Clinical trial NCT03193398
Conditions: Major Depressive Disorder
Keywords: Major Depressive Disorder Anhedonia antidepressant Nociceptin NOPR
Sponsor: BlackThorn Therapeutics, Inc.
Start date: 2017-06-12; Completion date: 2018-12-12
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will determine the efficacy, safety, and tolerability of a once-daily (QD) dose of up to 80 mg of BTRX-246040 for 8 weeks in participants with MDD.

Detailed description:

Arms: arm 1: 40 mg administered orally as 1 capsule QD for 1 week, followed by 80 mg as 2 capsules QD for 7 weeks. arm 2: administered orally as 1 capsule QD for 1 week, followed by 2 capsules QD for 7 weeks.
Interventions: intervention 1: BTRX-246040 oral capsule(s) intervention 2: Placebo oral capsule(s)
Intervention descriptions: intervention 1: BTRX-246040 administered once daily to patients with MDD for 8 weeks intervention 2: administered once daily to patients with MDD for 8 weeks

Protocol documents:
Prot_000.pdf: 
BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
 1 
 
 
 
PROTOCOL NEP-MDD-201 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP 
EFFICACY AND SAFETY STUDY OF BTRX-246040 ADMINISTERED ONCE DAILY IN 
PATIENTS WITH MAJOR DEPRESSIVE DISORDER WITH OR WITHOUT ANHEDONIA 
 
Sponsor: 
 
BlackThorn Therapeutics, Inc. 
780 Brannan Street 
San Francisco, CA 94103 
Date: 
November 20, 2018 
 
 
The information contained in this protocol is confidential and is intended for the use of clinical 
Investigators. It is the property of BlackThorn Therapeutics, Inc. and should not be copied by or 
distributed to persons not involved in the clinical investigation of BTRX-246040, unless such 
persons are bound by a confidentiality agreement with BlackThorn Therapeutics, Inc. This 
document and its associated attachments are subject to United States Freedom of Information 
Act (FOIA) Exemption 4. 
 
 
 
 


BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
 2 
1 SYNOPSIS 
Name of Investigational Study Product: 
BTRX-246040 
Title of Study:  A Randomized, Double-blind, Placebo-Controlled, Parallel-group Efficacy 
and Safety Study of BTRX-246040 Administered Once Daily in Patients with Major 
Depressive Disorder with or without Anhedonia 
Approximate Number of Planned Patients: 
100 patients randomized with treatment 
Phase of Development: 
2a 
Length of Study:  Approximately 17 months 
Primary Objective: 
To evaluate the effects of BTRX-246040 on symptoms of depression in adult patients with 
Major Depressive Disorder (MDD) after 8 weeks of double-blind treatment 
Secondary Objectives: 
1) To evaluate the effects of BTRX-246040 on anhedonia in adult patients with MDD  
2) To evaluate the safety and tolerability of BTRX-246040 in adult patients with MDD 
3) To evaluate the effects of BTRX-246040 on the performance of tasks as measured by 
the Facial Expression Recognition Task (FERT), Probabilistic Reward Task (PRT), and 
Effort Expenditure for Reward Task (EEfRT) in adult patients with MDD 
Exploratory Objectives: 
1) To evaluate the effects of BTRX-246040 on anxiety-related symptoms in adult patients 
with MDD  
2) To evaluate the effects of BTRX-246040 on pain-related symptoms in adult patients 
with MDD 
3) To evaluate the effects of BTRX-246040 as measured by biomarkers in adult patients 
with MDD 
Study Design: Study NEP-MDD-201 is an 8-week, randomized, double-blind, placebo- 
controlled, parallel-group, multicenter study to evaluate the effects of BTRX-246040 on 
symptoms of depression in adult patients with MDD after 8 weeks of double-blind treatment. 
There will be a 28-day screening period, 8-week active treatment period (during which 
patients will receive either BTRX-246040 or placebo), and an approximate 1- to 2-week off-
drug safety follow-up period.  
Patients will be consented and screened (Visit 1) for the study until approximately 100 patients 
are randomized.  Randomization will be performed in a 1:1 ratio to one of 2 treatment arms 
(placebo or BTRX-246040 QD) after meeting DSM-5 diagnostic criteria for MDD and study 
inclusion (see section 8). Randomization will be stratified by anhedonia symptom severity, as 
indicated by a SHAPS total score ≤ 4 and > 4. The BTRX-246040 starting dose for all eligible 


BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
 3 
patients will be 40 mg QD, initiated at Visit 2 (baseline).  A dose escalation to 80 mg QD will 
occur at Visit 3 (week 1) for all patients.  Patients who tolerate the dose increase will remain at 
a dose of 80 mg QD for the subsequent 7 weeks.  The dose may be decreased back to 40 mg 
QD anytime through Visit 4 (week 2), if required, for tolerability. Patients who cannot tolerate 
40 mg daily will be discontinued from participation in the study. Subsequent visits include 
Visit 5 (week 4), Visit 6 (week 6), and the end of the treatment period, Visit 7 (week 8). All 
patients will return to the study site for an off-drug safety follow-up visit approximately 1 to 2 
weeks after discontinuation of study drug. Overall duration in the study for each patient is 
expected to be approximately 14 weeks.  
Diagnosis and Main Criteria for Inclusion and Exclusions (see section 8 of this protocol 
for complete list of criteria): The study population will consist of men and women aged 18 to 
65 years (inclusive) with a diagnosis of MDD as defined by DSM-5 criteria and have had at 
least 1 prior major depressive episode in the past 10 years. Patients must present with a new 
current episode of MDD and the duration of the current episode must be at least 4 weeks but 
not longer than 18 months. At Visit 1 (screening) and Visit 2 (baseline), patients must have 
clinically significant depressive symptoms defined by tandem (investigator- and computer-
administered) Montgomery-Asberg Depression Rating ScaleÒ (MADRS) total scores ≥ 26 
with a difference of ≤ 7 points between the Investigator- and computer-administered MADRS 
total scores, a CGI-S score ≥ 4. Patients will be excluded from the study if they present with 
any current DSM-5 disorder other than MDD which is the focus of treatment. Are homicidal in 
the opinion of the Investigator or are at suicidal risk (any suicide attempts within 12 months 
prior to Visit 1 [screening] or any suicidal intent, including a plan, within 3 months prior to 
Visit 1 [screening]; C-SSRS answer of “YES” on item 4 or 5 [suicidal ideation]; Investigator- 
or computer-administered MADRS score of ≥ 5 on item 10 [suicidal thoughts]; by Investigator 
clinical evaluation). Patients cannot have any history of substance or alcohol use disorder 
within 12 months prior to Visit 1 (screening) per DSM-5 criteria or clinically significant 
comorbid disease. 
Investigational Study Product, Dose and Mode of Administration: 
A starting dose of BTRX-246040 40 mg (1 capsule) QD at Visit 2 (baseline), orally for the 
first 7 days. A dose escalation to 80 mg QD (2 capsules) will occur at Visit 3 (week 1) and this 
dose will be maintained for the subsequent 7 weeks. The dose may be decreased back to 40 mg 
QD anytime through Visit 4 (week 2), if required, for tolerability. Patients who cannot tolerate 
40 mg daily will be discontinued from participation in the study. 
Reference Therapy, Dose and Mode of Administration: 
Placebo will be assigned as 1 capsule QD at Visit 2 (baseline), orally for the first 7 days.  Two 
placebo capsules will be given at Visit 3 (week 1) for the subsequent 7 weeks.  Placebo 
capsules will consist of inactive ingredients and look identical to BTRX-246040. Placebo may 
be decreased back to 1 capsule QD anytime through Visit 4 (week 2), if required, for 
tolerability. Patients who cannot tolerate 1 capsule daily will be discontinued from 
participation in the study. 
Planned Duration of Treatment: 
Double-blind Treatment period: 8 weeks 


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Protocol NEP-MDD-201 v6.0 
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Criteria for Evaluation:  
Primary Efficacy:  Primary efficacy will be determined using change from baseline to Week 
8 on the Investigator-administered MADRS total score in the Full Analysis Set of patients. 
Secondary Efficacy:  Secondary efficacy will be assessed using change from baseline to 8 in 
the following endpoints:  
• Investigator-administered MADRS-6 subscale 
• Investigator-administered MADRS individual items 
• Hospital Anxiety and Depression Scale (HADS) subscales: anxiety subscale (HADS-A) 
and depression subscale (HADS-D) 
• Dimensional Anhedonia Rating Scale (DARS) 
• Snaith-Hamilton Pleasure Scale (SHAPS) 
In addition, outcome measures from the following performance tasks will be analyzed. 
• FERT 
• PRT 
• EEfRT 
Exploratory Efficacy & Tolerability:  
• Change in HAM-A total score from baseline to Week 4 and from baseline to Week 8 
• Change from baseline to Week 8 on the average pain in the last 24 hours 
• Changes in plasma levels of nociceptin, and changes in serum levels of interleukin 1 
beta, 2, 6 and 10 (IL-1ß, IL-2, IL-6, IL-10), tumor necrosis factor alpha (TNFa), 
interferon gamma (IFNg) and C-reactive protein (CRP) from baseline to Week 8, 
correlated to treatment outcome and exposure 
All efficacy endpoints will be summarized by visit, including change from baseline 
information. 
Digital Assessments: Vocal and behavioral digital assessment data are collected in this study. 
These data will be in a separate report. 
Safety: Safety and tolerability will be assessed by clinically significant events. Safety 
assessments include AEs, SAEs, vital signs, weight and BMI, laboratory values, neurological 
exams, C-SSRS, SHSF, SHFU, and ECGs. 
Bioanalytical: nonpharmacogenetic biomarkers: changes in plasma levels of nociceptin and 
serum levels of IL-1ß, IL-2, IL-6, IL-10, TNFa, IFNg, and CRP. 
Pharmacokinetics: Pharmacokinetic (PK) data collected in this study will be listed. 
Population PK analysis of the plasma concentrations in this study will be reported separately 
and the results of multiple clinical trials may be combined for this analysis. 


BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
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Statistical Methods:  
The sample size determination was based on the primary endpoint, change from baseline in the 
Investigator-administered MADRS total score, at Visit 7 (week 8). Approximately 100 
patients will be randomized to either BTRX-246040 or placebo in a 1:1 allocation ratio.  A 
sample size of 44 patients per treatment group will provide 75% power to detect a relative 
effect size of 0.5 on the MADRS total score, based on a two-sample t-test and a significance 
level of 0.10. All tests are two-sided. To account for patients who may discontinue early and 
be excluded from the analysis population, a sample size of approximately 50 patients per 
treatment group (total of 100 patients) will be randomized. 
All statistical tests will be 2-sided. In this Phase 2 study, statistical tests that are significant at 
the level of 10% will be considered as demonstrating a trend.  Statistical tests that are 
significant at the 5% level will be considered as demonstrating a strong trend. Where 
appropriate, analyses of the secondary efficacy parameters and the exploratory endpoints will 
report nominal p-values to aid the interpretation of results. No adjustments for multiplicity will 
be made for secondary and exploratory analyses.  
The primary efficacy analysis will be on the Investigator-administered MADRS total score and 
the key comparison will be the contrast between BTRX-246040 and placebo at the last visit of 
the 8-week double-blind treatment period (Visit 7/Week 8) from a mixed-model repeated 
measures (MMRM) analysis on the change from baseline in the Investigator-administered 
MADRS. This primary efficacy analysis will be performed on the Full Analysis Set of patients 
that includes all randomized patients who received at least one dose of study drug and have at 
least one post-dose efficacy assessment. 
The following secondary efficacy endpoints will be analyzed by the MMRM model: 
1. Change from baseline to Week 8 on the Investigator-administered MADRS-6 subscale 
2. Change from baseline to Week 8 on the Investigator-administered MADRS individual 
items 
3. Change from baseline to Week 8 on the total scores of the HADS subscales, the anxiety 
subscale (HADS-A) and the depression subscale (HADS-D) 
4. Change from baseline to Week 8 on the DARS 
5. Change from baseline to Week 8 on the SHAPS (using the original 0 – 14 scoring method 
and also using an alternative scoring method ranging from 14 – 56) 
The following secondary endpoints will be analyzed by logistic regression with fixed effects 
for treatment and investigative site with the addition of the baseline Investigator-administered 
MADRS as a covariate. 
Responder rates defined by: 
6. Proportion of patients who demonstrate clinical response, where response was defined 
by a reduction of at least 50% in the baseline Investigator-administered MADRS total 


BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
 6 
score at Week 8. 
7. Proportion of patients with MDD who achieved remission, where remission was 
defined by a total score of ≤10 on the Investigator-administered MADRS at Week 8. 
8. Proportion of patients who demonstrate significant clinical improvement, where 
improvement is defined by a score of 1 (very much improved) or 2 (much improved) 
on the CGI-I at Week 8.   
The following secondary efficacy endpoints based on the performance tasks will be analyzed 
and presented in summary and graphical displays. 
9. Outcome measures from the FERT  
10. Outcome measures from the PRT 
11. Outcome measures from the EEfRT 
The exploratory endpoints will include: 
1. Change in HAM-A total score from baseline to Week 4 and from baseline to Week 8 
2. Change from baseline to Week 8 on the average pain in the last 24 hours 
3. Changes in plasma levels of nociceptin, and changes in serum levels of IL-1ß, IL-2, IL-6, 
IL-10, TNFa, IFNg, and CRP from baseline to Week 8, correlated to treatment outcome 
and exposure 
Exploratory endpoints will be summarized and, where appropriate, represented graphically.  
All safety data will be listed and summarized for the Safety Analysis Set of patients who 
received at least one dose of study drug. 
 
 


BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
 7 
2 TABLE OF CONTENTS 
 
1 
Synopsis .................................................................................................................................... 2 
2 
Table of Contents .................................................................................................................... 7 
3 
Protocol Signature Page ....................................................................................................... 14 
4 
Abbreviations ........................................................................................................................ 15 
5 
Introduction ........................................................................................................................... 18 
6 
Objectives ............................................................................................................................... 22 
6.1 
Primary Objective ....................................................................................................................... 22 
6.2 
Secondary Objectives .................................................................................................................. 22 
6.3 
Exploratory Objectives ............................................................................................................... 22 
7 
Investigational Plan .............................................................................................................. 23 
7.1 
Summary of Study Design .......................................................................................................... 23 
7.2 
Study Design and Control .......................................................................................................... 24 
8 
Study Population ................................................................................................................... 25 
8.1 
Inclusion Criteria ........................................................................................................................ 25 
8.2 
Exclusion Criteria ....................................................................................................................... 26 
8.2.1 
Rationale for Exclusion of Certain Patients ........................................................................... 28 
8.3 
Discontinuations .......................................................................................................................... 28 
8.3.1 
Early Discontinuation ............................................................................................................ 28 
8.3.2 
Discontinuation of the Study ................................................................................................. 30 
9 
Study Procedures .................................................................................................................. 31 
9.1 
Visit 1: Screening ......................................................................................................................... 31 
9.2 
Visit 2: Baseline (Day 1) .............................................................................................................. 32 
9.3 
Visit 3: Week 1 (Day 8) Dose Escalation ................................................................................... 33 
9.4 
Visit 4: Week 2 (Day 15) ............................................................................................................. 34 


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9.5 
Visit 5, Week 4 (Day 29) ............................................................................................................. 35 
9.6 
Visit 6, Week 6 (Day 43) ............................................................................................................. 36 
9.7 
Visit 7, Week 8 (Day 57) End of Treatment .............................................................................. 37 
9.8 
Visit 8, Safety Follow-up ............................................................................................................. 38 
10 Treatment .............................................................................................................................. 41 
10.1 Treatments Administered ........................................................................................................... 41 
10.2 Materials and Supplies ............................................................................................................... 41 
10.3 Method of Assignment to Treatment ......................................................................................... 41 
10.4 Rationale for Selection of Doses in the Study ........................................................................... 42 
10.5 Selection and Timing of Doses ................................................................................................... 42 
10.6 Blinding ........................................................................................................................................ 43 
10.7 Concomitant Therapies .............................................................................................................. 43 
10.8 Treatment Compliance with Investigational Product ............................................................. 43 
11 Safety, Efficacy Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements .............................................................................................................................. 44 
11.1 Efficacy Measures ....................................................................................................................... 44 
11.1.1 
Montgomery-Asberg Depression Rating Scale (MADRS) .................................................... 44 
11.1.2 
Snaith Hamilton Pleasure Scale (SHAPS) ............................................................................. 45 
11.1.3 
Clinical Global Impression Scale – Severity (CGI-S) ........................................................... 45 
11.1.4 
Clinical Global Impression Scale – Improvement (CGI-I) .................................................... 45 
11.1.5 
Pain Question ......................................................................................................................... 45 
11.1.6 
Hamilton Anxiety Rating Scale (HAM-A) ............................................................................ 46 
11.1.7 
Dimensional Anhedonia Rating Scale (DARS) ..................................................................... 46 
11.1.8 
Probabilistic Reward Task (PRT) .......................................................................................... 46 
11.1.9 
Effort Expenditure for Reward Task (EEfRT) ....................................................................... 46 
11.1.10 
The Facial Expression Recognition Task (FERT) ............................................................. 47 
11.1.11 
Digital Assessments ........................................................................................................... 47 


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11.1.12 
Hospital Anxiety and Depression Scale (HADS) .............................................................. 47 
11.2 Assessments Only at Visit 1 (Screening) ................................................................................... 47 
11.2.1 
The Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-CT) ............. 47 
11.2.2 
Lifetime Illness Characteristics Questionnaire (LICQ) ......................................................... 48 
11.3 Safety Measures ........................................................................................................................... 48 
11.3.1 
Adverse Events ...................................................................................................................... 48 
11.3.2 
Overdose ................................................................................................................................ 49 
11.3.3 
Pregnancy ............................................................................................................................... 49 
11.3.4 
Serious Adverse Events ......................................................................................................... 49 
11.3.5 
Suspected Unexpected Serious Adverse Reactions ............................................................... 50 
11.4 Sample Collection and Testing ................................................................................................... 50 
11.4.1 
Hepatic Safety ........................................................................................................................ 53 
11.4.2 
Urine drug screen ................................................................................................................... 54 
11.4.3 
Samples for Drug Concentration Measurements Pharmacokinetics ...................................... 55 
11.4.4 
Pharmacogenetic Samples ..................................................................................................... 55 
11.4.5 
Nonpharmacogenetic Biomarker Samples ............................................................................. 56 
11.5 Other Safety Measures ............................................................................................................... 56 
11.5.1 
Vital Sign Measurements ....................................................................................................... 56 
11.5.2 
Height and Weight ................................................................................................................. 56 
11.5.3 
Physical Examination ............................................................................................................. 57 
11.5.4 
Neurological Examination ..................................................................................................... 57 
11.5.5 
Collection of Electrocardiograms .......................................................................................... 57 
11.5.6 
Suicidal Ideation/Suicidality .................................................................................................. 58 
11.5.7 
Safety Monitoring .................................................................................................................. 58 
11.6 Pharmacokinetic Analysis .......................................................................................................... 59 
11.7 Appropriateness of Measurements ............................................................................................ 59 
12 Data Quality Assurance ........................................................................................................ 60 


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12.1 Data Capture System .................................................................................................................. 60 
13 Sample Size and Statistical Methods ................................................................................... 61 
13.1 Determination of Sample Size .................................................................................................... 61 
13.2 Statistical and Analytical Plans .................................................................................................. 61 
13.2.1 
General Considerations .......................................................................................................... 61 
13.2.2 
Analysis Sets .......................................................................................................................... 62 
13.2.3 
Patient Disposition ................................................................................................................. 62 
13.2.4 
Baseline Patient Characteristics ............................................................................................. 62 
13.2.5 
Concomitant Therapies .......................................................................................................... 63 
13.2.6 
Treatment Compliance with Investigational Product ............................................................ 63 
13.2.7 
Multiplicity Issue ................................................................................................................... 63 
13.2.8 
Efficacy Analysis ................................................................................................................... 63 
13.2.9 
Digital Assessments ............................................................................................................... 67 
13.2.10 
Pharmacokinetic/Pharmacodynamic Analyses .................................................................. 67 
13.2.11 
Safety Analyses .................................................................................................................. 67 
13.2.12 
Subgroup Analyses ............................................................................................................. 67 
13.2.13 
Interim Analysis ................................................................................................................. 68 
14 Informed Consent, Ethical Review, and Regulatory Considerations .............................. 69 
14.1 Informed Consent ........................................................................................................................ 69 
14.2 Ethical Review ............................................................................................................................. 69 
14.3 Regulatory Considerations ......................................................................................................... 69 
14.3.1 
Investigator Information ........................................................................................................ 70 
14.3.2 
Protocol Signatures ................................................................................................................ 70 
15 References .............................................................................................................................. 71 
 
 
 


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List of Tables 
Table 1  Schedule of Assessments ................................................................................................. 39 
Table 2 Treatment Regimens ......................................................................................................... 41 
Table 3 Clinical Laboratory Testsa ................................................................................................ 52 
Table 4 Hepatic Monitoring Tests ................................................................................................. 54 
 
 


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List of Figures 
Figure 1 Study Design ................................................................................................................... 23 
 
 


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Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
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List of Appendices 
 
Appendix 1 
Examples of Inhibitors and Inducers of CYP3A4 .................................................. 73 
 
 
 


BlackThom Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
3 PROTOCOL SIGNATURE PAGE 
This protocol hazed by: 
~ 
Atul R. Mahableshwarkar, M.D. 
Date 
VP Clinical Development & Responsible Medical Officer 
BlackThorn Therapeutics, Inc. 
Principal Investigator Declaration: 
I have read and understood the requirements and conditions of the study protocol. I am aware of 
my responsibilities as an Investigator under the guidelines of the Internal Conference on 
Harmonization Good Clinical Practice (ICH GCP) standards, the Declaration of Helsinki, local 
regulations ( as applicable) and the study protocol. I agree to conduct the study according to these 
guidelines and to appropriately direct and assist the study team assigned to me who will be 
involved in the study. 
I agree to use the study material, including investigational treatment medication, only as 
specified in the protocol. 
I understand that the protocol must be approved by the Ethics Committee and Regulatory 
Authorities prior to its implementation. I confirm that if I or any of my staff are members of the 
ethical review board, we will abstain from deliberation and voting on this protocol. 
I understand that non-compliance with the study protocol may lead to early termination of the 
study. 
Principal Investigator Signature 
Date 
Principal Investigator Name (printed) 
CONFIDENTIAL 
14 


BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
CONFIDENTIAL 
 
 15 
4 ABBREVIATIONS 
 
Ab 
Antibody 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ANCOVA 
Analysis of the Covariance 
ANOVA 
Analysis of the Variance 
AUC 
AUD 
Area Under the Curve 
Alcohol Use Disorder 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
CI 
CIOMS 
Clinical Global Impression of Change 
Confidence Interval 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum Plasma Drug Concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRP 
C-reactive protein 
C-SSRS 
Columbia Suicidality Severity Rating Scale 
DARS 
DSM-5 
Dimensional Anhedonia Rating Scale 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture  
EEfRT 
EPD 
Effort Expenditure for Reward Task 
Edinburgh Postnatal Depression Scale 
ETB 
P1vital® Oxford Emotional Test Battery 
FAS 
Full Analysis Set 
FERT 
Facial Expression Recognition Task 


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 16 
FOIA 
Freedom of Information Act 
GCP 
GEE 
Good Clinical Practice 
Generalized Estimating Equation 
HADS 
Hospital Anxiety and Depression Scale 
HADS-A 
Hospital Anxiety and Depression Scale - Anxiety Subscale 
HADS-D 
Hospital Anxiety and Depression Scale - Depression Subscale 
HAM-A 
Hamilton Anxiety Rating Scale 
HAV 
Hepatitis A Virus 
HAV-Ab [IgM]  
Hepatitis A Virus Antibody 
HBc Ab 
HBs Ag 
Hepatitis B Core Antibody 
Hepatitis B Surface Antigen  
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IFNg 
interferon gamma  
IL-1ß, IL-2, IL-6, IL-10 
interleukin 1 beta, 2, 6 and 10  
IgM 
IND 
INR 
IRB 
IWRS 
Immunoglobulin M 
US Investigational New Drug Application 
International Normalized Ratio 
Investigational Review Board 
Interactive Web-response System 
LC-MS/MS 
Liquid Chromatography-tandem Mass Spectrometry  
LICQ 
Lifetime Illness Characteristics Questionnaire  
LS Means 
Least-square means 
MADRS 
MDD 
Montgomery-Asberg Depression Rating ScaleÒ 
Major Depressive Disorder 
MMRM 
Mixed-model Repeated Measures 


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Noc/OFQ 
Nociceptin/Orphanin FQ 
MOS 
Margin of Safety 
NOAEL 
No-Observed- Adverse-Effect-Level 
NONREM 
Nonlinear Mixed Effect Modeling 
NOPR 
Nociceptin Receptor 
PET 
Positron Emission Tomography 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
PRF 
Pre-Randomization Form 
PRT 
Probabilistic Reward Task 
QD 
Once Daily 
QTcF 
Fridericia’s correction method for QT Interval 
RO 
Receptor Occupancy 
SAE 
SAP 
Serious Adverse Event 
Statistical Analysis Plan 
SCID-CT 
Structured Clinical Interview for DSM Disorders-Clinical Trials 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SHFU 
Self-Harm Follow-up Form 
SHSF 
Self-Harm Supplement Form 
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TEAE 
Treatment-emergent Adverse Event 
TNFa 
Tumor necrosis factor alpha  
TPO 
Third-party Organization 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
WHODD 
United States 
World Health Organization Drug Dictionary 
 


CONFIDENTIAL 
 18 
BlackThorn Therapeutics, Inc. 
Protocol NEP-MDD-201 v6.0 
5 INTRODUCTION 
Major depressive disorder (MDD) is the most common mood disorder and imposes considerable 
economic and humanitarian suffering, such as decreased quality of life, functional impairment, 
and increased mortality rate. By 2020, depressive disorders are expected to be the second highest 
cause of morbidity in the world (Murray et al., 2006) and has been predicted to become the 
leading cause of disease burden by the year 2030 (WHO, 2008). The lifetime prevalence of 
MDD is approximately 16.6% in the United States (US) (Kessler et al., 2003). Less than one 
quarter of patients with MDD are correctly identified and appropriately treated (Olfson et al., 
2005). Patients who receive appropriate medications with available drugs are often under-treated, 
which is attributed to poor compliance and tolerability, and lack of efficacy. Episodes of MDD 
are often chronic and recurrent, with a relapse chance rate of 55% to 90% for individuals who 
experienced one or two prior depressions. More than 80% of the individuals who experience a 
second episode and who are not treated will experience a third episode within 3 years (Thase and 
Sullivan, 1995).  
A clinical diagnosis of MDD is made based on the continuous presence of at least 5 of 9 
symptoms over at least two weeks. One of these symptoms must be either depressed mood or 
anhedonia which is defined as diminished interest or pleasure in response to rewarding stimuli 
(American Psychiatric Association, 2013: Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition). This diagnostic classification assigns equal importance to depressed 
mood and anhedonia thus highlighting anhedonia as a core feature of the disorder. The 
classification system also acknowledges that anhedonia may be present in a subset of individuals 
with MDD. Estimates of significant anhedonia among patients with MDD are rare, one report 
describes an anhedonia rate of approximately 37% among a sample of 65 individuals diagnosed 
with MDD (Pelizza and Ferrari, 2009). Moreover, published data indicates that the presence of 
anhedonia may represent a distinct physiologically based subset of patients with MDD. Evidence 
from functional neuroimaging assessments indicates that anhedonia is linked to disruptions in 
central reward system functioning and is an important aspect of depression pathophysiology 
(Keedwell et al., 2005). 
The current mainstays of pharmacological treatments for depression include the use of selective 
serotonin reuptake inhibitors (SSRIs) (Fava et al., 2007; Zupancic et al., 2006) and serotonin-
norepinephrine reuptake inhibitors (SNRIs) (Stahl et al., 2005), which provide reasonable 
treatment options; however, these therapies are not effective in all patients, and are often 
associated with undesirable side effects, such as weight gain and sexual dysfunction. The lack of 
efficacy and the adverse events (AEs) associated with the use of these antidepressants lead to 
high levels of treatment discontinuation (Zajecka, 2000). Even with multiple consecutive 
treatments, only a small proportion of patients remain asymptomatic (Rush, 2007). Thus, there 
continues to be a substantial unmet medical need for new antidepressants with greater response 
rates and improved tolerability.  


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The presence of anhedonia is associated with difficulty in treating MDD.  Research findings 
indicate that available therapies such as SSRIs do not target depression-related motivational and 
reward-processing deficits sufficiently (APA, 2000; Dunlop and Nemeroff, 2007; McCabe et al., 
2009; Nutt et al., 2007; Price et al., 2009; Shelton and Tomarken, 2001) and that anhedonic 
symptoms predict inadequate treatment response (Spijker et al., 2001). 
Nociceptin/Orphanin FQ (Noc/OFQ) is a neuropeptide that acts as a natural ligand for a G 
protein-coupled receptor (Meunier et al., 1995; Reinscheid et al., 1995) encoded by the gene 
OPRL1. OPRL1 is expressed in brain regions associated with mood disorders and obesity (Florin 
et al., 2000; Berthele et al., 2003) and regulates neuronal activity in regions underlying hedonic 
processing and motivation (Norton et al., 2002). In non-clinical animal models, nociceptin 
modulates several physiological functions and behaviors including depression, stress and 
anxiety, feeding, locomotor activity, body temperature, substance abuse, memory, and pain 
(Lambert, 2008; Zaveri, 2016).  
BTRX-246040 is a potent and selective antagonist of human nociceptin receptors (NOPR). 
Preclinical evidence indicates that it has anxiolytic, ethanol-consumption reducing/relapse 
preventing, antidepressant-like, body weight-reducing and analgesic effects (Witkin et al., 2014; 
Rorick-Kehn et al., 2016; Statnick et al., 2016). Open-label studies have documented increased 
plasma levels of nociceptin in different subpopulations of depressive disorder patients, including 
bipolar depressed and postpartum patients, as compared to non-depressed controls, which were 
found to be correlated with severity of the depressed symptoms as assessed by Hamilton 
Depression Rating Scale (HAM-D) and Edinburgh Postnatal Depression (EPD) Scale score (Gu 
et al. 2003; Wang et al. 2009).  
Completed Phase 1 studies showed that BTRX-246040 was well-tolerated in healthy males after 
single administrations of doses ranging from 2 to 800 mg and after multiple daily doses of 40 to 
200 mg (n = 78). There were no deaths, serious adverse events (SAEs), or severe AEs, and the 
overall incidence of treatment-emergent adverse events (TEAEs) in the entire Phase 1 program 
was relatively low. There were no findings noted in the clinical laboratory, electrocardiogram 
(ECG), and physical examination, including neurological examination. No suicidal ideation or 
behavior was detected following BTRX-246040 administration, as assessed by the Columbia 
Suicide Severity Rating ScaleÒ (C-SSRS). All vital signs were within normal ranges, with no 
notable dose- or treatment-related changes noted following single and multiple doses of 
BTRX-246040 at any dose tested. BTRX-246040 showed a predictable pharmacokinetic (PK) 
profile with low- moderate variability. The terminal half-life of BTRX-246040 was estimated to 
be 66 to 96 hours.  
Completed Phase 2 studies in male and female patients with MDD (Study I5J-MC-NOAC 
[NOAC]) and male and female patients with Alcohol Use Disorder (AD) (Study I5J-MC-NOAD 
[NOAD]) showed BTRX-246040 was well tolerated at doses of 40 mg QD over an 8-week 
period.  The dose of 40 mg QD was chosen because results from a single-dose study assessing 
brain Noc/OFQ receptor occupancy (Study I5J-MC-NOAB [NOAB]) predicted that this dose 


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would result in receptor occupancy (RO) above 80% for 24-hours in at least 75% of patients at 
steady state. There were no deaths or SAEs with BTRX-246040 administration in either study. In 
study NOAC, the most common TEAEs that occurred more frequently with BTRX-246040 than 
placebo were nausea (7/69 [10.1%] vs. 1/65 [1.5%] patients), insomnia (7/69 [10.1%] vs. 0/65 
patients) and dizziness (5/69 [7.2%] vs. 0/65 patients). In study NOAD, the frequency of TEAEs 
reported was similar between the BTRX-246040 and placebo treatment groups. In both studies, 
most TEAEs were mild or moderate in severity. There were no notable treatment-related clinical 
laboratory findings or abnormal ECGs. Vital signs were generally within normal range, with no 
notable treatment-related changes reported following 40 mg QD BTRX-246040. In Study 
NOAC, no increase in suicidal ideation or behavior relative to placebo was detected following 
BTRX-246040 administration, as assessed by the C-SSRS. In Study NOAD, there was no 
suicidal ideation or behavior following BTRX-246040 administration, as assessed by the 
C-SSRS. In general, the observed BTRX-246040 concentration time data in patients with MDD 
were in a similar range to the concentrations observed in the healthy subject study (Study I5J-
MC-NOAA [NOAA]) when the data were compared after normalizing for administered dose.  
Based on data from rat and rabbit reproduction toxicity studies, BTRX-246040 does not pose a 
significant safety hazard to a developing embryo or fetus. In rats, BTRX-246040 did not cause 
major malformations or effects on embryo-fetal survival.  Slightly reduced fetal growth and an 
increase in minor fetal anomalies occurred at the maternally toxic dose of 200 mg/kg/day which 
corresponded to an AUC of 204485 ng.h/mL on Gestation Day 17. The Margin of Safety (MOS) 
for the AUC at the no-observed- adverse-effect-level (NOAEL) of 75 mg/kg/day relative to the 
AUC at the 40 mg in study NOAA is 69-fold and 57-fold above the expected AUC at the 80 mg 
dose. In rabbits, BTRX-246040 did not cause major or minor fetal anomalies or adversely affect 
embryo-fetal survival. A slight reduction in fetal weights occurred concurrently with significant 
maternal toxicity (body weight loss and reduced food consumption) at 100 mg/kg/day (AUC – 
11381 ng.h/mL). The MOS for the AUC at the NOAEL of 30 mg/kg/day relative to the AUC at 
the 40 mg dose in study NOAA is 2.5-fold and 0.9-fold at the expected AUC at the 80 mg dose.  
In general toxicity studies, dose-limiting toxicity was mainly related to dose- and exposure-
dependent increases in severity of central nervous system (CNS) effects in rats and dogs 
including ataxia, tremors (dogs only), and convulsions (dogs only). The lowest maximum drug 
plasma concentration (Cmax) that produced convulsions in dogs (the most sensitive preclinical 
species) was 2400 ng/mL (approximately 19-fold above the mean Cmax anticipated with 40 mg 
QD and 7-fold above the mean Cmax anticipated with 80 mg QD).  
The current study will use a starting dose of 40 mg QD for which observed Cmax estimates after 
dosing for 14 days to healthy male patients in Study NOAA ranged from 87.9 to 183 ng/mL 
(mean=127 ng/mL). The exposure multiple to the lowest convulsive dose in dogs is 19-fold and 
the exposure multiple to 1/10th the convulsive threshold in dogs is approximately 2-fold based on 
the mean Cmax at 40 mg observed in Study NOAA. Since this dose was well-tolerated in two 
separate Phase 2 studies (n = 113 male and female patients treated with BTRX-246040) in which 


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a trend towards efficacy was observed, dose escalation to 80 mg QD based on individual patient 
tolerability will be employed in the current study to further explore the effective dose range. PK 
data are available for the dose regimens of 40, 120, and 200 mg QD, but not for 80 mg QD. The 
mean Cmax on Day 14 of dosing with 120 mg QD to healthy male patients in Study I5J-MC-
NOAA (NOAA) was 570 ng/mL. Thus, the mean Cmax and AUC0-24 with steady-state dosing 
with 80 mg QD is anticipated to be approximately 350 ng/mL and 3550 ng.h/mL, respectively 
(intermediate between that of 40 mg QD and 120 mg QD). 
More information about the known and expected benefits, risks and reasonably anticipated AEs 
may be found in the Investigator’s Brochure (IB).  
 
 


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6 OBJECTIVES 
6.1 PRIMARY OBJECTIVE 
To evaluate the effects of BTRX-246040 on symptoms of depression in adult patients with Major 
Depressive Disorder after 8 weeks of double-blind treatment. 
6.2 SECONDARY OBJECTIVES 
• To evaluate the effects of BTRX-246040 on anhedonia in adult patients with MDD 
• To evaluate the safety and tolerability of BTRX-246040 in adult patients with MDD 
• To evaluate the effects of BTRX-246040 on the performance of tasks as measured by the 
Facial Expression Recognition Task (FERT), Probabilistic Reward Task (PRT), and 
Effort Expenditure for Reward Task (EEfRT) in adult patients with MDD 
6.3 EXPLORATORY OBJECTIVES 
• To evaluate the effects of BTRX-246040 on anxiety-related symptoms in adult patients 
with MDD  
• To evaluate the effects of BTRX-246040 on pain-related symptoms in adult patients with 
MDD 
• To evaluate the effects of BTRX-246040 as measured by biomarkers in adult patients 
with MDD 
 
 


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7 INVESTIGATIONAL PLAN 
7.1 SUMMARY OF STUDY DESIGN 
Study NEP-MDD-201 is an 8-week, randomized, double-blind, placebo-controlled, parallel-
group, multicenter study. There will be a 28-day screening period, 8-week active treatment 
period (during which patients will receive either BTRX-246040 or placebo), and an approximate 
1- to 2-week off-drug safety follow-up period (Figure 1).  
 
Figure 1 Study Design 
Patients will be consented and screened for the study until approximately 100 patients are 
randomized. Randomization will be performed at Visit 2 (baseline) in a 1:1 ratio to one of two 
treatment arms (placebo or BTRX-246040 QD) after meeting disease diagnostic criteria for 
MDD and study inclusion (see section 8). Randomization will be stratified by anhedonia 
symptom severity, as indicated by a SHAPS total score ≤ 4 and > 4. The BTRX-246040 starting 
dose for all eligible patients will be 40 mg QD.  A dose escalation to 80 mg QD will occur at 
Visit 3 (week 1) visit for all patients.  Patients who tolerate the dose increase will remain at a 
dose of 80 mg QD for the subsequent 7 weeks.  The dose may be decreased back to 40 mg QD 
anytime through Visit 4 (week 2), if required, for tolerability. Patients who cannot tolerate 40 mg 
daily will be discontinued from participation in the study. Subsequent visits include Visit 5 
(week 4), Visit 6 (week 6), and the end of the treatment period, Visit 7 (week 8). All patients will 
return to the study site for a safety follow-up visit approximately 1 to 2 weeks after 
discontinuation of study drug. Overall duration in the study for each patient is expected to be 
approximately 14 weeks.  
 
 
Screening 
Placebo 
40 mg  
Double-blind Treatment 
Baseline 
Wk 1 
Wk 4 
Wk 8 
Wk 2 
Wk 6 
Safety 
Follow-up 
Day 1 
Dose Escalation 
Assess 
Tolerability 
Placebo 
80 mg 
Placebo 
80 mg or 40 mg 
for 7 weeks 
Wk 9-10 
-7 to -28 Days* 
*The screening visit may be 
extended to 42 days if needed 
>IL---___ 
)1._____) 
'------~ 
! 
! 
! 


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7.2 STUDY DESIGN AND CONTROL 
The initial screening period is designed to ensure patients meet the required inclusion and 
exclusion criteria, including diagnosis and stability of depressive symptoms and absence of 
psychiatric and medical conditions that would preclude study participation.  
The randomization, investigational product blinding, and placebo controls will serve to minimize 
the chance of bias in the implementation and execution of the study. Randomization to treatment 
assignment reduces the likelihood that results will reflect selection bias. Having both 
Investigators and patients blinded to treatment assignment (double-blind) controls for 
expectation bias relative to any particular treatment condition. A placebo arm is included to 
control the patient and Investigator expectations of improvement during the study that could 
confound interpretation of pharmacological effects of treatment.  
Double-blind, placebo-controlled studies are the standard in assessment of efficacy in 
randomized clinical trials evaluating patients with conditions such as MDD. These patients can 
be significantly responsive to placebo and it is important to use a placebo comparator to discern 
this effect despite the risk of a possible worsening of symptoms. There have been estimates of 
placebo response rates in MDD clinical trials between 30% and 50%. Certain factors are 
associated with improvement in placebo-treated patients. These include therapeutic effects 
secondary to interaction with a medical professional, misdiagnosis of the psychiatric disorder, 
clinicians overestimating baseline symptom severity or symptom change, and regression to the 
mean in patients who began the study with more severe symptoms of illness (Fava et al. 2003). 
In this study, we take several measures to mitigate these influences.   
Patients will complete a computer-administered diagnostic validation assessment, the Lifetime 
Illness Characteristics Questionnaire (LICQ), at Visit 1 (screening) using a secure computer 
device provided to the site. The patient’s diagnostic information, based on the responses to the 
computerized interview, will be reviewed by the Sponsor-designated independent clinical 
reviewer.  Any uncertainty raised by the patient’s responses on the diagnostic interview will be 
discussed with the Investigator.  
A tandem assessment process will be used to administer and rate the MADRS. Two MADRS 
administrations will be conducted at each study visit using a secure computer device provided to 
the site.  One will be administered by a qualified site Investigator. The second will be computer-
administered and will consist of a series of probe and follow-up questions with multiple-choice 
response options to be completed by the patient. 
The Investigator-administered MADRS scores will be compared with the computer-administered 
MADRS scores. This will ensure that the MADRS is administered in a reliable, consistent 
manner throughout the study and avoids potential introduction of bias. 
 
 


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8 STUDY POPULATION 
Patients who meet all Inclusion Criteria and are subsequently not excluded by the Exclusion 
Criteria will be randomized to double-blind treatment at Visit 2.  
8.1 INCLUSION CRITERIA 
Patients are eligible to be included in the study only if they meet all the following criteria:  
1. Are adult men or women 18 to 65 years of age (inclusive) at informed consent, who 
provide informed consent by signing the appropriate informed consent forms (ICFs).   
2. Have a diagnosis at screening of Major Depressive Disorder as assessed by the 
Investigator using the Structured Clinical Interview for DSM Disorders-Clinical Trials 
(SCID-CT). 
a. Must have had at least 1 other major depressive episode previously diagnosed 
and/or treated in the past 10 years Note: Patients who did not receive treatment 
will require adequate explanation for discussion with the Medical Monitor. 
b. Must present with a new episode of MDD and the duration of the current episode 
must be at least 4 weeks but not longer than 18 months 
3. Total scores of ≥ 26 on both the Investigator-administered and computer-administered 
Montgomery-Asberg Depression Rating ScaleÒ (MADRS) at Visit 1 (screening) and 
Visit 2 (baseline). 
4. A difference of ≤ 7 points between rater and computer MADRS total scores at Visit 1 
(screening) and Visit 2 (baseline). 
5. Clinical Global Impression - Severity score of ≥ 4 at Visit 1 (screening) and Visit 2 
(baseline). 
6. Agree to the following birth control:  
a. Male patients agree to use a reliable method of birth control during the study and 
for at least 90 days following the last dose of BTRX-246040 or placebo.  
b. Female patients of child-bearing potential (women not surgically sterilized and 
between menarche and 2 years postmenopausal) who test negative for pregnancy 
at the time of enrollment based on a serum pregnancy test and agree to use a 
reliable method of birth control (e.g., oral contraceptives or Norplant®; a reliable 
double barrier method of birth control [diaphragms with contraceptive jelly; 
cervical caps with contraceptive jelly; condoms with contraceptive foam]; 
intrauterine devices; partner with vasectomy; or abstinence) during the study and 
for 8 weeks following the last dose of the investigational product BTRX-246040 
or placebo.  
7. Willing and able to give written informed consent to participate. 
8. Patient must have a personal smartphone (iOS or Android operating system). 
9. Able to understand and comply with instructions in English. 
10. Are judged to be reliable and agree to keep all appointments for clinic visits, tests, and 


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procedures, including venipuncture, and examinations required by the protocol. 
11. Body mass index (BMI) between 18-40 kg/m2. 
8.2 EXCLUSION CRITERIA 
Patients will be excluded from the study if they meet any of the following criteria:  
1. Are homicidal in the opinion of the Investigator or are at suicidal risk by any of the 
following criteria: 
a. any suicide attempts within 12 months prior to Visit 1 (screening) or any suicidal 
intent, including a plan, within 3 months prior to Visit 1 (screening) 
b. C-SSRS answer of “YES” on item 4 or 5 (suicidal ideation) within 3 months prior 
to Visit 1 (Screening)  
c. Investigator- or computer-administered MADRS score of ≥ 5 on item 10 (suicidal 
thoughts) 
d. by Investigator clinical evaluation 
2. Have a current or previous diagnosis of OCD, PTSD, eating disorder, bipolar I or II 
disorder, psychotic depression, schizophrenia or other psychotic disorder. 
3. Have any other current Axis I DSM-5 disorder other than MDD, which is the focus of 
treatment. 
4. Have any other clinically significant medical condition or circumstance prior to 
randomization that, in the opinion of the Investigator, could affect patient safety, preclude 
evaluation of response, interfere with the ability to comply with study procedures, or 
prohibit completion of the study, such as uncontrolled diabetes mellitus, renal or hepatic 
impairment, coronary artery disease, evidence of significant active cardiac, respiratory, or 
hematologic disease, cancer with < 5 year remission (basal cell carcinoma is not 
excluded), chronic pain, fibromyalgia or gastric bypass. 
5. Have had prior seizures (other than remote history of childhood febrile seizure) or other 
condition that would place the patient at increased risk of seizures or is taking 
anticonvulsants for seizure control. 
6. Have a history of serious head injury (e.g., skull fracture, cerebral contusion, or trauma 
resulting in prolonged unconsciousness), intracranial neoplasm or hemorrhage. 
7. Have had electroconvulsive treatment, transcranial magnetic stimulation or vagal 
stimulation in the 6 months prior to Visit 2 (baseline). 
8. Have initiated psychotherapy or have had a change in psychotherapy (such as Cognitive 
Behavioral Therapy) or other non-pharmacological therapies (such as acupuncture or 
hypnosis) within 6 weeks prior to Visit 2 (baseline) or at any time during the acute phase 
of the study. 
9. Have a visual or physical motor impairment that could interfere with the study tasks. 
10. Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 2x 
upper limit of normal (ULN) or glomerular filtration rate ≤ 60 mL/min at Visit 1 
(screening). 


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11. Positive HCV antibody (Ab), hepatitis B surface antigen (HBs Ag), HAV IgM antibody 
(HAV-Ab [IgM]) or HIV test at Visit 1 (screening).  
12. Have nephritic syndrome, end-stage renal disease (and using renal replacement therapy 
such as hemodialysis or peritoneal dialysis), or a serum creatinine ≥ 2 mg/dL (≥ 172 
µmol/L) at Visit 1 (screening).  
13. Have a thyroid-stimulating hormone (TSH), free T4, or total T3 level outside of the 
established reference range that is deemed clinically significant by the Investigator at 
Visit 1 (screening). Patients previously diagnosed with hyperthyroidism or 
hypothyroidism who have been treated with a stable dose of thyroid supplement for at 
least 3 months prior to Visit 1 (screening) and are clinically and chemically (normal free 
T4) euthyroid will be allowed to participate in the study.  
14. Have any other clinically significant abnormalities (significant would include laboratory 
deviations requiring acute medical intervention or further medical evaluation) in 
laboratory results at screening, including clinical chemistries, hematology, and urinalysis, 
and any clinical information that, in the judgment of the Investigator, should preclude a 
patient’s participation at study entry. 
15. Have ECG abnormalities obtained at Visit 1 (screening) or Visit 2 (baseline) that, in the 
judgment of the Investigator, are clinically significant regarding the patient’s 
participation e.g. QTcF > 450 msec in males, > 470 msec in females, Left Bundle Brunch 
Block, Myocardial Infarction findings with current coronary artery disease. 
16. Have a history of substance or alcohol use disorder within 12 months prior to Visit 1 
(screening) as defined by DSM-5. Note: Nicotine and caffeine use disorder are not 
excluded. 
17. Have a positive urine drug screen at Visit 1 (screening) or Visit 2 (baseline) that has not 
been deemed acceptable by the Medical Monitor (see section 11.4.2). 
18. Use of the following concomitant medications (contact the Sponsor-designated medical 
monitor to determine eligibility when in doubt):  
a. psychoactive medication including stimulants, benzodiazepines and anxiolytics, 
oral antipsychotics, mood stabilizers (carbamazepine, lamotrigine, etc.), lithium, 
antidepressants and hypnotics/sedatives within 5 half-lives of Visit 2 (baseline). 
b. proton pump inhibitors within 5 half-lives of Visit 2 (baseline) 
c. depot antipsychotics, fluoxetine and irreversible monoamine oxidase inhibitors 
within 4 weeks of Visit 2 (baseline) 
19. Are currently taking or have taken within 5 half-lives of Visit 2 (baseline) any 
medications or supplements that are strong inhibitors or inducers of CYP3A4 (see 
Appendix 1). 
20. Have a known hypersensitivity to gelatin capsules. 
21. Are women who are either pregnant or breastfeeding. 
22. Are Investigator site personnel directly affiliated with this study, and/or their immediate 
families.  Immediate family is defined as a spouse, parent, child, or sibling, whether 


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biological or legally adopted. 
23. Are employees of the Sponsor or are employees of any third-party organizations (TPOs) 
involved in study who require exclusion of their employees. 
24. Have participated in a clinical trial or any other type of medical research judged by the 
Investigator to be scientifically or medically incompatible with this study within 30 days 
prior to Visit 1 (screening).  Contact the Sponsor-designated medical monitor to 
determine eligibility when in doubt.  
25. Have previously completed or withdrawn from this study or any other study investigating 
BTRX-246040 (previously called LY2940094). 
26. Not willing to install and maintain smartphone applications for the digital assessments 
throughout participation in the study 
8.2.1 RATIONALE FOR EXCLUSION OF CERTAIN PATIENTS 
The exclusion criteria in section 8.2 are intended to ensure that patients with conditions that 
could be exacerbated by participation in the study are excluded, and that patients with conditions 
that could confound the interpretation of efficacy or safety results are excluded. No patient is to 
be excluded on the basis of race, ethnicity, or gender.  
8.3 DISCONTINUATIONS 
8.3.1 EARLY DISCONTINUATION  
Patients who discontinue from the study early will have end of treatment assessments performed 
as shown in the Schedule of Assessments, Table 1. Every effort will be made to encourage them 
to complete all Visit 7 (week 8) assessments and follow-up visit assessments. 
If early discontinuation occurs, the primary reason will be determined and reported on the study 
completion CRF.  Reasons for early discontinuation listed in the CRF are: Investigator/Physician 
decision, patient decision (withdrawal of consent), Sponsor decision, AE(s), unsatisfactory 
therapeutic effect, and loss to follow-up.  
1. Investigator/Physician Decision 
a. The Investigator/physician decides that the patient should be withdrawn from the study 
for any reason.  For example, the patient is significantly noncompliant with the study 
drug regimen (see section 10.8; Patients with investigational product compliance 
≤ 70% over any 2-week visit interval) 
b. After Visit 2 (baseline) the patient is found to have met an exclusionary criterion or not 
met an entry criterion required for study participation.  
c. The patient is enrolled in any other clinical trial involving an investigational product or 
is enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 


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2. Patient Decision 
a. The patient requests to be withdrawn from the study for any reason. If the reason to 
request withdrawal is an adverse event this should be documented as the primary 
reason for discontinuation. 
3. Sponsor Decision  
a. An Investigator, site personnel performing assessments or patient is unblinded (see 
section 10.6). 
4. The Sponsor stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory or other reasons consistent with applicable laws, regulations and good 
clinical practice (GCP). 
5. Adverse Event  
a. The patient experiences an AE that would necessitate discontinuation of 
investigational product.  If this decision is made because of an SAE or a clinically 
significant laboratory value, the investigational product is to be discontinued and 
appropriate measures are to be taken (see item 5. d. below). The Sponsor or its 
Medical Monitor designee is to be alerted immediately (see section 11.3). 
b. Discontinuation should be considered by the Investigator after consultation with the 
Sponsor or its Medical Monitor designee when a patient has the following abnormal 
liver tests:  
i. ALT or AST > 8 x ULN 
ii. ALT or AST > 5 x ULN for more than 2 consecutive weeks 
iii. ALT or AST > 3 x ULN and total bilirubin level > 2 x ULN 
iv. ALT or AST > 3 x ULN and prothrombin time > 1.5 x ULN 
v. ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%).  
c. If the patient is thought to be at risk of harm to him/herself or others at any time 
during the study, a further psychiatric assessment by the Investigator must be 
conducted. Patients must be discontinued from study participation if they:  
i. are assessed as homicidal 
ii. are actively suicidal (any suicidal ideation with intent or specific plan or 
any suicide attempt) 
iii. are at serious suicidal risk as assessed by the C-SSRS (score of “YES” on 
item 4 or 5) 
iv. score ≥ 5 on item 10 of either the computer- or Investigator-administered 
MADRS item 10.  
The Investigator must assure that these patients receive the appropriate psychiatric 
care and follow-up. 


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d. Any patient who is discontinued from investigational product due to AEs or clinically 
significant laboratory abnormalities will be followed until resolution or clinical 
stabilization. 
e. The Investigator remains responsible for following, through an appropriate healthcare 
option, AEs that caused the patient to discontinue study drug. 
6. Unsatisfactory Therapeutic Effect 
a. If the patient requires treatment with another therapeutic agent for MDD, 
discontinuation from the study will occur prior to introduction of the new agent. 
7.  Loss to Follow-Up 
a. For patients who are lost to follow-up, all steps performed to contact them (dates of 
telephone calls, registered letters, etc.) will be reported in the source documents. The 
Investigators are required to make at least two attempts to contact the patient for a 
follow-up safety visit.  
8. Pregnancy 
a. Study drug treatment will be discontinued for female patients who become pregnant 
during study.  See section 11.3.3 for additional information. 
8.3.2 DISCONTINUATION OF THE STUDY 
The study will be discontinued if the Sponsor judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP.  
 


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9 STUDY PROCEDURES  
A visit window of +/- 1 day is acceptable for all visits with the exception of Visit 2 
(randomization) and Visit 8 (safety follow-up).  Every effort should be made to have the same 
qualified rater perform scales at each visit for a given patient.  As much as possible, schedule the 
patient to complete the PRT/EEfRT tasks at approximately the same time at all visits where they 
are conducted. Only outcome measures or assessment tools provided by the Sponsor for this 
study are allowed to be used. Study drug is administered in clinic at Visits 2, 3, 4, 5, and 6 and 
patients should be reminded to withhold home-dosing on these days. 
9.1 VISIT 1: SCREENING  
Before any screening procedure is performed, patient informed consent must be obtained. After 
obtaining the patient’s informed consent, these procedures will be conducted. The following 
order of procedures is recommended to prioritize eligibility and safety assessments: 
1. The Investigator will conduct/administer the following assessments (*or his/her designee 
where asterisked):  
a. Enter patient information in IWRS* 
b. Height* 
c. Weight* 
d. Allow patient to complete the LICQ*  
e. Computer-administered MADRS followed by the Investigator-administered 
MADRS 
f. Psychiatric history to complete the SCID-CT including personal history of 
traumatic events  
g. C-SSRS  
h. CGI-S 
i. Previous and current MDD psychiatric therapy / pharmacologic / non-
pharmacologic  
j. Self-Harm Supplement Form (SHSF) and if applicable, Self-Harm Follow-up 
Form (SHFU) 
k. Medical history review 
l. Identify substance or alcohol abuse or dependence 
m. Concomitant therapies review* 
n. Physical examination and neurological examination 
o. Vital signs (BP and pulse both supine and standing, respiratory rate, 
temperature)* 
p. 12-lead ECG* 


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q. Blood and urine collection for central laboratory analysis (including urine drug 
screen and serum pregnancy test for women of child-bearing potential)* 
r. Assist patient to download, register and launch digital applications on their 
smartphone device* 
s. Collect and/or monitor digital assessments, as applicable* 
t. Complete the Pre-Randomization Form (PRF) if the PI determines that the patient 
is eligible for randomization. There is no need to submit the PRF if the patient is a 
known screen failure.*  
The screening visit may be completed over two days for scheduling convenience and must be 
completed between 7 and approximately 28 days prior to Visit 2 (baseline). The screening visit 
may be extended to 42 days if needed for washout of concomitant medications, to receive lab or 
ECG reports, or to accommodate scheduling of assessments.  Any additional extension requires 
prior approval from the Sponsor-designated Medical Monitor.   
The Investigator will review the results of the central laboratory tests for inclusion/exclusion 
criteria and submit the PRF to the Sponsor-designated Medical Monitor.  The PRF will be 
reviewed and the Investigator will be notified of the Medical Monitor’s eligibility decision prior 
to Visit 2 (baseline).   
9.2 VISIT 2: BASELINE (DAY 1) 
The following order of procedures is recommended to prioritize eligibility and safety and 
assessments: 
1. The Investigator will conduct/administer the following assessments (*or his/her designee 
where asterisked):  
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. Allow patient to complete Hospital Anxiety and Depression Scale (HADS), Snaith-
Hamilton Pleasure Scale (SHAPS), Dimensional Anhedonia Rating Scale (DARS), 
and pain question; reviewed by site personnel qualified to oversee completeness* 
d. Hamilton Anxiety Rating Scale (HAM-A) 
e. C-SSRS  
f. CGI-S and CGI-I 
g. SHSF and if applicable, SHFU 
h. Concomitant therapies review* 
i. Adverse events review 
j. Neurological examination  
k. Vital signs (BP and pulse both supine and standing, respiratory rate, 
temperature)* 


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l. 12-lead ECG* 
m. Urine drug screen and urine pregnancy test for women of child-bearing potential* 
The Investigator will confirm the patient’s eligibility prior to completing the remaining 
randomization visit procedures. The following order of these procedures is recommended: 
2. Complete randomization via IWRS 
3. The rater will administer the FERT (Note the FERT must not immediately precede or 
follow the EEfRT or PRT)  
4. Blood and urine collection for central laboratory analysis. Note: blood and urine may be 
collected earlier in the visit as long as it precedes administration of the FERT by > 1 
hour. 
5. The rater will administer the Probabilistic Reward Task (PRT) and Effort Expenditure for 
Reward Task (EEfRT) in the order assigned by IWRS 
6. Collect and/or monitor digital assessments, as applicable 
7. After completing all study procedures, the patient will take their first dose of 
investigational study drug (one capsule) with a light snack at the site from the bottle 
dispensed at this visit 
8. Collect two blood samples for pharmacokinetic analysis (one between 15 min and 2 
hours after dosing and another between 4 and 8 hours after dosing) 
9. Dispense allocated study drug and instruct patient on the importance of compliance and 
returning the dispensed bottle with any unused study drug at each visit.   
10. Instruct all patients to take one capsule of their assigned study drug daily and not 
take study drug the day of their next visit.  
The Investigator will review the results of the central laboratory tests for safety prior to the next 
visit. 
9.3 VISIT 3: WEEK 1 (DAY 8) DOSE ESCALATION 
The following order of procedures is recommended to prioritize safety and efficacy assessments: 
1. The Investigator will conduct/administer the following assessments (*or his/her designee 
where asterisked): 
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. Allow patient to complete SHAPS; reviewed by site personnel qualified to oversee 
completeness* 
d. C-SSRS  
e. CGI-I 
f. SHSF and if applicable, SHFU  
g. Concomitant therapies review* 
h. Adverse events review 


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i. Neurological examination 
j. Vital signs (BP and pulse both supine and standing, respiratory rate, 
temperature)* 
2. The rater will administer the FERT  
3. Collect and/or monitor digital assessments, as applicable 
4. Blood and urine collection for central laboratory analysis (including urine pregnancy test 
for women of child-bearing potential). Note: blood and urine may be collected earlier in 
the visit as long as it precedes administration of the FERT by > 1 hour. 
5. The patient-returned investigational study drug will be accounted for and patient will be 
re-instructed if found to be out of compliance 
6. Complete IWRS and dispense allocated study drug 
7. Collect three blood samples for pharmacokinetic analysis at the following time points: (1) 
prior to dosing, (2) between 15 min and 2 hours after dosing, and (3) between 4 and 8 
hours after dosing 
8. After completing the pre-dose pharmacokinetic blood sample, the patient will take the 
increased dose of investigational study drug (i.e., two capsules) with a light snack at 
the site from the bottle dispensed at this visit 
9. Dispense allocated study drug and instruct patient on the importance of compliance and 
returning the dispensed bottle with any unused study drug at each visit.   
10. Instruct all patients to take two capsules of their assigned study drug daily, and not 
take study drug the day of their next clinic visit. 
The Investigator will review the results of the central laboratory tests for safety prior to the next 
visit.  
9.4 VISIT 4: WEEK 2 (DAY 15)  
The following order of procedures is recommended to prioritize safety and efficacy assessments: 
1. The Investigator will conduct/administer the following assessments (*or by his/her 
designee where asterisked): 
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. Allow patient to complete SHAPS and pain question; reviewed by site personnel 
qualified to oversee completeness* 
d. C-SSRS  
e. CGI-I 
f. SHSF and if applicable, SHFU  
g. Concomitant therapies review* 
h. Adverse events review 
i. Neurological examination 


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j. Vital signs (BP and pulse both supine and standing, respiratory rate, 
temperature)* 
2. The rater will administer the FERT  
3. Collect and/or monitor digital assessments, as applicable  
4. The patient-returned investigational study drug will be accounted for and patient will be 
re-instructed if found to be out of compliance 
5. The Investigator will assess tolerability and decrease the investigational study drug 
dose via IWRS if deemed appropriate 
6. Complete IWRS 
7. Blood and urine collection for central laboratory analysis (including urine pregnancy test 
for women of child-bearing potential). Note: blood and urine may be collected earlier in 
the visit as long as it precedes administration of the FERT by > 1 hour. 
8. After completing all study procedures, the patient will take their investigational study 
drug at the tolerated dose (i.e., either two capsules or one capsule) with a light snack at 
the site from the bottle dispensed at this visit  
9. Dispense allocated study drug and instruct patient on the importance of compliance and 
returning the dispensed bottle with any unused study drug at each visit.  
10. Instruct all patients to take their assigned study drug dose daily, and not take study drug 
the day of their next clinic visit. 
The Investigator will review the results of the central laboratory tests for safety prior to the next 
visit. 
9.5 VISIT 5, WEEK 4 (DAY 29) 
The following order of procedures is recommended to prioritize safety and efficacy assessments: 
1. The Investigator will conduct/administer the following assessments (*or by his/her 
designee where asterisked): 
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. Allow patient to complete HADS, SHAPS, DARS, and pain question; reviewed 
by site personnel qualified to oversee completeness* 
d. HAM-A 
e. C-SSRS  
f. CGI-I 
g. SHSF and if applicable, SHFU  
h. Concomitant therapies review* 
i. Adverse events review 
j. Neurological examination 
k. Vital signs (BP and pulse both supine and standing, respiratory rate, 


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temperature)* 
l. 12-lead ECG* 
2. Blood and urine collection for central laboratory analysis (including urine pregnancy test 
for women of child-bearing potential) 
3. The patient-returned investigational study drug will be accounted for and patient will be 
re-instructed if found to be out of compliance 
4. Complete IWRS 
5. The rater will administer the PRT and EEfRT in the order assigned by IWRS 
6. Collect and/or monitor digital assessments, as applicable 
7. Collect three blood samples for pharmacokinetic analysis at the following time points: (1) 
prior to dosing, (2) between 15 min and 2 hours after dosing, and (3) between 4 and 8 
hours after dosing 
8. After completing all study procedures including the pre-dose pharmacokinetic blood 
sample, the patient will take their dose of investigational study drug from the bottle 
dispensed at this visit with a light snack at the site 
9. Dispense allocated study drug and instruct patient on the importance of compliance and 
returning the dispensed bottle(s) with any unused study drug at each visit.  
10. Instruct all patients to take their assigned study drug dose daily, and not take study drug 
the day of their next clinic visit. 
The Investigator will review the results of the central laboratory tests for safety prior to the next 
visit. 
9.6 VISIT 6, WEEK 6 (DAY 43) 
The following order of procedures is recommended to prioritize safety and efficacy assessments: 
1. The Investigator will conduct/administer the following assessments (*or his/her designee 
where asterisked): 
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. C-SSRS  
d. Allow patient to complete pain question; reviewed by site personnel qualified to 
oversee completeness* 
e. CGI-I 
f. SHSF and if applicable, SHFU  
g. Concomitant therapies review* 
h. Adverse events review 
i. Neurological examination 
j. Vital signs (BP and pulse both supine and standing, respiratory rate, 


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temperature)* 
2. Blood and urine collection for central laboratory analysis (including urine pregnancy test 
for women of child-bearing potential) 
3. Collect and/or monitor digital assessments, as applicable 
4. The patient-returned investigational study drug will be accounted for and patient will be 
re-instructed if found to be out of compliance 
5. Complete IWRS and dispense allocated study drug  
6. After completing all study procedures, the patient will take their investigational study 
drug with a light snack at the site from the bottle dispensed at this visit  
7. Instruct patient on the importance of compliance and returning the dispensed bottle(s) 
with any unused study drug at each visit.  
8. Instruct all patients to take their assigned study drug dose daily and not take study drug 
the day of their next clinic visit. 
The Investigator will review the results of the central laboratory tests for safety prior to the next 
visit. 
9.7 VISIT 7, WEEK 8 (DAY 57) END OF TREATMENT 
Special effort will be made by the site to encourage patients who discontinue from the study 
early to complete all Visit 7 (week 8) assessments and safety follow-up visit assessments. If the 
patient does not attend the discontinuation visit, the C-SSRS should be completed if the site has 
become aware of a potential suicide-related thought of behavior by other communications.  The 
following order of procedures is recommended to prioritize safety and efficacy assessments: 
1. The Investigator will conduct/administer the following assessments (*or his/her designee 
where asterisked): 
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. Allow patient to complete HADS, SHAPS, DARS, and pain question; reviewed 
by site personnel qualified to oversee completeness* 
d. HAM-A 
e. C-SSRS  
f. CGI-I 
g. SHSF and if applicable, SHFU 
h. Concomitant therapies review* 
i. Adverse events review 
j. Neurological examination 
k. Vital signs (BP and pulse both supine and standing, respiratory rate, 
temperature)* 
l. 12-lead ECG * 


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2. Blood, pharmacokinetic, and urine collection (including urine drug screen and local urine 
pregnancy test for women of child-bearing potential)* 
3. Collect and/or monitor digital assessments, as applicable 
4. The patient-returned investigational study drug will be accounted for 
5. Complete IWRS  
6. The rater will administer the PRT and EEfRT in the order assigned by IWRS. 
The Investigator will review the results of the central laboratory tests for safety prior to the next 
visit. 
9.8 VISIT 8, SAFETY FOLLOW-UP 
This visit will be conducted approximately 7-14 days after patients complete their study drug. 
The following order of procedures is recommended to prioritize safety and efficacy assessments: 
1. The Investigator will conduct/administer the following assessments (*or his/her designee 
where asterisked): 
a. Weight* 
b. Investigator-administered MADRS followed by the computer-administered 
MADRS  
c. C-SSRS  
d. CGI-I 
e. SHSF and if applicable, SHFU  
f. Concomitant therapies review* 
g. Adverse events review 
h. Neurological examination 
i. Vital signs (BP and pulse both supine and standing, respiratory rate, 
temperature)* 
2. Collect and/or monitor digital assessments, as applicable 
3. Blood and urine collection (including local urine pregnancy test for women of child-
bearing potential) 
4. Any remaining patient-returned investigational study drug will be accounted for 
5. Complete IWRS 
6. After all study assessments are complete, assist patient to remove digital applications 
from their smartphone device, as applicable. 


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Table 1  Schedule of Assessments  
 
Schedule of Assessments 
Screening 
Period 
Baseline 
Study Drug Treatment   
End of 
Treatment l 
Safety 
Follow-Up 
 
Visit 
1a 
2 
3 
4 
5 
6 
7 
8 
 
Day 
D (-7 to -28) 
D1 
D8 
D15 
D29 
D43 
D57 
  
 
Week 
  
W0 
W1 
W2 
W4 
W6 
W8 
W9  - 10 
 
Clinician-administered Clinical Assessments  
 
SCID-CT  
X 
  
  
  
  
  
  
  
 
CGI-S  
X 
X 
  
  
  
  
  
  
 
CGI-I  
  
X 
X 
X 
X 
X 
X 
X 
 
HAM-A 
  
X 
  
  
X 
  
X 
  
 
C-SSRS   
X 
X 
X 
X 
X 
X 
X 
X 
 
Investigator- and computer-administered 
MADRS   
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/exclusion criteria  
X 
X b 
  
  
  
  
  
  
 
Neurological examination  
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical/psychiatric history  
X 
  
  
  
  
  
  
  
 
Previous and current MDD psychiatric 
therapy/pharmacologic and non-pharmacologic  
X 
 
 
 
 
 
 
 
 
Personal history: traumatic events 
X 
 
 
 
 
 
 
 
 
Demographics & baseline habits 
X 
  
  
  
  
  
  
  
 
Physical examination  
X 
  
  
  
  
  
  
  
 
Study Assessments 
 
Informed consent (before procedures/tests)  
X 
  
  
  
  
  
  
  
 
Height  
X 
  
  
  
  
  
  
  
 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Medication Activities  
 
Dispense and administer /study drug c 
  
Xc1 
Xc2 
Xc3 
X 
X 
  
  
 
Study drug compliance 
  
X 
X 
X 
X 
X 
X 
  
 
Safety Assessments  
 
Adverse events review 
  
X 
X 
X 
X 
X 
X 
X 
 
Vital signs d  
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG  
X 
X 
 
 
X 
  
X 
  
 
Concomitant therapies review  
X 
X 
X 
X 
X 
X 
X 
X 
 
SHSF, and SHFU as appropriate 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine drug and alcohol screen  
X 
X 
  
  
  
  
X 
  
 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test e 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry, including Amylase and 
Lipase 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function tests  
X 
  
  
  
  
  
  
  
 
Hepatitis screen  
X 
  
  
  
  
  
  
  
 
Hepatic monitoring f 
X 
  
  
  
  
  
  
  
 


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Schedule of Assessments 
Screening 
Period 
Baseline 
Study Drug Treatment   
End of 
Treatment l 
Safety 
Follow-Up 
 
Visit 
1a 
2 
3 
4 
5 
6 
7 
8 
 
Day 
D (-7 to -28) 
D1 
D8 
D15 
D29 
D43 
D57 
  
 
Week 
  
W0 
W1 
W2 
W4 
W6 
W8 
W9  - 10 
 
Other Blood Collections 
 
PK sample 
  
X 
X 
  
X 
  
X 
  
 
Nonpharmacogenetic biomarker samples  
  
X 
  
  
  
  
X 
  
 
Pharmacogenetic sample 
  
X 
  
  
  
  
  
  
 
ePatient Reported Outcome Assessments  
 
LICQ 
X g 
  
  
  
  
  
  
  
 
Pain question 
  
X 
  
X 
X 
X 
X 
  
 
HADS 
  
X 
  
  
X 
  
X 
  
 
DARS 
  
X 
  
  
X 
  
X 
  
 
SHAPS 
  
X 
X 
X 
X 
  
X 
  
 
Emotional Tasks 
 
FERT h 
  
X 
X 
X 
  
  
  
  
 
Behavioral Tasks i 
 
PRT 
  
X 
  
  
X 
  
X 
  
 
EEfRT 
  
X 
  
  
X 
  
X 
  
 
Digital Assessments j 
 
Collect/monitor digital assessments k 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Visit 1 procedures may be completed over 2 days, if necessary and extended for up to 42 days if needed for washout. 
b 
Eligibility must be re-confirmed prior to randomization. 
c 
 
c1 
c2 
c3 
Patients will take their study drug in the clinic from the bottle dispensed that day with a light snack. If a patient discontinues before completing the study 
drug treatment, an effort should be made to obtain a blood sample at the time of discontinuation 
All patients initiate dosing with 40 mg (one capsule) through week 1 
All patients increase dosing to 80 mg (two capsules)  
The dose may be decreased back to 40 mg (one capsule) anytime through Visit 4 (week 2), if required, for tolerability 
d 
Collect BP and pulse in supine and standing; collect RR and temperature in any position 
e 
Serum pregnancy test at Visit 1 (screening) performed by a Sponsor-designated laboratory; urine pregnancy tests will be performed at subsequent visits 
by the site for all women of childbearing potential (women not surgically sterilized and between menarche and 2 years postmenopausal). 
f 
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient follow-up, in consultation with the 
Sponsor-designated Medical Monitor. 
g 
Patient completes the LICQ before clinician SCID-CT interview. 
h 
The rater administers the FERT prior to blood draw collections or at least 1 hour after blood draw collection.  The FERT should not immediately precede 
or follow the PRT/EEfRT. 
i 
As much as possible, schedule the patient to complete the PRT/EEfRT tasks at approximately the same time at all visits where they are conducted. The 
patient will complete the tasks in the order assigned by IWRS. 
j 
At the screening visit, assist patient to download, register and launch digital applications on their smartphone device, as applicable. 
k 
Schedule assignments for patients who have downloaded the app to complete “in clinic” and  “out of  clinic”  vocal samples. Out of clinic assignments 
should be assigned on a weekday approximately 2-3 days after a clinic visit. 
l 
Patients who discontinue early from the study should be encouraged to complete the End of Treatment visit assessments.  If the patient does not attend 
the discontinuation visit, the C-SSRS should be completed if the site has become aware of a potential suicide-related thought of behavior by other 
communications.  
 
 


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10 TREATMENT 
10.1 TREATMENTS ADMINISTERED 
This study involves a comparison of BTRX-246040 versus placebo taken orally once daily for 8 
weeks. Treatment will be initiated at 40 mg (1 capsule) once daily for approximately one week 
then will be increased to 80 mg (2 capsules) once daily at Visit 3 (week 1). One dose reduction 
back to 40 mg (1 capsule) once daily will be allowed through Visit 4 (week 2) for patients who 
cannot tolerate the 80 mg (2 capsule) dose. Refer to section 10.5 for timing of dose 
administration.  Table 2 shows the treatment regimens.  
Table 2 Treatment Regimens  
Treatment Group 
Regimen* 
BTRX-246040 
40 mg (1 capsule BTRX-246040) orally QD x 1 week, then  
80 mg (2 capsules BTRX-246040) orally QD x 7 weeks 
Placebo 
 1 capsule orally QD x 1 week, then 
 2 capsules orally QD x 7 weeks 
* dose reduction back to 40 mg (1 capsule) once daily will be allowed through Visit 4 (week 2) 
The Investigator or his/her designee is responsible for explaining the correct use of the 
investigational product to the patient and site personnel, verifying that instructions are followed 
properly, maintaining accurate records of investigational product dispensing and collection, and 
returning all unused medication to the Sponsor or its designee at the end of the study.  
10.2 MATERIALS AND SUPPLIES 
BTRX-246040 and placebo capsules and packaging will be identical to maintain Investigator and 
patient blinding. Patients should be instructed to swallow capsules whole and not crush or chew 
and store the capsules in their original packaging at the temperature listed on the package label. 
Clinical trial materials will be labeled according to the regulatory requirements.  
10.3 METHOD OF ASSIGNMENT TO TREATMENT 
Patients who meet all inclusion criteria and are subsequently not excluded by the exclusion 
criteria will be randomized to double-blind treatment at Visit 2 (baseline) using an interactive 
web-response system (IWRS). Patients will be randomized in a 1:1 ratio to one of two treatment 
arms (placebo or BTRX-246040 QD). Randomization will be stratified by anhedonia symptom 
severity, as indicated by SHAPS total score ≤ 4 and total score > 4. The order in which the PRT 
and EEfRT administrations are conducted will be assigned via IWRS.   
The IWRS will be used to assign bottles containing double-blind investigational product or 
placebo to each patient. Site personnel may be required to confirm that they have located the 
correct bottles by entering a confirmation number found on the package label into the IWRS 
prior to dispensing the bottle(s) to the patient (see section 10.5).  


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10.4 RATIONALE FOR SELECTION OF DOSES IN THE STUDY 
The starting dose for this study will be 40 mg QD taken for 1 week.  A dose of 40 mg BTRX-
246040 given QD has been tested and was well-tolerated in two efficacy studies, in male and 
female patients with MDD (Study NOAC) and male and female patients with AD (Study 
NOAD).  There were no deaths or SAEs with BTRX-246040 administration in either study. In 
study NOAC, the most common TEAEs that occurred more frequently with BTRX-246040 than 
placebo were nausea (7/69 [10.1%] vs. 1/65 [1.5%] patients), insomnia (7/69 [10.1%] vs. 0/65 
patients) and dizziness (5/69 [7.2%] vs. 0/65 patients). In study NOAD, the frequency of TEAEs 
reported was similar between the BTRX-246040 and placebo treatment groups. In both studies, 
most TEAEs were mild or moderate in severity. There were no notable treatment-related clinical 
laboratory findings or abnormal ECGs. Vital signs were generally within normal ranges, with no 
notable treatment-related changes reported following 40 mg QD BTRX-246040. In both studies, 
no increase in suicidal ideation or behavior relative to placebo was detected following BTRX-
246040 administration, as assessed by the C-SSRS.  
In male healthy volunteer study NOAA, BTRX-246040 was shown to be safe and well-tolerated 
up to 800 mg given as a single dose and up to 200 mg QD after multiple dosing for 14 days. In 
general, the observed BTRX-246040 concentration time data in patients with MDD were in a 
similar range to the concentrations observed in this healthy subject study when the data were 
compared after normalizing for administered dose.  In this study, observed Cmax estimates after 
dosing 40 mg QD for 14 days ranged from 87.9 to 183 ng/mL (mean=127 ng/mL). The exposure 
multiple to the lowest convulsive dose in the nonclinical study in dogs is 19X and the exposure 
multiple to 1/10th the convulsive threshold in dogs is approximately 2X based on the mean 
Cmax at 40 mg.  
The 40 mg dose was well-tolerated in two separate Phase 2 studies (n = 113 male and female 
patients treated with BTRX-246040) and a trend towards efficacy in MDD was observed 
although the MDD study did not meet the success criteria of the primary endpoint.  For this 
reason, dose titration from 40 mg to 80 mg QD based on individual patient tolerability will be 
employed in the current study to further explore the effective dose range. A dose decrease to 40 
mg QD will be allowed if the 80 mg QD dose is not tolerated.   
10.5 SELECTION AND TIMING OF DOSES 
BTRX-246040 has only been dosed with a light breakfast in clinical pharmacology studies to 
date; there are currently no PK data available for BTRX-246040 when dosed in the fasted 
state. Therefore, in the current study, patients will take the investigational study drug orally 
at approximately the same time every morning with a light breakfast.   
All patients will be instructed to take their first dose of BTRX-246040 or placebo on the day 
of Visit 2 (baseline) after completing all baseline study procedures. Patients will take their 
study drug in the clinic with a light snack.  


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Patients will be instructed to refrain from taking their investigational study drug at home on 
the morning of Visits 3, 4, 5, and 6. Study drug will be administered with a light snack at the 
site from the bottle dispensed at the visit. 
10.6 BLINDING 
This is a double-blind study. Patients, site personnel, and the Sponsor will be blinded to 
treatment.  
Emergency unblinding for AEs must be performed through the IWRS. This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment. All 
requests resulting in an unblinding event are recorded and reported by the IWRS.  
The Investigator should make every effort to contact the medical monitor prior to unblinding a 
patient’s treatment assignment. If an Investigator, site personnel performing the assessments, or 
patient is unblinded, the patient must be discontinued from the study. In cases where there are 
ethical reasons to have the patient remain in the study, the Investigator must obtain specific 
approval from the Sponsor-designated Medical Monitor for the patient to continue in the study.  
10.7 CONCOMITANT THERAPIES 
In general, concomitant medications with primarily CNS activity are not allowed in the study. 
The Investigator should instruct the patient to notify the study site about any new medications 
he/she takes and about any significant non-pharmacological therapies administered after the start 
of the study drug (e.g. acupuncture, hypnosis etc.). All medications, including over the counter 
medications and supplements, and also significant non-pharmacological therapies, administered 
after the patient starts treatment with study drug must be listed on the corresponding CRFs.  
10.8 TREATMENT COMPLIANCE WITH INVESTIGATIONAL PRODUCT 
Each patient will be instructed to return all investigational product packaging and unused 
material to the study site at each visit. The study site will keep a record of all drug dispensed to 
and returned by the patients throughout the study.  
Patient compliance with BTRX-246040 or placebo will be assessed by direct questioning and 
counting returned capsules.   
For patients who demonstrate noncompliance (patient has taken < 80% or ≥120% of the 
prescribed dosage for a visit interval), investigative sites must counsel patients on the importance 
of investigational product compliance. Any missed investigational product or extra dose of 
investigational product will be recorded as a protocol deviation.  
Patients with investigational product (BTRX-246040 or placebo) compliance ≤ 70% over any 2-
week visit interval (beginning with the Visit 2 [baseline] to Visit 4 [week 2] interval) will require 
early discontinuation.  


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11 SAFETY, EFFICACY EVALUATIONS, SAMPLE COLLECTION AND TESTING, AND 
APPROPRIATENESS OF MEASUREMENTS  
Study procedures and their timing are summarized in the Schedule of Assessments (Table 1).  
All scales and tasks will be completed and/or administered by qualified and trained site raters 
who meet the training requirements and qualifications of the scale or task standards set by the 
Sponsor and training vendors. 
11.1 EFFICACY MEASURES 
11.1.1 MONTGOMERY-ASBERG DEPRESSION RATING SCALE (MADRS) 
The MADRS is a semi-structured, Investigator-administered interview to assess the severity of 
depression among patients with a diagnosis of depression. It is designed to be sensitive to change 
resulting from antidepressant therapy. (Montgomery, 1979). 
The MADRS includes 10 items assessing the following symptoms: apparent sadness, reported 
sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, 
inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (absence 
of symptom) to 6 (severe symptom); the overall score ranges from 0 to 60. MADRS total scores 
from 0 to 6 indicate normal/symptom absent, from 7 to 19 indicate mild depression, from 20 to 
34 indicate moderate depression, and from 35 to 60 indicate severe depression.  
The MADRS-6 subscale focuses on the core symptoms of depression and is the sum of items 
about the following symptoms: apparent sadness, reported sadness, inner tension, lassitude, 
inability to feel, and pessimistic thoughts. Overall score ranges from 0 to 36. 
The MADRS will be administered by qualified and trained Investigator site raters.  Every effort 
should be made to have the same rater perform this scale at each visit for a given patient.   
A tandem assessment process will be used to administer and rate the MADRS. Two MADRS 
administrations will be conducted using a secure computer device.  One will be administered by 
a qualified site Investigator. The second will be computer-administered and will consist of a 
series of probe and follow-up questions with multiple-choice response options to be completed 
by the patient.  
The Investigator-administered MADRS scores will be compared the computer-administered 
MADRS scores. This will ensure that the MADRS is administered in a reliable, consistent 
manner throughout the study and avoids potential introduction of bias. 
At Visit 1 (screening), the computer-administered MADRS will be conducted prior to the 
Investigator-administered MADRS.  At all other visits, the Investigator-administered MADRS 
will be conducted first. 


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The Investigator-administered MADRS data will be collected and maintained independently 
from the computer-administered MADRS data. Investigator-administered MADRS scores will 
never be altered or adjusted.  
11.1.2 SNAITH HAMILTON PLEASURE SCALE (SHAPS) 
The SHAPS is a 14-item self-report instrument which measures anhedonia. It has been shown to 
be valid and reliable in normal and clinical samples. The scale will be completed by the patient 
and reviewed by site personnel qualified to oversee completeness. Each of the 14 items has a set 
of four responses, two of which endorse agreement (Definitely Agree, Agree) and two of which 
endorse disagreement (Disagree, Strongly Disagree). Under the original scoring method, 
responses endorsing agreement receives a score of 0 and responses endorsing disagreement 
receive a score of 1. The total score ranges from 0 to 14. A higher total score indicates higher 
levels of state anhedonia (Snaith 1995).  In this study, in additional to the traditional scoring 
method, an alternative scoring method will assign 1 = Strongly Agree, 2 = Agree, 3 = Disagree, 4 
= Strongly Disagree.  Under this scoring method, total score ranges from 14 to 56, with higher 
scores indicating higher levels of anhedonia. 
11.1.3 CLINICAL GLOBAL IMPRESSION SCALE – SEVERITY (CGI-S) 
The Clinical Global Impression Scale – Severity (CGI-S) is a clinician-rated instrument that 
measures the severity of depression at the time of assessment.  This rating is based upon 
observed and reported symptoms, behavior, and function in the past seven days. The score 
should reflect the average severity level across the seven days.  The CGI-S is scored on a 7-point 
scale where a score of 1 indicates that the patient is “normal, not at all ill” a score of 4 indicates 
that the patient is "moderately ill" and a score of 7 indicates that the patient is “among the most 
extremely ill patients.” (Guy 1976). 
This scale will be completed by qualified and trained Investigator site raters. Every effort should 
be made to have the same rater perform this scale at each visit for a given patient. 
11.1.4 CLINICAL GLOBAL IMPRESSION SCALE – IMPROVEMENT (CGI-I) 
The CGI-I scale (Guy 1976) is a clinician-rated instrument that measures the improvement of the 
patient’s symptoms. It is a 7-point scale where a score of 1 indicates that the patient is “very 
much improved,” a score of 4 indicates that the patient has experienced “no change,” and a score 
of 7 indicates that the patient is “very much worse.” 
This scale will be completed by qualified and trained Investigator site raters. Every effort should 
be made to have the same rater perform this scale at each visit for a given patient. 
11.1.5 PAIN QUESTION 
The patient will rate a single item to assess their average pain in the last 24 hours.  The item will 
be reviewed by site personnel qualified to oversee completeness. The pain question is scored 
from 0 (no pain) to 10 (pain as severe as you can imagine). 


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11.1.6 HAMILTON ANXIETY RATING SCALE (HAM-A) 
The HAM-A is administered to assess severity of anxiety, its improvement during the course of 
treatment, and the timing of such improvement (Hamilton 1960). This instrument will be 
completed by qualified and trained Investigator site raters based on his/her assessment of the 
patient. The scale consists of 14 items. Each item is rated on a scale of 0 (feeling not present) to 
4 (very severe prevalence of the feeling). The HAM-A total score is the sum of the 14 items and 
the score ranges from 0 to 56. 
11.1.7 DIMENSIONAL ANHEDONIA RATING SCALE (DARS) 
The DARS is a dynamic self-report scale that measures desire, motivation, effort and 
consummatory pleasure across hedonic domains.  The patient will complete the scale and it will 
be reviewed by site personnel qualified to oversee completeness. It is a 17-item self-report 
measure that consists of 4-component structure mapping onto the domains of anhedonia: 
hobbies, food/drink, social activities, and sensory experience (Rizvi, et al. 2015). 
11.1.8 PROBABILISTIC REWARD TASK (PRT) 
The PRT is a measure of reward learning consisting of trials in which patients are asked to 
respond to two hardly distinguishable cues, of which one is more frequently rewarded.  The task 
will be administered to the patient and reviewed by site personnel qualified to oversee 
completeness. Response bias for the rewarded category is the main outcome of interest 
(Pizzagalli, et al, 2008).  Other outcomes include discriminability (subject’s ability to 
differentiate between the two cues), accuracy (hit rates), and reaction time.  This task will be 
completed by the patient using the Sponsor-provided study equipment. The order of 
administration of the PRT will be assigned by IWRS. 
11.1.9 EFFORT EXPENDITURE FOR REWARD TASK (EEFRT) 
The EEfRT was developed in an effort to dissociate reward components in anhedonia. The task 
will be administered to the patient and reviewed by site personnel qualified to oversee 
completeness. The EEfRT task is a multi-trial game in which participants are given an 
opportunity on each trial to choose between two different task difficulty levels in order to obtain 
monetary rewards.  Patients are required to complete the task with a specific number of button 
responses within a constrained period of time in order to obtain a monetary reward.  This task 
isolates patient willingness to exert effort relative to size and likelihood of reward that measures 
reward "wanting", in contrast to commonly used anhedonia questionnaires, which focus on 
reward "liking”. (Treadway et al, 2009).  This task will be completed by the patient using the 
Sponsor-provided study equipment. The order of administration of the EEfRT will be assigned 
by IWRS. 
 
 


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11.1.10 
THE FACIAL EXPRESSION RECOGNITION TASK (FERT) 
The FERT is a computer test used to assess attention to, and perception of, social cues and 
affective information. The task will be administered to the patient and reviewed by site personnel 
qualified to oversee completeness. Faces with 6 different basic emotions (happiness, fear, anger, 
disgust, sadness, surprise) are displayed on the screen and the patient is required to indicate the 
expression of the face via a button-press.  Different intensity levels of each emotion are 
presented, which increases the ambiguity of the facial expression and the sensitivity of the task 
(Harmer et al, 2009).  This task will be completed by the patient using the Sponsor-provided 
study equipment. The FERT will be completed prior to blood draw collections and should not 
immediately precede or follow the PRT/EEfRT. 
11.1.11 
DIGITAL ASSESSMENTS 
Vocal and/or behavioral digital assessments will be conducted with HIPAA compliant digital 
applications that have been download onto the patient’s smartphone with an iOS or Android 
operating system. The applications will be used for active collection of brief vocal samples for 
subsequent analysis of acoustic features that are associated with affective states and for passive 
acquisition of metadata to assess behavioral patterns that are associated with affective or 
cognitive states. Baseline values will be collected during the screening period prior to the first 
dose of study drug. Post-baseline values will be collected at periodic intervals during the study to 
be analyzed for potential treatment effects (analysis to be performed in a separate report). Digital 
samples will be reviewed by site personnel qualified to oversee completeness. 
11.1.12 
HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) 
The HADS measures levels of anxiety and depression without regards to somatic symptoms 
(Zigmond and Snaith, 1983). The scale consists of 14 items.  Seven of the items are used to 
evaluate anxiety and seven evaluate depression. Each item on the questionnaire is scored from 0 
to 3. Therefore, the anxiety subscale (HADS-A) and the depression subscale (HADS-D) each 
range from 0 to 21.  Higher scores indicate higher levels of anxiety and depression, respectively. 
11.2 ASSESSMENTS ONLY AT VISIT 1 (SCREENING) 
11.2.1 THE STRUCTURED CLINICAL INTERVIEW FOR DSM-5, CLINICAL TRIALS VERSION 
(SCID-CT) 
The SCID-CT will be completed by qualified and trained Investigator site raters. The interview 
begins with an overview section, which is abridged to entail questions relevant to the current 
clinical trial. In this version of the SCID, only essential elements for MDD incorporating typical 
inclusion and exclusion criteria are included. Also, the subtypes and specifiers have been 
eliminated, and criteria ratings have been streamlined into a “-” and “+” format. Current and 
lifetime history will be collected. 


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11.2.2 LIFETIME ILLNESS CHARACTERISTICS QUESTIONNAIRE (LICQ)   
Patients will complete a computer-administered diagnostic validation assessment, ideally prior to 
the Investigator-administered SCID-CT, on a secure computer device provided to the site. The 
LICQ will collect data about the patient’s history relative to a lifelong history of MDD and the 
current major depressive episode. The patient’s diagnostic information, based on the responses to 
the computerized interview, will be reviewed by the Sponsor-designated independent clinical 
reviewer.  Any uncertainty raised by the patient’s responses on the diagnostic interview will be 
discussed with the Investigator/site clinician. 
11.3 SAFETY MEASURES 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  
The Investigator is responsible for the appropriate medical care of patients during the study.  
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the patient to discontinue before completing the study. The 
patient should be followed until the event is resolved or explained. Frequency of follow-up 
evaluation is left to the discretion of the Investigator.  
11.3.1 ADVERSE EVENTS 
An AE is any sign, symptom, illness, clinically significant abnormal laboratory value or ECG 
finding, or other untoward medical occurrence associated with the use of an investigational 
product that appears or worsens in a subject during a clinical study.  This definition does not 
imply a causal relationship between the AE and the investigational product.   
Adverse events beginning with the initial dose of investigational product or during the 
subsequent duration of their enrollment in the study will be considered treatment-emergent AEs 
(TEAE).  TEAEs will be recorded on the AE CRF to include the event, date of onset, whether 
the AE is associated with an episode of self-harm, severity, frequency, seriousness, date of 
resolution, action taken with respect to the AE (e.g., discontinue study drug, begin concomitant 
medication, begin non-pharmacological treatment, etc.), outcome, and relationship to the 
investigational product.  All TEAEs related to study drug will be followed through resolution or 
30 days after the patient terminates from the study, whichever occurs first.   
Medical conditions present or AEs occurring prior to the first dose of investigational product will 
be captured as medical history in the CRF.  Any AE occurring during the study that is related to 
a pre-existing condition or event that worsens in intensity or frequency after the first dose of 
investigational product will be recorded as a TEAE.  
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect.  


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11.3.2 OVERDOSE 
In the event of an overdose of study drug, the Investigator should use clinical judgment in 
treating the overdose and contact the Sponsor-designated Medical Monitor, or designee.  The 
Investigator should refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the study 
drug.  Such documentation may include, but not be limited to the Investigator’s Brochure. 
11.3.3 PREGNANCY 
Any pregnancy that occurs from baseline after study drug exposure until study completion must 
be reported to the Sponsor-designated Medical Monitor on a Pregnancy Notification Form within 
24 hours of learning of its occurrence. 
Each pregnancy must be reported as well to the Sponsor-designated Medical Monitor within 24 
hours of learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child. 
11.3.4 SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that results in one of the following outcomes, 
regardless of the Investigator’s opinion of causation: 
1. death 
2. initial or prolonged inpatient hospitalization 
a. Surgeries planned prior to signing the ICF will not be considered SAEs. However, 
worsening of the underlying medical condition during the study will be considered 
an AE and must be captured as serious if any SAE-defining outcomes occur as a 
result. 
3. a life-threatening experience (that is, immediate risk of dying) 
4. persistent or significant disability/incapacity 
5. congenital anomaly/birth defect 
6. other medically important serious event as determined by the Investigator (for example, an 
AE that jeopardizes the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition).    
If a patient experiences an SAE after signing informed consent, but prior to receiving 
investigational product, the event will be captured as medical history in the CRF and not 
submitted as reportable-event unless the Investigator feels the event may have been caused by a 
protocol procedure. 
SAEs reported after a patient has taken the last dose of investigational product will be collected 
in the pharmacovigilance system for 30 days after the last dose of investigational product. 


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Thereafter, only SAEs that the Investigator feels were related to the investigational product or a 
protocol procedure must be reported. 
All SAEs must be captured on a study-specific SAE form in addition to the AE CRF.  Study site 
personnel must alert the Sponsor-designated Medical Monitor of the SAE and must submit the 
completed study-specific SAE form to the Sponsor-designated Medical Monitor within 24 hours 
of the site’s awareness of the SAE. 
The Investigator and supporting personnel responsible for patient care should discuss with the 
Sponsor-designated Medical Monitor or designee any need for supplemental investigations of 
SAEs. The results of these additional assessments conducted must be reported to the Sponsor-
designated Medical Monitor. If a patient death occurs during participation in the study and a 
post-mortem examination is performed and a copy of the autopsy report is available, it should be 
submitted to the Sponsor-designated Medical Monitor. 
The Investigator is responsible for safety reporting in compliance with their Institutional Review 
Board (IRB). 
11.3.5 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the Investigator identifies as related to investigational product or procedure.  
The Sponsor is responsible for IND safety reporting as per 21 CFR 312.32.  
11.4 SAMPLE COLLECTION AND TESTING 
Standard clinical laboratory tests will be performed at times specified in the Schedule of 
Assessments. Chemistry laboratory tests should be conducted after a minimum of fasting 8 hours 
to avoid the need of repeat testing. Laboratory analyte results that could unblind the study will 
not be reported to investigative sites or other blinded personnel until the study has been 
unblinded.  
Samples collected for safety laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results. Tests are run and confirmed promptly whenever scientifically appropriate. 
When scientific circumstances warrant, however, it is acceptable to retain samples to batch the 
tests run, or to retain the samples until the end of the study to confirm that the results are valid. 
Certain samples may be retained for a longer period, if necessary, to comply with applicable 
laws, regulations, or laboratory certification standards.  
Table 1 lists the schedule for sample collections in this study. Table 3 lists the specific 
laboratory analyses that will be performed for this study.  
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as 
part of patient follow-up as described in Table 4. 


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Detailed instructions on sample requirements and preparation are described in the central 
laboratory manual. 
Investigators must document their review of each safety laboratory report.  
 
 


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Table 3 Clinical Laboratory Testsa 
Hematology:  
Hemoglobin   
Hematocrit  
Erythrocyte count (red blood cell [RBC])  
Mean cell volume (MCV)  
Mean cell hemoglobin concentration (MCHC)  
Leukocytes (white blood cell [WBC])  
Neutrophils, segmented 
Absolute Neutrophil Count (ANC) 
Lymphocytes  
Monocytes 
Eosinophils 
Basophils 
Platelets 
Urinalysis: 
Specific gravity  
pH  
Protein  
Glucose  
Ketones  
Blood  
Urine leukocyte esterase 
Clinical Chemistry: Serum concentrations 
of: 
Sodium 
Potassium  
Sodium bicarbonate  
Chloride 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase/serum glutamic 
pyruvic transaminase (ALT/SGPT) 
Aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase (AST/SGOT) 
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
Phosphorous 
Calcium 
Glucose (random) 
Albumin 
Total cholesterol 
Creatine kinase (CK)b 
Magnesium 
Urine Drug Screenc 
Amphetamines 
Barbiturates 
Benzodiazepine 
Cannabinoids 
Cocaine 
Ethyl alcohol 
Opiates 
Phencyclidine 
Propoxyphene 
Methadone 
Thyroid function: 
Thyroid stimulating hormone (TSH) 
Viral Serology: 
Hepatitis B Surface Antigen (HBs Ag) 
Hepatitis B Core Antibody (HBc Ab) 
Hepatitis C Antibody (HC Ab) 
Hepatitis A Antibody (HAV-Ab [IgM]) 
HIV 


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Total triiodothyronine (T3) 
Free thyroxine (T4) 
Pregnancy Test (females of child bearing 
potential only)d   
 
Pancreas: 
Amylase, total 
Lipase 
Nonpharmacogenetic biomarkers: 
Nociceptin 
IL-1ß 
IL-2 
IL-6 
IL-10 
TNFa 
 IFNg 
CRP 
Pharmacogenetic sample 
Pharmacokinetic (PK) concentration of 
BTRX-246040 
a  Assayed by a Sponsor-designated laboratory, unless specified otherwise. 
b  Creatine kinase muscle-brain isoenzyme (CK-MB) is to be assayed if CK results >1000 IU/L. 
c  Performed at screening and baseline  and at the Investigator's discretion throughout the study 
(see below). 
d  Serum pregnancy test at Visit 1 (screening) performed by a Sponsor-designated laboratory; 
urine pregnancy tests will be performed at subsequent visits by the site. 
e  Performed at entry. 
11.4.1 HEPATIC SAFETY 
If a study patient experiences elevated ALT or AST > 3X ULN or elevated total bilirubin > 2X 
ULN, clinical and laboratory monitoring should be initiated by the Investigator. Details for hepatic 
monitoring depend upon the severity and persistence of observed laboratory test abnormalities. To 
ensure patient safety and comply with regulatory guidance, the Investigator is to consult with the 
Sponsor-designated medical monitor regarding collection of specific recommended clinical 
information and follow-up laboratory tests as guided in Table 4.  
These results will be reviewed in a timely fashion by the Sponsor-designated medical monitor, 
along with the patient’s clinical case, to determine possible cause. Patients may be discontinued 
from the investigational drug or the study based on hepatotoxicity criteria outlined in section 8.3.  
 
 


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Table 4 Hepatic Monitoring Tests 
Hepatic Hematologya 
Hemoglobin 
Hematocrit   
RBC  
WBC  
Neutrophils, segmented 
Lymphocytes   
Monocytes 
Eosinophils 
Basophils 
Platelets 
Haptoglobina  
 
Anti-smooth muscle antibodya 
 
Anti-nuclear antibodya 
 
Hepatic Coagulationa 
Prothrombin Time 
Prothrombin Time, INR 
Hepatic Chemistrya 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
ALT 
AST 
GGT 
CPK 
Hepatic Serologiesa,b 
Hepatitis A antibody Total 
HAV-Ab [IgM] 
HBs Ag  
Hepatitis B surface antibody (anti-HBs) 
HBc Ab  
HC Ab  
Hepatitis E antibody, IgG 
Hepatitis E antibody, IgM 
 
a Assayed by a Sponsor-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
11.4.2 URINE DRUG SCREEN 
A urine drug screen for drug abuse will include: amphetamines, barbiturates, benzodiazepine, 
cannabinoids, cocaine, ethyl alcohol, opiates, phencyclidine, propoxyphene, and methadone.  No 
retest is allowed for a positive result with a drug of abuse (e.g., cocaine, cannabinoids, 
phencyclidine, and methadone).   
The site must contact the Sponsor-designated Medical Monitor or designee for pre-approval 
before a retest of other drugs that presented as positive as long as the patient has a valid 
prescription and there is no evidence of a Substance Use Disorder. In the case of Alcohol (Ethyl 
Alcohol) as long as there is clear justification for the finding and no history nor lab pattern 
consistent with Alcohol Use Disorder. If the results from an allowed repeat urine drug screen are 
negative, the patient may be included. If the repeat results are positive, the patient must be 
excluded from the study. A second retest is not admissible. 
 
 


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11.4.3 SAMPLES FOR DRUG CONCENTRATION MEASUREMENTS PHARMACOKINETICS 
Two blood samples will be collected on the day of randomization and three blood samples will 
be collected at the Week 1 and Week 4 visits, at sporadic time points. Population 
pharmacokinetic analysis will be conducted at a later time.  An additional blood sample will be 
collected at Visit 7 (end of treatment) to monitor compliance with study medication. 
Approximately 2 mL of blood will be drawn at each collection time point at the visits specified 
in the Schedule of Assessments for determination of plasma concentrations of BTRX-246040. 
Samples will be analyzed for BTRX-246040 at a laboratory approved by the Sponsor using a 
validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. It is intended 
that the blood samples collected from patients receiving placebo will not be analyzed.  
If a patient discontinues before study completion, an effort should be made to obtain a blood 
sample at the time of discontinuation.  
The approximate time of the dose administration should be recorded on the day of the blood 
sampling and for the 2 days preceding the day of blood sampling. Blood samples should be 
drawn at or within the time period specified and the actual date and time of sample collection 
will be recorded on the laboratory requisition.  
Bioanalytical samples collected to measure study drug concentrations will be retained for a 
maximum of 1 year following the last patient visit for the study. During this time, samples 
remaining after the bioanalyses may be pooled and used for exploratory analyses such as 
metabolic profiling and/or protein binding work.  
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.  
11.4.4 PHARMACOGENETIC SAMPLES 
There is growing evidence that genetic variation may impact a patient’s response to therapy. 
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated. Therefore, where local 
regulations allow, a blood sample will be collected for pharmacogenetic analysis. It is a one-time 
collection, as noted in the Schedule of Assessments.  
Samples will be stored and analysis may be performed on genetic variants thought to play a role 
in the nociceptin signaling pathway including, but not limited to OPRL1, to evaluate their 
association with observed clinical outcomes to BTRX-246040.  
In the event of an unexpected AE or the observation of unusual response, the samples may be 
genotyped and analysis may be performed to evaluate a genetic association with response to 
BTRX-246040. These investigations may be limited to a focused candidate gene study as 
described above or, if appropriate, genome-wide association studies may be performed to 


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identify regions of the genome associated with the variability observed in drug response. 
Samples will only be used for investigations related to the disease and the drug or class of drugs 
under study in the context of this clinical program. They will not be used for broad exploratory 
unspecified disease or population genetic analysis.  
Samples will be identified by the patient number (coded) and stored for up to a maximum of 15 
years after the last patient visit for the study at a facility selected by the Sponsor. The sample and 
any data generated from it can only be linked back to the patient by Investigator site personnel. 
The duration allows the Sponsor to respond to regulatory requests related to the study drug. 
11.4.5 NONPHARMACOGENETIC BIOMARKER SAMPLES 
Collection of samples for nonpharmacogenetic biomarker research is a required part of this 
study. Blood samples, including sampling for nociceptin plasma levels assessments will be 
collected at the times specified in the Schedule of Assessments. The study will assess changes in 
plasma levels of nociceptin, and changes in serum levels of IL-1ß, IL-2, IL-6, IL-10, TNFa, 
IFNg, and CRP from Visit 2 (baseline) to Visit 7 (week 8) in patients treated with BTRX-246040 
versus placebo to better understand the relationships between nociceptin levels, depressive 
symptoms, and the relationship to clinical features and treatment response.  
Stored samples may be used to conduct biomarker research related to better understanding the 
drug target, the mechanism of BTRX-246040 drug action and the disease process. Stored 
specimens might also be used to develop or evaluate a potential biomarker method.  
Samples will be identified by patient number (coded) and may be stored for a maximum of 15 
years after the last patient visit for the study at a facility selected by the Sponsor.  
11.5 OTHER SAFETY MEASURES 
11.5.1 VITAL SIGN MEASUREMENTS 
Vital signs (respiratory rate, oral temperature, blood pressure, and pulse) will be measured at 
each visit throughout the screening and treatment periods of the study after resting for 10 
minutes. Blood pressure and pulse will be measured in standing and supine position; respiratory 
rate and oral temperature will be measured in any position at each visit throughout the study (see 
Table 1).  
11.5.2 HEIGHT AND WEIGHT 
Height and weight will be measured during the study as indicated in the Schedule of 
Assessments. Height should be measured only once at screening with no shoes for correct 
measurement. The BMI will be calculated based on height measured at screening and weight 
measured at each visit. 
 
 


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11.5.3 PHYSICAL EXAMINATION 
Examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, and vascular status will be conducted at the 
screening visit.   
11.5.4 NEUROLOGICAL EXAMINATION 
Neurological examination of cranial nerves, motor system, sensory, and reflexes will be 
conducted at screening and all subsequent study visits. 
11.5.5 COLLECTION OF ELECTROCARDIOGRAMS 
For each patient, single 12-lead digital ECGs will be collected as indicated in the Schedule of 
Assessments after resting for 5 min.  
The ECGs will initially be interpreted by a qualified physician (the Investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified.  
After enrollment, if a clinically significant increase in the Fridericia’s correction method for the 
QT (QTcF) interval from baseline (e.g. QTcF ≥500 msec and/or QTcF increased ≥ 60 msec) or 
other clinically significant quantitative or qualitative change from baseline is identified, the 
patient will be assessed by the Investigator for symptoms (e.g., palpitations, near syncope, 
syncope) and to determine whether the patient can continue investigational product. The 
Investigator or qualified designee is responsible for determining if any change in patient 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation for each time point.  
All digital ECGs will be electronically transmitted to a designated central ECG laboratory. A 
cardiologist at the central ECG laboratory will then conduct a full over-read. A report based on 
data from this over-read will be issued to the investigative site. All data from the over-reads will 
be placed in the Sponsor database for analytical and study report purposes. Any clinically 
significant finding that was present on the fully over-read ECG will be reported to the 
Investigator and to the Sponsor. 
When there are differences in ECG interpretation between the Investigator (or qualified 
designee) and the cardiologist at the central ECG laboratory, the Investigator’s (or qualified 
designee’s) interpretation will be used for study entry and immediate patient management. 
Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report writing purposes.  
The Investigator (or qualified designee) must document his/her review of ECGs printed at the 
time of collection, the final over-read ECG report issued by the central ECG laboratory, and any 
alert reports.  


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11.5.6 SUICIDAL IDEATION/SUICIDALITY  
Suicide-related events (behavior and/or ideation) will be assessed and evaluated at every 
scheduled and unscheduled visit with the administration of the C-SSRS (Posner 2009). The C-
SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors 
during the assessment period. The scale includes suggested questions to solicit the type of 
information needed to determine if a suicide-related thought or behavior occurred. The C-SSRS 
was developed by the Columbia group (Posner 2009) to prospectively categorize suicide-related 
events. The ‘Baseline’ version will be used at Visit 1 (screening) and ‘Since Last Visit’ will be 
used for all subsequent visits. 
If a suicide-related event is identified at any time during the study, a thorough evaluation should 
be performed by a study physician and appropriate medical care should be provided. In some 
patients taking antidepressants, worsening of depression, suicidal events (suicidal thinking and/or 
behavior), or unusual changes in behavior have been reported, especially, at the beginning of the 
drug therapy, at the time of dose changes, or early after treatment discontinuation. It is important 
that patients are instructed to notify their doctor immediately if they have any distressing 
thoughts or feelings at any time related to harm to either self or others.   
The Self-Harm Supplement Form (SHSF) captures the number of discrete events of suicidal 
behavior, possible suicidal behavior, and non-suicidal self-injurious behavior. This scale must be 
administered by the Investigator at every visit.  
The Self-Harm Follow-up Form (SHFU) captures the details of each episode counted on the 
SHSF.  These details include episode description, start and end dates, associated adverse events, 
severity, relationship to study drug, method, intentions, cognition, actions taken, plan, stressors, 
and follow-up hospital visits.  The SHFU is completed at any time that the SHSF number of 
discrete events is ≥1. 
11.5.7 SAFETY MONITORING 
The Sponsor-designated Medical Monitor and the study team will monitor blinded safety data 
throughout the course of the study. This will include review of AEs, SAEs, any AEs of special 
interest, ECG findings, neurological exams, laboratory results, vital signs, and other safety data. 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, a data monitoring committee will be formed to protect the integrity of data and 
to evaluate additional analyses of the safety data. 
11.5.7.1 COMPLAINT HANDLING 
The Sponsor collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, to monitor quality, and 
to facilitate process and product improvements. 


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Patients will be instructed to contact the Investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.  
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by the Sponsor or its delegate will be reported. 
The Investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study: 
1. recording a complete description of the product complaint reported and any associated AEs 
using the study-specific complaint forms provided for this purpose 
2. submitting the completed product complaint form within 24 hours to the Sponsor or its 
designee.   
11.6 PHARMACOKINETIC ANALYSIS 
Plasma concentrations of BTRX-246040 will be listed by patient, visit, date, time, and when 
available, time lapse between the last dose and collection of the pharmacokinetic sample.  
Population PK analysis of the plasma concentrations in this study will be reported separately and 
the results of multiple clinical trials may be combined for that analysis. 
11.7 APPROPRIATENESS OF MEASUREMENTS 
Efficacy and safety assessments used in the study are generally regarded as reliable, accurate, 
and relevant in this patient population. The change from Visit 2 (baseline) to Visit 7 (week 8) in 
the Investigator-administered MADRS total score is the primary efficacy measure. Its 
psychometric properties have been established in various study samples. This study will include 
secondary and exploratory outcome measures. 
 
 


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12 DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
1. provide instructional material to the study sites, as appropriate 
2. provide start-up training to instruct the Investigators and study site personnel. This training 
will give instruction on the protocol, the completion of the eCRFs, study procedures, and 
on handling and administering the study drug 
3. make periodic visits to the study site 
4. be available for consultation and stay in contact with the study site personnel by email and 
telephone 
5. review and evaluate eCRF data and standard computer edits to detect errors in data 
collection 
6. conduct a quality review of the database. 
In addition, the Sponsor or its representatives may periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by the Sponsor, 
its representatives, and/or applicable regulatory agencies at any time. Investigators will be given 
notice before an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable IRBs with 
direct access to original source documents.   
12.1 DATA CAPTURE SYSTEM 
The Sponsor will select an electronic data capture system (EDC) and provide appropriately 
trained site personnel user permissions to enter information on the electronic CRFs (Case Report 
Forms). The site maintains a separate source for the data entered onto CRFs. 
Electronic data collected on other devices will be transferred to the Sponsor’s selected EDC, as 
applicable. 
An identification code assigned by IWRS to each patient will be used in lieu of the patient’s 
name to protect the patient’s identity when reporting study-related data.  
 
 


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13 SAMPLE SIZE AND STATISTICAL METHODS 
13.1 DETERMINATION OF SAMPLE SIZE 
The sample size determination was based on the primary endpoint, change from baseline in the 
Investigator-administered MADRS total score, at Visit 7 (week 8). Approximately 100 patients 
will be randomized to either BTRX-246040 or placebo in a 1:1 allocation ratio.  A sample size of 
44 patients per treatment group will provide 75% power to detect a relative effect size of 0.5 on 
the MADRS total score, based on a two-sample t-test and a significance level of 0.10. All tests 
are two-sided. To account for patients who may discontinue early and be excluded from the 
analysis population, a sample size of approximately 50 patients per treatment group (total of 100 
patients) will be randomized.   
13.2 STATISTICAL AND ANALYTICAL PLANS 
13.2.1 GENERAL CONSIDERATIONS 
Data collected from eCRFs, IWRS, ECG, performance tasks, and clinical laboratory evaluations 
will be listed by treatment group and patient identification. 
Generally, if not specified, continuous data will be summarized by descriptive statistics, 
including number of patients with data, mean, standard deviation, median, and range. Categorical 
data will be summarized by the number and percentage of patients for each category or 
classification.  
All statistical tests will be 2-sided. In this Phase 2 study, statistical tests that are significant at the 
level of 10% will be considered as demonstrating a trend.  Statistical tests that are significant at 
the 5% level will be considered as demonstrating a strong trend. Where appropriate, analyses of 
the secondary efficacy parameters and the exploratory endpoints will report nominal p-values to 
aid the interpretation of results. No adjustments for multiplicity will be made for secondary and 
exploratory analyses. Data analysis will be performed using SAS® version 9.2 or greater. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report. Additional exploratory analyses of the data will be conducted as 
deemed appropriate.  
All total and subscale scores are derived from individual items. Unless otherwise specified, if 
any individual item is missing, the corresponding total and subscale scores may be considered 
missing. 
A detailed statistical analysis plan (SAP) describing the statistical methodologies will be 
developed by the Sponsor or its designee and will be finalized before locking the study database. 
 
 


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13.2.2 ANALYSIS SETS 
• All Patients Enrolled Set: includes all patients who provided informed consent for this 
study. 
• Full Analysis Set (FAS): includes all randomized patients who received at least one dose 
of study drug and have at least one post-dose efficacy assessment. 
• Safety Analysis Set: includes all patients who received at least one dose of study drug.  
• Pharmacokinetic Analysis Set: includes all randomized patients with any PK data. 
• Per-Protocol Analysis Set: The Per-Protocol analysis set will include only those patients 
who completed the study with no major protocol deviations. 
• Completers Analysis Set: All patients in the Full Analysis Set who completed the 
treatment period.  
• MADRS Non-responders at Week 2 Analysis Set: All patients in the Full Analysis Set 
who have a Week 2 Investigator-administered MADRS total score that is 
>50% of the baseline MADRS total score.  This analysis set excludes patients who 
exhibited an early response at Week 2 on the Investigator-administered MADRS. 
Unless otherwise specified, all efficacy analyses will be conducted on the Full Analysis Set. 
Analyses will be performed according to the treatment the patient received. Efficacy analyses 
will be repeated on a Per-Protocol Analysis Set, the Completers Analysis Set, and the MADRS 
Non-responders at Week 2 Analysis Set for the primary efficacy endpoint and other selected 
secondary efficacy endpoints of interest. Safety analyses will be conducted on the Safety 
Analysis Set. The Pharmacokinetic listing will include the Pharmacokinetic Analysis Set. 
13.2.3 PATIENT DISPOSITION 
The number of randomized patients will be summarized by investigative site and treatment 
group. Frequency counts and percentages of all patients who are randomized and complete the 
treatment period or discontinue early will be presented for each treatment group. Reasons for 
discontinuation from the treatment period will be summarized. The proportion of subjects who 
discontinue early will be compared between treatment groups using Fisher’s exact test. The 
number of subjects who complete and reasons for failing to complete the follow-up visit will be 
presented for each treatment group. These analyses will be conducted on all patients enrolled, the 
Full Analysis Set, and the Safety Analysis Set. 
13.2.4 BASELINE PATIENT CHARACTERISTICS 
Baseline characteristics including age, sex, and ethnic origin will be summarized for all 
randomized patients by treatment group and for patients overall. Comparisons between treatment 
groups will be performed using Fisher’s exact test for categorical data and an ANOVA with 
treatment and investigative site in the model for continuous data. These analyses will be 
conducted on the Full Analysis Set, the Safety Analysis Set, the Per-Protocol Analysis Set, the 
Completers Analysis Set, and the MADRS Non-responders at Week 2 Analysis Set. Baseline 


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habits, including alcohol consumption and smoking status, will also be compared between 
treatment groups.  This analysis will be conducted on the Safety Analysis Set. 
13.2.5 CONCOMITANT THERAPIES 
Previous and concomitant drug therapy will be coded to Anatomical, Therapeutic, or Chemical 
(ATC) level and preferred drug name according to the World Health Organization Drug 
Dictionary (WHODD). These medications will be summarized by treatment group, ATC 
classification, and preferred drug name. This analysis will be conducted on the Safety Analysis 
Set. 
All Non-pharmacological therapies will be listed.  Use of Cognitive Behavioral Therapy will be 
summarized. Changes in therapy (e.g. start, stop) during the study will be summarized. This 
analysis will be conducted on the Safety Analysis Set. 
13.2.6 TREATMENT COMPLIANCE WITH INVESTIGATIONAL PRODUCT 
A patient is defined to be compliant if he/she has taken ≥80% and <120% of the number of doses 
expected to be taken during the study overall. The proportion of compliant patients will be 
summarized by treatment group. This analysis will be conducted on the Full Analysis Set, the 
Safety Analysis Set, and the MADRS Non-responders at Week 2 Analysis Set. 
13.2.7 MULTIPLICITY ISSUE 
No adjustments will be made for multiple comparisons.  
13.2.8 EFFICACY ANALYSIS 
All efficacy endpoints will be summarized by visit, including change from baseline information. 
13.2.8.1 PRIMARY EFFICACY ANALYSIS 
The primary efficacy analysis will be on the change in Investigator-administered MADRS total 
score from Visit 2 (baseline) to the last visit of the 8-week double-blind treatment period Visit 7 
(week 8). The key comparison will be the contrast between BTRX-246040 and placebo at Visit 7 
(week 8) from a mixed-model repeated measures (MMRM) analysis. The primary analysis will 
use the Full Analysis Set. 
A repeated measures analysis refers to a restricted-maximum-likelihood- (REML-) based, 
MMRM analysis using all the longitudinal observations at each post-baseline visit. The model 
for this analysis will include the fixed class effects of treatment, investigative site, visit, and 
treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline 
Investigator-administered MADRS total score. An unstructured covariance structure will be used 
to model the within-patient errors. If the unstructured covariance matrix results in a lack of 
convergence, the heterogeneous autoregressive variance-covariance structure will be used. Least-
square means (LS Means) for the difference to placebo at Week 8, with corresponding 2-sided 
95% confidence intervals will be presented in tabular and graphical displays.  


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13.2.8.2 SENSITIVITY ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT  
The following sensitivity analyses will be conducted on the primary efficacy endpoint to ensure 
robustness of the primary analysis. 
The first sensitivity analysis will use the same mixed model repeated measures (MMRM) 
analysis used for the primary efficacy endpoint.  The change from baseline in Investigator-
administered MADRS total score at each post-baseline visit will be analyzed to provide 
information on the onset and the time course of efficacy. No imputation will be applied to 
missing data. 
The second sensitivity analysis will utilize an ANCOVA method. This ANCOVA model will be 
used to analyze the change in Investigator-administered MADRS total score from baseline to 
Visit 7 (week 8).  This ANCOVA model will include treatment group and investigative site as 
fixed effects and baseline MADRS total score as a covariate. The ANCOVA will be applied 
utilizing two methods of imputation for missing values.  
• Multiple imputation for missing values: The results from the ANCOVA on multiple 
imputed datasets will be combined using the usual Rubin’s rules for multiple imputation.  
• Single imputation for missing values: The last observation carried forward (LOCF) 
imputation will be used. 
The primary endpoint will be also analyzed based on the Per-Protocol Analysis Set, the 
Completer Analysis Set, and the MADRS Non-responders at Week 2 Analysis Set using 
MMRM. 
An analysis of change from baseline in the computer-administered MADRS will also be 
performed using MMRM. 
13.2.8.3 SECONDARY EFFICACY ANALYSES 
The analysis of the secondary and exploratory endpoints will be based on the Full Analysis Set. 
All statistical tests will be 2-sided with a significance level of 10%. Where appropriate, 
secondary efficacy analyses will report nominal p-values to aid the interpretation of results. No 
adjustments for multiplicity will be made for these secondary analyses.   
Analysis of each of the secondary efficacy variables will be based on patients with available data 
at respective time points used in defining the specific secondary efficacy variable. Missing data 
for secondary endpoints will not be imputed. 
The MMRM models used for the primary efficacy endpoint will be used to analyze continuous 
secondary efficacy endpoints collected longitudinally similar to the primary endpoint (#1-6 listed 
below).  The MMRM models will contain fixed effects for treatment, investigative site, visit, and 
treatment-by-visit interaction as well as the continuous fixed covariates of baseline measurement. 
Change from baseline will be the response parameter of interest.  
 
 


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The following secondary efficacy endpoints will be analyzed by the MMRM model:  
1. Change from baseline to Week 8 on the Investigator-administered MADRS-6 subscale 
2. Change from baseline to Week 8 on the Investigator-administered MADRS individual 
items 
3. Change from baseline to Week 8 on the total scores of the HADS subscales, the anxiety 
subscale (HADS-A) and the depression subscale (HADS-D). 
4. Change from baseline to Week 8 on the DARS 
5. Change from baseline to Week 8 on the SHAPS (using the original 0 – 14 scoring method 
and also using an alternative scoring method ranging from 14 – 56) 
The following secondary endpoints will be used to assess the proportion of responders.  They 
will be analyzed by logistic regression with fixed effects for treatment and investigative site with 
the addition of the baseline Investigator-administered MADRS as a covariate. 
Responder rates defined by: 
6. Proportion of patients who demonstrate clinical response, where response was defined by 
a reduction of at least 50% in the baseline Investigator-administered MADRS total score 
at Week 8. 
7. Proportion of patients with MDD who achieved remission, where remission was defined 
by a total score of ≤10 on the Investigator-administered MADRS at Week 8. 
8. Proportion of patients who demonstrate significant clinical improvement, where 
improvement is defined by a score of 1 (very much improved) or 2 (much improved) on 
the CGI-I at Week 8.   
The following secondary efficacy endpoints based on the performance tasks will be analyzed and 
presented in summary and graphical displays. 
Data for the FERT will be summarized (mean, standard deviation, range) for each treatment 
group at each visit.  All treatment differences will be estimated with 95% CI. No adjustments 
will be made for multiple comparisons. The analysis will employ ANOVA models without 
adjusting for covariates. However, if significant confounds are identified, a secondary analysis 
will be performed to examine the relationship between FERT outcome measures and other 
covariates. A full description of the statistical analysis methods for FERT outcome measures will 
be provided in in the SAP. 
9. Outcome measures from the FERT  
a) Accuracy   
b) Misclassification   
c) Average reaction time   
d) Target sensitivity   
e) Response bias 


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Data for all PRT outcome measures will be summarized (mean, standard deviation, range) for 
each treatment group at each visit.  The ANOVA models will be used to compare between 
treatment groups. For “Response bias” and “Discriminability,” treatment group, block, and 
treatment-by-block interactions will be considered fixed effects. For “Reaction time” and “Hit 
rates,” the stimulus type will be included as an additional fixed effect. The details of the analysis 
methods for these outcome measures will be described in the SAP. 
10. Outcome measures from the PRT 
a) Response bias  
b) Discriminability  
c) Reaction time  
d) Hit rates  
Data for all EEfRT outcome measures will be summarized (mean, standard deviation, range) for 
each treatment group at each visit.  Statistical analyses of the Preference during the EEfRT trial 
will be performed using Generalized Estimating Equation (GEE) models. A binary logistic 
distribution will be used to model the probability of the Preference. The relationship and 
interactions between Preference and independent variables of reward magnitude, reward 
probability, expected value, age, sex, and efficacy parameters will be explored. The ANOVA 
model will be used to compare the completion rates between treatment groups. The details of the 
analysis method for these outcome measures will be described in the SAP. 
11. Outcome measures from the EEfRT 
a) Preference (hard or easy task choice) 
b) Completion rates 
13.2.8.4 EXPLORATORY EFFICACY AND HEALTH OUTCOMES ANALYSES 
The exploratory endpoints will include: 
1. Change in HAM-A total score from baseline to Week 4 and from baseline to Week 8 
2. Change from baseline to Week 8 on the average pain in the last 24 hours. 
3. Changes in plasma levels of nociceptin, and changes in serum levels of IL-1ß, IL-2, IL-6, 
IL-10, TNFa, IFNg, and CRP from baseline to Week 8, correlated to treatment outcome 
and exposure 
Exploratory endpoints will be summarized and, where appropriate, represented graphically. The 
analysis of the continuous exploratory endpoints will depend on the frequency of their 
measurements. If they are measured at baseline and multiple post-baseline visits, then an 
MMRM approach will be used.  If they are measured at baseline and Week 8, an ANCOVA will 
be used.  If the endpoint is only measured after treatment, an ANOVA will be used.   
Further details on the analyses will be provided in the SAP. 


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13.2.8.5 SENSITIVITY ANALYSIS 
Analyses will be conducted to assess the validity of assumptions inherent to the primary analysis 
and to assess the sensitivity of results to untestable assumptions. The primary analysis will also 
be repeated using the Per-Protocol Analysis Set, the Completer Analysis Set, and the MADRS 
Non-responders at Week 2 Analysis Set. In addition, analyses will be conducted to assess the 
impact of missing data. Departures from the assumed missing at random mechanism will be 
assessed by implementing inclusive models for dropout within the multiple imputation 
frameworks. Full details of these analyses will be provided in the SAP. 
13.2.9 
DIGITAL ASSESSMENTS 
Vocal and behavioral digital assessment data are collected in this study. These data will be in a 
separate report. 
13.2.10 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
Pharmacokinetic data collected in this study will be listed for the Pharmacokinetic Analysis Set. 
Population PK analysis of the plasma concentrations in this study will be reported separately. 
Pharmacokinetic data in this study may be combined with data from other studies to obtain 
improved model estimates and have adequate data for analysis.  
Other exploratory analyses, such as the relationship between BTRX-246040 exposure and 
efficacy measures or AEs or other safety endpoints, may be undertaken as deemed appropriate. 
13.2.11 SAFETY ANALYSES 
Safety assessments include AEs, SAEs, vital signs, weight and BMI, laboratory values, 
neurological exams, C-SSRS, SHSF, SHFU, and ECGs. All safety analyses will be performed on 
the Safety Analysis Set unless otherwise specified.  
The safety/tolerability of BTRX-246040 and placebo will be compared for rates of 
spontaneously reported TEAEs, SAEs, AEs associated with self-harm episodes, early study 
discontinuations, discontinuations from BTRX-246040 or placebo, and AEs leading to 
discontinuation from the study or from BTRX-246040 or placebo.  
Data will be pooled from all investigative sites for the analyses. 
Safety results will be summarized by treatment. For categorical variables, frequencies and 
percentages will be reported and for continuous endpoints by visit and change from baseline 
summaries will be presented.  
13.2.12 SUBGROUP ANALYSES 
Subgroup analysis based on gender, baseline severity of anhedonia symptoms (SHAPS total 
score ≤ 4 and > 4; also SHAPS total score ≤ 7 and > 7) and baseline severity of anxiety (HAM-A 
total score < 20 and ≥ 20) will be performed. Subgroups based on other characteristics may be 
considered. All subgroup analyses will be exploratory in nature. 


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13.2.13 INTERIM ANALYSIS 
No interim analyses are planned for this study. 
 


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14 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS  
14.1 INFORMED CONSENT 
The Investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.  
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.  
The Investigator is responsible for ensuring that informed consent is given by each patient. This 
includes obtaining the appropriate signatures and dates on the ICF prior to the performance of 
any protocol procedures and prior to the administration of investigational product. 
14.2 ETHICAL REVIEW 
The Sponsor or its representatives must approve all ICFs before they are submitted to the IRB 
and are used at investigative sites(s). All ICFs must be compliant with the ICH guideline on 
GCP.  
Documentation of IRB approval of the protocol and the ICF must be provided to the Sponsor 
before the study may begin at the investigative site(s). The IRB(s) will review the protocol as 
required.  
Any member of the IRB who is directly affiliated with this study as an Investigator or as site 
personnel must abstain from the IRB’s vote on the approval of the protocol.  
14.3 REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with: 
1. consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
2. the ICH GCP Guideline [E6] 
3. applicable laws and regulations. 
The Sponsor certifies that this study is being conducted under an active US Investigational New 
Drug (IND) application.  
Some of the obligations of the Sponsor will be assigned to a TPO.  


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14.3.1 INVESTIGATOR INFORMATION 
Physicians with a specialty in psychiatry or physicians with experience or with medical site staff 
with experience in treating MDD will participate as Investigators in this clinical trial. 
14.3.2 PROTOCOL SIGNATURES 
The Sponsor’s responsible medical officer will approve the protocol, confirming that to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal Investigator will sign the protocol signature page and 
provide a copy of the signed page to a Sponsor representative. 
 
 


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15 REFERENCES 
 
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American Psychiatric Association, 2010: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
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brain. Neuroscience. Vol 121, Issue 3, Oct 2003. 629–640. 
Dunlop and Nemeroff. The Role of Dopamine in the Pathophysiology of Depression. Arch Gen Psychiatry. 
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Fava GA, Tomba E, Grandi S. The road to recovery from depression-don't drive today with yesterday's map. 
Psychother Psychosom. 2007;76:260–265. 
Fava M, Evins AE, Dorer DJ, Schoenfeld DA. The problem of the placebo response in clinical trials for 
psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother 
Psychosom. 2003;72:115-127. 
Florin et al., Autoradiographic localization of [3H] nociceptin binding sites in the rat brain. Brain 
Research. Vol 880, Issues 1-2; Oct 2000;1–16 
Gooding and Pflum. Theory of Mind and psychometric schizotypy. July 30, 2011. Vol. 188; Issue 2; 217–223 
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Appendix 1 
Examples of Inhibitors and Inducers of CYP3A4 
Per exclusion criterion 19: Are currently taking or have taken within 5 half-lives of Visit 2 
(baseline) any medications or supplements that are strong inhibitors or inducers of 
CYP3A4. The listed moderate inhibitors/inducers below are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm
093664.htm. 
Table 1.a         Inhibitors of CYP3A4 
Strong inhibitors a 
Moderate inhibitors b 
boceprevir 
amprenavir 
clarithromycin 
aprepitant 
conivaptan 
atazanavir 
grapefruit juice 
ciprofloxacin 
indinavir 
darunavir 
itraconazole 
diltiazem 
ketoconazole 
erythromycin 
lopinavir 
fluconazole 
mibefradil 
fosamprenavir 
nefazodone 
imatinib 
nelfinavir 
verapamil 
posaconazole 
  
ritonavir 
  
saquinavir 
  
telaprevir 
  
telithromycin 
  
voriconazole 
  
a    Increases the area under the curve (AUC) of the substrate by ≥ 5-fold. 
b     Increases the AUC of the substrate by 2- to 5-fold.  


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Table 1.b 
 Inducers of CYP3A4 
Strong inducers a 
Moderate inducers b 
avasimibe 
bosentan 
carbamazepine 
efavirenz 
enzalutamide 
  
phenytoin 
etravirine 
rifampin 
modafinil 
St John’s wort 
nafcillin 
a     Decreases the AUC of the substrate by ≥ 80%. 
b     Decreases the AUC of the substrate by 50–80%. 
 
 
 

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STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL NEP‐MDD‐201 
A RANDOMIZED, DOUBLE‐BLIND, PLACEBO‐CONTROLLED, PARALLEL‐GROUP EFFICACY 
AND SAFETY STUDY OF BTRX‐246040 ADMINISTERED ONCE DAILY IN PATIENTS WITH 
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AUTHOR: SABINA RICH 
VERSION NUMBER AND DATE: V1.0, 06DEC2018 
 
 
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MODIFICATION HISTORY 
 
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Contents 
1. 
INTRODUCTION ............................................................................................................................ 9 
2. 
STUDY OBJECTIVES ..................................................................................................................... 9 
2.1. 
Primary Objective..................................................................................................................................... 9 
2.2. 
Secondary Objectives ............................................................................................................................... 9 
2.3. 
Exploratory Objectives ............................................................................................................................. 9 
3. 
STUDY DESIGN ........................................................................................................................... 10 
3.1. 
General Description ................................................................................................................................ 10 
3.2. 
Schedule of Assessments ........................................................................................................................ 10 
3.3. 
Changes to Analysis from Protocol .......................................................................................................... 10 
4. 
PLANNED ANALYSES ................................................................................................................ 11 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................ 11 
4.2. 
Interim Analysis ..................................................................................................................................... 11 
4.3. 
Final Analysis ......................................................................................................................................... 11 
5. 
ANALYSIS SETS ........................................................................................................................... 11 
5.1. 
All Patients Enrolled Set [ENR] ................................................................................................................ 11 
5.2. 
All Patients Randomized Set [RND] ......................................................................................................... 11 
5.3. 
Full Analysis Set [FAS]............................................................................................................................. 12 
5.4. 
Per Protocol Analysis Set [PPAS] ............................................................................................................. 12 
5.5. 
Safety Analysis Set [SAF] ........................................................................................................................ 12 
5.6. 
Pharmacokinetic Analysis Set [PK] .......................................................................................................... 12 
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5.7. 
Completers Analysis Set [CAS] ................................................................................................................ 12 
5.8. 
MADRS Non‐Responders Analysis Set [MNRAS] ...................................................................................... 13 
6. 
GENERAL CONSIDERATIONS ................................................................................................. 13 
6.1. 
Reference Start Date and Study Day ....................................................................................................... 13 
6.2. 
Baseline ................................................................................................................................................. 13 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 13 
6.4. 
Windowing Conventions ........................................................................................................................ 14 
6.5. 
Statistical Tests ...................................................................................................................................... 14 
6.6. 
Common Calculations ............................................................................................................................. 15 
6.7. 
Software Version .................................................................................................................................... 15 
7. 
STATISTICAL CONSIDERATIONS .......................................................................................... 15 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ......................................................... 15 
7.2. 
Multicenter Studies ................................................................................................................................ 15 
7.3. 
Missing data ........................................................................................................................................... 15 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................ 16 
7.5. 
Examination of Subgroups ...................................................................................................................... 16 
8. 
OUTPUT PRESENTATIONS ..................................................................................................... 16 
9. 
DISPOSITION AND WITHDRAWALS .................................................................................... 16 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 17 
10.1. 
Derivations ......................................................................................................................................... 17 
11. 
MEDICAL AND PSYCHIATRIC HISTORY ............................................................................. 18 
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12. 
CONCOMITANT ILLNESSES ..................................................................................................... 18 
13. 
MEDICATIONS ............................................................................................................................ 18 
13.1. 
Non‐Pharmacological Therapies .......................................................................................................... 18 
14. 
STUDY MEDICATION EXPOSURE AND COMPLIANCE .................................................... 19 
14.1. 
Derivations ......................................................................................................................................... 19 
15. 
EFFICACY OUTCOMES .............................................................................................................. 20 
15.1. 
Primary Efficacy .................................................................................................................................. 20 
15.1.1. 
Primary Efficacy Variable & Derivation .....................................................................................................20 
15.1.2. 
Missing Data Methods for the Primary Efficacy Variable .........................................................................20 
15.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................20 
15.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................21 
15.2. 
Secondary Efficacy .............................................................................................................................. 21 
15.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................21 
15.2.1.1. MADRS Total Score ................................................................................................................................21 
15.2.1.2. MADRS‐6 Subscale .................................................................................................................................21 
15.2.1.3. MADRS Individual Item Scores ..............................................................................................................22 
15.2.1.4. Hospital Anxiety and Depression Scale subscales .................................................................................22 
15.2.1.5. Dimensional Anhedonia Rating Scale ....................................................................................................22 
15.2.1.6. Snaith Hamilton Pleasure Scale .............................................................................................................22 
15.2.1.7. Response ...............................................................................................................................................22 
15.2.1.8. The Facial Expression Recognition Task .................................................................................................22 
15.2.1.9. Probabilistic Reward Task ......................................................................................................................23 
15.2.1.10. Effort Expenditure for Reward Task ....................................................................................................24 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .......................................................................24 
15.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................24 
15.2.3.1. 
MADRS Total Score ...........................................................................................................................24 
15.2.3.2. 
MADRS‐6 Subscale ............................................................................................................................24 
15.2.3.3. 
MADRS Individual Item Scores..........................................................................................................25 
15.2.3.4. 
Hospital Anxiety and Depression Scale subscales.............................................................................25 
15.2.3.5. 
Dimensional Anhedonia Rating Scale ...............................................................................................25 
15.2.3.6. 
Snaith Hamilton Pleasure Scale ........................................................................................................25 
15.2.3.7. 
Response ...........................................................................................................................................26 
15.2.3.8. 
The Facial Expression Recognition Task ............................................................................................26 
15.2.3.9. 
Probabilistic Reward Task .................................................................................................................26 
15.2.3.10. 
Effort Expenditure for Reward Task .................................................................................................26 
15.3. 
Exploratory Efficacy ............................................................................................................................ 27 
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15.3.1. 
Exploratory Efficacy Variables & Derivations............................................................................................27 
15.3.1.1. 
Hamilton Anxiety Rating Scale ..........................................................................................................27 
15.3.1.2. 
Pain Question....................................................................................................................................27 
15.3.1.3. 
Nonpharmacogenetic Biomarkers ....................................................................................................28 
15.3.2. 
Missing Data Methods for Exploratory Efficacy Variable(s) .....................................................................28 
15.3.3. 
Analysis of Exploratory Efficacy Variables ................................................................................................28 
15.3.3.1. 
Hamilton Anxiety Rating Scale ..........................................................................................................28 
15.3.3.2. 
Pain Question....................................................................................................................................28 
15.3.3.3. 
Nonpharmacogenetic Biomarkers ....................................................................................................28 
15.3.4. 
Subgroup Analysis .....................................................................................................................................28 
16. 
SAFETY OUTCOMES .................................................................................................................. 29 
16.1. 
Adverse Events ................................................................................................................................... 29 
16.1.1. 
All TEAEs ...................................................................................................................................................29 
16.1.1.1. 
Severity .............................................................................................................................................29 
16.1.1.2. 
Relationship to Study Medication ....................................................................................................30 
16.1.2. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................30 
16.1.3. 
TEAE’s Leading to Early Study Discontinuation ........................................................................................30 
16.1.4. 
Serious Adverse Events .............................................................................................................................30 
16.1.5. 
Adverse Events Associated with Self‐harm Episodes ...............................................................................30 
16.2. 
Deaths ................................................................................................................................................ 30 
16.3. 
Laboratory Evaluations ....................................................................................................................... 31 
16.3.1. 
Laboratory Reference Ranges and Abnormal Criteria ..............................................................................31 
16.4. 
ECG Evaluations .................................................................................................................................. 31 
16.4.1. 
ECG Markedly Abnormal Criteria ..............................................................................................................32 
16.5. 
Vital Signs ........................................................................................................................................... 32 
16.5.1. 
Vital Signs Abnormal Criteria ....................................................................................................................33 
16.6. 
Suicide Ideation/Suicidality ................................................................................................................ 34 
16.7. 
Physical and Neurological Examination ............................................................................................... 34 
17. 
DIGITAL ASSESSMENTS ........................................................................................................... 34 
18. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................................. 34 
19. 
PHARMACOGENETIC ANALYSIS ........................................................................................... 35 
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20. 
REFERENCES ............................................................................................................................... 36 
APPENDIX 1.  PROGRAMMING CONVENTIONS FOR OUTPUTS ........................................... 37 
APPENDIX 2.  PARTIAL DATE CONVENTIONS .......................................................................... 38 
 
 
 
 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for Protocol NEP-MDD-201. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 6.0, dated 20 November 2018. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to evaluate the effects of BTRX-246040 on symptoms of depression in adult 
patients with Major Depressive Disorder after 8 weeks of double-blind treatment. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are as follows. 
 
To evaluate the effects of BTRX‐246040 on anhedonia in adult patients with MDD. 
 
To evaluate the safety and tolerability of BTRX‐246040 in adult patients with MDD. 
 
To evaluate the effects of BTRX‐246040 on the performance of tasks as measured by the Facial Expression 
Recognition Task (FERT), Probabilistic Reward Task (PRT), and Effort Expenditure for Reward Task (EEfRT) 
in adult patients with MDD. 
2.3.  EXPLORATORY OBJECTIVES 
The exploratory objectives are as follows. 
 
To evaluate the effects of BTRX‐246040 on anxiety‐related symptoms in adult patients with MDD. 
 
To evaluate the effects of BTRX‐246040 on pain‐related symptoms in adult patients with MDD. 
 
To evaluate the effects of BTRX‐246040 as measured by biomarkers in adult patients with MDD. 
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3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
Study NEP-MDD-201 is an 8-week, randomized, double-blind, placebo-controlled, parallel group, 
multicenter study. There will be a 28-day screening period, 8-week active treatment period (during 
which patients will receive either BTRX-246040 or placebo), and an approximate 1- to 2-week off-drug 
safety follow-up period (Figure 1). 
 
 
Figure 1: 
Study Design 
Patients will be consented and screened for the study until approximately 100 patients are randomized. 
Randomization will be performed at Visit 2 (baseline) in a 1:1 ratio to one of two treatment arms 
(placebo or BTRX-246040 QD) after meeting disease diagnostic criteria for MDD and study inclusion 
(see section 8). Randomization will be stratified by anhedonia symptom severity, as indicated by a 
SHAPS total score ≤ 4 and > 4.  
3.2. SCHEDULE OF ASSESSMENTS 
The schedule of assessments can be found in Table 1 in Section 9.8 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
There are no planned changes from the protocol.  
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4. PLANNED ANALYSES 
There are no analyses for data monitoring committees or interim analyses planned for this study. Thus, 
the only analysis planned for this study is the final analysis following database lock. 
4.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC for this study. 
4.2. INTERIM ANALYSIS  
There will be no interim analysis for this study. 
4.3. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following 
sponsor authorization of this statistical analysis plan, database lock, sponsor authorization of analysis 
sets and unblinding of treatment groups. 
5. ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set will be conducted 
prior to the unblinding of the study. The analysis for the Full-Analysis Set population defined in section 
5.3 will be performed according to the treatment patients were randomized to.  All other analyses will be 
performed according to the treatment the patient received.   
5.1. ALL PATIENTS ENROLLED SET [ENR] 
The all patients enrolled (ENR) set will contain all patients who provide informed consent for this study. 
5.2. ALL PATIENTS RANDOMIZED SET [RND] 
The all patients randomized (RND) set will contain all patients in the ENR set who were randomized to 
study medication. 
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5.3. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain all patients in the RND set who received at least one dose of 
study medication and have at least one post-dose efficacy assessment. The intent-to-treat principle is 
preserved, despite the exclusion of patients randomized who did not take the study medication or do not 
have post-baseline efficacy data, because the decision of whether or not to begin the treatment could 
not be influenced by knowledge of the assigned treatment due to the study blinding.   
5.4. PER PROTOCOL ANALYSIS SET [PPAS] 
The per-protocol analysis set (PPAS) will contain all patients in the FAS who did not experience any 
major protocol deviations which impact the efficacy conclusions of the study. Examples of major 
protocol deviations which may affect inclusion in the PPAS include: 
 
Treatment compliance of <80% or ≥120% of the prescribed dosage.  
 
Clinically significant discrepancies between planned and actual treatment. 
 
Receipt of prohibited medications.   
 
Violations of the entry criteria. 
5.5. SAFETY ANALYSIS SET [SAF] 
The safety analysis set (SAF) will contain all patients in the RND set who receive at least one dose of 
study drug.  
If there is any doubt whether a patient was treated or not, they will be assumed treated for the purposes 
of analysis.  
5.6. PHARMACOKINETIC ANALYSIS SET [PK] 
The pharmacokinetic analysis set (PK) will include all patients in the RND with at least one valid PK 
measurement.  
5.7. COMPLETERS ANALYSIS SET [CAS] 
The completers analysis set (CAS) will contain all patients in the FAS who completed the full treatment 
period, as recorded in treatment disposition page of the eCRF. 
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5.8. MADRS NON‐RESPONDERS ANALYSIS SET [MNRAS] 
The MADRS non-responders analysis set (MNRAS) will contain all patients in the FAS who have a 
Week 2 investigator-administered MADRS total score that is >50% of the baseline MADRS total score. 
This determination will be made programmatically using the Baseline and Week 2 MADRS total scores. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events.  
Reference start date is defined as the day of the first dose of study medication (Day 1).  
 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference start date) + 1. 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference start date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the 
listings, and Study Day, and any corresponding durations will be presented based on the imputations 
specified in Appendix 2; Partial Date Conventions. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
reference start date (including unscheduled assessments). For this study, the reference date will be the 
date of first study drug dosing. In the case where the last non-missing measurement and the reference 
start date coincide, collection time, where available, will be compared with first dose time to determine 
whether the measurement is pre-baseline or post-baseline. If time is not available the measurement will 
be considered pre-baseline, but Adverse Events (AEs) and medications commencing on the reference 
start date will be considered post-baseline. 
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded closest to the nominal visit day will be presented. 
Section 6.4 includes more details regarding visit windowing conventions and data handling for by-visit 
summaries.  
Early termination data will be considered when assigning values to a visit window. 
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Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
For each visit, a window will be defined such that the lower and upper bounds of each window is 
generally the midpoint between 2 consecutive study visits. 
 Visit Analysis Windows for Efficacy and Safety Variables Evaluated by Visit 
 
Baseline 
Week 1 
Week 2 
Week 4 
Week 6 
Week 8 
Scheduled Visit Daya 
1 
8 
15 
29 
43 
57 
MADRS and other 
tests scheduled at 
each visit 
≤1 
2 – 11 
12 – 22 
23 – 36 
37 – 50 
≥51 
HAM-A, PK, ECGs, 
and other tests 
scheduled at similar 
visits 
≤1 
 
 
2 – 43 
 
≥44 
Pain Questionnaire 
≤1 
 
2 – 22 
23 – 36 
37 – 50 
≥51 
SHAPS 
≤1 
2 – 11 
12 – 22 
23 – 43 
 
≥44 
FERT 
≤1 
2 – 11 
12 – 22 
 
 
 
Urine Drug and 
Alcohol Screen 
1 
8 
 
29 
43 
57 
a Days are relative to the first dose of study medication. 
Note: Any value collected after the administration of first dose on Day 1 will be grouped under Day 2. 
Visit windowing will be applied to remap early termination visit data only. Thus, more than one result for 
a parameter may be obtained in a visit window. In such an event, the result from the scheduled visit will 
be used over the early termination visit.  
The study window convention will not be applied to the eCRF data listings. The data listings for eCRF 
data will display the raw data as collected and entered in the eCRF. 
Windowing will be applied to the data prior to any missing data calculations. 
6.5. STATISTICAL TESTS 
Confidence intervals will be reported at the 95% level and all tests will be two-sided, unless otherwise 
specified in the description of the analyses. P-values will be presented to identify trends in the study. 
That is, statistical tests that are significant at the 10% level will be considered as demonstrating a trend 
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and statistical tests that are significant at the 5% level will be considered as demonstrating a strong 
trend. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
 
Test Value at Visit X – Baseline Value 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4.  
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the 
models, see the specific analysis section. 
 
Baseline score (continuous variable) 
 
Treatment group (BTRX‐246040 or placebo) 
 
Pooled Investigative Site 
 
Study visit (Weeks 1 – 8) 
 
Treatment‐by‐visit Interaction 
If over parameterization means analyses cannot be performed pooling of investigative sites will be 
considered, if an appropriate pooling is possible, otherwise investigative site will be removed from the 
analysis.  
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers within the United States. 
Randomization to treatment arms is not stratified by center.  
7.3. MISSING DATA 
In general, missing data will not be imputed. However, partial dates will contribute to analyses as 
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described in Appendix 2. All available data will be included in the safety analysis. 
Details for the imputation algorithm for the missing endpoint values for the sensitivity analyses are 
described in Section 15.1.4 of this analysis plan.  
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
The nature of this study is to establish trends and is powered with that intent. Thus, no adjustments will 
be made for multiple comparisons. 
7.5. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the exploratory analysis sections. It should be noted 
that the study was not designed to detect treatment differences with high statistical power within 
subgroups. 
The following subgroups will be assessed and described within the exploratory analysis sections: 
 
Gender.  
 
Baseline severity of anhedonia symptoms (SHAPS) score (≤4, >4). 
 
Baseline severity of anhedonia symptoms (SHAPS) score (≤7, >7). 
 
Baseline anxiety, as assessed by the Hamilton Anxiety Rating Scale (HAMA‐A) score (<20, ≥20) 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The shell templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings (TFLs) that will be provided by IQVIA 
Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
Patient disposition, withdrawals and reasons for withdrawal will be presented for the ENR set by 
treatment group, investigative site and overall.  
The number and percentage of patients completing the treatment period will be provided by treatment 
group and overall. Reasons for discontinuation from the treatment period will be summarized. The 
proportion of subjects that discontinue early will be compared between treatment groups using Fisher’s 
exact test. The number of subjects that complete and reasons for failing to complete the follow-up visit 
will be presented for each treatment group. These analyses will be conducted on all patients enrolled, 
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the full Analysis Set and the Safety Analysis Set.   
In addition, major protocol deviations which lead to exclusion for the PPAS will be summarized by 
treatment group and protocol violation category for the FAS. Inclusion in all analysis sets will be 
summarized by treatment group and overall for the RND set.    
Listings will be produced to display the information collected in the eCRF regarding patient disposition. 
Listings will also be generated to show patient randomization assignment, analysis set assignment and 
all key protocol violations.  
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented by treatment group and overall. 
The following variables will be summarized: 
 
Age at screening (years) ‐ calculated relative to date of consent 
 
Sex 
 
Race  
 
Ethnicity 
 
Childbearing potential (females only) 
 
Height at Screening (cm) 
 
Weight as Baseline (kg) 
 
BMI at Baseline (kg/m2) 
 
Alcohol consumption status (occurrence, average number of drinks per week) 
 
Smoking status (occurrence, average number of packs per week) 
 
Hand Dominance 
 
Glasses Usage 
Categorical variables like sex and ethnicity will be compared between treatment groups using Fisher’s 
exact test for categorical data and continuous variables like age and height will be compared using an 
ANOVA model with treatment and investigative site as covariates. This analysis will be performed for 
the FAS, SAF PPAS, CAS and MNRAS sets. Similar comparisons will be conducted for alcohol 
consumption and smoking status, but only using the SAF set.  
All demographic data collected within the eCRF will be listed.  
10.1. DERIVATIONS 
BMI (kg/ m2) = weight (kg)/ height (m)2 
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11. MEDICAL AND PSYCHIATRIC HISTORY 
Medical and psychiatric history information will be presented for the SAF set. Medical and psychiatric 
history conditions are defined as those conditions which stop prior to or at Screening. Conditions will be 
coded using MedDRA version 20.0 and presented by treatment group, SOC and PT.   
Data collected from the Structured Clinical Interview for DSM Disorders-Clinical Trials (SCID-CT) 
including personal history of traumatic events and Lifetime Illness Characteristics Questionnaire (LICQ) 
at screening will be presented in listings. 
12. CONCOMITANT ILLNESSES 
Concomitant medical and psychiatric information will be presented for the SAF set. Concomitant 
illnesses are defined as those conditions which start prior to or at Screening and are ongoing at the date 
of screening. Concomitant illnesses will be coded using MedDRA version 20.0 and presented by 
treatment group, SOC and PT.  
Information regarding all concomitant illnesses will be listed alongside information for historical medical 
and psychiatric conditions  
13. MEDICATIONS 
Prior and concomitant medications will be presented using the SAF set and coded using WHO Drug 
Dictionary (WHODD) 05 June 2017. Summaries will be presented by treatment group, Anatomical, 
Therapeutic, or Chemical (ATC) level 5 and preferred drug name for prior and concomitant medications 
separately. 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior or concomitant, the medication will be classified by the worst case; i.e. 
concomitant.  
 
‘Prior’ medications are medications which started and stopped prior to the first dose of study drug.  
 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the first dose of study drug  
o 
AND ended on or after the date of first dose of study drug or were ongoing at the end of the study. 
All information recorded in the eCRF with regards to medications will be listed.  
13.1. NON‐PHARMACOLOGICAL THERAPIES 
Use of Cognitive Behavioral Therapy (CBT) will be summarized by treatment group, including a 
summary of the number of patients who started or stopped CBT whilst receiving study medication.  
All Non-pharmacological therapies will be listed.  
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14. STUDY MEDICATION EXPOSURE AND COMPLIANCE 
The proportion of patients compliant to study medication will be presented for the SAF, FAS and 
MNRAS analysis sets. A patient will be considered compliant if they received ≥80% and <120% of the 
expected number of doses during the study. In addition, the proportion of patients who have a dose 
reduction during week 2 from 80mg to 40mg as permitted in the protocol will be displayed. Compliance 
and exposure to study drug will also be summarized through descriptive statistics. 
14.1. DERIVATIONS 
Compliance will be calculated according to the following formula: 





100
mg
 
doses
 
Expected
mg
 
received
 
Doses
%
Compliance









 
The expected dosage is 7 daily doses at 40mg followed by 49 daily doses at 80mg. Therefore, the sum 
of all expected doses for a patient who completes the trial is 7 x 40mg + 49 x 80mg = 4200mg.  
If a patient discontinues the study early, the sum of all planned doses will be adjusted accordingly so the 
compliance calculation is not influenced by the time on treatment. The calculation will use the last dose 
date recorded on the patient disposition page of the eCRF. E.g. if a patient takes their final dose on day 
28 the sum of all expected doses will be calculated as the following: 7 x 40mg + 21 x 80mg = 1960mg. 
In addition, as the protocol allows for a dose reduction during week 2 this will also be accounted for in 
the compliance calculation. For example, if a patient decides to reduce the daily dosage to 40mg on day 
10 and then went on to complete the treatment period, the sum of all expected doses would be 
calculated as the following: 7 x 40mg + 2 x 80mg + 47 x 40mg = 2320mg. Any dose reductions after 
week 2 would be considered a protocol violation and therefore the compliance calculation would not be 
adjusted. 
The sum of all doses received will be calculated using drug accountability data collected on site. The 
number of capsules dispensed (calculated as the number of bottles dispensed x 16), the number of 
capsules returned will be recorded. Each capsule is 40mg, therefore the sum of all doses received will 
be calculated as: 

40
returned
 
Capsules
dispensed
 
Capsules
 
(mg)
 
received
 
Doses






 
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15. EFFICACY OUTCOMES  
15.1. PRIMARY EFFICACY 
15.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is the change from Baseline in investigator-administered Montgomery-
Asberg Depression Rating Scale (MADRS) total score at Week 8. The MADRS is a 10-item rating scale 
for the evaluation of depressive symptoms.  Each item is rated on a 0 to 6 scale with higher scores 
indicating higher levels of depressive symptoms.  Thus, the total score can range from 0 to 60.  The 
MADRS total score will be taken as recorded by the Investigator (i.e., not altered or adjusted) from the 
vendor dataset provided by Data Management. Change from baseline values will be computed as the 
MADRS total score at Week 8 – the MADRS total score at Baseline.  
15.1.2. 
MISSING DATA METHODS FOR THE PRIMARY EFFICACY VARIABLE 
No missing data imputation is required for the primary analysis, LS means estimates will be adjusted for 
missing data through the mixed model for repeated measures (MMRM) methods used in the analysis. If 
data is missing at Week 8 for a patient then they will not be included in the analysis. However, a 
sensitivity analysis will be conducted with imputed data as described in section 15.1.4. 
15.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary objective of this study is to evaluate the effects of BTRX-246040 on symptoms of 
depression in adult patients with Major Depressive Disorder after 8 weeks of double-blind treatment. To 
meet this objective the hypothesis that BTRX-246040 is superior to placebo will be tested as follows: 
H0: µBTRX-246040 = µplacebo vs. Ha: µBTRX-246040 ≠ µplacebo 
Where µ is the change from baseline in investigator-administered MADRS total score at week 8.  
The primary efficacy analysis will be performed for the full analysis set (FAS). 
The primary analysis will be a MMRM. A repeated measures analysis refers to a restricted-maximum-
likelihood- (REML-) based, MMRM analysis using all the longitudinal observations at each post-baseline 
visit. The model for this analysis will include the fixed class effects of treatment, investigative site, visit, 
and the treatment-by-visit interaction as well as the continuous covariate of baseline investigator-
administered MADRS total score. An unstructured covariance structure will be used to model the within-
patient errors. If the unstructured covariance matrix results in a lack of convergence, the heterogeneous 
autoregressive variance-covariance structure will be used. The difference in least square means (LS 
Means) between BTRX-246040 and placebo at Week 8, with corresponding 2-sided 95% confidence 
intervals and estimated P-values will be presented.  
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15.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The following sensitivity analyses will be conducted on the change from baseline in investigator-
administered MADRS total score to ensure robustness of the primary efficacy analysis. The FAS will be 
used for all sensitivity analyses unless otherwise specified. 
 
The primary efficacy analysis will be repeated on the PPAS, CAS, and MNRAS analysis sets. 
 
The MMRM model used for the primary efficacy analysis will be used to analyze the change from Baseline 
in investigator‐administered MADRS total score at each post‐Baseline visit. For each visit the difference in 
LS  Means  between  BTRX‐246040  and  placebo  will  be  presented  alongside  the  2‐sided  95%  confidence 
interval and P‐value. 
 
ANCOVA will be used to analyze the change in investigator‐administered MADRS total score from baseline 
to week 8, with missing data imputed. The ANCOVA model will include treatment group, investigative site 
as fixed effects and baseline investigator‐administered MADRS total score as a covariate. Only the MADRS 
total score will be imputed where missing, the individual component scores will not be imputed. Imputation 
will be performed following visit window remapping. The following two methods of data imputation will be 
used: 
o 
Multiple imputation using Rubin’s rules with SAS Proc MI and MIANALYSIS. 
o 
Single imputation by last observation carried forward (LOCF). 
 
Finally, the change from baseline in the computer‐administered MADRS total score will be analyzed using 
the same method as the primary efficacy analysis. 
Forest plots of the treatment difference and confidence intervals will be created for the primary analysis 
and each of the efficacy analyses.  
15.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the FAS unless otherwise specified. 
15.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. MADRS Total Score 
The derivation of the MADRS total score is defined in section 15.1.1. 
15.2.1.2. MADRS‐6 Subscale 
The MADRS-6 subscale focuses on the core symptoms of depression and is the sum of items about the 
following symptoms: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and 
pessimistic thoughts. Overall score ranges from 0 to 36. 
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15.2.1.3. MADRS Individual Item Scores 
The MADRS individual item scores refer to the 10 items, on a scale 0 – 6 which comprise the MADRS 
total score.  
15.2.1.4. Hospital Anxiety and Depression Scale subscales 
The Hospital Anxiety and Depression Scale (HADS) subscales comprises of 7 questions regarding 
Depression and 7 questions regarding Anxiety. Each question is rated on a scale from 0 – 3. The 
outcome of the HADS questionnaire is two total scores, the HADS-A (for anxiety) and the HADS-D (for 
depression). Both total scores are graded on a scale of 0 – 21 and can be categorized as Normal (0 – 
7), Borderline Abnormal (8 – 10) and Abnormal (11 – 21). Higher scores indicate higher levels of anxiety 
and depression.   
15.2.1.5. Dimensional Anhedonia Rating Scale 
The Dimensional Anhedonia Rating Scale (DARS) is a 17-item questionnaire with each answer between 
0 and 4 on a Likert scale grading (0=Not at all, 1=Slightly, 2=Moderately, 3=Mostly, 4=Very Much). 
Therefore, the DARS total score is on a scale of 0 – 68. The DARS Total score is broken down into four 
dimensions; Hobbies, Food/Drink, Social Activities and Sensory Experience. 
15.2.1.6. Snaith Hamilton Pleasure Scale 
The Snaith Hamilton Pleasure Scale (SHAPS) is a 14-item questionnaire. The SHAPS is scored two 
different ways.  Under the original scoring method, each question has 4 responses, 2 of which imply 
agreement (Definitely Agree, Agree; each scored as 0) and 2 which imply disagreement (Disagree, 
Strongly Disagree; each scored as 1). Therefore, the SHAPS total score ranges 0 – 14.  In this study, in 
addition to the traditional scoring method, an alternative scoring method will assign 1 - Strongly Agree, 2 
- Agree, 3 – Disagree, and 4 – Strongly Disagree. Using this alternative scoring method, the total score 
ranges 14-56.  In both scoring systems, higher scores indicate greater anhedonia. 
15.2.1.7. Response 
Response will be defined in the following three ways: 
 
Clinical response will be defined as a reduction in the investigator-administered MADRS total 
score of 50% between baseline and week 8. 
 
Remission will be defined as an investigator-administered MADRS total score of ≤10 at week 
8.  
 
Improvement will be defined as a Clinical Global Impression Scale – Improvement (CGI-I) 
score of 1 or 2 at week 8. The CGI-I is a 7-point scale that relates to an improvement in patients 
symptoms when compared to the Clinical Global Impression Scale – Severity (CGI-S), which is 
also measured on a 7-point scale. 
15.2.1.8. The Facial Expression Recognition Task  
The FERT is a computer test used to assess attention to, and perception of, social cues and affective 
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information. Faces with 6 different basic emotions (happiness, fear, anger, disgust, sadness, surprise) 
are displayed on the screen and the patient is required to indicate the expression of the face via a 
button-press. Different intensity levels (10) of each emotion are presented, which increases the 
ambiguity of the facial expression and the sensitivity of the task (Harmer et al, 2009). In addition, neutral 
faces will be displayed on screen during the task and is a button-press option. Intensity levels do not 
apply to the neutral face but the 5 outcome measures will be reported for neutral faces as well. 
There are 5 outcome measures from the FERT for each emotion. They are: 
 
Accuracy (%) 
 
Misclassification (%) 
 
Average reaction time (ms) 
 
Target sensitivity 
 
Response bias 
These measures, along with the accuracy response for each intensity level, for each emotion will be 
provided by the vendor data and will be used in the analysis described in section 15.2.3.8. 
15.2.1.9. Probabilistic Reward Task 
The PRT is a measure of reward learning consisting of trials in which patients are asked to respond to 
two hardly distinguishable cues, of which one is more frequently rewarded. Patients complete a total 
300 trials in 3 blocks of 100. Response bias for the rewarded category is the main outcome of interest 
(Pizzagalli, et al, 2008). In addition, the following outcome measures will be provided: 
 
Discriminability (subject’s ability to differentiate between the two cues) 
 
Reaction time 
 
Accuracy (hit rates) 
All measures will be computed and provided by the vendor in the source data for each block and as an 
overall total. The response bias and discriminability measures will also have log-linear adjusted values 
provided. The adjusted values for response bias and discriminability and original values for reaction 
time and hit rates at each block will be utilized in the analyses. 
Additionally, there will be a series of checks on the data to insure validity of the data used in the analysis. 
Only subjects with data meeting the following criteria will be used in the analysis. 
 
The number of valid trials is >80% for each block  
 
Reward ratio of rich:lean is greater than 25:10 (ratio: 2.5) in each block. 
 
The number of rich rewards is between 24 and 30, inclusively. 
 
The number of lean rewards is between 7 and 10, inclusively.  
 
The lean accuracy in each block is greater than or equal to 40%. 
 
The rich accuracy in each block is greater than or equal to 40%.  
 
For combination of blocks e.g. Main, Total: If one block is not usable, then the combo is not 
usable (i.e. if block 2 is not usable, then total is not usable).  
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15.2.1.10. Effort Expenditure for Reward Task 
The EEfRT task is a multi-trial game in which participants are given an opportunity on each trial to 
choose between two different task difficulty levels in order to obtain monetary rewards. Patients are 
required to complete the task with a specific number of button responses within a constrained period of 
time in order to obtain a monetary reward. The outcome measures of the EEfRT are: 
 
Preference (hard or easy task) 
 
Completion rates  
These measures will be provided by the vendor data and will be used in the analysis described below. 
Additionally, there will be a series of checks on the data to insure validity of the data used in the analysis. 
Only subjects with data meeting the following criteria will be used in the analysis. 
 
Proportion of completed tasks > 75%.  
 
No more than 10 failed tasks in a row, which would suggest the subject ‘took a break’. 
 
The subject does not time out on >10% of trials 
 
Average reaction times of ≥500ms (0.5s). 
15.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
No missing data imputation will be used for the secondary efficacy variables.  
15.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
15.2.3.1. MADRS Total Score 
The following analyses will be produced for both the investigator-administered MADRS assessment and 
the computer-administered MADRS assessment in addition to the analyses described above.  
The MADRS total score and change from baseline in MADRS total score will be summarized through 
descriptive statistics (mean, standard deviation, median, and range) by treatment group and visit. The 
MADRS total score will also be summarized as a categorical variable by classifying the MADRS total 
score as Normal (0 – 6), Mild Depression (7 – 19), Moderate Depression (20 – 34) or Severe 
Depression (35 – 60) for each treatment group and visit.  
In addition, the difference for each patient between the investigator-administered MADRS total score 
and the computer-administered MADRS total score will be summarized for each treatment group and 
visit alongside the 95% confidence interval p-value from a paired t-test.  
15.2.3.2. MADRS‐6 Subscale 
The change from baseline in the investigator-administered MADRS-6 subscale to week 8 will be 
analyzed using the same method as the primary efficacy endpoint, substituting the baseline MADRS-6 
subscale as the covariate in place of the MADRS total score. In addition, the MADRS-6 subscale and 
the change from baseline in investigator-administered MADRS-6 subscale will be summarized through 
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descriptive statistics by treatment group and visit. 
15.2.3.3. MADRS Individual Item Scores 
The change from baseline for each individual item comprising the investigator-administered MADRS 
total score to week 8 will be analyzed using the same method as the primary efficacy endpoint, 
substituting each individual item as covariates in place of the MADRS total score. The investigator-
administered MADRS individual item scores and their change from baseline will also be summarized 
through descriptive statistics by treatment group and visit.  
The MADRS individual item scores, total scores and MADRS-6 total scores will be listed for all patients 
and visits.  
15.2.3.4. Hospital Anxiety and Depression Scale subscales 
The change from baseline for both the HADS-A total score and HADS-D total score to week 8 will be 
analyzed using the same method as the primary efficacy endpoint, substituting the baseline HADS-A 
and HADS-D total score as appropriate as the covariate in place of the MADRS total score. The HADS-
A total score and HADS-D total score and change from baseline in HADS-A total score and HADS-D 
total score will be summarized through descriptive statistics by treatment group and visit. The HADS-A 
total score and the HADS-D total score will also be summarized as categorical variables using the 
classification of Normal/Borderline Abnormal/Abnormal described above by treatment group and visit. 
Finally, the number and percentage of patients within each result category will be presented by 
treatment group, item and visit. 
All HADS-A and HADS-D total scores and individual item scores will be listed.  
15.2.3.5. Dimensional Anhedonia Rating Scale 
The change from baseline for the DARS total score to week 8 will be analyzed using the same method 
as the primary efficacy endpoint, substituting the baseline DARS total score as the covariate in place of 
the MADRS total score. The DARS total score and change from baseline in DARS total score will be 
summarized through descriptive statistics by treatment group and visit. In addition, the number and 
percentage of patients within each result category will be presented by treatment group, item and visit. 
Each DARS dimensions score (Hobbies, Food/Drink, Social Activities, Sensory Experience) and change 
from baseline in DARS dimensions score will be summarized through descriptive statistics by treatment 
group and visit. 
All DARS individual item scores and total scores will be listed.  
15.2.3.6. Snaith Hamilton Pleasure Scale 
The change from baseline for the SHAPS total score to week 8 will be analyzed using the same method 
as the primary efficacy endpoint, substituting the baseline SHAPS total score as the covariate in place 
of the MADRS total score. The SHAPS total score and change from baseline in SHAPS total score will 
be summarized through descriptive statistics by treatment group and visit. In addition, the number and 
percentage of patients who agree or disagree to each question will be presented by treatment group, 
item and visit. 
All SHAPS individual item scores and total scores will be listed.  
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15.2.3.7. Response 
The difference in the proportion of responders at week 8 between each treatment group will be 
estimated for each response variable using a logistic regression model with treatment and investigator 
site as a fixed effect and baseline investigator-administered MADRS total score as a continuous 
covariate, using Firth’s Penalized Likelihood with CI and p-values based on individual Wald tests. 
In addition, the number and percentage of patients within each CGI-S and CGI-I result category will be 
presented by treatment group and visit. Both CGI-S and CGI-I results will be available at the baseline 
visit, the CGI-I at baseline will refer to the CGI-S assessment at screening. All subsequent CGI-I 
assessments will refer to the baseline CGI-S assessment.  
Results of each response category at week 8 will be listed for all randomized patients. In addition, all 
CGI-S and CGI-I results will also be listed.  
15.2.3.8. The Facial Expression Recognition Task  
For each emotion of the FERT, each outcome measure will be summarized (mean, standard deviation, 
median, and range) by treatment group at each visit. Line plots of means (+/-SD) will also be presented 
by treatment group and visit. Additionally, accuracy will be summarized by intensity level for each 
emotion and plotted versus intensity level in scatterplots. 
At each scheduled visit, an ANOVA model with a term for treatment will be used to analyze treatment 
differences. LS Means and standard errors (SEs) will be presented for each treatment group. A second 
ANOVA model will be fit with additional factors of gender, baseline MADRS total score, and baseline 
FERT outcome measure. The difference in LS Means with corresponding SEs, 95% confidence 
intervals for differences, and p-values will also be presented. No adjustments will be made for multiple 
comparisons.  
All data, including the accuracy response for each intensity level, will be listed by treatment and patient. 
15.2.3.9. Probabilistic Reward Task 
Each outcome measure of the PRT will be summarized (mean, standard deviation, median, and range) 
at each visit. Response bias and discriminability will be summarized by block and treatment. Reaction 
time and hit rates will be summarized by stimulus (rich vs. lean), block and treatment. Line plots of 
means (+/-SD) will also be presented by treatment group and visit.  
At each scheduled visit, an ANOVA model will be used to compare treatment groups. The models for 
response bias and discriminability will include terms for treatment, block, and treatment-by-block will be 
used to analyze treatment differences. The models for reaction time and hit rates will include terms for 
treatment, block, stimulus, and treatment-by-block will be used to analyze treatment differences. The 
models LS Means and standard errors (SEs) will be presented for each treatment group. The difference 
in LS Means with corresponding SEs, 95% confidence intervals for differences, and p-values will also 
be presented. No adjustments will be made for multiple comparisons.  
All data, including the overall total scores, will be listed by treatment and patient. 
15.2.3.10. Effort Expenditure for Reward Task 
Each outcome measure of the EEfRT will be summarized (mean, standard deviation, median, and 
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range) by treatment group at each visit. Line plots of means (+/-SD) will also be presented by treatment 
group and visit.  
The analysis of completion rates will use an ANOVA model with a term for treatment to analyze 
treatment differences at each scheduled visit. The models LS Means and standard errors (SEs) will be 
presented for each treatment group. The difference in LS Means with corresponding SEs, 95% 
confidence intervals for differences, and p-values will also be presented. No adjustments will be made 
for multiple comparisons. 
The analysis of preference will be completed utilizing Generalized Estimating Equation (GEE) models. A 
binary logistic distribution will be used to model the dichotomous outcome of preference at each 
scheduled visit. At each visit a series of models using a variety of factors will be fit. All models in the 
series will include explanatory variables reward magnitude, reward probability, and expected value 
(reward magnitude X probability) as a base. For each series, four models will be fit. The first will include 
the base variables with the additional variable of interest with no interactions. The next three models will 
include the same but with an interaction term between the variable of interest and each base variable in 
order. The variables of interest that will be explored include: 
 
Age 
 
Sex 
 
Treatment 
 
MADRS Total Score 
 
SHAPS Score (0 – 14 scoring method) 
 
DARS Total Score 
The parameter estimates, standard error, 95% confidence interval, degrees of freedom and p-values will 
be presented to for each model.  
All data will be listed by treatment and patient. 
15.3. EXPLORATORY EFFICACY  
15.3.1. 
EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
15.3.1.1. Hamilton Anxiety Rating Scale 
The Hamilton Anxiety Rating Scale (HAM-A) consists of 14 items. Each item is rated on a scale of 0 
(feeling not present) to 4 (very severe prevalence of the feeling). The HAM-A total score is the sum of 
the 14 items and the score ranges from 0 to 56. 
15.3.1.2. Pain Question 
The Pain question is a single item which assesses the average pain over the last 24 hours. The 
response is scored from 0 (no pain) to 10 (pain as severe as you can imagine). 
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15.3.1.3. Nonpharmacogenetic Biomarkers 
Results for the following nonpharmacogenetic biomarkers will be available: plasma nociception, serum 
IL-1ß, IL-2, IL-6, IL-10, TNFα, IFNγ and CRP. If applicable biomarker results below the limit of 
quantification (BLOQ) will be imputed as BLOQ/2 and biomarker results above the limit of quantification 
(ALOQ) will be imputed as the ALOQ for the purpose of change from baseline calculations. 
15.3.2. 
MISSING DATA METHODS FOR EXPLORATORY EFFICACY VARIABLE(S) 
No missing data imputation will be used for the exploratory efficacy variables. 
15.3.3. 
ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
15.3.3.1. Hamilton Anxiety Rating Scale 
The change from baseline for the HAM-A total score to week 8 will be analyzed using the same method 
as the primary efficacy endpoint, substituting the baseline HAM-A total score as the covariate in place of 
the MADRS total score. Using the same model, the difference in between treatment groups will also be 
presented for the change from baseline to week 4. The HAM-A total score and change from baseline in 
HAM-A total score will be summarized through descriptive statistics by treatment group and visit.  
15.3.3.2. Pain Question 
The change from baseline for the Pain score to week 8 will be analyzed using the same method as the 
primary efficacy endpoint, substituting the baseline Pain score as the covariate in place of the MADRS 
total score. The Pain score and change from baseline in Pain score will be summarized through 
descriptive statistics by treatment group and visit.  
15.3.3.3. Nonpharmacogenetic Biomarkers 
The change from baseline to week 8 for each nonpharmacogenetic biomarker will be analyzed using an 
ANCOVA model with treatment group and investigative site as fixed effects and baseline biomarker 
result as a continuous covariate. The change from baseline in nonpharmacogenetic biomarker result will 
be summarized through descriptive statistics by biomarker, treatment group and visit. The number and 
percentage of BLOQ/ALOQ results at each visit will also be presented. In addition, panel plots 
displaying the correlation of the change from baseline to week 8 in biomarker level with the change from 
baseline to week 8 in MADRS total score and total treatment exposure will be presented.   
15.3.4. 
SUBGROUP ANALYSIS 
Analysis by the subgroups defined in section 7.5 will be performed on efficacy endpoints according to 
the following table. The change from baseline to week 8 for each endpoint will be analyzed using the 
same method as the endpoint in the main analysis. For the anhedonia severity subgroup analysis, that 
term will be dropped from the model. 
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Subgroup Analyses for Efficacy Endpoints 
Efficacy Endpoint  
Subgroup 
Gender 
Anhedonia Severity 
(SHAPS) 
Baseline 
HAM‐A (<20, 
>=20) 
(<=4, >4) 
(<=7, >7) 
MADRS total score  
X 
X 
X 
X 
PRT 
 
 
X 
 
EEfRT 
 
 
X 
 
  
16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Set.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified with the relevant section.  
16.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central 
coding dictionary, Version 20.0. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity 
on or after the first dose of study medication. 
See APPENDIX 2 for handling of partial dates for AEs.  In the case where it is not possible to define an 
AE as treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
An overall summary of number of patients within each of the categories described in the sub-section 
below will be provided as specified in the templates.  
Listings will include TEAEs and Non-TEAEs. 
16.1.1. 
ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and also 
broken down further by maximum severity and relationship to study medication. 
16.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first dose of 
study medication with a missing severity will be classified as severe. If a patient reports a TEAE more 
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than once within that SOC/ PT, the AE with the worst case severity will be used in the corresponding 
severity summaries. 
16.1.1.2. Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as ”not related”, “unlikely related”, “possibly 
related”, and “related” (increasing severity of relationship). A ”related” TEAE is defined as a TEAE with a 
relationship to study medication as ”possibly related” or ”related” to study medication. TEAEs with a 
missing relationship to study medication will be regarded as related to study medication. If a patient 
reports the same AE more than once within that SOC/ PT, the AE with the worst case relationship to 
study medication will be used in the corresponding relationship summaries.  
16.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified from the Adverse 
Event eCRF page where the action taken with the study treatment was selected as “Drug withdrawn”. 
For TEAEs leading to discontinuation of study medication, summaries of incidence rates (frequencies 
and percentages) by SOC and PT will be prepared. 
16.1.3. 
TEAE’S LEADING TO EARLY STUDY DISCONTINUATION 
TEAEs leading to early study discontinuation will be identified from the relevant question in the Adverse 
Event eCRF page. 
For TEAEs leading to early study discontinuation, summaries of incidence rates (frequencies and 
percentages) by SOC and PT will be prepared. 
16.1.4. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of 
the eCRF. A summary of serious TEAEs by SOC and PT will be prepared. 
16.1.5. 
ADVERSE EVENTS ASSOCIATED WITH SELF‐HARM EPISODES 
TEAEs associated with self-harm episodes will be identified from the relevant question in the Adverse 
Event eCRF page. 
For TEAEs associated with self-harm episodes, summaries of incidence rates (frequencies and 
percentages) by SOC and PT will be prepared. 
16.2. DEATHS 
If any patients die during the study, as recorded on the ”death details” page of the eCRF , the 
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information will be presented in a data listing. 
16.3. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, Clinical 
Chemistry (including Amylase and total Lipase) and Urinalysis. A list of laboratory assessments to be 
included in the outputs is included in the protocol, Section 11.4.  
Presentations will use SI Units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification, or 
“> X”, i.e. above the upper limit of quantification, will be converted to X/2 or X respectively for the 
purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the 
listings, where X has been converted into the SI unit. 
The following summaries will be provided for laboratory data: 
 
Summary tables of actual and change from baseline by visit (for quantitative measurements) 
 
Shift from baseline to each post‐baseline assessment according to normal range criteria (for quantitative 
measurements and categorical measurements) 
 
Listing of patients meeting abnormal criteria 
Laboratory tests related to patient screening, such as, urine drug screening, hepatitis screening and 
thyroid function, if available, will be listed only. Results from serum and urine Pregnancy tests will be 
listed.  
16.3.1. 
LABORATORY REFERENCE RANGES AND ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in 
SI units and categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
16.4. ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting of 
this study.  
The following ECG parameters will be reported for this study: 
 
PR Interval (msec) 
 
RR Interval (msec) 
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 
QRS Duration (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec)  
 
QTcB Interval (msec)  
 
Heart Rate (bpm) 
 
Axis and Voltage (deg) 
 
Overall assessment of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (ANCS) 
o 
Abnormal, Clinically Significant (ACS) 
Summary tables and boxplots of actual and change from baseline results for all quantitative ECG 
parameters will be presented.  
16.4.1. 
ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following 
predefined markedly abnormal criteria: 
 
Absolute values for QT interval, QTc interval, QTcB interval and QTcF will be classified as: 
o 
> 450 msec  
o 
> 480 msec  
o 
> 500 msec 
 
Change from Baseline for QT interval, QTc interval, QTcB interval and QTcF will be classified as: 
o 
>30 msec increase from baseline 
o 
>60 msec increase from baseline 
 
Results which meet the above criteria will be flagged in the listing.  
16.5. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 
Standing/ Supine Systolic Blood Pressure (mmHg) 
 
Standing/ Supine Diastolic Blood Pressure (mmHg) 
 
Standing/ Supine Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Temperature (⁰C) 
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 
Weight (kg) 
 
BMI (kg/m2) 
Summary tables and boxplots of actual and change from baseline results for all quantitative ECG 
parameters will be presented.  
16.5.1. 
VITAL SIGNS ABNORMAL CRITERIA 
Abnormal quantitative vital signs measurements will be identified in accordance with the following 
predefined abnormal criteria: 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg OR  
change from baseline 
≤ -20 mmHg OR 
difference between supine and 
standing (standing – supine) 
≤ -20 mmHg 
≥ 160 mmHg OR 
change from baseline 
≥ 20 mmHg OR 
difference between supine and 
standing (standing – supine) 
≥ 20 mmHg 
DBP 
mmHg 
≤ 50 mmHg OR 
change from ≤ -10 mmHg OR 
difference between supine and 
standing (standing – supine) 
≤ -10 mmHg 
≥ 100 mmHg OR 
change from baseline 
≥ 10 mmHg OR 
difference between supine and 
standing (standing – supine) 
≥ 10 mmHg 
Pulse rate 
Bpm 
≤ 50 bpm OR 
change from baseline ≤ -15 
bpm OR 
difference between supine and 
standing (standing – supine) 
≤ -15 mmHg 
≥ 120 bpm OR 
change from baseline ≥ 15 bpm 
OR 
difference between supine and 
standing (standing – supine) 
≥ 15 mmHg 
Body 
temperature 
˚C 
NA 
≥ 38.3 ˚C OR 
change from baseline ≥ 1.1 ˚C 
Weight 
Kg 
percentage change from 
baseline ≤ -7.0 % 
percentage change from 
baseline ≥ 7.0 % 
Results which meet the above criteria will be flagged in the listing. 
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16.6. SUICIDE IDEATION/SUICIDALITY 
The assessment of suicidality is based on changes from baseline in the incidence rates of suicidal 
behavior and suicidal ideation as measured by the Columbia Suicide Severity Rating (C-SSRS).  The 
post-baseline C-SSRS assesses the occurrence of suicidal behavior and suicidal ideation since the last 
visit.  The occurrence of suicidal behavior and suicidal ideation are determined as follows. 
 
Suicidal behavior: having answered “yes” to at least one of the following four suicidal behavior 
items (Items 12, 14, 15, and 16 — actual attempt, interrupted attempt, aborted attempt, and 
preparatory acts or behavior, respectively) at any post-baseline evaluation;  
 
Suicidal ideation: having answered “yes” to at least one of the following two suicidal ideation 
items (Items 1 and 2—wish to be dead and non-specific active suicidal thoughts, respectively.   
The number and percentage of patients who indicate suicidal behavior or suicidal ideation at any post-
baseline visit will be summarized.   
The number of discrete events of suicidal behavior, possible suicidal behavior, and non-suicidal self-
injurious behavior will be captured in the Self-Harm Supplement Form (SHSF). The number of events 
will also be summarized at each visit. The details of each episode are captured on the Self-Harm 
Follow-up Form (SHFU). The information captured in the SHFU will be listed.   
16.7. PHYSICAL AND NEUROLOGICAL EXAMINATION  
Listings will be generated for the physical and neurological examination data.  
17. DIGITAL ASSESSMENTS 
Vocal and/or behavioral digital assessments will be conducted with HIPAA compliant digital application 
that have been downloaded one the patient’s smartphone with an iOS or Android operating system. The 
applications will be used for active collection of brief vocal samples for subsequent analysis of acoustic 
features that are associated with affective states and for passive acquisition of metadata to assess 
behavioral pattern that are associated with affective or cognitive states. The data will be reported in a 
separate protocol.  
18. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
A summary table of concentrations by visit for patients randomized to BTRX-246040 including number 
of patients who are below the limit of quantification (BLQ) and will be presented. Pharmacokinetic data 
collected in this study will be listed for the Pharmacokinetic Analysis Set.  
Population PK analysis of the plasma concentrations in this study will be reported separately.  
Other exploratory analyses, such as the relationship between BTRX-246040 exposure and efficacy 
measures or AEs or other safety endpoints, may be undertaken as deemed appropriate. 
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19. PHARMACOGENETIC ANALYSIS 
Information regarding the collection of pharmacogenetic sample will be listed. Any analysis of 
pharmacogenetic sample will be reported separately.  
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20. REFERENCES  
None 
 
 
 
 
 
 
 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to IQVIA’s Global Biostatistics Standard Output Conventions.  
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
 
BTRX-246040 
 
Placebo 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Baseline  
BL 
Week 1 
W1 
Week 2 
W2 
Week 4 
W4 
Week 6 
W6 
Week 8 
W8 
Safety Follow Up 
SFU 
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LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
randomized treatment group, first by BTRX‐246040 and then placebo,  
 
center‐subject ID,  
 
date (where applicable), 
 
For  listings  where  non‐randomized  patients  are  included,  these  will  appear  in  a  category  after  the 
randomized treatment groups labeled ‘Not Randomized’. 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start date 
Known 
If stop date < study med start date, then not TEAE 
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START DATE 
STOP 
DATE 
ACTION 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date, assign as concomitant  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
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Protocol NEP-MDD-201
27 August 2019
42


 
Analysis Plan  
BlackThorn Therapeutics Inc.
NEP-MDD-201 
Page 40 of 40
 
Document: 
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Author: 
Sabina Rich 
Version Number:
1.0
 
 
Version Date: 
06Dec2018 
Template No:  CS_TP_BS016 Revision 4
Reference:  CS_WI_BS005
Effective Date: 01Apr2016 
 
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START 
DATE 
STOP 
DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown) and 
impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
 
Missing 
Assign as concomitant 
 
BlackThorn Therapeutics, Inc.
CSR Version No.1, Final
Protocol NEP-MDD-201
27 August 2019
43