................18 
4.2. 
General Statistical Methods and Data Handling ......................18 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
4
Section
Page
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Interim Analyses ..........................................................................21 
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4.4. 
Subject Disposition.......................................................................24 
4.5. 
Demographic and Baseline Characteristics...............................25 
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4.6. 
Efficacy Evaluation......................................................................26 
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4.7. 
Pharmacokinetic Evaluations .....................................................35 
4.8. 
Safety Analyses.............................................................................35 
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CHANGES TO PLANNED ANALYSES ..............................................42 
6. 
REFERENCES.........................................................................................43 
7. 
CLINICAL STUDY REPORT APPENDICES.....................................44 
7.1. 
Statistical Tables to be Generated ..............................................44 
7.2. 
Data Listings to be Generated.....................................................49 
7.3. 
Data Figures to be Generated .....................................................52 
 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
5
LIST OF IN-TEXT TABLES 
Table
Page
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
6
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
7
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
8
1.
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1.
Introduction 
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Objectives of Statistical Analysis 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
9
2.
STUDY DESIGN 
2.1.
Synopsis of Study Design 
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Stopping Rules and Unblinding 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
10
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
11
7DEOH


NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
12
Table 1 
Schedule of Assessments 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
13
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
14
2.5.
Efficacy, Pharmacokinetic, and Safety Variables 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
15
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
16
3.
SUBJECT POPULATIONS 
3.1.
Population Definitions 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
17
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
18
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
19
4.
STATISTICAL METHODS 
4.1.
Sample Size Justification 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
20
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
21
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
22

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Table 2 
Evaluation Intervals for Efficacy and Safety Analysis 
Evaluation
Targeted time 
point
Protocol-Specified Interval
Interval for Analysis
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
23
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
24
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
25
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Subject Disposition 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
26
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
27
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
28
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
29
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PROC MIXED DATA= dataset; 
CLASS region avisitn treat subjid;
MODEL chg=base treat region avisitn treat*avisitn / ddfm=KENWARDROGER;
REPEATED avisitn / subject=subjid type=un;
LSMEANS treat*avisitn / cl pdiff; 
ODS OUTPUT lsmeans=lsmeans_ tests3 = tests3_ diffs = diffs_
convergenceStatus=convergenceStatus_;
WHERE avisitn > xx; 
RUN;   
* chg represents the mean change from baseline variable; 
* base represents the mean daily frequency (or severity) at baseline; 
* treat represents the treatment group; 
* avisitn represents the analysis visits as defined in section 4.2.12. Only the 
post-baseline visits must be included 
* region represents the categorical covariate related to stratification factors; 
Further options to control the output may be added. 
From ODS OUTPUT, using the correct visit/treatment selection, the outputs will 
allow getting the following: 
- lsmeans_: LSM, SE and 95% CI for each treatment at each visit 
- diffs_: Difference in LSM, 95% CI and p value 
- tests3_: overall p values for the fixed effects.  
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PROC NPAR1WAY DATA= dataset WILCOXON; 
CLASS treat;
VAR chg;
EXACT Wilcoxon; 
WHERE avisit = “Week 4” and treat in ("Placebo","NT-814 40mg"); 
RUN;   
* chg represents the mean change from baseline variable; 
* treat represents the treatment group; 
* avisit represents the analysis visits as defined in section 4.2.12. 



NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
30
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PROC MIXED DATA=dataset; 
CLASS treat region; 
MODEL chg = treat base region; 
LSMEANS treat / pdiff (ref=’Placebo’) cl;
ODS OUTPUT lsmeans=lsmeans_ tests3 = tests3_ diffs = diffs_
convergenceStatus=convergenceStatus_;
WHERE avisit = “Week 4”;
RUN; 
* base represents the baseline value of the endpoint; 
* chg represents the change from baseline variable; 
* treat represents the treatment group; 
* region represents the categorical covariate related to stratification factors.
Further options to control the output may be added. See MMRM notes for ODS 
OUTPUT. 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
31
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PROC LOGISTIC DATA= dataset;
CLASS treat (ref=’Placebo’) region / param=ref; 
MODEL response (event=’1’) = base treat region; 
ODS OUTPUT OddsRatios=OddsRatios_ ParameterEstimates=ParameterEstimates_; 
RUN; 
* base represents the baseline value of the endpoint; 
* response represents the response variable; 
* treat represents the treatment group; 
* region represents the categorical covariate related to stratification factors; 
Further options to control the output may be added. 
From ODS OUTPUT, using the correct selection, the outputs will allow getting the 
following: 
- OddsRatios_: Odd ratio and 95% CI for each treatment
- ParameterEstimates_: p value.  
PROC FREQ DATA = dataset; 
Tables region*treat*response / cmh; 


NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
32
WHERE treat in ("Placebo","NT-814 40mg"); 
RUN; 
* The p-value would be for “Row Mean Scores Differ” in the SAS PROC FREQ output. 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
33
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
34
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
35
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
36
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Exposure variables definitions 
Variables
Definitions
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
37
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
39
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Table 4 
List of Laboratory Parameters 
Category
Parameters
Haematology
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NeRRe Therapeutics 
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11 DEC 2019 
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40
Biochemistry
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
41
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5.
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6.
REFERENCES 
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7.
CLINICAL STUDY REPORT APPENDICES 
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
49
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
50
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NeRRe Therapeutics 
Protocol 814-PM-02
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51
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
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52
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
53
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NeRRe Therapeutics 
Protocol 814-PM-02
11 DEC 2019 
CONFIDENTIAL 
54
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