Conditions: Anhedonia Major Depressive Disorder
Keywords: Anhedonia Major Depressive Disorder MDD NBI-1065846 TERPSIS Neurocrine Antidepressant Depression TAK-041
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 93
Healthy volunteers: no

Brief summary:
To evaluate the efficacy of NBI-1065846 compared with placebo on improving symptoms of anhedonia in participants with major depressive disorder (MDD).

Detailed description:

Arms:
arm 1: Participant follows Placebo schedule (57 days) arm 2: Participant follows NBI-1065846 schedule (57 days)

Interventions: intervention 1: Placebo intervention 2: NBI-1065846
Intervention descriptions: intervention 1: Tablets for oral administration intervention 2: Tablets for oral administration

Protocol document:
Prot_000.pdf: 
PROTOCOL TITLE   
A Randomized, Double-Blind, Placebo-Controlled, 
Proof-of-Concept Study to Evaluate the Efficacy and 
Safety of Once-Weekly Oral NBI-1065846 in the 
Treatment of Anhedonia in Major Depressive Disorder 
(TERPSIS STUDY) 
Protocol Identifier: 
NBI-1065846-MDD2020 
Phase: 
Phase 2 
Sponsor: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
United States 
Sponsor Medical Monitors: 
 
Telephone: 
Email: 
 
 
Telephone: 
Email: 
 
Serious Adverse Event 
Reporting 
Facsimile: 
+1 (888) 617 7551 or +1 (858) 617-7561
Email: 
cds@neurocrine.com 
Protocol Amendment 
3.0 – 21 March 2023 
CONFIDENTIAL 
This document contains information that is of confidential, trade secret, and/or proprietary nature 
to Neurocrine Biosciences, Inc. It is intended for your confidential review and to provide you, your 
staff, and your reviewing Institutional Review Board/Independent Ethics Committee with 
information regarding the specific clinical study in which you are participating. You may not 
disclose the contents of this document to parties, other than those previously mentioned, without 
prior written permission from Neurocrine Biosciences, Inc.; provided that you shall be entitled to 
disclose it to authorized representatives of national regulatory authorities under the condition that 
they respect its confidential nature. 
NCT #: NCT05165394


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PROTOCOL AMENDMENTS  
Protocol/Amendments 
Date 
Original Protocol 
09 August 2021 
Amendment 1.0 
01 July 2022 
Amendment 2.0 
18 November 2022 
Amendment 3.0 
21 March 2023 
 


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TABLE OF CONTENTS 
PROTOCOL TITLE ........................................................................................................................1 
PROTOCOL AMENDMENTS .......................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
1. 
SYNOPSIS .................................................................................................................11 
2. 
INTRODUCTION ......................................................................................................14 
2.1. 
Background .................................................................................................................14 
2.2. 
Benefit/Risk Assessment for NBI-1065846 ...............................................................15 
3. 
OBJECTIVES .............................................................................................................16 
3.1. 
Primary .......................................................................................................................16 
3.2. 
Secondary ...................................................................................................................16 
4. 
STUDY DESIGN .......................................................................................................17 
4.1. 
Overall Study Design ..................................................................................................17 
4.2. 
Rationale for Dose Selection ......................................................................................18 
4.3. 
End of Study Definition ..............................................................................................18 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
Inclusion Criteria ........................................................................................................21 
5.2. 
Exclusion Criteria .......................................................................................................23 
6. 
STUDY TREATMENT ..............................................................................................26 
6.1. 
General Information ....................................................................................................26 
6.2. 
Study Treatment Administration ................................................................................26 
6.3. 
Study Treatment Compliance .....................................................................................26 
6.4. 
Study Treatment Storage/Compliance ........................................................................27 
6.5. 
Study Treatment Accountability and Return ..............................................................27 
6.6. 
Direct-to-Subject Shipments of Study Treatment .......................................................27 
6.7. 
Blinding ......................................................................................................................27 
6.8. 
Procedures for Overdose .............................................................................................28 
7. 
SUBJECT RESTRICTIONS ......................................................................................29 
7.1. 
Prior and Concomitant Medications ...........................................................................29 
7.2. 
Dietary and Other Restrictions ...................................................................................31 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL ........................................................................................................31 


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8.1. 
Discontinuation of Study Treatment ...........................................................................31 
8.2. 
Withdrawal from Study ..............................................................................................33 
8.3. 
Sponsor’s Termination or Temporary Halt of Study or Study Site ............................33 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................34 
9.1. 
Screening Assessments and Procedures .....................................................................34 
9.1.1. 
Subject Registry Database Review Consent ...............................................................34 
9.1.2. 
Mini-International Neuropsychiatric Interview ..........................................................34 
9.1.3. 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire ..............................................................................................................35 
9.1.4. 
Hamilton Depression Rating Scale-17 Item ...............................................................35 
9.1.5. 
Snaith-Hamilton Pleasure Scale .................................................................................35 
9.1.6. 
SAFER Interview ........................................................................................................35 
9.2. 
Efficacy Assessments and Procedures ........................................................................36 
9.2.1. 
Placebo-Control Reminder Script ...............................................................................36 
9.2.2. 
Dimensional Anhedonia Rating Scale ........................................................................36 
9.2.2.1. 
Subject Exit Interview ................................................................................................36 
9.2.3. 
Montgomery Åsberg Depression Rating Scale...........................................................37 
9.2.4. 
Clinical Global Impression – Severity Scale ..............................................................37 
9.2.5. 
 ......................................................37 
9.2.6. 
 .....................................................................37 
9.2.7. 
 ............................................................................38 
9.2.8. 
 ...................................................................................38 
9.2.9. 
 ....................................................................38 
9.2.10. 
 ..........................................................................................38 
9.3. 
Safety Assessments .....................................................................................................39 
9.3.1. 
Vital Sign Measurements, Height, and Weight ..........................................................39 
9.3.2. 
Medical History ..........................................................................................................39 
9.3.3. 
Physical Examination .................................................................................................39 
9.3.4. 
Electrocardiogram .......................................................................................................39 
9.3.5. 
Clinical Laboratory Assessments ...............................................................................40 
9.3.6. 
Columbia-Suicide Severity Rating Scale ....................................................................40 
9.4. 
Pharmacokinetic Assessments ....................................................................................41 
9.5. 
Other Procedures ........................................................................................................41 


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9.5.1. 
Blood Sample for Pharmacogenomics (Optional) ......................................................41 
9.6. 
Specific Study Period Information .............................................................................42 
9.6.1. 
Screening Period (Day -28 to Day -1) ........................................................................42 
9.6.2. 
Baseline Visit and Study Treatment Period (Day 1 to Day 57) ..................................43 
9.6.3. 
Follow-Up Period (Day 58 to Day 106) .....................................................................44 
10. 
ADVERSE EVENTS..................................................................................................45 
10.1. 
Definition ....................................................................................................................45 
10.1.1. 
Intensity of Adverse Events ........................................................................................46 
10.1.2. 
Relationship to Study Treatment ................................................................................46 
10.2. 
Recording Adverse Events .........................................................................................47 
10.3. 
Poststudy Follow-Up of Adverse Events ....................................................................47 
10.4. 
Serious Adverse Events ..............................................................................................48 
10.4.1. 
Definition of a Serious Adverse Event .......................................................................48 
10.4.2. 
Managing Serious Adverse Events .............................................................................48 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................49 
10.4.4. 
Expedited Safety Reports ...........................................................................................49 
10.5. 
Urgent Safety Measures ..............................................................................................49 
10.6. 
Pregnancy ...................................................................................................................50 
11. 
STATISTICAL METHODS .......................................................................................51 
11.1. 
Statistical Hypothesis ..................................................................................................51 
11.2. 
Sample Size Determination ........................................................................................51 
11.3. 
Analysis Sets ...............................................................................................................51 
11.4. 
Endpoints ....................................................................................................................52 
11.4.1. 
Primary .......................................................................................................................52 
11.4.2. 
Secondary ...................................................................................................................52 
11.4.3. 
Other ...........................................................................................................................52 
11.4.4. 
Safety ..........................................................................................................................53 
11.5. 
Statistical Analyses .....................................................................................................53 
11.5.1. 
Efficacy Analyses .......................................................................................................53 
11.5.1.1. 
Procedure to Control for Multiple Comparisons ........................................................53 
11.5.1.2. 
Primary Endpoint ........................................................................................................53 
11.5.1.3. 
Secondary endpoints ...................................................................................................53 


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11.5.2. 
Safety Analyses ..........................................................................................................54 
11.5.3. 
Pharmacokinetic Analyses ..........................................................................................54 
11.6. 
Interim Analyses .........................................................................................................54 
12. 
SUPPORTING DOCUMENTATION ........................................................................55 
12.1. 
Case Report Forms .....................................................................................................55 
12.2. 
Data Capture, Review, and Validation .......................................................................55 
12.3. 
Coding Dictionaries ....................................................................................................56 
12.4. 
Ethics ..........................................................................................................................56 
12.5. 
General Legal References ...........................................................................................56 
12.6. 
Institutional Review Board/Independent Ethics Committee ......................................56 
12.7. 
Protocol Adherence – Amendments ...........................................................................57 
12.8. 
Required Documents ..................................................................................................57 
12.9. 
Informed Consent .......................................................................................................57 
12.9.1. 
Subject Registry Database Review Informed Consent ...............................................57 
12.9.2. 
Pharmacogenomic Informed Consent .........................................................................57 
12.10. 
Study Monitoring ........................................................................................................58 
12.11. 
Quality Assurance .......................................................................................................58 
12.12. 
Record Retention ........................................................................................................58 
12.13. 
Confidentiality and Data Protection ...........................................................................58 
12.14. 
Publication and Disclosure Policy ..............................................................................59 
13. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................59 
14. 
REFERENCES ...........................................................................................................60 
APPENDIX A. SCHEDULE OF ASSESSMENTS ...................................................................63 
APPENDIX B. INVESTIGATOR SIGNATURE ......................................................................68 
APPENDIX C. SPONSOR APPROVAL SIGNATURE ............................................................69 
APPENDIX D. LIVER FUNCTION TEST MONITORING .....................................................70 
 
 
 


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LIST OF TABLES 
Table 1: 
Study Treatments ........................................................................................................26 
Table 2: 
Prohibited Concomitant Medications .........................................................................29 
Table 3: 
Restricted Concomitant Medications ..........................................................................30 
Table 4: 
Intensity of Adverse Events ........................................................................................46 
Table 5: 
Relationship of Adverse Events to Study Treatment ..................................................47 
Table 6: 
Contact Information for Drug Safety and Pharmacovigilance ...................................49 
Table 7: 
Analysis Sets ...............................................................................................................52 
Table 8: 
Schedule of Assessments ............................................................................................64 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................20 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Ab 
Antibody 
AE 
Adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BA 
Behavioral activation 
β-hCG 
β-human chorionic gonadotropin 
BMI 
Body mass index 
CBT 
Cognitive behavioral therapy 
CFR 
Code of Federal Regulations 
 
 
CGI-S 
Clinical Global Impression – Severity Scale 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome 
DARS 
Dimensional Anhedonia Rating Scale 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECT 
Electroconvulsive therapy 
EDC 
Electronic data capture 
EDTA K2 
Dipotassium ethylenediaminetetraacetic acid 
ET 
Early termination 
FDA 
Food and Drug Administration 
FIH 
First in human 
FSH 
Follicle-stimulating hormone 
F/U 
Follow-up 
GCP 
Good Clinical Practice 


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GGT 
Gamma-glutamyl transferase 
GPR139 
G-protein-coupled receptor 139 
HAM-D17 
Hamilton Depression Rating Scale-17 Item 
HDPE 
High density polyethylene 
ICD-10 
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive web response system 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MAOI 
Monoamine oxidase inhibitor 
MAR 
Missing-at-random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDD 
Major depression disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH-ATRQ 
Massachusetts General Hospital - Antidepressant Treatment Response 
Questionnaire 
MGH-CTNI 
Massachusetts General Hospital Clinical Trials Network and Institute 
MINI 
Mini-International Neuropsychiatric Interview 
MMRM 
Mixed effects repeated measures 
MPV 
Mean platelet volume 
MRI 
Magnetic resonance imaging 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
No observed adverse effect level 
PCRS 
Placebo-Control Reminder Script 
 
 
 
 


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PK 
Pharmacokinetic(s) 
 
 
PT 
Prothrombin time 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RBC 
Red blood cell count 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SAFER 
State versus Trait, Assessability, Face Validity, Ecological Validity, Rule of 
Three P’s 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SHAPS 
Snaith-Hamilton Pleasure Scale 
TBILI 
Total bilirubin 
TCA 
Tricyclic antidepressant 
TEAE 
Treatment-emergent adverse event 
 
  
TMS 
Transcranial magnetic stimulation 
uCMS 
Unpredictable chronic mild stress 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 


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1. 
SYNOPSIS  
Title of study: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to Evaluate 
the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the Treatment of Anhedonia in Major 
Depressive Disorder (TERPSIS STUDY) 
Protocol number: NBI-1065846-MDD2020 
Phase of development: 2 
Study centers: Approximately 20 study centers in the United States 
Objectives 
Primary: 
• 
To evaluate the efficacy of NBI-1065846 compared with placebo on improving symptoms of 
anhedonia in subjects with major depressive disorder (MDD). 
Secondary: 
• 
To evaluate the efficacy of NBI-1065846 compared with placebo on symptoms of depression in 
subjects with MDD. 
• 
To evaluate the safety, tolerability, and pharmacokinetics of NBI-1065846 in subjects with 
MDD.  
Study design: 
This is a Phase 2, randomized, double-blind, parallel-group, proof-of-concept study comparing use of 
NBI-1065846 with placebo for improvement of anhedonia in patients with MDD. The study consists of 
a Screening Period of up to 28 days (Days -28 to -1), an 8-week Treatment Period (Days 1 to 57), and 
an 8-week Safety Follow-up Period (with visits at 4 and 8 weeks [Days 78 and 106] after last dose of 
study treatment). 
Approximately 88 subjects are planned to be enrolled in the study. Eligible subjects include patients 
with MDD who have been treated with antidepressant medication(s) and who continue to have 
anhedonia (Snaith-Hamilton Pleasure Scale [SHAPS] ≥30). Subjects currently receiving antidepressant 
medication(s) must be receiving them for ≥8 weeks prior to screening at or above the therapeutic dose 
based on the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ). Subjects not currently receiving pharmacological treatment for depression must have 
received ≥1 antidepressant medication(s) at a therapeutic dose per MGH-ATRQ for ≥8 weeks in the 
current or most recent episode of depression. To ensure adequate representation of subjects across 
ranges of depression severity, the Sponsor may add limits to prevent further enrollment in specific 
subgroups based on Hamilton Depression Rating Scale-17 Item (HAM-D17) scores at baseline. 
Study treatment will be administered as monotherapy or as adjunctive treatment to the subject’s current 
oral antidepressant medication(s); subjects receiving antidepressant medication(s) at screening are 
expected to continue using them at the same dose throughout the study. 
Subjects will be randomized in a 1:1 ratio in a double-blinded fashion to receive either NBI-1065846 or 
placebo, administered on a weekly basis, for a period of 8 weeks. The randomization will be stratified 
based on the HAM-D17 score at baseline: remission (HAM-D17 ≤7), mild illness (HAM-D17 from 8 
to 18), and moderate to severe illness (HAM-D17 ≥19). 
The data generated in this study will be used to support a separate effort to evaluate the psychometric 
properties of the Dimensional Anhedonia Rating Scale (DARS), included as the primary efficacy 
assessment in this study. Additionally, at the final study visit (Day 57 or Early Termination [ET] Visit), 
20 subjects, regardless of whether they complete the study, will participate in exit interviews with the 


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objective of understanding perceptions of meaningful change and treatment experience. The 
psychometric analysis plan and results from the exit interviews will be reported separately. 
The end-of-study will be the date of the last visit of the last subject or last scheduled procedure shown 
in the schedule of assessments for the last subject in the study. 
Study population: 
Subjects 18 to 65 years of age (inclusive) with MDD and who have been treated with antidepressant 
medication(s) but continue to have clinically significant anhedonia.  
Duration of study treatment and study participation: The expected duration of treatment for each 
subject is approximately 8 weeks. Total study participation is approximately 20 weeks, which includes 
a 4-week Screening Period and an 8-week Safety Follow-Up Period. 
Investigational product, dosage, and mode of administration: 
NBI-1065846 will be supplied as 40 mg tablets for oral administration. Subjects will be administered a 
loading dose of 160 mg on Day 1, followed by a once-weekly dose of 80 mg in Weeks 2 to 8. 
Reference therapy, dose, and mode of administration: 
Placebo tablets identical in appearance to the test product will be administered on an identical schedule 
as NBI-1065846. 
Endpoints 
Primary: 
• 
Change in anhedonia severity, as measured by change in DARS score from baseline to Day 57. 
Secondary: 
• 
Change in total Montgomery Åsberg Depression Rating Scale (MADRS) score from baseline 
to Day 57 in subjects with moderate or higher severity depression. 
• 
Change in Clinical Global Impression – Severity (CGI-S) score from baseline to Day 57. 
Other: 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
Safety: 
• 
Safety endpoints include the occurrence of treatment-emergent adverse events (TEAEs), 
observed and changes from baseline in clinical laboratory tests (hematology and clinical 
chemistry), vital sign measurements (including orthostatic blood pressure and pulse rate), 
12-lead electrocardiogram (ECG) parameters, and scores from the Columbia-Suicide Severity 
Rating Scale (C-SSRS). 


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Statistical methods: 
Efficacy analysis: 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with the 
outcome being the change in DARS score from baseline to Day 57. The model will include treatment 
group, illness severity (stratification factor), use of concomitant antidepressant medication(s) at time of 
randomization ([ie, yes vs no], covariate), and baseline DARS score (covariate).  
Continuous secondary efficacy endpoints will be analyzed using a similar ANCOVA model as 
described for the primary endpoint; categorical and ordinal secondary endpoints will be analyzed using 
the Cochran-Mantel-Haenszel Chi-square test. Psychometric properties of the DARS will be assessed 
and reported separately. 


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2. 
INTRODUCTION  
2.1. 
Background  
Anhedonia, defined as the loss of interest in the usually pleasurable activities, is a characteristic 
of depression and several other neuropsychiatric disorders. The original definition of anhedonia 
as the loss of capacity to experience pleasure applies in particular to major depression disorder 
(MDD), in which anhedonia is recognized as a core feature of the disorder (Hasler et al., 2004). 
Clinically, in addition to being associated with greater depression severity, greater social 
impairment, worse quality of life (Buckner et al., 2008; Yee et al., 2015), and higher risk of 
suicide (Fawcett et al., 1990), anhedonia is also predictive of poor clinical outcome 
(Uher et al, 2012; Vrieze et al., 2013), including in adolescents (McMakin et al., 2012). 
Moreover, anhedonia reportedly does not respond well to serotonergic antidepressants 
(Shelton and Tomarken, 2001; Nutt et al., 2007). Thus, MDD with anhedonia represents an 
important unmet therapeutic need. Recent advances in affective neuroscience have revealed an 
association of anhedonia with deficits in the appetitive reward system, specifically the 
anticipation, consumption, and learning of reward, and it has been hypothesized that a 
differential deficit in the components of pleasure could have important implications for therapy 
development (Edwards et al., 2015; Favrod et al., 2015). 
NBI-1065846 is a selective and potent agonist of the orphan G-protein-coupled receptor 139 
(GPR139) being developed for the treatment of symptoms of anhedonia in subjects with MDD. 
GPR139 has its highest levels of expression in the medial habenula, a subdivision of a brain 
nucleus controlling dopaminergic and serotonergic effector systems, which modulate reward, 
emotion, and cognition (Boulos et al., 2017). 
NBI-1065846, single-dose and repeat-dose, showed in vivo efficacy to reverse anhedonia caused 
by 4 weeks of unpredictable chronic mild stress (uCMS) in rats. The sweet drive test and sucrose 
consumption test were used as measures of anhedonic behavior in this rat model. NBI-1065846 
also reversed anxiety-related behavior in the novelty suppressed feeding test and depressive 
state-related behavior in the forced swim test in the uCMS rat model. Chronic dosing of 
NBI-1065846 for up to 20 days in the uCMS model did not result in diminished efficacy, 
indicating a low risk of tachyphylaxis or tolerance to its effects. 
Functional MRI was used in combination with the monetary incentive delay task in patients with 
schizophrenia to assess the effects of NBI-1065846 on activity in the ventral striatum, a brain 
region closely related to anhedonia. Relative to healthy controls, decreased ventral striatal 
activity during reward anticipation, which is associated with anhedonia, is observed in 
schizophrenia and MDD. NBI-1065846 increased ventral striatal activation in schizophrenic 
patients during reward anticipation, demonstrating that NBI-1065846 modulates key 
neurocircuitry that underlies anhedonia, and shifts activity in the normative direction. These data 
support further clinical development of NBI-1065846 for the treatment of anhedonia in MDD. 
NBI-1065846 was safe and well-tolerated across the dose ranges studied in clinical trials to date 
(5 to 160 mg in single- and multiple-ascending doses) in healthy subjects and subjects with 
schizophrenia. 


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This Phase 2 study is being conducted to evaluate the efficacy and safety of NBI-1065846 
compared with placebo (used as monotherapy or as adjunctive treatment to oral antidepressant 
medication[s]) in the treatment of symptoms of anhedonia in subjects with MDD. 
2.2. 
Benefit/Risk Assessment for NBI-1065846  
NBI-1065846 is a potential first-in-class drug; therefore, there are no known class effects. The 
GPR139 receptor is present in other species, including rats, dogs, and monkeys (NHRPR.org). 
Cholestatic liver injury was species-specific and observed in the 13-week no observed adverse 
effect level (NOAEL) toxicity study in dogs, but not in rats or monkeys. The NOAEL was 
30 mg/kg/day for both male and female dogs and attributed to hepatic cholestasis and renal 
tubule degeneration considered secondary to hepatic changes at 60 mg/kg/day, including 
elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), bile acids, blood 
urea nitrogen, creatinine, gamma-glutamyl transferase (GGT), phosphorus, and total bilirubin 
(TBILI). These findings were monitorable and partially reversible. In this study, monitoring for 
hepatobiliary injury includes elevation of liver enzymes (eg, ALT, AST, alkaline phosphatase 
[ALP], GGT, 5’-nucleotidase, and TBILI), physical examinations, and monitoring of 
treatment-emergent adverse events (TEAEs). Additional assessments may be completed as 
clinically indicated. 
In clinical studies, including the first in human (FIH) Study TAK-041-1001 and 
Study TAK-041-1002, there were no reported deaths, serious adverse events (SAEs), adverse 
events (AEs) leading to study treatment or study visit discontinuations, other significant AEs, 
clinically meaningful safety laboratory results (including ALP, ALT, AST, GGT, 
5’-nucleotidase, TBILI), clinically significant physical examination results, vital signs, and/or 
electrocardiogram (ECG) results.  
Although suicidality was not reported in subjects administered NBI-1065846 in the clinical 
development program, subjects at an imminent risk of suicide per the Columbia-Suicide Severity 
Rating Scale (C-SSRS) or according to the investigator’s clinical judgment will be excluded 
from this study. Subjects will be assessed for any signs of suicidal ideation or behaviors, and 
appropriate psychiatric interventions or other precautions will be instituted, if warranted. 
Additional information about the benefits and risks of NBI-1065846 is provided in the 
Investigator’s Brochure. 


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3. 
OBJECTIVES  
3.1. 
Primary  
The primary objective for this study is: 
• To evaluate the efficacy of NBI-1065846 compared with placebo on improving 
symptoms of anhedonia in subjects with MDD. 
3.2. 
Secondary  
The secondary objectives for this study are the following: 
• To evaluate the efficacy of NBI-1065846 compared with placebo on symptoms of 
depression in subjects with MDD. 
• To evaluate the safety, tolerability, and pharmacokinetics (PK) of NBI-1065846 in 
subjects with MDD. 


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4. 
STUDY DESIGN  
4.1. 
Overall Study Design  
This is a Phase 2, randomized, double-blind, parallel-group, proof-of-concept study comparing 
use of NBI-1065846 with placebo for improvement of anhedonia in patients with MDD. 
The study consists of a Screening Period of up to 28 days (Days -28 to -1), an 8-week Treatment 
Period (Days 1 to 57), and an 8-week Safety Follow-up Period (with visits at 4 and 8 weeks 
[Days 78 and 106] after last dose of study treatment). 
Approximately 88 subjects are planned to be enrolled in the study. Eligible subjects include 
patients with MDD who have been treated with antidepressant medication(s) and who continue 
to have anhedonia (Snaith-Hamilton Pleasure Scale [SHAPS] ≥30 [Krystal et al., 2020; 
Trostheim et al., 2020]). Subjects currently receiving antidepressant medication(s) must be 
receiving them for ≥8 weeks prior to screening at or above the therapeutic dose based on the 
Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ). Subjects not currently receiving pharmacological treatment for depression must 
have received ≥1 antidepressant medication(s) at a therapeutic dose per MGH-ATRQ for 
≥8 weeks in the current or most recent episode of depression. To ensure adequate representation 
of subjects across ranges of depression severity, the Sponsor may add limits to prevent further 
enrollment in specific subgroups based on Hamilton Depression Rating Scale-17 Item 
(HAM-D17) scores at baseline. 
Study treatment will be administered as monotherapy or as an adjunctive treatment to the 
subject’s current oral antidepressant medication(s); subjects receiving antidepressant 
medication(s) at screening are expected to continue using them at the same dose throughout the 
study. 
Subjects will be randomized in a 1:1 ratio in a double-blinded fashion to receive either 
NBI-1065846 or placebo, administered on a weekly basis, for a period of 8 weeks. The 
randomization will be stratified based on the Hamilton Depression Rating Scale-17 Item 
(HAM-D17) score at baseline: remission (HAM-D17 ≤7), mild illness (HAM-D17 from 8 to 18), 
and moderate to severe illness (HAM-D17 ≥19) (Zimmerman et al., 2013). 
The end-of-study will be the last scheduled visit assessments of the last subject or last scheduled 
procedure shown in the schedule of assessments (Table 8) for the last subject in the study. 
After providing informed consent, subjects will be screened for eligibility within 28 days prior to 
Day 1 (first day of dosing). Subjects may be rescreened once based on the clinical judgment of 
the investigator in collaboration with the sponsor or designee. The screening period may be 
extended by up to 14 days in extenuating circumstances in consultation with the Sponsor or 
designee. 
Eligible subjects will return to the study site on Day 1 for baseline assessments. Randomized 
subjects will receive a loading dose of 160 mg (consisting of four 40 mg tablets) in the clinic on 
Day 1 and subsequently 80 mg (consisting of two 40 mg tablets) once weekly (Weeks 2 to 8) 
thereafter or matching placebo. Subjects will also receive their second (Day 8), and fifth 
(Day 29) doses of study treatment at the study site in order to obtain ECG and PK pre- and 
post-dose assessments. Subjects will be instructed to take study treatment orally on the same day 


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each week (with or without food) and will be released from the study site after completion of all 
study assessments with sufficient study treatment supply between study visits. Compliance with 
study treatment will be assessed throughout the study. Subjects will have onsite and virtual study 
visits during the Treatment Period and complete study assessments as shown in the schedule of 
assessments (Table 8). 
Subjects who discontinue study treatment should not be automatically withdrawn from the study 
prior to completion of Day 57 assessments, regardless of study treatment compliance, unless 
consent for study participation has been withdrawn (Section 8.1). 
Subjects who withdraw from the study early will be asked to return to the study site for an Early 
Termination (ET) Visit and, unless consent has been withdrawn, will be asked to come back 
approximately 4 and 8 weeks after their last study treatment for Safety Follow-Up visits. 
The data generated in this study will be used to support a separate effort to evaluate the 
psychometric properties of the Dimensional Anhedonia Rating Scale (DARS), which is the 
primary efficacy assessment in this study. The psychometric analysis plan and results will be 
reported separately. Additionally, at the final study visit (Day 57 or ET Visit), 20 subjects, 
regardless of whether they complete the study, will participate in exit interviews with the 
objective of understanding perceptions of meaningful change and treatment experience. The 
protocol, interview guide, and results from the exit interview study will be reported separately.  
A schematic of the study design is shown in Figure 1. 
4.2. 
Rationale for Dose Selection  
The dose regimen planned for this study is a single loading dose of NBI-1065846 160 mg on 
Day 1, followed by once-weekly doses of 80 mg from Week 2 through Week 8. In the FIH study 
in healthy subjects (Study TAK-041-1001), NBI-1065846 was found to be safe and 
well-tolerated at single doses of up to 160 mg and in the multiple dose cohorts consisting of 
4 weekly doses, 1 loading dose ranging from 40 to 160 mg followed by weekly maintenance 
doses ranging from 20 to 80 mg for 3 weeks. No SAEs, no clinically meaningful abnormalities in 
safety laboratory results (including ALP, AST, ALT, GGT, 5’-nucleotidase, and TBILI), and no 
clinically significant abnormalities in physical examination, vital signs, or ECG results were 
reported from Study TAK-041-1001. In another study in subjects with stable schizophrenia 
(Study TAK-041-2001), subjects received 40 or 160 mg doses of NBI-1065846 and 
demonstrated an increase in ventral striatal activation at both dose levels on Day 14 following a 
single dose administration. 
Overall, the proposed dose regimen for this study is anticipated to achieve exposures that are 
expected to show pharmacodynamic activity while not exceeding doses demonstrated to be safe 
and well-tolerated in prior clinical studies. 
4.3. 
End of Study Definition  
Primary Completion: The primary completion date is defined as the date when the last subject 
is assessed or receives an intervention for the final collection of data used for the primary 
endpoint, whether the study concluded as planned or was terminated early. The planned primary 
completion date for this study is the date when the last subject has completed the assessments for 


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Day 57. If the study is terminated early, then the primary completion date will be the date of the 
last visit for the last subject in the study. 
End of Study: The end of study is defined as the date of the last visit of the last subject or last 
scheduled procedure shown in the schedule of assessments (Table 8) for the last subject in the 
study. 


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Figure 1: 
Study Design Schematic 
 
 
 
D=Day; MDD=major depressive disorder; no.=number 
a These are virtual visits.


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5. 
STUDY POPULATION  
Subjects must fulfill all inclusion and exclusion criteria to participate in the study. 
5.1. 
Inclusion Criteria  
Subjects must meet all of the following inclusion criteria: 
1. Completed written informed consent. 
2. Aged 18 to 65 years, inclusive, at the time of informed consent. 
3. The subject has a primary diagnosis of recurrent MDD (mild to severe, or in partial 
remission), persistent depressive disorder, or single episode MDD in remission meeting 
the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and 
International Statistical Classification of Diseases and Related Health Problems, 10th 
Revision (ICD-10) criteria codes 296.31 (F33.0), 296.3 (F33.40), 296.26 (F33.42), 
296.32 (F33.1), 296.35 (F33.41), 300.4 (F34.1). The diagnosis must be confirmed using 
the Mini-International Neuropsychiatric Interview (MINI) in a face-to-face evaluation. If 
the current episode of MDD is in remission, Criteria A1a and A2a on the MINI must be a 
“YES” and must meet criteria for MDD = Past. 
4. Subjects must meet one of the following criteria: 
• Subjects currently receiving pharmacological treatment for depression must have 
been taking ≥1 of the oral antidepressant medication(s) at or above the therapeutic 
dose per MGH-ATRQ (with the exception of the antidepressant medications excluded 
in Table 2) for ≥8 weeks prior to screening as confirmed by records/documentation 
(eg, medical, prescription, or pharmacy records; or a letter from a treating physician). 
Subjects must be willing and able to continue with current antidepressant 
medication(s) with no dose changes. All antidepressant medications for the previous 
2 months prior to baseline must be confirmed by records/documentation (as defined 
above) and be documented on the concomitant therapies electronic case report form 
(eCRF). 
• Subjects not currently receiving pharmacological treatment for depression must have 
received ≥1 antidepressant medication(s) at a therapeutic dose per MGH-ATRQ for 
≥8 weeks in the current or most recent episode of depression as confirmed by 
records/documentation (eg, medical, prescription, or pharmacy records; or a letter 
from a treating physician). Alternatively, this criterion may be satisfied based on the 
investigator’s assessment and with approval from the study Medical Monitor (or 
designee). 
Subjects receiving psychotherapy (including cognitive behavioral therapy [CBT]) or 
behavioral activation (BA) can continue receiving psychotherapy; however, CBT or BA 
must have been ongoing for the last 3 months prior to the start of the screening. No new 
therapy of any kind, including transcranial magnetic stimulation (TMS) or 
electroconvulsive therapy (ECT), is allowed to initiate during this study. 


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5. SHAPS score is ≥30 at screening and Day 1. The anhedonia should be associated with the 
subject’s current or most recent episode of depression based on investigator assessment. 
6. The subject’s current or most recent major depressive episode, depression symptom 
severity, and, if the subject is taking pharmacological treatment for depression, 
antidepressant treatment response in the current depressive episode must be confirmed by 
the “State versus Trait, Assessability, Face Validity, Ecological Validity, Rule of Three 
P’s” (SAFER) Interview and final agreement with the Sponsor or Sponsor designee. 
7. The subject is judged by the investigator to be in good health or have stable medical 
conditions, based on clinical evaluations, including laboratory safety tests (Screening 
Visit only), medical history, physical examination, 12-lead ECG, and vital sign 
measurements performed at the Screening Visit and Baseline (Day 1). 
8. A body mass index (BMI) of 17 to 39 kg/m2, inclusive (BMI is defined as the subject's 
weight in kilograms divided by the square of the subject's height in meters). 
9. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening 
and urine pregnancy test at Day 1, for females of childbearing potential. If a female of 
childbearing potential has an indeterminant β-hCG pregnancy test result, the test should 
be repeated during the screening period and the subject discussed with the medical 
monitor. 
10. Female subjects of childbearing potential must agree to use an acceptable method of 
contraception listed below consistently from screening until 55 days after the last dose of 
study treatment. Women are considered to not be of childbearing potential if they are 
either: 
• Postmenopausal, defined as no menses for 12 months without an alternative medical 
cause and confirmed by elevated follicle-stimulating hormone (FSH) consistent with 
a postmenopausal range, OR 
• Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy. 
Acceptable methods of contraception are required for women of childbearing 
potential and include the following: 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (which may be oral, intravaginal, or transdermal) 
beginning at least 3 months prior to screening and must be used in combination with a 
barrier method of contraception (preferably male condom). Use of combined 
hormonal contraception alone is not considered an acceptable method as 
NBI-1065846 may decrease the efficacy of hormonal contraceptives due to a 
potential drug interaction. 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(which may be oral, injected, or implanted) beginning at least 3 months prior to 
screening and must be used in combination with a barrier method of contraception 


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(preferably male condom). Use of progestogen-only hormonal contraception alone is 
not considered an acceptable method as NBI-1065846 may decrease the efficacy of 
hormonal contraceptives due to a potential drug interaction. 
• Bilateral tubal ligation. 
• Total abstinence from sexual intercourse (periodic abstinence is not acceptable). 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatment. 
• Sexual partner(s) who has been vasectomized at least 3 months prior to screening 
with medically confirmed successful procedure. 
• Male or female condom with or without spermicide. 
• Cap, diaphragm, or sponge with spermicide. 
Male subjects are not required to use barrier contraception in this study. 
11. Willing and able to comply with all study procedures and restrictions. 
5.2. 
Exclusion Criteria  
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Pregnant or breastfeeding or plan to become pregnant during the study. 
2. Other than MDD (primary focus of treatment), having a current psychiatric disorder, such 
as personality disorder, schizophrenia, schizoaffective disorder, other psychotic disorder, 
bipolar disorder, eating disorder, dementia, fibromyalgia, intellectual disability, or mental 
disorder due to a general medical condition, as defined by DSM-5, or has been treated 
with ECT within 6 months prior to screening. Comorbid anxiety disorders are not 
exclusionary. 


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3. With the exception of caffeine dependence and mild to moderate nicotine dependence, 
have a positive urine drug screen (UDS) at screening or Day 1 for disallowed substances, 
including barbiturates, phencyclidine, cocaine, amphetamines, or a history of illicit drug 
or alcohol abuse within 1 year prior to screening judged by the investigator to be 
excessive or compulsive, or currently using drugs of abuse or any prescribed or over 
the-counter medication in a manner that the investigator considers indicative of abuse or 
dependence. 
Note: Subjects testing positive for cannabinoids at screening may be eligible for 
participation in the study if all of the following criteria are met: 
• The subject does not meet the diagnostic criteria for moderate or severe substance use 
disorder within the 6 months before screening based on the MINI 
• Based on the investigator’s clinical assessment, the subject’s marijuana use is limited 
to ≤3 times per week and is not expected to interfere with their ability to adhere to 
study procedures 
• Marijuana is legal per local law 
4. Have a significant risk of suicidal or violent behavior. Subjects with any suicidal ideation 
of type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 
(active suicidal ideation with specific plan and intent) or any suicidal behavior in the past 
12 months before screening based on the C-SSRS or according to the investigator's 
clinical judgment should be excluded. 
5. A history of seizure disorder, stroke, Alzheimer disease, Parkinson disease, multiple 
sclerosis, head injury associated with loss of consciousness for more than 15 minutes, or 
other neurodegenerative disorder. 
6. Have a known or suspected diagnosis of Acquired Immune Deficiency Syndrome 
(AIDS). 
7. Other clinically significant laboratory or vital sign abnormalities that are not attributed to 
a stable, well-controlled medical condition. 
8. A clinically significant ECG abnormality confirmed by central rater at screening or prior 
to randomization confirmed by the site investigator. 
9. An unstable medical condition or chronic disease (including history of neurological 
[including cognitive impairment, myasthenia gravis], hepatic, renal, cardiovascular, 
gastrointestinal, pulmonary, autoimmune, or endocrine disease that may affect study 
participation or results) within 3 months before Day 1, or malignancy within 6 months 
before Day 1, or any history of gallstones, endoscopic retrograde cholangio 
pancreatography or cholestasis. 
10. QT interval corrected for heart rate using Fridericia’s correction (QTcF) >450 msec 
(males) or >470 msec (females) either at screening (per central rater) or Day 1 (per 
investigator), confirmed with 1 repeat test; or the subject has long QT syndrome or is 
under the treatment with Class 1A (eg, quinidine, procainamide) or Class 3 
(eg, amiodarone, sotalol) antiarrhythmic drugs. 


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11. Evidence of chronic renal or liver disease based on any of these screening laboratory test 
abnormalities: 
• Serum creatinine >1.5×upper limit of normal (ULN) for males and >1.2×ULN for 
females. 
• AST >2×ULN. 
• ALT >2×ULN. 
• ALP >1.5×ULN. 
• GGT >2×ULN. 
• TBILI >1.5×ULN unless due to a documented diagnosis of Gilbert syndrome. 
12. Have any of the following laboratory abnormalities at screening: 
• Prothrombin time (PT) expressed as international normalized ratio (INR) >1.3, unless 
the subject is on anticoagulant treatment that affects INR. 
• Hemoglobin <10 g/dL. 
• White blood cell (WBC) count <3.0 × 103/mm3. 
• Platelet count <100,000/mm3. 
• Absolute neutrophil count <1.0 × 103/mm3. 
13. Are currently taking any of the prohibited medications listed in Section 7.1 Table 2. 
Subjects who have received these medications in the past must have been off them for at 
least 30 days prior to Day 1. 
14. Have ingested grapefruit juice, grapefruit products, Seville oranges, or Seville orange 
products within 7 days before Day 1. 
15. Used any active investigational drug in the context of a clinical study within 3 months 
before baseline or plans to use such an investigational drug (other than the study 
treatment) during the study. 
16. Blood loss ≥550 mL within 8 weeks before Day 1. 
17. Has previously participated in this study, has participated in more than 2 investigational 
drug studies in the previous 12 months, is currently participating in another clinical study 
per subject registry database query, or has participated in a clinical study for a psychiatric 
condition that is exclusionary per this protocol. This criterion does not pertain to 
participation in an investigational vaccine clinical study, which is allowed if completed 
more than 30 days before screening. This criterion must be reconfirmed prior to the first 
dose of study treatment on Day 1. 
18. In the investigator’s opinion, the subject is not capable of adhering to the protocol 
requirements, or has a history of poor or suspected poor compliance in clinical research 
studies, or the subject has a history of poor or suspected poor compliance to 
antidepressant medication. 


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6. 
STUDY TREATMENT  
6.1. 
General Information  
Study treatments are summarized in Table 1. 
Table 1: 
Study Treatments 
Treatment Group 
Active (NBI-1065846)  
Placebo  
Treatment administration 
NBI-1065846 will be 
administered orally once weekly, 
at a loading dose of 160 mg on 
Day 1 followed by a once 
weekly 80 mg dose on 
Weeks 2 to 8. 
Placebo tablets identical in 
appearance to the active product 
will be administered in the same 
manner and on an identical 
schedule as NBI-1065846 
Unit dose strength 
40 mg per tablet 
Not applicable 
Dose formulation 
Tablet 
Tablet 
Route of administration 
Oral 
Oral 
Sourcing 
Provided centrally by Sponsor 
Provided centrally by Sponsor 
Packaging and labeling 
Provided in HDPE bottles 
labeled in accordance with 
applicable regulatory 
requirements. 
Provided in HDPE bottles labeled 
in accordance with applicable 
regulatory requirements. 
HDPE=high density polyethylene 
6.2. 
Study Treatment Administration  
Study treatment will be administered orally once weekly (every 7 days ± 2 days), with each dose 
taken at least 5 days apart. Subjects receive a loading dose of 160 mg (consisting of four 40 mg 
tablets) in the clinic on Day 1 (Week 1) and subsequently 80 mg (consisting of two 40 mg 
tablets) once weekly (Weeks 2 to 8) thereafter. Subjects will also receive their second (Day 8), 
and fifth (Day 29) doses of study treatment in the clinic. Subjects will take study treatment at 
home on Days 15, 22, 36, 43, and 50. Study treatment will be administered with 240 mL of water 
and may be administered with or without food. 
If a subject forgets or is unable to take the study treatment, the dose can be taken ± 2 days from 
the scheduled weekly dose (with each dose taken at least 5 days apart); otherwise the study 
treatment should be taken at the next dosing time. 
6.3. 
Study Treatment Compliance  
At each onsite or virtual study visit (except the Day 1 visit), the investigator or designee will 
remind subjects to take their study medication on the next scheduled day as specified in 
Section 6.2. For weeks with no study visit scheduled, this reminder should occur via telephone. 
The subject should also be reminded that if they forget or are unable to take the study treatment, 


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the dose can be taken ± 2 days from the scheduled weekly dose (with each dose taken at least 
5 days apart); otherwise the study treatment should be taken at the next dosing time. 
A compliance check will be performed by counting the tablets of study treatment returned at 
each specified study visit; details are provided in Section 6.4. Assessment of study treatment 
compliance will be determined by the investigator at each visit based on all available 
information. 
6.4. 
Study Treatment Storage/Compliance  
The designated personnel are responsible for maintaining records of the quantity and dates of all 
study treatment supplies received, dispensed, returned, lost, and destroyed, according to 
applicable regulations and study procedures. Study treatment should be stored in a locked area 
accessible only to the designated pharmacist or qualified personnel. A detailed description of 
how study treatment should be dispensed, stored, and any stability changes will be provided in 
the Pharmacy Manual. 
6.5. 
Study Treatment Accountability and Return  
Subjects will bring all unused study treatment and empty packaging material to the center at 
specified study visits for study treatment accountability and reconciliation by study center 
personnel. A compliance check will be performed by counting the tablets returned at each on-site 
study visit. 
The quantity of study treatment dispensed, used, and returned will be recorded on a dispensing 
log or otherwise documented. The quantity of study treatment lost or destroyed must also be 
accounted for and documented. The designated pharmacist or qualified personnel will be 
responsible for maintaining accurate records of the quantity and dates of all study treatment 
supplies received, dispensed, and returned. 
If unused study treatment is not returned to the Sponsor or its designee, alternative disposition of 
study treatment must be documented and follow local laws and regulations. 
6.6. 
Direct-to-Subject Shipments of Study Treatment  
To ensure continued access to study treatment, if a subject is unable to go to the site when study 
treatment is to be dispensed, study treatment may be delivered to the subject’s residence by a 
distributor independent from the Sponsor. The subject’s name, address, and other contact details 
will not be accessible to the Sponsor, and the distributor will not have access to the subject’s 
health information. 
6.7. 
Blinding  
This is a double-blind, placebo-controlled study during which the subject, investigator, all study 
center personnel, pharmacist, and the Sponsor, with the exception of clinical study material 
supply chain personnel who are not involved in decisions regarding subject’s study treatment, 
will be blinded to the subject’s study treatment assignment (NBI-1065846 or placebo). 


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The randomization code will be broken for an individual subject only if the subject is pregnant, 
experiences an SAE that the investigator feels cannot be adequately treated without knowing the 
subject’s study treatment assignment, or for regulatory reporting requirements. In the case of a 
medical emergency in which knowledge of the identity of the study treatment is important for 
subject management, the investigator has the responsibility to decide whether to break the blind; 
study treatment assignments would be unblinded using interactive web response system (IWRS). 
It is recommended that the investigator contact the Study Medical Monitor (or designee) before 
unblinding if it would not result in unnecessary delay to the immediate medical management of 
the subject. The investigator must document the date, time, and the reason the blind was broken. 
6.8. 
Procedures for Overdose  
Any dose of study treatment administered in excess of the protocol-specified dose will be 
considered an overdose. 
In the event of a suspected overdose, the investigator and/or treating physician should: 
1. Closely monitor the subject for any AE/SAE and laboratory abnormalities and follow the 
AE reporting process. The Study Medical Monitor should be contacted for AEs related to 
an overdose. 
2. Document the total quantity of the excess dose(s) as well as the date(s) on which 
additional dose(s) were taken, if this information is available. 
Subjects who overdose will be counseled on correct dosing and administration of study 
treatment, as necessary. Decisions regarding study discontinuation, dose interruptions, or dose 
modifications will be made by the investigator in consultation with the Study Medical Monitor 
based on the clinical evaluation of the subject. 


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7. 
SUBJECT RESTRICTIONS  
7.1. 
Prior and Concomitant Medications  
All prescription and over-the-counter medications, dietary supplements (including vitamins), and 
herbal supplements taken by the subject within 30 days (6 months for antidepressant therapy) 
before Day 1 (Visit 2) will be recorded on the Prior and Concomitant Medications page of the 
eCRF. 
No antidepressant medication or dose changes are permitted from Day 1 through Day 57 (or ET 
visit) unless approved by the Study Medical Monitor (or designee). 
The following medications listed in Table 2 are prohibited for all subjects beginning 30 days 
before Day 1 (Visit 2) until the end of the Study Treatment Period (Day 57 or ET visit). If a 
subject is prescribed treatment with a prohibited medication during the conduct of the study, the 
investigator should contact the Sponsor or designee to review the relevant clinical information 
and medication treatment to determine subject disposition. 
Table 2: 
Prohibited Concomitant Medications 
Prohibited Concomitant Medication 
Glutamate modulators, eg, esketamine or ketamine, memantine, riluzole 
Salvinorin A (Sal A) or salvia divinorum (street names include Maria Pastora, Sally-D, and 
Salvia) 
Other antidepressant medications including tricyclic (eg, clomipramine) or tetracyclic 
(eg, maprotiline) antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) 
Antipsychotics, including injectable/depot antipsychotics (lifetime)  
Stimulants (eg, amphetamines, dextroamphetamine, methylphenidate, methamphetamine, 
modafinil, armodafinil) 
Kappa opioid antagonists (eg, buprenorphine) 
Dopamine agonists such as pramipexole 
Strong and moderate CYP3A4 inhibitors, including but not limited to, clarithromycin, 
itraconazole, ketoconazolea, nefazodone, saquinavir, suboxone, and telithromycin    
Strong and moderate CYP3A4 inducers, including but not limited to avasimibe, phenytoin, 
rifampin, St John’s wort, bosentan, efavirenz, etravirine, modafinil, and nafcillin 
Antiepileptics 
Investigational drugsb    
CYP=cytochrome P450 
a Topical ketoconazole is permitted. 
b Any active investigational drug in the context of a clinical study within the 3 months before baseline or plans to 
use such an investigational drug (other than the study treatment) during the study. 
 


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Benzodiazepines and non-benzodiazepine hypnotics are permitted to be used within specific 
restricted parameters during the study beginning from screening (Visit 1) until the end of the 
study treatment period (Day 57 or ET visit) as detailed in Table 3. Restrictions include maximum 
dosage allowed and the timing of use around assessments, ie, restricted medications should not 
be administered within 6 hours before any efficacy assessments (SHAPS, DARS, HAM-D17, 
Montgomery Åsberg Depression Rating Scale [MADRS], Clinical Global Impression – Severity 
[CGI-S], 
 
 
Any usage of restricted 
medications should be documented, including the date and the time of last dose taken, prior to 
the visits specified in the table. If the subject has taken any restricted concomitant medications 
within 6 hours of these scheduled assessments, then the site should reschedule these assessments 
to the next day (or within 2 to 3 calendar days). 
Benzodiazepines must be at a stable dose equal to or less than the equivalent of 6 mg/day of 
lorazepam for 2 weeks before screening (Visit 1). As needed (prn) use of benzodiazepines is 
restricted; benzodiazepines should not be administered 6 hours prior to the subject's clinic visit 
(Table 3). 
 
Table 3: 
Restricted Concomitant Medications  
Medication Class 
Dosage Allowed 
Timing Restrictions 
Benzodiazepines  
Maximum of 6 mg/day of lorazepam or 
equivalent dose of another 
benzodiazepine for chronic use 
Not permitted within 6 hours 
before any efficacy 
assessments (SHAPS, DARS, 
HAM-D17, MADRS, CGI-S, 
 
, and [if applicable] 
 performed on any 
study visit they are 
administered; refer to the 
schedule of assessments 
(see Table 8).  
Maximum of 2 mg/day of lorazepam or 
equivalent dose of another 
benzodiazepine for episodic use; up to 3 
days per week 
Non-Benzodiazepine 
Hypnotics  
Zolpidem up to 10 mg/day; zaleplon up 
to 20 mg/day; eszopiclone up to 3 
mg/day; zopiclone 7.5 mg/day; or 
doxepin up to 6 mg/day for sleep 
Narcotic Analgesics 
Only episodic use is allowed with 
Sponsor and/or Study Medical Monitor 
approval. 
; CGI-S=Clinical Global Impression – Severity; 
DARS=Dimensional Anhedonia Rating Scale; HAM-D17=Hamilton Depression Rating Scale-17 Item; 
MADRS=Montgomery Åsberg Depression Rating Scale; 
 
 
 SHAPS=Snaith-Hamilton Pleasure Scale; 
 
 
 


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7.2. 
Dietary and Other Restrictions  
Grapefruit juice, grapefruit products, Seville oranges, and Seville orange products are prohibited 
from 7 days before Day 1 until the end of the study. 
Any positive UDSs for disallowed substances (as specified in exclusion criterion #3) during 
conduct of the study must be discussed with the Sponsor or designee to determine the subject’s 
disposition. 
On the day of study visits, subjects may not use marijuana or alcohol until all assessments have 
been completed If a subject appears intoxicated at a study visit, efficacy assessments should not 
be performed that day and the site should reschedule these assessments to the next day (or within 
the window defined in the Schedule of Assessments (Table 8). 
Subjects receiving psychotherapy (including CBT or BA) can continue receiving psychotherapy; 
however, CBT or BA must have been ongoing for the last 3 months prior to the start of the 
screening. With the exception of new CBT or BA, which is prohibited, no new psychotherapy is 
allowed during this study. Furthermore, the use of TMS and/or ECT is also prohibited during this 
study. Any change in existing therapy or new therapy must be documented on the concomitant 
therapies form. 
8. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL  
At any time during the study subjects can discontinue study treatment or withdraw their consent 
to participate in the study. The investigator must discontinue study treatment or withdraw any 
subject from the study at their request. 
8.1. 
Discontinuation of Study Treatment  
If a subject prematurely discontinues study treatment, the investigator will record the reason for 
discontinuation on the relevant eCRF. Data for any outcome measures, particularly the primary 
and secondary endpoints, as well as safety follow-up, are important to collect. Subjects will not 
be automatically withdrawn from the study and should continue participation in the study, 
regardless of study treatment compliance, unless consent for study participation has been 
withdrawn. For any subsequent study visits after study treatment is prematurely discontinued, 
subjects should have 1 final PK sample collected (ie, subsequent PK samples are not required); 
however, subjects should continue with study assessments at the study site or with virtual visits. 
If medically indicated, treatment with medication listed under Section 7.1 is no longer prohibited 
after study treatment discontinuation. 
Reasons for discontinuation from study treatment include but are not limited to: 
• Withdrawal by subject 
• Death 
• Lost to follow-up 


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• Site termination by the Sponsor 
• Study termination by the Sponsor 
• AE 
• Pregnancy 
• Lack of efficacy 
• Protocol deviation 
• Investigator decision 
• Sponsor decision 
The investigator must discontinue study treatment if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE becomes unacceptable/intolerable 
• If the subject is unable to tolerate the lowest allowable dose (80 mg or placebo) 
• QTcF of >500 msec (cardiologist verified) on any ECG tracing 
• If the subject is confirmed to be pregnant 
• Withdrawal of consent for study treatment administration by subject 
• If the subject exhibits suicidal behavior, or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal 
ideation with specific plan and intent) based on the C-SSRS or according to the 
investigator’s clinical judgement 
• Study treatment should be discontinued with appropriate clinical follow-up (including 
repeat laboratory tests) until a subject’s laboratory profile has returned to 
normal/baseline status), if any of the following occur (see Appendix D for additional 
detail): 
− ALT or AST >8×ULN, or 
− ALT or AST >5×ULN and persists for more than 2 weeks, or 
− ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
INR >1.5 
− ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
− ALP elevations >1.5×ULN in conjunction with elevated TBLI >1.5×ULN, or 
− 5’nucleotidase >2×ULN, or GGT >5×ULN, or AST/ALT >3×ULN. 
Every effort should be taken to obtain follow-up data for any subject who discontinues study 
treatment because of an AE, abnormal laboratory test, vital sign measurement, physical 
examination, or ECG finding. 


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8.2. 
Withdrawal from Study  
If a subject prematurely withdraws from the study, the investigator will record the reason for 
withdrawal on the relevant eCRF. All subjects who withdraw from the study prematurely will be 
asked to have all ET assessments performed and, unless consent has been withdrawn, will be 
asked to come back for 2 safety follow-up visits at 4 and 8 weeks after last dose of study 
treatment. If a subject’s last dose of study treatment was >8 weeks before the ET visit, the Safety 
Follow-Up visits are not needed. If a subject’s last dose of study treatment was >3 weeks but 
<8 weeks before the ET visit, only the Week 16 Safety Follow-Up visit is needed (ie, only one 
Safety Follow-Up visit approximately 8 weeks after the last dose of study treatment is needed). 
Reasons for withdrawal from study include, but are not limited to: 
• Withdrawal by the subject 
• AE 
• Death 
• Lost to follow-up 
• Site terminated by Sponsor 
• Study terminated by Sponsor 
• Protocol deviation 
• Investigator decision 
• Sponsor decision 
8.3. 
Sponsor’s Termination or Temporary Halt of Study or Study Site  
The Sponsor or designee reserves the right to close a study site, terminate, or temporarily halt the 
entire study, or terminate or temporarily halt the study at individual sites, at any time for any 
reason. If the study is prematurely terminated or temporarily halted, the Sponsor shall promptly 
inform the investigators, the Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), the regulatory authorities, and any contract research organizations (CROs) used in the 
study of the reason for termination or temporary halt, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the subject and should assure appropriate 
therapy and/or follow-up. 
 


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9. 
STUDY ASSESSMENTS AND PROCEDURES  
A schedule of assessments is provided in Table 8 (Appendix A). No study procedures should be 
performed until after the subject has signed the informed consent form (ICF). Subject-related 
events and activities including specific instructions, procedures, concomitant medications, 
dispensing of study treatment, and descriptions of AEs should be recorded in the appropriate 
source documents and eCRFs. 
When the following assessments are scheduled to be performed at the same timepoint, the order 
of priority will be as follows: vital signs, physical and neurological examination, questionnaires, 
ECG, and blood sampling for safety and PK. 
9.1. 
Screening Assessments and Procedures  
9.1.1. 
Subject Registry Database Review Consent  
Clinical study subject registries seek to reduce subjects from enrolling into multiple clinical 
studies by identifying potential duplicates before enrollment. This study will utilize 1 or more 
subject registry database(s) at sites where they are available. At the time of providing informed 
consent for the study, the investigator or designee will explain the subject registry database 
review process to the subject and witness the signature. 
During screening, site staff who have received training and login information to access the 
registry will enter the subject identification number and authorized subject identifiers on the 
registry website. An immediate report based on matches to exclusion criterion #17 in Section 5.2 
will be generated and should be printed for source documentation. The report will specify either 
(1) no matches found, (2) a potential match was found to 1 or more specified criteria, and/or 
(3) the subject matches 1 or more specified criteria. The registry database check should be 
performed as early as possible at the screening visit to avoid unnecessary procedures. 
9.1.2. 
Mini-International Neuropsychiatric Interview  
The MINI is a structured diagnostic interview that was originally developed for DSM-IV and 
ICD-10 disorders, for multicenter clinical studies and epidemiology studies (Lecrubier et al., 
1997; Sheehan et al., 1997; Sheehan et al., 1998). The MINI has been validated against the 
Structured Clinical Interview for DSM Patients and Composite International Diagnostic 
Interview for ICD-10. The MINI has been translated and validated in over 70 languages and has 
been updated to match DSM-5 (MINI 7.0.2). 
The MINI may be administered by a healthcare professional with a clinically relevant 
qualification (eg, psychiatrist, psychiatric nurse or psychologist) and documented experience 
assessing patients with MDD. Raters must be trained and certified for administration of MINI in 
this study.  
Specific timepoints for collection are provided in Table 8. 


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9.1.3. 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire  
The MGH-ATRQ is a clinician-rated scale used to determine treatment resistance in MDD. The 
MGH-ATRQ defines 8 weeks on an adequate dose of antidepressant medication as an adequate 
duration of treatment. The MGH-ATRQ has been validated in the ADAPT-A study by 
independent clinician raters (Chandler et al., 2010). 
Specific timepoints for collection are provided in Table 8. 
9.1.4. 
Hamilton Depression Rating Scale-17 Item  
The HAM-D17 is administered via a clinician-rated interview with the subject. HAM-D17 
ratings must be performed by qualified study personnel who have been trained and certified for 
the purpose of performing ratings in this study. 
The HAM-D17 is a 17-item clinician-rated scale that assesses the range of symptoms that are 
commonly seen in patients with MDD (Hamilton, 1960). With well-known psychometric 
properties, it is widely accepted as a standard measure of symptom change in studies of 
psychopharmacological agents. 
Specific timepoints for collection are provided in Table 8. 
9.1.5. 
Snaith-Hamilton Pleasure Scale  
The SHAPS (Snaith et al., 1995) is a well-validated 14-item questionnaire used to assess 
anhedonia. The SHAPS is a self-rated scale that asks participants to agree or disagree with 
statements of hedonic response in usually pleasurable situations (eg, “I would enjoy my favorite 
television or radio program”). Four responses are possible: Strongly disagree, Disagree, Agree, 
or Strongly agree. A total score can be derived by summing the responses to each item. Items 
answered with “strongly agree” are coded as “1”, while a “strongly disagree” response was 
assigned a score of “4.” Therefore, scores on the SHAPS can range from 14 to 56, with higher 
scores corresponding to higher levels of anhedonia. The SHAPS covers four domains of hedonic 
experience: interest/pastimes, social interaction, sensory experience, and food/drink. 
Specific timepoints for collection are provided in Table 8. 
9.1.6. 
SAFER Interview  
The subject’s current or most recent major depressive episode, depression symptom severity, 
and, if the subject is taking pharmacological treatment for depression, antidepressant treatment 
response in their current depressive episode must be deemed valid for participation in the clinical 
study based on the SAFER Interview, which is a site-independent qualification assessment. The 
SAFER Interview for subject eligibility verification will be performed by the Massachusetts 
General Hospital Clinical Trials Network and Institute (MGH-CTNI). This interview is 
performed remotely (Freeman et al., 2017; Desseilles et al., 2013). 
Specific timepoints for collection are provided in Table 8. 


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9.2. 
Efficacy Assessments and Procedures  
9.2.1. 
Placebo-Control Reminder Script  
To mitigate expectation bias leading to increased placebo response, the Placebo-Control 
Reminder Script (PCRS) will be utilized in this study (Cohen et al, 2021). The PCRS is a script 
which carefully reviews placebo response factors with research subjects with the goal of 
reducing placebo effect through increased awareness of its impact. A trained rater will read the 
PCRS script to each subject prior to the administration of efficacy assessments. It is followed by 
a discussion between the rater and subject about the key points, including understanding of 
double-blind clinical studies, recognition of the rater’s neutral position regarding subject 
responses, and the importance of providing honest feedback. Specific timepoints for 
administered are provided in Table 8. 
9.2.2. 
Dimensional Anhedonia Rating Scale  
The DARS (Rizvi et al., 2015) is a dynamic scale that measures desire, motivation, effort and 
consummatory pleasure across hedonic domains. The DARS is a self-report questionnaire that 
measures anhedonia across 4 domains: hobbies/past-times, food/drinks, social activities, and 
sensory experiences.  
The data generated in this study will be used to support a separate effort to evaluate the 
psychometric properties of the DARS. Additionally, at the final study visit (Day 57 or ET visit), 
20 subjects, regardless of whether they complete the study, will participate in exit interviews 
with the objective of understanding perceptions of meaningful change and treatment experience 
(Section 9.2.2.1). The psychometric analysis plan and results from the exit interviews will be 
reported separately. 
Specific timepoints for collection are provided in Table 8. 
9.2.2.1. 
Subject Exit Interview  
The purpose of the exit interview is to explore meaningful change in anhedonia in subjects with 
MDD, as measured by the DARS and related questionnaires. Specific aims of the exit interview 
include understanding changes in subjects’ responses to the DARS, 
and 
 and 
whether the changes/responses were meaningful, and understanding subjects’ overall 
expectations and experience with the clinical study. 
At the final study visit, subjects will be asked to participate in an exit interview until 20 subjects 
have completed the exit interview. The objective of the subject exit interview is to understand 
perceptions of meaningful change and treatment experience; additional details are provided 
below. The exit interview enrollment and scheduling process will begin after the subject has 
completed study treatment at Day 57 (or ET visit in subjects who discontinue study treatment). 
The exit interview will be conducted within a 14-day window following Day 57 (or ET visit in 
subjects who discontinue study treatment). The exit interview will be audio recorded by the 
interviewer and subsequently transcribed, but data will not be collected in the electronic data 
capture (EDC) system. 


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The exit interview is not designed to assess the subjects’ experience with aspects of the clinical 
study engagement, such as enrollment, compliance requirements, or interactions with sites. 
Subjects will need to sign a separate consent to agree to participate in this optional assessment. 
9.2.3. 
Montgomery Åsberg Depression Rating Scale  
The MADRS is a validated rating scale designed to measure changes in the severity of 
depressive symptoms (Montgomery and Åsberg, 1979). The MADRS consists of 10 items scored 
on a 7-point scale (0 to 6) with increasing number value indicating increasing severity for each 
item with anchor points provided at 2-point intervals. 
Specific timepoints for collection are provided in Table 8. 
9.2.4. 
Clinical Global Impression – Severity Scale  
The CGI-S scale, which is based on a 7-point scale (range: 1=normal, not all ill to 7=among the 
most extremely ill patients), will be used to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subject’s who have the same 
diagnosis (Guy, 1976). 
The investigator or qualified clinician designee will rate the scale at the scheduled times. Every 
effort should be made to have the same person rate the CGI-S at all timepoints. 
Specific timepoints for collection are provided in Table 8. 
9.2.5. 
  
 
 
 
 
 
 
 
9.2.6. 
  
 
 
 
 
 
 


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9.2.7. 
  
 
 
  
 
9.2.8. 
  
 
 
 
 
9.2.9. 
  
 
 
 
 
9.2.10. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.3. 
Safety Assessments  
For any abnormal safety assessment deemed clinically significant, the investigator will perform 
appropriate follow-up assessments, until the cause of the abnormality is determined and/or until 
the value returns to baseline (or within normal limits) or the investigator deems the abnormality 
to be of no clinical significance. 
Appropriate psychiatric evaluation and intervention will be provided for any study 
treatment-emergent suicidal behavior or clinically significant suicidal ideation. 
9.3.1. 
Vital Sign Measurements, Height, and Weight  
Vital signs will be measured for the following: orthostatic systolic and diastolic blood pressure, 
orthostatic pulse rate, respiratory rate, and body temperature. 
The same method should be used to take body temperature throughout the study. Body 
temperature may be measured orally or at the forehead, ear, or rectum. 
Blood pressure and pulse rate will be measured using a calibrated non-invasive blood pressure 
cuff after the subject has been supine for at least 5 minutes and after approximately 2 minutes 
standing, if possible. 
Vital sign measurements will be obtained before any scheduled blood sample collection at 
screening and then at the time points specified in the schedule of assessments (Table 8). 
Height will be measured at screening only. Height and weight will be measured with subjects not 
wearing shoes; and weight will be measured with subjects not wearing outerwear (eg, jackets or 
coats). 
9.3.2. 
Medical History  
A medical history will be taken at the screening visit and updated on Day 1 (baseline) and as 
needed throughout the study. 
9.3.3. 
Physical Examination  
The complete physical examination will consist of an assessment of general appearance, skin and 
mucosae, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest/lungs, 
cardiovascular, abdomen, extremities, musculoskeletal, and neurological system. 
The physical examination schedule is provided in Table 8. 
9.3.4. 
Electrocardiogram  
Triplicate 12-lead ECG will be recorded (at least 1 minute apart and within 15 minutes) after the 
subject has rested supine for at least 5 minutes. The ECG parameters that will be assessed 
include heart rate, PR interval, QRS duration, QT interval, and QTcF (machine readings or 
calculated). Additionally, the occurrence of de- and re-polarization, ectopic cardiac activity and 
rhythm disorders or other abnormalities will be assessed. Based on the review of these 
parameters, the investigator will note if the ECG is Normal, Abnormal not Clinically Significant, 
or Abnormal Clinically Significant. If the ECG is Abnormal Clinically Significant, the 


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investigator will provide a description of the abnormality recorded on the AE eCRF. The ECG 
schedule is provided in Table 8. 
9.3.5. 
Clinical Laboratory Assessments  
All clinical laboratory assessments will be performed by a central laboratory. The central 
laboratory will provide instructions and supplies to the study staff before study initiation and 
instructions will be included in a laboratory manual. The following clinical safety laboratory 
assays will be performed: 
Hematology: complete blood count including WBC count with differential, red blood cell (RBC) 
count, hemoglobin, hematocrit, and platelet count, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red cell 
distribution width (RDW), mean platelet volume (MPV). 
Clinical Chemistry: sodium, potassium, calcium, magnesium, phosphorus, chloride, blood urea 
nitrogen, bicarbonate, creatinine, uric acid, albumin, ALP, 5’ nucleotidase, lactate 
dehydrogenase, AST, ALT, GGT, creatine kinase (CK), TBILI, direct bilirubin, total protein, and 
glucose. See Appendix D for further detail on liver function test monitoring. 
Coagulation: PT and INR. 
Urinalysis: casts, crystals, specific gravity, nitrite, ketones, protein, urobilinogen, glucose, 
bilirubin, leukocyte esterase, occult blood, and pH; microscopic examination of sediment will be 
performed only if the results of the urinalysis dipstick evaluation are positive for nitrite, protein, 
leukocyte esterase, or blood. 
The following additional laboratory tests will be performed: 
Drug Screen: The UDS will test for amphetamines, barbiturates, benzodiazepines, cocaine, 
phencyclidine, cannabinoids, and opiates. The UDS will be performed at screening by the central 
laboratory. A UDS kit provided by the central laboratory will be used at the site to confirm 
eligibility on Day 1. Drug/alcohol screening may be repeated at any time per the investigator’s 
clinical judgment. Any positive UDSs during conduct of the study must be discussed with the 
Sponsor or designee to determine the subject’s disposition. 
Pregnancy Test: Pregnancy tests will be performed throughout the study for female subjects of 
childbearing potential. A serum β-hCG pregnancy test will be performed at screening and a urine 
pregnancy test (using a urine pregnancy kit provided by the central laboratory) will be performed 
at the time points indicated in Table 8. 
FSH: An FSH level will be tested at screening (Visit 1) only in postmenopausal woman. 
9.3.6. 
Columbia-Suicide Severity Rating Scale  
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(http://www.cssrs.columbia.edu). There are versions of the questionnaire designed for use at 
screening (Baseline/Screening version) and at baseline and visits throughout the study (Since 
Last Visit version). All versions of the C-SSRS include a series of screening questions related to 
suicidal ideation and suicidal behavior. Subject responses of “yes” to one or more screening 


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questions will prompt additional questions that evaluate frequency and intensity of suicidal 
ideation and/or behavior.  
The C-SSRS will be administered and scored by the investigator or qualified study center 
personnel when conducted at the study center. When the study visit is conducted at the subject's 
home the site will administer the C-SSRS virtually. The C-SSRS will be assessed at the time 
points indicated in Table 8. 
Suicidal ideation type 4, suicidal ideation type 5, and all reports of suicidal behavior must be 
documented as an AE or SAE (if SAE criterion is met). Suicidal ideation type 1, 2, or 3 must be 
documented as AEs or SAEs (if SAE criterion is met) if considered clinically significant by the 
investigator. For reporting instructions and definitions of AE and SAE, please refer to 
Section 10. 
9.4. 
Pharmacokinetic Assessments  
Blood samples for determination of plasma concentrations of NBI-1065846 will be collected at 
the timepoints identified in the schedule of assessments (Table 8). If the subject discontinues 
study treatment early, a blood sample for PK is needed at any time during the ET visit (Table 8). 
For each sample, blood will be collected in tubes containing dipotassium 
ethylenediaminetetraacetic acid (EDTA K2). The exact time of sampling in hours and minutes 
will be recorded for all PK blood samples. The blood samples will be processed and stored 
according to the procedure as specified in the laboratory manual. Samples will be shipped on dry 
ice to the central laboratory for analysis. 
9.5. 
Other Procedures  
9.5.1. 
Blood Sample for Pharmacogenomics (Optional)  
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect DNA to allow 
the identification of genetic and/or epigenetic factors that may influence the PK, 
pharmacodynamics, efficacy, safety, or tolerability of NBI-1065846 in subjects with MDD and 
anhedonia and to identify genetic factors associated with MDD and anhedonia. 
Participation of study subjects in pharmacogenomic sample collection is optional and requires 
additional consent from the subject (see ICF in Section 12.9.2). A blood sample for DNA 
isolation will be collected from participating subjects at the timepoints indicated in the schedule 
of assessments (Table 8). Subjects who do not wish to participate in the pharmacogenomic 
research may still participate in the study. 
Analyses may be conducted if it is hypothesized that this may help resolve issues with the 
clinical data. DNA samples will be used for research related to NBI-1065846 or MDD with 
anhedonia. For example, in the event of an unusual response or observation of unexplained AEs, 
DNA samples may be used to determine if there are any pharmacogenetic associations with drug 


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response. They may also be used to develop tests/assays related to NBI-1065846 and MDD with 
anhedonia.  
DNA samples may be used for research related to MDD with anhedonia for the assessment of 
genetic and epigenetic changes in genes known to be in pathways relevant to depression (eg, ion 
channels, monoamine transporters, growth factors, inflammation) and NBI-1065846. 
Pharmacogenomic research may consist of the analysis of one or more candidate genes, the 
analysis of genetic markers throughout the genome, or analysis of the entire genome (as 
appropriate) in relation to NBI-1065846 or MDD with anhedonia clinical endpoints, including, 
but not limited to, candidate gene, single nucleotide polymorphism analysis, genome-wide 
association study, next generation sequencing, and whole genome sequencing. In the future, as 
the understanding of a disease increases, additional genetic analyses may be warranted to refine 
the knowledge of the molecular basis of the disease and the drug response and to advance the 
development of novel therapeutics. 
The DNA samples will be coded with the subject’s identification number and stored for 15 years 
or a duration dictated by local, national, or regional laws or regulations. No genotyping or 
genetic data will be provided to the subject. Subjects may withdraw consent and request to have 
their sample destroyed at any time, and no further genetic data will be generated; any data 
already generated will not be destroyed. 
In addition, where local regulations and ethics committee approval allow, an optional genetic 
consent will be offered to subjects to allow samples to be stored for future unspecified genetic 
research related to other diseases and traits of interest to sponsor. 
Details on processes for collection and shipment and destruction of these samples can be found 
in the laboratory manual. 
9.6. 
Specific Study Period Information  
9.6.1. 
Screening Period (Day -28 to Day -1)  
After consent is obtained, the subject registry database review should be performed as early as 
possible at the Screening Visit to avoid unnecessary procedures. 
Subjects will undergo screening procedures that may be completed in 1 or more visits during the 
Screening Period of up to 4 weeks. Subjects may be rescreened once based on the clinical 
judgment of the investigator in collaboration with the sponsor or designee. The screening period 
may be extended by up to 14 days in extenuating circumstances in consultation with the Sponsor 
or designee. 
Vital signs should be collected prior to the collection of blood for clinical laboratory tests. 
The SAFER Interview will be conducted by interview remotely during the Screening Period and 
is a site-independent qualification assessment (see Section 9.1.6 for further details). 
Training should be provided on the use of concomitant medications (Section 7.1). 
Eligible subjects will return to the study site on Day 1 for baseline assessments. 


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9.6.2. 
Baseline Visit and Study Treatment Period (Day 1 to Day 57)  
If the subject has taken any restricted concomitant medications (Table 3) within 6 hours before 
any efficacy assessments (SHAPS, DARS, HAM-D17, MADRS, CGI-S, 
 
, and 
 then the site should 
reschedule these study visit assessments to the next day (or within 2 to 3 calendar days). 
Subjects should not use marijuana or alcohol on the day of study visits. If a subject appears 
intoxicated at a study visit, efficacy assessments should not be performed that day and the site 
should reschedule these assessments to the next day (or within the window defined in the 
Schedule of Assessments (Table 8). 
After completing baseline assessments on Day 1, subjects will be randomized 1:1 to receive 
NBI-1065846 or placebo. The first dose of study treatment will be administered in the clinic at 
the end of Day 1; the date and time of first dose should be recorded in the eCRF. Subjects will be 
instructed to take study treatment as described in Section 6.2. Subjects will have onsite and 
virtual study visits as specified in the schedule of assessments (Table 8). 
After administering the PCRS, the efficacy assessments applicable to each study visit should be 
performed in the following order throughout the study: 
Subject-Reported Outcomes: 
1. SHAPS 
2. DARS 
3. 
 
4. 
 
5. 
 
6. 
 
7. 
 
 
Clinician-Reported Outcomes: 
1. MADRS 
2. HAM-D17 
3. CGI-S 
4. 
 
At each onsite or virtual study visit (except the Day 1 visit), the investigator or designee will 
remind subjects to take their study medication on the next scheduled day as specified in 
Section 6.2. For weeks with no study visit scheduled, this reminder should occur via telephone. 
The subject should also be reminded that if they forget or are unable to take the study treatment, 
the dose can be taken ± 2 days from the scheduled weekly dose (with each dose taken at least 
5 days apart); otherwise the study treatment should be taken at the next dosing time. 


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Schedule the exit interview in approximately 20 subjects at Day 57 (or ET visit in subjects who 
discontinue study treatment). 
9.6.3. 
Follow-Up Period (Day 58 to Day 106)  
The follow-up visits (±3 days) will be conducted at the study site. 


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10. 
ADVERSE EVENTS  
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or identified by other means, will be recorded from the time the subject has signed the 
ICF until the subject’s final study visit/contact (or upon ET). 
10.1. 
Definition  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that occurs after enrollment into the study and which does 
not necessarily have a causal relationship with the study treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
AEs include, but are not limited to, any of the following: 
• Worsening or change in nature, severity, or frequency of conditions present at the 
start of the study 
• Subject deterioration beyond what would be expected due to the primary illness 
• Intercurrent illness 
• Drug interaction 
C-SSRS suicidal ideation type 4, C-SSRS suicidal ideation type 5, and all reports of suicidal 
behavior and clinically significant suicidal ideation must be documented as an AE or SAE (if 
SAE criterion is met). C-SSRS suicidal ideation types 1, 2, or 3 must be documented as AEs or 
SAEs (if SAE criterion is met) if considered clinically significant by the investigator. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms. Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
treatment, must be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice and on the AE eCRF. Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
study treatment. 
The following are not considered AEs: 
• Continuous persistent disease/symptom present before study treatment administration, 
unless it unexpectedly progresses, or increases in severity following study treatment 
administration 
• Study treatment failure or lack of efficacy 
• Pregnancy 


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• Overdose of either study treatment or concomitant medication without any clinical 
signs or symptoms 
10.1.1. 
Intensity of Adverse Events  
Adverse events must be graded for intensity. An intensity category of mild, moderate, or severe, 
as defined in Table 4, must be entered on the AE eCRF. It should be noted that the term “severe” 
used to grade intensity is not synonymous with the term “serious.” 
Table 4: 
Intensity of Adverse Events 
Grade 
Intensity 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
research subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AE=adverse event 
10.1.2. 
Relationship to Study Treatment  
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study treatment using the criteria outlined in Table 5. An AE is deemed associated with the use 
of the study treatment “if there is a reasonable possibility that the treatment caused the AE” 
(otherwise referred to as a suspected adverse reaction). Reasonable possibility means there is 
evidence to suggest a causal relationship between the study treatment and the AE (Title 21 Code 
of Federal Regulations [CFR] 312.32 [a]). 


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Table 5: 
Relationship of Adverse Events to Study Treatment 
Relationship 
Description 
Definite 
The AE follows a reasonable temporal sequence from administration of the study 
treatment, abates upon discontinuation of the study treatment, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears when the study 
treatment is reintroduced. 
Possible 
The AE follows a reasonable temporal sequence from administration of the study 
treatment and cannot be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental, or toxic factors, or other modes of therapy 
administered to the subject. There should be some evidence to support a causal 
relationship between the study treatment and the AE. 
Unlikely 
The temporal sequence between the AE and the study treatment is such that the 
study treatment is not likely to have any reasonable association with the AE or other 
plausible explanations exist for the AE (eg, disease, other drugs). 
Not related 
The AE does not follow a reasonable temporal sequence from administration of the 
study treatment, may not abate upon discontinuation of the study treatment, does not 
follow a known or hypothesized cause-effect relationship, and (if applicable) may 
not reappear when the treatment is reintroduced, furthermore, there may exist a clear 
alternative medical explanation (eg, underlying disease state) or association with 
study procedure or study conduct. 
AE=adverse event 
10.2. 
Recording Adverse Events  
For randomized subjects, each AE will be listed as a separate entry on an AE eCRF. Screen 
failure subjects who experience an AE will have the information noted only in the source 
document (not in the EDC system). The investigator (or designee) will provide information on 
dates of onset and resolution, intensity, seriousness, frequency, action(s) taken, changes in study 
treatment usage, relationship to study treatment, and outcome. 
10.3. 
Poststudy Follow-Up of Adverse Events  
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up. 
Adverse events ongoing at the final visit or at ET will be followed for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes, resolves, or the subject is 
lost to follow-up. The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality of the 
AE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals, as is practical. 


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10.4. 
Serious Adverse Events  
All SAEs will be recorded from the time the subject has signed the ICF until the final study visit. 
Investigators are not obligated to actively seek SAEs after a subject has withdrawn from or 
completed the study. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been withdrawn from or has completed the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the Sponsor as described in Section 10.4.3. 
10.4.1. 
Definition of a Serious Adverse Event  
An SAE is any AE that results in any of the following outcome: 
• Death 
• A life-threatening AE. Life-threatening means that the subject was, in the view of the 
investigator or Sponsor, at immediate risk of death from the reaction as it occurred. It 
does not mean that hypothetically the event might have caused death if it occurred in 
a more serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization. Hospitalization 
for elective treatment or a preexisting condition that did not worsen during the 
clinical investigation is not considered an AE. Hospitalization or nursing home 
admission for the purpose of caregiver respite is not considered an AE. Complications 
that occur during hospitalization are AEs, and if a complication prolongs 
hospitalization, the event is considered serious. Treatment in a hospital emergency 
room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization. These events may be considered serious when, based on appropriate 
medical judgment, they may jeopardize the health of the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed. Any other 
event thought by the investigator to be serious should also be reported, following the 
reporting requirements detailed in this section. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias, convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
10.4.2. 
Managing Serious Adverse Events  
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The physician in attendance will do whatever is medically needed for the safety 
and well-being of the subject. The subject will remain under observation as long as medically 
indicated. Appropriate laboratory studies will be conducted until all parameters return to normal 


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or are otherwise explained or stable. The subject will be followed until the SAE resolves or until 
the subject is medically stabilized. 
10.4.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events  
SAEs and pregnancies must be reported immediately and no later than 24 hours of first 
knowledge of the event by study personnel to NBI Drug Safety and Pharmacovigilance (DSPV). 
Reports of SAEs and pregnancies must be followed by a fax or email of the SAE or Pregnancy 
Form (Table 6). It is important that the investigator provides his or her assessment of relationship 
to study treatment at the time of the initial SAE report. The investigator (or designee) will also 
notify the IRB/IEC, if necessary) of the SAE and the outcome of the SAE, as required by the 
IRB/IEC. 
Additionally, the following categories of medical events that could occur during participation in 
a clinical study must be reported within 24 hours to the Study Medical Monitor and must be 
followed by a fax or email of the Other Immediately Reportable Events Form (Table 6). 
• Treatment unblinding for any reason 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with 
some intent to act, without specific plan) or type 5 (active suicidal ideation with 
specific plan and intent) based on the C-SSRS. 
Table 6: 
Contact Information for Drug Safety and Pharmacovigilance 
Drug Safety and Pharmacovigilance 
Facsimile 
Email 
 
+1 (888) 617-7551 or +1 (858) 617-7561 
cds@neurocrine.com 
Study Medical Monitor 
+1 (858) 617-7387 
10.4.4. 
Expedited Safety Reports  
The Sponsor or its representatives will submit an Expedited Safety Report for any suspected 
adverse reaction (Section 10.1.2) that is considered both serious and unexpected within 
15 calendar days and for any unexpected fatal or life-threatening experience within 7 calendar 
days to the applicable regulatory authority(ies); or according to country-specific regulations. 
The Sponsor or its representatives will send copies of each safety report submitted to regulatory 
authorities to the investigators. The safety report must be submitted to the appropriate IRB/IEC 
as soon as possible. Documentation of the submission to the IRB/IEC and receipt by the 
IRB/IEC (if applicable) must be retained for each safety report. 
10.5. 
Urgent Safety Measures  
If an event occurs that is related to the conduct of the study or the development of the study 
treatment, and this new event is likely to affect the safety of subjects, the Sponsor and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard. The Sponsor will work with the investigator to ensure the IRB/IEC and local 
regulatory authority is notified within 3 days or in accordance with applicable local laws and 
regulations. 


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10.6. 
Pregnancy  
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met. However, all 
pregnancies in subjects who received NBI-1065846 will be followed to assess for pregnancy 
outcome. Subjects of childbearing potential must be counseled at all visits to continue using 
contraception until 55 days (females) (Section 5.1, inclusion criterion #10 after the last dose of 
study treatment. If a female subject believes she is pregnant at any time between signing the ICF 
and the last study visit, she should return to the study center within 24 hours and undergo a 
serum pregnancy test. Female subjects confirmed to be pregnant will be discontinued from study 
treatment, unblinded, and withdrawn from the study. 
All confirmed pregnancies in female subjects who received study treatment must be immediately 
reported to NBI (contact information is provided in Section 10.4.3), followed by fax or email of 
the pregnancy form to NBI DSPV. A first trimester ultrasound may be requested for all 
confirmed pregnancies. Pregnancies in subjects who received NBI-1065846 will be followed 
until resolution (ie, termination [voluntary or spontaneous] or birth). 


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11. 
STATISTICAL METHODS  
This section represents a brief description of the planned primary analysis of the primary and 
secondary objectives. A comprehensive and detailed statistical analysis plan (SAP) will be 
generated and finalized prior to study database lock and treatment unblinding. The SAP will 
provide additional details regarding the methods of analysis summarized in this protocol, will 
describe analysis methods for other endpoints, will describe analyses to characterize the study 
conduct and population, and may describe sensitivity and supplementary analyses for selected 
endpoints. 
11.1. 
Statistical Hypothesis  
The null hypothesis for the primary endpoint is that the mean change in DARS from baseline to 
Day 57 in the placebo group is greater than or equal to that in the NBI-1065846 group. The 
alternative hypothesis is that the mean change in DARS from baseline to Day 57 in the placebo 
group is less than that in the NBI-1065846 group. 
The null hypothesis to be tested is: 
H0: µ1 ≥ µ2  
The alternative hypothesis is: 
H1: µ1 < µ2 
where µ1 is the mean change in DARS from baseline to Day 57 in the placebo group, and µ2 is 
the mean change in DARS from baseline to Day 57 in the NBI-1065846 group. 
11.2. 
Sample Size Determination  
Assuming that 85% of the 88 subjects (randomized in a 1:1 ratio to NBI-1065846 and placebo 
groups) complete the Day 57 assessment, the study has approximately 80% power to detect an 
effect size of 0.5 for the primary endpoint at 1-sided significance level of 0.1. 
11.3. 
Analysis Sets  
Statistical analysis sets used in this study are defined in Table 7. Additional analysis sets may be 
specified in the SAP. 


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Table 7: 
Analysis Sets 
Population 
Description 
Full analysis set  
The Full Analysis Set includes all randomized subjects. Subjects 
will be analyzed according to their randomized treatment group, 
regardless of compliance with study treatment administration and 
availability of postbaseline data. 
Safety analysis set 
The Safety Analysis Set will include all randomized subjects who 
take at least 1 dose of study treatment. Subjects will be analyzed 
according to their randomized treatment group, unless they receive 
the incorrect study treatment for the entire treatment duration. 
PK Analysis Set  
The PK Analysis Set will include all randomized subjects who 
received at least 1 dose of study treatment and who have any 
measurable NBI-1065846 plasma concentration data. 
PK=pharmacokinetic 
11.4. 
Endpoints  
11.4.1. 
Primary  
• Change in anhedonia severity, as measured by change in DARS score from baseline 
to Day 57. 
11.4.2. 
Secondary  
• Change in total MADRS score from baseline to Day 57 in subjects with moderate or 
higher severity depression. 
• Change in CGI-S score from baseline to Day 57. 
11.4.3. 
Other  
• 
 
  
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 


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11.4.4. 
Safety  
• Safety endpoints include the occurrence of TEAEs, observed and changes from 
baseline in clinical laboratory tests (hematology and clinical chemistry), vital sign 
measurements (including orthostatic blood pressure and pulse rate), 12-lead ECG 
parameters, and scores from the C-SSRS. 
11.5. 
Statistical Analyses  
Descriptive and inferential statistical methods will be used to evaluate and summarize the data 
from this study. Descriptive statistics typically include the number of subjects (n), mean, 
standard deviation (SD) or standard error (SE), median, first (Q1) and third (Q3) quartile, 
minimum, maximum, and confidence intervals for continuous variables; and refers to the number 
and percentage of subjects for categorical variables. The term “inferential statistics” refers to the 
analysis results from hypothesis tests, which will be performed to assess differences between 
treatment groups. The overall level of significance (Type I error) for this study is 0.1. 
11.5.1. 
Efficacy Analyses  
This section is a summary of the planned statistical methods for the primary analysis of the 
primary and secondary endpoints. Additional details of the analyses will be described in the 
SAP. Unless otherwise specified, efficacy analyses will be conducted using the Full Analysis 
Set. 
11.5.1.1. Procedure to Control for Multiple Comparisons  
P-values will not be adjusted for multiplicity and should be interpreted as nominal p-values. 
11.5.1.2. Primary Endpoint  
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with 
outcome being the change in DARS score from baseline to Day 57. The model will include 
treatment group, illness severity (stratification factor), use of concomitant antidepressant 
medication(s) at time of randomization ([ie, yes vs. no], covariate), and baseline DARS score 
(covariate). Subjects who are missing the DARS score at Day 57 will have their data imputed 
through a multiple imputation procedure. Missing data will be imputed for subjects in the NBI-
1065846 treatment group using retrieved data (ie, observed data from subjects who discontinued 
study treatment) in the same treatment group, provided there is sufficient retrieved data. 
Otherwise, missing data will be imputed using observed data from subjects in the placebo 
treatment group. For subjects in the placebo treatment group, missing data will be imputed using 
observed data from subjects in the placebo treatment group. Additional analyses to address 
sensitivity to missing data will be specified in the SAP. 
11.5.1.3. Secondary endpoints  
Continuous secondary efficacy endpoints will be analyzed using a similar ANCOVA model as 
described for the primary endpoint; categorical and ordinal secondary endpoints will be analyzed 
using the Cochran-Mantel-Haenszel Chi-square test. Psychometric properties of the DARS will 
be assessed and reported separately. 


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11.5.2. 
Safety Analyses  
Safety data from this study will be analyzed using the safety analysis set. The subject incidence 
of TEAEs will be tabulated by treatment group for AEs, SAEs, fatal AEs, and AEs leading to 
discontinuation of study treatment. TEAEs are those AEs with onset dates on or after the date of 
the first dose of study treatment and on or before 55 days after the date of the last dose of study 
treatment. Descriptive statistics by treatment group will be generated for additional safety data, 
including selected laboratory analytes, vital signs, ECG parameters, C-SSRS, which will be 
further described in the SAP. 
11.5.3. 
Pharmacokinetic Analyses  
The plasma concentration data for NBI-1065846 and metabolites, if appropriate, will be 
summarized by sampling time point using the PK Analysis Set. The number and percentage of 
subjects with data, with quantifiable results, and with values below the limit of quantification 
will be provided. 
11.6. 
Interim Analyses  
Other than the ongoing monitoring of the study as described in Section 9.3, there is no planned 
interim analysis in this study. 


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12. 
SUPPORTING DOCUMENTATION  
12.1. 
Case Report Forms  
The eCRF data for this study are being collected with an EDC system (Rave®) provided by 
Medidata Solutions Incorporated, NY, USA. The EDC system and the study-specific eCRFs will 
comply with US Food and Drug Administration (FDA) Title 21 CFR Part 11. The documentation 
related to the validation of the EDC system is available through the vendor, Medidata, while the 
validation of the study specific eCRFs will be conducted by the Sponsor and the required 
documentation will be maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs. All data 
entered into the eCRF will be supported by source documentation. The investigator should 
review the eCRFs as soon as possible after the subject visit has occurred and electronically sign 
the eCRFs as soon as possible after the subject completes or discontinues from the study. 
The investigator or an authorized member of the investigator’s staff will make any necessary 
additions/corrections to the eCRF. All change information, including the date, person performing 
the corrections, and reason for the change will be available via the electronic audit trail, which is 
part of the EDC system. The eCRFs will be reviewed periodically for completeness, legibility, 
and acceptability by the Sponsor (or designee). The Sponsor will also be allowed access to all 
source documents and medical records pertinent to the study in order to verify eCRF entries. The 
Principal Investigator will review the eCRFs for completeness and accuracy and enter his or her 
electronic signature on the eCRFs as evidence thereof. 
Medidata will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access. Such access will be removed from study 
centers at the end of the center’s participation in the study. Data from the EDC system will be 
archived on appropriate data media or uploaded to a secure location with restricted access, in 
order to provide the investigator with a durable record of the center’s eCRF data. 
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
regulations. This includes an inspection by the Sponsor and/or health authority representatives at 
any time. The Principal Investigator will agree to the inspection of study-related records by 
health authority representatives and/or the Sponsor. 
12.2. 
Data Capture, Review, and Validation  
Data entered in the EDC system will be verified against the source data by the Sponsor (or 
designee); the percentage of source data verification will be determined by risk assessment. Any 
discrepancies will be corrected on-line by authorized study center personnel. After data are 
entered into EDC, automated (computer-generated) logic checks will run in order to identify 
items such as inconsistent study dates. In addition, manual review/checks may be performed by 
the Sponsor on the data. Any inconsistencies/errors/omissions identified will be sent to the study 
center (via an electronic query) for the necessary corrections to be made to the eCRF. Once 


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entered and saved in an eCRF, data immediately become part of the study database and are 
available to the Sponsor. 
12.3. 
Coding Dictionaries  
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA), per the Sponsor. Prior and concomitant medications will be 
coded using the chosen version of the World Health Organization Drug Dictionary, per the 
Sponsor. 
12.4. 
Ethics  
The Sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) GCP guidelines, and with the laws and regulations of the 
country in which the study is conducted. 
The investigator and/or Sponsor/CRO will submit this protocol and any related document(s) to 
be provided to the subject to an IRB/IEC and to the national competent (health) authority (as 
applicable). Approval documentation (as applicable) from both the IRB/IEC and the national 
competent (health) authority must be obtained before starting the study. 
12.5. 
General Legal References  
The study will be carried out according to provisions of the US CFR, the US FDA, the laws and 
regulations of the country in which the study is conducted, and the ICH Guidelines for GCP. All 
clinical work conducted under this protocol is subject to GCP regulations. This includes an 
inspection by the Sponsor or its representative, health authority, or IRB/IEC representatives at 
any time. The investigator must agree to the inspection of study related records by health 
authority representatives and/or the Sponsor or its designee. 
12.6. 
Institutional Review Board/Independent Ethics Committee  
The final approved protocol and the ICF will be reviewed by the IRB/IEC at the study center. 
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to the Sponsor. The investigator must agree to make 
any required progress reports to the IRB/IEC, as well as reports of SAEs, life threatening 
problems, or death. 
A list of members participating in the IRB/IEC meetings must be provided, including the names, 
qualifications, and functions of these members. If that is not possible, the attempts made to 
obtain this information along with an explanation as to why it cannot be obtained or disclosed 
must be documented in the study documentation. 
If a member of the site study personnel was present during an IRB/IEC meeting, it must be clear 
that this person did not vote. 


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12.7. 
Protocol Adherence – Amendments  
The protocol must be read thoroughly, and the instructions must be followed exactly. Any 
changes in the protocol will require a formal amendment. Such amendments will be agreed upon 
and approved in writing by the investigator and the Sponsor. The IRB/IEC and local health 
authorities will be notified of all amendments to the protocol in accordance with local 
regulations. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator and/or Sponsor/CRO to the IRB/IEC and to the 
national competent (health) authority in accordance with local procedures and regulations. 
12.8. 
Required Documents  
The investigator must provide the Sponsor or its designee with the following documents before 
the enrollment of any subject (originals should be kept by the investigator in the investigator’s 
study regulatory document binder): 
• Signed copy of the protocol signature page 
• Investigator’s Brochure acknowledgement page 
• Completed and signed statement of investigator qualifications, as applicable 
• Financial disclosure documentation as required 
• Curriculum vitae and current medical license of the investigator and subinvestigators 
• Letter of approval from the IRB/IEC for protocol and ICF 
• Copy of the IRB/IEC approved written ICF to be used 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided 
by a central laboratory 
12.9. 
Informed Consent  
Subjects must provide written informed consent. 
Each subject’s chart will include the signed ICF for study participation. When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file. Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the study. 
12.9.1. 
Subject Registry Database Review Informed Consent  
At the time of providing informed consent for the study, the investigator or designee will explain 
the subject registry database review process to the subject and witness signature. 
12.9.2. 
Pharmacogenomic Informed Consent  
Informed consent pertaining to collection, usage and storage of any sample which may be used 
for pharmacogenomic analysis must be obtained prior to collecting for pharmacogenomic 


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research for this study. The provision of consent to collect and analyze the pharmacogenomic 
sample is independent of consent to the other aspects of the study. 
12.10. 
Study Monitoring  
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator. This will include telephone calls and on-site visits. During the on-site visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol. As part of the data 
audit, source documents will be made available for review by the study monitor. The study 
monitor will also perform treatment accountability checks and may periodically request review 
of the investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and will respond to inquiries. In addition, the 
investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
12.11. 
Quality Assurance  
The study will be conducted in accordance with the Sponsor’s standard operating procedures 
designed to ensure that all procedures are in compliance with GCP and the laws and regulations 
of the country in which the study is conducted. Quality assurance audits may be performed at the 
discretion of the Sponsor. 
12.12. 
Record Retention  
Study records should be retained in compliance with federal, national, and/or local regulations of 
the clinical site. 
The Sponsor may request these records to be retained for a longer period if required by 
applicable regulatory requirements or Sponsor contractual obligations. If the investigator is 
unable to retain the study documents for the required amount of time, the Sponsor must be 
informed of the individual who will be assuming this responsibility. 
12.13. 
Confidentiality and Data Protection  
The Sponsor or its designee, and the study center affirm and uphold the principle of the subject’s 
right to protection against invasion of privacy. Throughout this study, all data will be identified 
only by an identification number. Information technology systems used to collect, process, and 
store study-related data are secured by technical and organizational security measures designed 
to protect such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of the 


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Sponsor; it shall not be disclosed to others without written consent of the Sponsor; and shall not 
be used except in the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by the Sponsor as deemed necessary. To 
allow the use of the information derived from this clinical study and to ensure compliance with 
the laws and regulations of the country in which the study is conducted, the investigator is 
obliged to provide the Sponsor with the complete test results and all data compiled in this study. 
12.14. 
Publication and Disclosure Policy  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. Authorship will be 
determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements. 
The Sponsor will submit study results for posting on public registry(ies) as required for 
compliance with applicable laws and/or regulations in the region(s) where the study is being 
conducted. For the purposes of study results disclosure, study completion is defined as the date 
of the last visit or procedure for the last subject in the study globally. 
13. 
STUDY COMMENCEMENT AND DISCONTINUATION  
Upon satisfactory receipt of all required regulatory documents, the Sponsor (or designee) will 
arrange that all study materials be delivered to the study site. Subject entry should not begin until 
after the required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred. All personnel expected to be involved in the conduct of 
the study will undergo orientation to include review of the study protocol, instructions for eCRF 
completion, AE reporting, and overall responsibilities including those for treatment 
accountability and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow-up examination. Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 


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APPENDIX A. SCHEDULE OF ASSESSMENTS  


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Table 8: 
Schedule of Assessments 
 
Screening 
Perioda  
Treatment Period 
Safety Follow-Up 
Period 
Study Day 
(Study Week) 
Day -28 
to 
Day -1 
(W-4 to 
D-1) 
Day 1b 
Baseline 
(W1)  
Day 8 
(±2)  
(W2) 
Day 22 
(±2)  
(W4) 
Day 29 
(±2)  
(W5) 
Day 43 
(±2)  
(W7) 
Day 57 
(±2) 
OR 
ET 
Visit 
Day 78c 
(±3)  
(W12) 
Day 
106c 
(±3)  
(W16) 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Onsite Visit 
X 
X 
X 
 
X 
 
X 
X 
X 
Virtual Visit 
 
 
 
X 
 
X 
 
 
 
Informed consent 
X 
Subject registry 
database review 
informed consent 
X 
Pharmacogenomic 
informed consent 
X 
 
 
 
 
 
 
 
 
Subject registry 
database reviewd  
X 
Inclusion/exclusion 
criteria 
X 
update 
 
 
 
 
 
 
 
Medical history 
X 
update 
Medication history 
X 
update 
Physical examination 
(including height and 
weight)e  
X 
X 
X 
X 
Triplicate 12-Lead 
ECGf 
X 
X 
 
 
X 
 
X 
 
 
Vital signsg  
X 
X 
X 
 
X 
 
X 
X 
X 
Pregnancy test:  
Urine (u) Serum (s) 
X (s)h  
X (u) 
 
 
X (u) 
 
X (u) 
X (u) 
X (u) 
FSHi 
X 
Clinical laboratory 
tests 
X 
X 
X 
X 
X 
X 
X 
Drug/alcohol screenj  
X 
X 
X 
Pharmacogenomics 
sample (optional) 
X 
MINI 
X 
 
 
 
 
 
 
 
 
SAFER Interview 
X 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
HAM-D17k  
X 
X 
PCRSk 
X 
X 
X 
 
 


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Screening 
Perioda  
Treatment Period 
Safety Follow-Up 
Period 
Study Day 
(Study Week) 
Day -28 
to 
Day -1 
(W-4 to 
D-1) 
Day 1b 
Baseline 
(W1)  
Day 8 
(±2)  
(W2) 
Day 22 
(±2)  
(W4) 
Day 29 
(±2)  
(W5) 
Day 43 
(±2)  
(W7) 
Day 57 
(±2) 
OR 
ET 
Visit 
Day 78c 
(±3)  
(W12) 
Day 
106c 
(±3)  
(W16) 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Onsite Visit 
X 
X 
X 
 
X 
 
X 
X 
X 
Virtual Visit 
 
 
 
X 
 
X 
 
 
 
SHAPSk 
X 
X 
 
 
DARSk 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
X 
 
 
,l  
X 
Xc    
MADRSk 
X 
X 
X 
 
 
CGI-Sk 
X 
X 
X 
 
 
 
X 
X 
 
 
C-SSRS 
Baseline/Screening 
Version 
X 
 
 
 
 
 
 
 
 
C-SSRS Since Last 
Visit Version 
 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood sample up 
to 2 hours predose  
X 
X 
X 
PK blood samples at 
0.5-2 hours and 2-36 
hours postdose 
(samples must be 
obtained ≥30 minutes 
apart) 
X 
X 
PK blood sample at 
any timem  
X 
Dispensen/Collecto  
study treatment 
Xn 
Xn 
Xo 
Dose study 
treatmentp  
 
 
X (once weekly)p 
 
 
Remind subjects to 
take study treatmentp 
 
X (once weekly)p 
 
 
Compliance checkq  
X 
X 
X 
X 
X 


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Screening 
Perioda  
Treatment Period 
Safety Follow-Up 
Period 
Study Day 
(Study Week) 
Day -28 
to 
Day -1 
(W-4 to 
D-1) 
Day 1b 
Baseline 
(W1)  
Day 8 
(±2)  
(W2) 
Day 22 
(±2)  
(W4) 
Day 29 
(±2)  
(W5) 
Day 43 
(±2)  
(W7) 
Day 57 
(±2) 
OR 
ET 
Visit 
Day 78c 
(±3)  
(W12) 
Day 
106c 
(±3)  
(W16) 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Onsite Visit 
X 
X 
X 
 
X 
 
X 
X 
X 
Virtual Visit 
 
 
 
X 
 
X 
 
 
 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule exit 
interview 
 
 
 
 
 
 
X 
 
 
 
AE=adverse event; 
; CGI-S= Clinical Global 
Impression – Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; DARS=Dimensional Anhedonia Rating 
Scale; ECG=electrocardiogram; ET=early termination; FSH=follicle-stimulating hormone; HAM-D17=Hamilton 
Depression Rating Scale-17; MADRS=Montgomery-Åsberg Depression Rating Scale; MGH-ATRQ=Massachusetts 
General Hospital - Antidepressant Treatment Response Questionnaire; MINI=Mini-International Neuropsychiatric 
Interview; PCRS=Placebo-Control Reminder Script; 
 
 PK=pharmacokinetics;  
; SAFER= State versus Trait, Assessability, Face Validity, Ecological Validity, 
Rule of Three P’s; SHAPS=Snaith-Hamilton Pleasure Scale;
 
W=week 
a Subjects will undergo screening procedures that may be completed in 1 or more visits during the Screening Period 
of up to 4 weeks. Subjects may be rescreened once based on the clinical judgment of the investigator in 
collaboration with the sponsor or designee. The screening period may be extended by up to 14 days in extenuating 
circumstances in consultation with the Sponsor or designee. 
b Assessments on Day 1 should be performed prior to study treatment administration. 
c Subjects will return to the clinic approximately 4 and 8 weeks following their final dose for safety follow-up or 7 
days (±2) for the ET visit assessments if the subject discontinues study treatment or withdraws consent to 
participate in the study.  
d After consent is obtained, the registry database check should be performed as early as possible at the screening 
visit to avoid unnecessary procedures. 
e Height will be collected at screening only. 
f Triplicate 12-lead ECGs will be performed (at least 1 minute apart and within 15 minutes) after the subject has 
rested supine for at least 5 minutes on screening, Day 1, Day 29, and Day 57 or ET visit. On Day 1 and Day 29, 
ECGs will be performed at predose and 2 hours postdose. ECGs are also needed on Day 78 and Day 106 if ECG(s) 
during the Treatment Period were abnormal. 
g Vital signs will be measured for the following: orthostatic systolic and diastolic blood pressure, orthostatic pulse 
rate, respiratory rate, and body temperature. The same method should be used to take body temperature throughout 
the study. 
h If a female of childbearing potential has an indeterminant β-hCG pregnancy test result, the test should be repeated 
during the screening period and the subject discussed with the medical monitor. 
i Only for postmenopausal women. 
j Urine drug screen (UDS) will be analyzed at screening by the central lab. A UDS kit provided by the central 
laboratory will be used at the site to confirm eligibility on Day 1. Drug/alcohol screening may be repeated at any 


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time per the investigator’s clinical judgment. Any positive UDSs during conduct of the study must be discussed 
with the Sponsor or designee to determine the subject’s disposition. 
k A trained rater will read the PCRS to the subject prior to administration of the efficacy rating assessments. After 
administering the PCRS, the efficacy assessments should be performed in the following order throughout the 
study: SHAPS (at screening and baseline only), DARS, 
 
 MADRS, HAM-D17 (at screening and baseline only), CGI-S, 
 
l 
 
 
. 
m If the subject discontinues study treatment, a blood sample for PK is needed at any time during early ET visit.  
n One bottle will be dispensed to the site at Baseline/Day 1 and will remain in the clinic for onsite subject dosing (ie, 
on Days 1, 8, and 29). A second bottle will be dispensed to the subject at Day 8 to take home for at-home dosing 
(ie, on Days 15, 22, 36, 43, and 50). 
o Collect any remaining study treatment from the subject at Day 57 or ET visit if the subject discontinues study 
treatment.  
p Each dose of study treatment should be taken at least 5 days apart. Onsite dosing in the clinic will occur on Day 1, 
Day 8, and Day 29. Subjects should hold morning study treatment dose until instructed to take at the study site in 
order to collect predose PK blood samples. Subjects will take study treatment at home on Days 15, 22, 36, 43, and 
50. At each onsite or virtual study visit (except the Day 1 visit), the investigator or designee will remind subjects 
to take their study medication on the next scheduled day. For weeks with no study visit scheduled, this reminder 
should occur via telephone. The subject should also be reminded that if they forget or are unable to take the study 
treatment, the dose can be taken ± 2 days from the scheduled weekly dose (with each dose taken at least 5 days 
apart); otherwise the study treatment should be taken at the next dosing time. 
q A compliance check will be performed by counting the tablets returned at each on-site study visit.  


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APPENDIX B. INVESTIGATOR SIGNATURE  
CLINICAL STUDY TITLE: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-
Concept Study to Evaluate the Efficacy and Safety of Once-Weekly Oral NBI-1065846 in the 
Treatment of Anhedonia in Major Depressive Disorder (TERPSIS STUDY) 
 
PROTOCOL No.: 
NBI-1065846-MDD2020 
 
 
As Agreed: 
 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
 
 
Date 
 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
 
STUDY CENTER: 
 
________________________________________________________ 
(Print Study Center Name) 
 


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APPENDIX C. SPONSOR APPROVAL SIGNATURE  
The undersigned has reviewed and approves the content of this document. 
 
 
 
 
 
 
 
 
 
 
Electronically signed and dated 
_________________________ 
_______________________  
__________ 
 
 
Signature 
 
 
 
Date 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
 


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APPENDIX D. LIVER FUNCTION TEST MONITORING  
If a subject is noted to have ALT or AST elevated >3×ULN, the investigator will take the 
following actions: 
• Obtain follow-up laboratory tests: ALT, AST, ALP, GGT, and total bilirubin, direct 
bilirubin, PT, and INR within 48 to 72 hours after the abnormality was noted. 
• Assess whether the subject has experienced any clinical manifestations such as 
fatigue, low-grade fever, anorexia, nausea/vomiting, right upper quadrant pain, 
jaundice, or pruritus. 
• Inform the Study Medical Monitor. 
If symptoms persist or repeat testing shows ALT or AST >3×ULN, repeat ALT, AST, ALP, 
GGT, total bilirubin, direct bilirubin, and INR two or three times weekly. The frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study treatment has 
been discontinued and the subject is asymptomatic. Serial testing should continue until the liver 
function tests return to baseline values. Further assessment will be conducted as clinically 
indicated, in consultation with the Study Medical Monitor. The study treatment may be 
discontinued by the investigator in consultation with the Study Medical Monitor, or at the 
request of the Study Medical Monitor 
The Study Medical Monitor should also be promptly notified if any of the following criteria are 
met:  
• ALP >1.5×ULN in conjunction with elevated TBILI >1.5×ULN, or 
• 5’nucleotidase >1.5×ULN, or GGT >2×ULN, or AST/ALT:>1.5×ULN 
• ALP >2×ULN persisting for longer than 3 days;  
• ALP >3×ULN; 
• Total bilirubin >2.0×ULN;  
• Creatinine >2 mg/dL;  
• Baseline elevations in liver enzymes <3×ULN, yet worsen by 2-fold increases above 
Baseline values after study drug exposure. 
Additionally, the study treatment should be discontinued immediately if any of the following 
criteria has been meet: 
• ALT or AST >8×ULN, or 
• ALT or AST >5×ULN and persists for more than 2 weeks, or 
• ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
INR >1.5. 
• ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
• ALP elevations >1.5×ULN in conjunction with elevated TBLI >1.5×ULN or 
• 5’nucleotidase >2×ULN or GGT >5×ULN or AST/ALT >3×ULN 


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SAP_001.pdf: 
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Si g nat ure  
Date  
 
 
 
T his  d oc u me nt  has  b ee n  re vi e we d b y:  
 
 
 
 
, Bi ostatistics 
Ne ur ocri ne Bi oscie nces, I nc.  
e Si g ne d a n d Date d  
 
Si g nat ure  
Date  
 
 
 
 
 
 
 
Ne ur ocri ne  Bi oscie nces,  I nc. 
e Si g ne d a n d Date d  
 
Si g nat ure  
Date  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
T A B L E  O F  C O N T E N T S  
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N S  O F  T E R M S  .................................................. 6  
1.    
I N T R O D U C TI O N......................................................................................................... 8  
2.    
S T U D Y  O BJ E C TI V E S  ................................................................................................. 9  
3.    
S T U D Y  D E SI G N  ........................................................................................................ 1 0  
3. 1.    
Ra n d o mizati o n  ............................................................................................................ 1 0  
3. 2.    
Bli n di n g  ....................................................................................................................... 1 1  
3. 3.    
Sa m ple  Size  C o nsi derati o ns  ........................................................................................ 1 1  
4.    
E N D P OI N T S  .............................................................................................................. 1 2  
4. 1.    
Pri mar y  Efficac y  ......................................................................................................... 1 2  
4. 2.    
Sec o n dar y  Efficac y  ..................................................................................................... 1 2  
4. 3.    
Ot her  E n d p oi nts  .......................................................................................................... 1 2  
4. 4.    
Safet y  E n d p oi nts  ......................................................................................................... 1 2  
4. 5.    
P har mac o ki n eti cs  E n d p oi nt  ......................................................................................... 1 3  
5.    
G E N E R A L  C O N SI D E R A TI O N S  F O R  D A T A  A N A L Y SI S  ..................................... 1 4  
5. 1.    
Ge ner al  Statistical  Pr oce d ures ..................................................................................... 1 4  
5. 2.    
A nal ysis  Sets  ............................................................................................................... 1 4  
5. 3.    
Baseli ne  Defi niti o n ...................................................................................................... 1 5  
5. 4.    
Deri ve d  a n d Tra nsf or me d  Data  ................................................................................... 1 5  
5. 5.    
St u d y  Da y  .................................................................................................................... 1 5  
5. 6.    
Visit Wi n d o ws  ............................................................................................................ 1 5  
5. 7.    
Ha n dli n g  of Missi n g  Data  ........................................................................................... 1 6  
5. 7. 1.  
Start  Dates  f or A d verse  E ve nts  ................................................................................... 1 6  
5. 7. 2.  
Start  a n d St o p  Dates  f or Me dicati o ns  .......................................................................... 1 7  
5. 8.    
C o di n g  Dicti o naries  .................................................................................................... 1 7  
5. 9.    
I m pact of  C O VI D -1 9  .................................................................................................. 1 7  
6.    
S T U D Y  P O P U L A TI O N  ............................................................................................. 1 9  
6. 1.    
Dis p ositi o n  .................................................................................................................. 1 9  
6. 2.    
S u m mar y  of  A nal ysis  Sets  .......................................................................................... 1 9  
6. 3.    
Pr ot oc ol  De viati o ns  ..................................................................................................... 1 9  
6. 4.    
De m o gra p hic  a n d Baseli ne  C haracteristics  ................................................................. 2 0  
6. 5.    
Me dical  Hist or y ........................................................................................................... 2 0  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
4  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
7.    
E F FI C A C Y  .................................................................................................................2 2  
7. 1.    
M ulti ple  C o m paris o ns  a n d M ulti pli cit y  A dj ust me nt  ..................................................2 2  
7. 2.    
I nteri m A nal ysis  ..........................................................................................................2 2  
7. 3.    
Statisti cal  H y p ot hesis  a n d Esti ma n d  ...........................................................................2 2  
7. 3. 1.  
Statisti cal  H y p ot hesis  ..................................................................................................2 2  
7. 3. 2.  
Esti ma n d ......................................................................................................................2 2  
7. 4.    
Pri mar y  Effi cac y  E n d p oi nt  ..........................................................................................2 3  
7. 4. 1.  
Se nsiti vit y  A nal ysis  of  Pri m ar y  Effica c y  Varia ble  .....................................................2 6  
7. 4. 2.  
S u p ple me nt ar y  A nal ysis of Pri m ar y  Effi cac y  Varia ble  ..............................................2 6  
7. 5.    
Sec o n dar y  Effi cac y  E n d p oi nts  ....................................................................................2 7  
7. 5. 1.  
C ha n ge  i n t otal M A D R S  sc ore fr o m baseli n e  t o Da y  5 7  i n s u bjects wit h  
m o derat e or  hi g her se verit y  de pressi o n  .......................................................................2 7  
7. 5. 2.  
C ha n ge  i n C GI-S  sc ore fr o m baseli ne t o Da y 5 7  ........................................................2 7  
7. 6.    
Ot her  Effica c y  E n d p oi nts  ............................................................................................2 7  
7. 6. 1.  
. ................................................................................................................... 2 7  
7. 6. 2.  
 2 8  
7. 6. 3.  
 2 8  
7. 6. 4.  
. ............................................... 2 8  
7. 6. 5.  
. ........................................................................................................................ 2 8  
7. 6. 6.  
 2 8  
7. 6. 7.  
E xa mi n ati o n  of  s u b gr o u ps .......................................................................................... 2 9  
8.    
P H A R M A C O KI N E TI C S  ............................................................................................ 3 0  
8. 1.    
C o nce ntrati o ns  of  N BI -1 0 6 5 8 4 6  ................................................................................. 3 0  
9.    
S A F E T Y  ..................................................................................................................... 3 1  
9. 1.    
St u d y  Treat m e nt D osi n g  a n d C o m plia nce  .................................................................. 3 1  
9. 2.    
Pri or  a n d C o nc o mita nt Me dicati o ns ............................................................................ 3 1  
9. 3.    
A d verse  E ve nts  ........................................................................................................... 3 2  
9. 3. 1.  
A d verse  E ve nts Lea di n g  t o Disc o nti n uati o n  of  St u d y  Treat me nt  ............................... 3 2  
9. 3. 2.  
Deat hs  a n d Ot her  Seri o us  A d verse  E ve nts .................................................................. 3 3  
9. 4.    
La b orat or y  Safet y  Para meters  ..................................................................................... 3 3  
9. 5.    
Vital Si g ns  ................................................................................................................... 3 4  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
5  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
9. 6.    
B o d y  Wei g ht  ...............................................................................................................3 4  
9. 7.    
Electr ocar di o gra m  ( E C G) ...........................................................................................3 4  
9. 8.    
Ot her Safet y  E n d p oi nts  ...............................................................................................3 5  
9. 8. 1.  
C ol u m bia -S ui ci de  Se verit y  Rati n g  Scal e ( C -S S R S)  ...................................................3 5  
1 0.    
P E R F O R M A N C E  Q U A LI FI C A TI O N  O F  S A S ®  P R O G R A M S  ................................3 7  
1 1.    
R E F E R E N C E S  ............................................................................................................3 8  
 
LI S T  O F  T A B L E S  
Ta ble  1:   
A nal ysis  Visit  Wi n d o ws  f or Effi cac y  A nal ysis  ...........................................................1 5  
Ta ble  2:   
A nal ysis  Visit  Wi n d o ws  f or Safet y  A nal ysis  ..............................................................1 6  
 
LI S T  O F  FI G U R E S  
Fi g ure  1:  
St u d y  Desi g n Sc he matic  .............................................................................................1 0  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
6  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N S  O F  T E R M S  
 
A b bre vi ati o n  
Ter m  
A E  
A d verse  e ve nt 
A L P  
Al kali ne  p h os p hatase  
A L T  
Ala ni ne  a mi n otra nsferase 
A N C O V A  
A nal ysis  of  C o varia nce  
A S T  
As partate  a mi n otra nsferase 
A T C  
A nat o mic al  T hera p e uti c  C he mical  
B MI  
B o d y  mass  i n de x 
B U N  
Bl o o d  urea  nitr o ge n  
 
 
 
 
C GI -S  
Cli nic al  Gl o bal  I m pressi o n-Se verit y  
C O VI D -1 9  
C or o na vir us  Disease  2 0 1 9  
C -S S R S  
C ol u m bia -S ui ci de  Se verit y  Rati n g  Scale  
C V  
C oeffici e nt  of  variati o n  
D A R S  
Di me nsi o nal  A n he d o ni a Rati n g  Scale  
D S M -V  
T he  Dia g n ostic  a n d Statistical  Ma n ual  of  Me ntal  Dis or ders,  5t h 
E diti o n  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic  case re p ort f or m 
E T  
Earl y  ter mi nati o n 
F A S  
F ull  a nal ysis  set 
G G T  
Ga m ma -gl uta m yl  tra nsferase 
H A M -D 1 7  
Ha milt o n  De pressi o n  Rati n g  Scale,  1 7 -ite m 
I C H 
I nter nati o nal C o u ncil  f or Har m o niz ati o n  of  T ec h nic al 
Re q uire m e nts f or P har ma ce uti cals f or H u ma n Use  
I P D 
I m p orta nt pr ot oc ol  de viati o n  
L S  
Least -s q uares 
M A D R S  
M o nt g o mer y  Ås ber g  De pressi o n Rati n g  Scale  
M C M C  
Mar k o v  C hai n M o nte  Carl o  
M D D  
Maj or  De pressi ve  Dis or der  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
7  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
W orl d  Healt h  Or ga nizati o n  
W H O  
U nite d  States  
U S  
U p per  li mit of n or mal  
Me dical  Dicti o nar y  f or Re g ulat or y  Acti vities  
Me d D R A  
Ter m  
A b bre vi ati o n  
P har mac o ki netics  
P K  
P C S  
P ote ntiall y  cli ni call y si g nifica nt 
MI  
N BI  
T E A E  
Missi n g  n ot  at ra n d o m 
S S RI  
S yste m  Or ga n  Class  
S O C  
Sta n dar d  err or 
S E  
Sta n dar d  de viati o n  
S D  
Statisti cal  a nal ysis  pla n  
S A P  
Seri o us  a d verse e ve nt 
S A E  
C orrecte d  Q T  i nter v al usi n g  Fre deri cia’s f or m ula 
Q Tc F  
Preferre d  ter m 
P T  
Ne ur ocri ne  Bi oscie nces,  I nc. 
Treat me nt -e mer ge nt a d v ers e e ve nt 
M N A R  
S electi ve  Ser ot o ni n  Re u pta ke  I n hi bit or 
M ulti ple i m p utati o n 
U L N  
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
8  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
1.    
I N T R O D U C TI O N 
T he  p ur p ose  of  t his statistic al a nal ysis  pla n  ( S A P) is t o descri be  t he pla n ne d  a n al yses  a n d  dat a 
dis pla ys t hat will be pr e pare d t o s u m mari ze t h e dat a fr o m t he P hase 2 St u d y N BI -1 0 6 5 8 4 6 - 
M D D 2 0 2 0.  
T his  S A P  was  de vel o pe d  i n acc or da n ce wit h  I nter nati o nal C o u ncil  f or Har m o nizati o n  (I C H) E 9 
g ui da nce. All decisi o ns re gar di n g t h e fi nal a nal ysis will be m a de pri or t o dat a base l oc k a n d 
u n bli n di n g of t h e st u d y dat a a n d will be d oc u me nte d i n t his S A P. C ha n ges t o t he pl a n ne d 
a nal yses descri b e d i n t his S A P will be statisticall y j ustifie d a n d d escri be d i n t he st u d y re p ort.  
F urt her  i nf or m ati o n r elate d t o st u d y desi g n a n d met h o d ol o g y  ca n be f o u n d i n t he st u d y pr ot oc ol.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
9  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
2.    
S T U D Y  O B J E C TI V E S  
Pri m ar y  St u d y  O bjecti ve:  
T he  pri m ar y  o bje cti v e f or t his  st u d y is: 
• T o  e val u ate t he effic ac y  of  N BI -1 0 6 5 8 4 6  c o m p are d  wit h  plac e b o  o n  i m pr o vi n g 
s y m pt o ms of a n he d o ni a i n s u bje cts wit h M D D. 
 
Sec o n d ar y  St u d y  O bjecti ves:  
T he  sec o n dar y o bje cti v es  f or t his st u d y are t he f oll o wi n g: 
• T o  e val uat e t he effica c y  of  N BI -1 0 6 5 8 4 6  c o m p are d  wit h  pla ce b o  o n  s y m pt o ms of 
de pressi o n i n s u bjects wit h M D D.  
• T o  e val u ate t he saf et y, t olera bilit y, a n d p h ar ma c o ki n etics  ( P K) of  N BI -1 0 6 5 8 4 6  i n 
s u bjects wit h M D D. 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 0  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
3.    
S T U D Y  D E SI G N  
T his  is a P hase  2,  ra n d o mize d, d o u ble -bli n d,  parallel -gr o u p,  pr o of -of -c o nce pt st u d y c o m p ari n g 
use of N BI -1 0 6 5 8 4 6 wit h place b o f or i m pr o ve m e nt of a n he d o nia i n s u bjects 1 8 t o 6 5 years of 
a ge (i ncl usi ve) wit h M D D w h o ha ve bee n tr eat e d or are c urre ntl y bei n g treate d wit h 
a nti de pr essa nt me dicati o n(s) b ut c o nti n ue t o h a ve cli nicall y si g nifi ca nt a n he d o nia. St u d y 
treat me nt will be a d mi nistere d as m o n ot hera p y or as a n a dj u ncti ve treat me nt t o t he s u bj ect’s 
c urre nt oral a nti de pressa nt m e dic ati o n(s); s u bj ects re cei vi n g a nti d e pressa nt me dicati o n(s) at 
scree ni n g ar e e x pecte d t o c o nti n u e usi n g t he m at t he sa me d ose t hr o u g h o ut t he st u d y.  
T he  st u d y c o nsists  of  a Scre e ni n g  Peri o d  of  u p  t o 2 8 da ys  ( Da ys -2 8  t o -1),  a n 8 -wee k  Treat me nt 
Peri o d ( Da ys 1 t o 5 7), a n d a n 8 -wee k Safet y F oll o w -u p Peri o d ( wit h visits at 4 a n d 8 wee ks 
[ Da ys 7 8 a n d 1 0 6] after last d ose of st u d y treat me nt). 
A p pr o xi matel y  8 8  s u bjects are pla n ne d  t o be  e nr olle d  i n t h e st u d y. 
T he st u d y desi g n sc he matic is s h o w n i n Fi g ure 1 . 
Fi g ure  1:    
St u d y  Desi g n  Sc he m atic  
 
D =  Da y;  M D D = maj or  de pressi ve  dis or der;  n o. = n u m ber  
a T hese  are virt ual  visits.  
 
 
3. 1.    
R a n d o miz ati o n  
A pla n ne d t ot al of a p pr o xi matel y 8 8 s u bje cts will b e ra n d o miz e d i n a 1: 1 rati o i n a d o u bl e- 
bli n de d fas hi o n t o rec ei ve eit her N BI -1 0 6 5 8 4 6 or pl a ce b o, a d mi nister e d o n a wee kl y b asis, f or a 
peri o d  of  8  wee ks.  T h e  ra n d o miz ati o n will  be  str atifi e d base d  o n  t he Ha milt o n  De pressi o n  Rati n g 
Scale -1 7 It e m  ( H A M-D 1 7)  sc ore at baseli ne:  re missi o n ( H A M-D 1 7  ≤7),  mil d  ill ness ( H A M-D 1 7 
fr o m 8 t o 1 8), a n d m o d erat e t o se vere ill n ess ( H A M-D 1 7 ≥1 9).  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 1  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
3. 2.    
Bli n di n g  
T his  is a d o u ble -bli n d,  pl ace b o -c o ntr oll e d  st u d y d uri n g  w hic h  t he s u bjects, i n vesti gat or, all  st u d y 
ce nter p ers o n nel, p har m acists, a n d t he S p o ns or, wit h t he e xc e pti o n of t he cli nic al st u d y m aterial 
s u p pl y c hai n pers o n nel w h o are n ot i n v ol ve d i n d ecisi o ns re gar di n g s u bje ct’s treat me nt, will b e 
bli n de d t o t he s u bje ct’s tre at me nt assi g n me nt.  
3. 3.    
S a m ple  Size  C o nsi der ati o ns  
Ass u mi n g  t hat 8 5 %  of  t he 8 8  s u bjects (ra n d o mize d i n a 1: 1  rati o t o N BI -1 0 6 5 8 4 6  a n d place b o 
gr o u ps)  c o m plet e t he Da y  5 7  assess me nt,  t he st u d y h as a p pr o xi mat el y  8 0 %  p o wer  t o detect  a n 
effect si ze of 0. 5 f or t he pri mar y e n d p oi nt at 1 -si de d si g nifica n ce l e vel of 0. 1. 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 2  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
4.    
E N D P OI N T S  
T he effi cac y, safet y, p har m ac o ki n eti cs ( P K) a n d ot her e n d p oi nts ar e briefl y d escri be d b el o w. 
Detail e d  defi niti o ns  a n d pla n n e d  m et h o ds  of  a n al ysis  are pr o vi d e d  i n t he f oll o wi n g se cti o ns o n 
effica c y ( Secti o n 7 ), p h ar ma c o ki netics (Secti o n 8 ), a n d safet y (Secti o n 9 ). 
4. 1.    
Pri m ar y  Effic ac y  
• C ha n ge  i n a n he d o nia se verit y, as meas ure d  b y  c ha n g e i n Di me nsi o nal  A n he d o ni a 
Rati n g Scale ( D A R S) sc ore fr o m baseli n e t o Da y 5 7.  
4. 2.    
Sec o n d ar y  Effic ac y  
• C ha n ge  i n t otal M o nt g o m er y  Ås ber g  De pressi o n  Rati n g  Scale ( M A D R S)  sc ore fr o m 
baseli ne t o Da y 5 7 i n s u bje cts wit h m o d erate or hi g h er se verit y d e pressi o n.  
• C ha n ge  i n Cli nical  Gl o bal  I m pressi o n-Se verit y  ( C GI-S)  sc ore fr o m b aseli n e  t o Da y 
5 7.  
4. 3.    
Ot her E n d p oi nts  
• 
 
• 
 
• 
• 
 
• 
 
• 
4. 4.    
S afet y  E n d p oi nts  
• Occ urre nce  of  T E A Es  
• Val ues  a n d c ha n g es  fr o m baseli ne  f or cli nical la b or at or y tests ( he mat ol o g y a n d 
cli ni cal c he mistr y)  
• Val ues  a n d c ha n g es  fr o m baseli ne  f or vital  si g n para meters  (i ncl u di n g ort h ostatic 
bl o o d press ure a n d p ulse rate)  
• Val ues  a n d c ha n ges  fr o m baseli ne f or 1 2 -l ea d el ectr o car di o gra m  ( E C G) para meters  
• Sc ores  fr o m t he C ol u m bia -S uici de  Se verit y  Rati n g  Scale  ( C-S S R S)  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 3  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
4. 5.    
P h ar m ac o ki netics  E n d p oi nt  
T he  P K  e n d p oi nt is plas m a  c o nce ntr ati o ns  f or N BI -1 0 6 5 8 4 6  after a si n gle d ose  a n d at stea d y 
state. 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 4  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
5.    
G E N E R A L  C O N SI D E R A TI O N S  F O R  D A T A  A N A L Y SI S  
5. 1.    
Ge ner al  St atistic al  Pr oce d ures  
Descri pti ve a n d i nfere ntial statistic al m et h o ds will b e use d t o e val uat e a n d s u m marize t he data 
fr o m t his st u d y. T he ter m “ descri pti ve statisti cs” refers t o t he n u m ber of s u bj ects ( n), m ea n, 
me dia n,  sta n dar d de vi ati o n  ( S D) or  sta n dar d err or ( S E), mi ni m u m,  a n d ma xi m u m f or  c o nti n u o us 
varia bl es. Or di nal cate g ori cal d ata will be s u m mari z e d usi n g me di a n, mi ni m u m a n d ma xi m u m 
val ues. N u m ber a n d p erce nt a ge of s u bje cts will b e s u m mari ze d f or cate g ori cal v aria bles. T he 
ter m “i nfere ntial statistics” ref ers t o h y p ot hesis t ests w hic h will be p erf or me d t o assess 
differe nc es bet wee n t h e N BI -1 0 6 5 8 4 6 treat me nt gr o u p a n d t he pl ace b o gr o u p f or sel ect e d 
effica c y varia bles. T he o v erall le v el of si g nifica n ce ( T y pe I err or) f or t his st u d y is 0. 1.  
S u m mar y statistics will be prese nte d usi n g t h e f oll o wi n g deci m al pre cisi o n (ie, n u m ber of di gits 
t o t he ri g ht of t he d eci mal p oi nt): t he mi ni m u m a n d ma xi m u m will h a ve t h e sa me n u m ber of 
deci m al pl aces as t he d ata; t he mea n, me di a n, S D a n d sta n dar d err or ( S E) will ha ve o ne m ore 
deci m al pl ace t ha n t he d ata b ei n g s u m m ariz e d;  t he s a m ple si ze ( N) will b e re p orte d as a n 
i nte ger; perc e nta ges will be re p orte d t o o n e deci mal place ( p erce nt a ges f or zer o c o u nts are 
o mitt e d a n d 1 0 0 % will be re p orte d as a n i nte ger); a n d p -val ues will b e dis pla y e d usi n g f o ur 
deci m al  plac es.  P -val ues  less t ha n 0. 0 0 0 1  will  b e  dis pla ye d  as <  0. 0 0 0 1  a n d p -val u es  greater  t h a n 
0. 9 9 9 9 dis pla ye d as > 0. 9 9 9 9. C o nfi d e nce i nter v als ( CI) f or mea ns will b e re p orte d t o t he sa me 
n u m ber of deci mal plac es as mea n v al ues; a n d c o nfi de nce i nter vals f or perce nt a ges will b e 
re p orte d t o o n e deci mal plac e. T hese r ules ma y b e m o difie d if warr a nte d, base d o n pr actical 
c o nsi derati o ns. 
All a vaila bl e st u d y dat a will b e i ncl u d e d i n rele va nt data dis pl a ys, i ncl u di n g dat a f or s u bjects 
wit h  i nc o m plete or  missi n g  val ues.  Re pl ace m e nt  of  missi n g  data  val u es  wit h  i m p ut e d val ues  will 
ge nerall y n ot be p erf or me d u nl ess s pecifie d ot her wis e i n rel e va nt e n d p oi nt s u bsecti o ns.  
5. 2.    
A n al ysis  Sets  
T he  f oll o wi n g a nal ysis  sets will  be  defi n e d  f or t his st u d y: 
• T he Safet y A nal ysis Set will i ncl u d e all ra n d o mi ze d s u bjects w h o recei ve d at least 
o ne  d ose  of  st u d y treat me nt. S u bjects  will  be  a nal y ze d  acc or di n g t o t heir ra n d o mi ze d 
treat me nt gr o u p, u nless t he y rec ei ve d t he i n c orrect st u d y treat me nt f or t he e ntire 
treat me nt d ur ati o n. 
• T he  F ull  A nal ysis  Set  ( F A S) will  i n cl u de all ra n d o mi ze d s u bjects. S u bjects will  b e 
a nal yz e d acc or di n g  t o t heir ra n d o mi ze d treat me nt gr o u p, re gar dless of  c o m plia nc e 
wit h st u d y treat me nt a d mi nistrati o n a n d a v ail a bilit y of p ost baseli ne d ata.  
• T he  P K  a nal ysis  set will  i ncl u de all ra n d o miz e d s u bjects w h o  recei ve d at least 1  d ose 
of  st u d y treat me nt a n d  w h o  ha ve  a n y  me as ura ble  N BI -1 0 6 5 8 4 6  plas ma  c o nce ntrati o n 
data.  
S u m maries  of  s u bj ect dis p ositi o n,  ra n d o mizati o n b y  st u d y site, a nal ysis  set i ncl usi o n/e xcl usi o n 
stat us, a n d i m p orta nt pr ot oc ol d e viati o ns (I P Ds) will be base d o n all ra n d o mize d s u bje cts.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 5  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
5. 3.    
B aseli ne  Defi niti o n  
F or  effica c y  a n d  safet y a nal ysis  p ur p ose,  u nl ess  ot her wise  s pecifi e d, t h e assess me nts  c oll ect e d  at 
t he ra n d o mi zati o n visit  (i e, Da y 1  [ Visit 2])  pri or  t o d osi n g  will  ser ve as t he baseli ne val u e. If  t he 
ra n d o miz ati o n visit val ue is n ot a vaila ble, t he n t h e last meas ure m e nt c ollecte d pri or t o 
ra n d o miz ati o n will ser ve as baseli ne. 
5. 4.    
Deri ve d  a n d  Tr a nsf or me d  D at a  
C ha n ge fr o m baseli ne will be c alc ulat e d as t he p ost -baseli ne v al ue mi n us t he b aseli ne v al ue; a 
ne gati v e val u e will re pr ese nt a d ecre ase at t he p ost -b aseli ne visit. Perc e nt c ha n g e fr o m baseli ne 
will be c alc ulat e d as (c ha n ge fr o m baseli ne/ b aseli n e val ue × 1 0 0).  If eit her t he baseli ne or 
p ost baseli ne  v al ue  is missi n g,  t he c ha n g e fr o m baseli ne  a n d/ or  perce nt  c h a n ge fr o m b aseli n e  will 
als o be missi n g. If t h e baseli ne val ue is e q ual t o z er o, t he perc e nt c ha n g e fr o m baseli ne will be 
missi n g.  
5. 5.    
St u d y D a y  
St u d y  da y  will  be  calc ul ate d  relati ve t o t h e date  of t h e  first st u d y treat me nt ( St u d y Da y  1) f or 
dates o n or aft er Da y 1:  
St u d y  Da y  = Date  of  I nterest –  Date  of  St u d y  Da y  1  +  1 
St u d y  da y  will be cal c ulate d rel ati v e t o St u d y  Da y 1 f or dates bef ore Da y  1:  
St u d y  Da y  =  Date  of  I nterest –  Dat e  of  St u d y  Da y  1  
5. 6.    
Visit  Wi n d o ws  
St u d y  da y is calc ulat e d rel ati v e t o t h e dat e of t he Da y 1 visit. F or effic ac y data a nal ysis, t he 
n o mi nal  visit  n u m ber  f or eac h visit,  i ncl u di n g sc he d ule d a n d earl y ter mi nati o n/e n d of  st u d y visits 
will be re -ma p pe d b ase d o n t he a ct ual st u d y da y a cc or di n g t o Ta ble 1 . 
T a ble  1:    
A n al ysis  Visit  Wi n d o ws  f or Effic ac y  A n al ysis  
 
 
S c h e d ule d  Visit  
 
T ar get  St u d y  D a y  
A n al ysis  Wi n d o w  
( A n al ysis D a y  R a n ge)  
Baseli ne  
1  
1  
Da y  2 9  
2 9  
2 -4 3  
Da y  5 7  
5 7  
4 4 +  
 
F or  s afet y d at a  a n al ysis,  t he n o mi n al  visit  n u m ber  f or e ac h visit,  i ncl u di n g sc he d ule d, u nsc he d ule d, 
re pe at e d a n d e arl y ter mi n ati o n/e n d of st u d y visits, will be re -m a p pe d t o a n 
a n al ysis visit acc or di n g t o T a ble 2:  A n al ysis Visit Wi n d o ws f or S afet y 
A n al ysis  
. 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 6  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
T a ble  2:    
A n al ysis  Visit  Wi n d o ws  f or S afet y  A n al ysis  
 
 
S c h e d ule d  Visit  
 
T ar get  St u d y  D a y  
A n al ysis  Wi n d o w  
( A n al ysis D a y  R a n ge)  
Baseli ne  
1  
1  pri or  t o first d osi n g  
Da y  1  P ost  Baseli ne  
1  
1  p ost  first d osi n g  
Da y  8 
8  
2 -1 5  
Da y  2 2  
2 2  
1 6 -2 5  
Da y  2 9  
2 9  
2 6 -3 6  
Da y  4 3  
4 3  
3 7 -5 0  
Da y  5 7  
5 7  
5 1 -last d ose  da y  
 
Da y  7 8  
 
Last  d ose  da y + 2 8  
Last  d ose  da y + 1 -last d ose 
da y + 4 2  
Da y  1 0 6    
Last  d ose  da y + 5 6    
last d ose  da y + 4 3 +  
If m ulti ple  meas ure me nts  occ ur  wit hi n  t he sa me visit  wi n d o w  after ma p pi n g,  t he meas ure m e nt  t hat is 
cl osest t o t he tar get st u d y da y will be use d f or t he s u m mar y  ta bles w here o ne o bser vati o n per visit is 
nee de d, u nless ot her wise s pecifie d. W her e t here ar e ties bet wee n t he earlier a n d later o bser vati o n 
wit hi n t he visit wi n d o w, t he earlier o bser vati o n will be use d.  
 
 
5. 7.    
H a n dli n g  of  Missi n g  D at a  
5. 7. 1.  
St art  D ates  f or A d verse E ve nts  
A  treat m e nt e mer g e nt a d verse e v e nt ( T E A E) is a n a d verse e ve nt n ot  prese nt  pri or  t o t he i nitiati o n 
of st u d y dr u g d osi n g or is a n alre a d y prese nt e v e nt t h at w orse ns eit her i n i nt e nsit y or fre q ue n c y 
f oll o wi n g t he i nitiati o n of st u d y dr u g d osi n g. 
I n vesti gat ors will be as ke d t o res p o n d “ Yes” or “ N o” o n t he C R F as t o w het her t he A E starte d 
after t he s u bject t o o k t he first d ose  of  st u d y treat me nt. A n  A E  wit h  a res p o nse of  “ Yes” a n d wit h 
a n o nset dat e o n or bef ore 1 0 da ys after t h e last d ose of st u d y treat me nt will be classifie d as a 
T E A E.  If t he i n vesti g at or’s res p o nse is missi n g, t he n t he tre at m e nt e mer ge nt st at us will b e 
deri ve d base d o n t he A E o nset date a n d ti m e rel ati v e t o t he date a n d ti m e of t he s u bje ct’s first 
d ose of st u d y treat me nt, as f oll o ws: if t h e A E o nset d ate a n d ti m e are u n k n o w n, it will be 
ass u me d t hat t he A E is a T E A E; if t he A E o nset ti m e is u n k n o w n b ut t he A E o nset date is t h e 
sa me dat e as t he first d ose of st u d y treat me nt, it will be ass u me d t hat t he A E is a T E A E.  
A d verse  e ve nts  t h at occ ur  m ore  t ha n 1 0  da ys  aft er t he last d ose  will  n ot  be  c o nsi dere d  tre at m e nt 
e mer ge nt a n d will be ta b ulat e d b y tre at m e nt gr o u p se paratel y.  
Missi n g  a n d i nc o m plet e (“ partial”) d ates  f or A Es  will  be  i m p ut e d f or t he p ur p ose  of  esti m ati n g 
t he ti me of t h e e ve nt or me di cati o n usa ge i n r elati o ns hi p t o st u d y tre at m e nt. A n y dat a listi n gs 
will dis pla y t he ori gi nal d ates as re p ort e d i n t h e dat a base.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 7  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
T he  missi n g  a n d i nc o m plet e (“ partial”) dates  f or A Es  will be  i m p ut e d usi n g  t h e f oll o wi n g 
al g orit h m f or start dates:  
• missi n g da y: if t he sa m e m o nt h a n d year as t h e first d ose of ra n d o miz e d st u d y 
treat me nt, i m p ute t he first d ose  date  of  ra n d o mize d st u d y treat me nt; ot her wise  i m p ut e 
t he 1st of t h e m o nt h.  
• missi n g da y a n d m o nt h: if t he sa m e year as t h e first d ose of ra n d o miz e d st u d y 
treat me nt, i m p ute t h e first d ose  d ate  of  ra n d o mize d st u d y treat me nt; ot her wise  i m p ut e 
1 st Ja n uar y. 
T here  will be  n o i m p utati o n  f or A E  st o p dates.  
If a n y of  t he a b o ve i m p utati o ns res ult i n a start date  t hat is later t ha n a n e xisti n g  ( n ot i m p ute d) 
st o p date f or t h e e ve nt, t he start dat e will b e i m p ute d as t he st o p dat e. 
 
 
5. 7. 2.  
St art  a n d  St o p  D ates  f or Me dic ati o ns  
T o  ha n dl e  missi n g/ partial  dates,  t he f oll o wi n g al g orit h m will  be  e m pl o y e d  t o esti mat e t h e ti me of 
me dic ati o n usa g e relati ve t o st u d y tre at m e nt. F or start date:  
• missi n g  da y:  i m p ut e t h e 1 st of  t he m o nt h  u nless  t he sa me m o nt h  a n d y ear  as t he st u d y 
treat me nt, ot her wise i m p ute t he first d ose date of st u d y dr u g; 
• missi n g  da y  a n d m o nt h:  i m p ute 1 st Ja n u ar y, u nl ess  t he sa me ye ar as t he st u d y treat me nt, 
ot her wise i m p ute t h e first d ose date of st u d y dr u g. 
F or  st o p date:  
• missi n g  da y:  i m p ute t he last da y  of  t he m o nt h  u nless  t he sa m e m o nt h  a n d year  as t he 
st u d y treat me nt, ot her wise i m p ute t he last d ose d ate of st u d y dr u g; 
• missi n g  da y  a n d  m o nt h:  i m p ute 3 1 st De ce m b er,  u nl ess  t he sa m e year as t he st u d y 
treat me nt, ot her wise i m p ute t he last d ose d ate of st u d y dr u g. 
If a n y of  t he a b o ve i m p utati o ns res ult i n a start date  t hat is later t ha n a n e xisti n g  ( n ot i m p ute d) 
st o p date f or t h e e ve nt, t he start dat e will b e i m p ute d as t he st o p dat e. If a n y of t he a b o ve 
i m p utati o ns res ult i n a st o p date t h at is e arlier t ha n a n e xisti n g ( n ot i m p ut e d) start d ate f or t he 
e ve nt, t h e st o p dat e will b e i m p ute d as t he st art date.  
 
 
5. 8.    
C o di n g  Dicti o n aries  
Me dical  hist or y  a n d A Es  will  be  c o de d usi n g  t he Me dical  Dicti o nar y  f or R e g ulat or y  Acti vities 
( Me d D R A). Pri or a n d c o nc o mit a nt m e dicati o ns will be c o de d usi n g t h e W orl d Healt h 
Or ga nizati o n ( W H O) Dr u g Dicti o nar y.  
5. 9.    
I m p act of  C O VI D -1 9  
D ue t o t he gl o b al C or o na vir us Disease 2 0 1 9 ( C O VI D -1 9) pa n de mic a n d i n ali g n me nt wit h 
g ui da nce  p ut  f ort h b y  t he U S  F o o d  a n d Dr u g  A d mi nistrati o n  ( F D A; C o n d uct  of  Cli nical  Trials  of  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 8  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
Me dical Pr o d ucts D uri n g t he C O VI D -1 9 P u blic Healt h E mer g e nc y [ Marc h 2 0 2 0, u p date d 
Ja n uar y 2 0 2 1]), Healt h C a na da ( Ma na g e me nt of Cli nical Trials D uri n g t he C O VI D -1 9  
Pa n de mic: N otic e t o Cli nic al Trial S p o ns ors [ Ma y 2 0 2 1]), a n d E ur o pea n Me dici nes 
A ge nc y( E M A;  P oi nts t o C o nsi der o n I m plic ati o ns of C or o na vir us Disease [ C O VI D -1 9] o n 
Met h o d ol o gic al  As pects  of  O n g oi n g  Cli nical  Trials  [ Marc h 2 0 2 0]),  t he f oll o wi n g s u m mari es will 
be c o n d uct e d t o e v al uat e t he i m pa ct of t h e C O VI D -1 9 pa n de mi c, i ncl u di n g b ut n ot li mit e d t o:  
• A  listi n g of  all s u bjects affecte d  b y  t he C O VI D -1 9  pa n de mic  o ver  t he c o urse of  st u d y 
partici pati o n will b e ge nerate d. T h e listi n g will i de ntif y s u bjects t h at e x p erie nc e o ne 
or m ore of t he f oll o wi n g sit u ati o ns d ue t o t he C O VI D -1 9 pa n de mic ( a d diti o nal 
sit uati o ns m a y be i n cl u de d): 
− Disc o nti n ue d  st u d y tre at me nt or wit h dre w  fr o m st u d y 
− Pres u me d  or  c o nfir m e d  dia g n osis  of  C O VI D -1 9  
− Ha d  at le ast o ne  C O VI D -1 9  pa n de mic -rel ate d maj or  pr ot oc ol  de viati o n  
− Misse d  at least o ne st u d y  visit or assess me nt 
− Ha d  at le ast o ne assess me nt c olle cte d i n  a n o n -sta n dar d wa y (e g, re m otel y) 
− Ha d  at least o ne st u d y  tre at m e nt i nterr u pti o n 
• A  ta ble a n d/ or listi n g will  s u m m arize t he C O VI D -1 9  pa n de mi c -rel ate d r eas o ns f or 
treat me nt a n d st u d y disc o nti n uati o n. 
• A  ta ble a n d/ or listi n g will  s u m m arize t he C O VI D -1 9  pa n de mi c -rel ate d maj or  pr ot oc ol 
de viati o ns.  
• A  ta ble a n d/ or  listi n g will  s u m mari ze assess me nts  aff ecte d  b y  t h e C O VI D -1 9 
pa n de mi c (e. g., missi n g, parti al, c ollecte d re m otel y).  
T he  a b o ve  listi n gs m a y  be  o mitt e d  if it is k n o w n  t here was  n o  i m pact of  t he C O VI D -1 9 
pa n de mi c o n t he st u d y c o n d uct.  
A d verse  e ve nts  of  dia g n ose d  or  pres u m e d  C O VI D -1 9  i nfecti o ns will  be  i ncl u de d i n t h e 
sta n dar d s u m maries of T E A Es a n d S A Es.  
T he  i m p act of  t h e C O VI D -1 9  pa n de mic  o n  t he pri mar y  effica c y  e n d p oi nt  will  be 
e val uate d as descri b e d i n Secti o n 7. 4. 2 . 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
1 9  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
6.    
S T U D Y  P O P U L A TI O N  
6. 1.    
Dis p ositi o n  
T he  s u m mar y of s u bj ect  e nr oll me nt a n d dis p ositi o n will i ncl u de: 
• T he  t ot al n u m ber of  s u bjects w h o  pr o vi de d i nf or me d  c o nse nt a n d were  scree ne d 
• T he  f oll o wi n g cate g ori es  will  be  pr ese nte d  b y  tr eat m e nt gr o u p  a n d o ver all.  T he 
n u m ber of s u bjects ra n d o mi ze d will ser v e as t he d e n o mi nat or t o calc ul ate 
perce nta ges.  
− Ra n d o miz e d  s u bjects 
− Ra n d o miz e d  b ut  n ot  tre ate d s u bjects 
− C o m plet e d st u d y  treat me nt 
− Disc o nti n ue d  st u d y treat me nt pr e mat urel y, i n cl u di n g reas o ns f or disc o nti n uati o n.  
− C o m plet e d  st u d y 
− Disc o nti n ue d  st u d y, i n cl u di n g r eas o ns f or disc o nti n uati o n.  
A  se parate s u m m ar y of  ra n d o mizati o n b y  st u d y site will  be  prese nte d.  T his  s u m mar y will 
dis pla y t he n u m ber of s u bje cts ra n d o mize d t o eac h tr eat m e nt gr o u p b y sit e. 
6. 2.    
S u m m ar y  of  A n al ysis  Sets  
A  s u m mar y of  t he n u m ber  a n d p erce nt a ge  of  s u bje cts i ncl u d e d i n ea c h of  t he f oll o wi n g a nal ysis 
sets will be pr o vi d e d f or eac h treat me nt gr o u p: 
• F ull  A nal ysis  Set  
• Safet y  A nal ysis  Set  
• P K  A nal ysis  Set  
T he  n u m ber  a n d per ce nta g e  of  s u bj ects e xcl u de d  fr o m ea c h a nal ysis  set b y  re as o n f or e x cl usi o n 
will als o be pr o vi de d.  
6. 3.    
Pr ot oc ol  De vi ati o ns  
Pr ot oc ol  de vi ati o ns  descri be d  i n t he st u d y-s pecific Pr ot oc ol  De vi ati o n  Pla n  will  be  e nt ere d i nt o 
t he cli nic al trial ma na ge me nt s yste m. Pri or t o data base l oc k, all maj or pr ot oc ol de viati o ns t hat 
ha ve bee n e ntere d i nt o t h e cli nic al trial ma na g e me nt s yste m will be e x p orte d t o a file a n d 
i nte grate d i nt o t he st u d y d ata. 
I m p orta nt pr ot oc ol d e viati o ns (I P Ds) are pr ot oc ol de viati o ns t h at mi g ht si g nifica ntl y aff ect t h e 
c o m plete ness, ac c urac y a n d/ or relia bilit y of t he st u d y data or t h at mi g ht si g nifica ntl y affe ct a 
s u bject’s ri g hts, safet y, or  well -bei n g.  A n  assess me nt of  I P Ds will  be  perf or me d  pri or  t o data b ase 
l oc k a n d u n bli n di n g of t h e ra n d o mize d tr eat me nt assi g n me nts. T he st u d y tea m will r e vie w a 
listi n g of all pr ot o c ol de viati o ns re p orte d i n t he st u d y data base a n d deter mi ne w hi c h de vi ati o ns 
are I P Ds.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 0  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
A  s u m mar y of  t he n u m ber  a n d perc e nta g e  of  s u bjects wit h I P Ds  b y  de viati o n  c ate g or y  a n d 
treat me nt gr o u p will be pr o vi de d. 
All  maj or  pr ot o c ol  d e viati o ns  will  be  prese nte d  i n a d ata  listi n g a n d a n y t hat ar e cl assifie d  as 
I P Ds will be fla g ge d i n t he listi n g. 
T he  C O VI D -1 9  pa n de mic -relat e d maj or  pr ot oc ol  de viati o ns  will  be  s u m mariz e d a n d liste d. 
6. 4.    
De m o gr a p hic  a n d  B aseli ne  C h ar acteristics  
De m o gra p hic  a n d baseli ne  c hara cteristics  data  will  b e  s u m mari ze d usi n g  descri pti ve  statistics f or 
c o nti n u o us vari a bles, a n d fre q u e nc y c o u nts a n d perc e nta ges f or c ate g ori cal v aria bles. Res ults 
will be prese nte d b y tr eat m e nt gr o u p a n d o v erall bas e d o n t he F A S.  
De m o gra p hics  i ncl u de: 
• A ge  ( years) 
• A ge  gr o u ps  (< 3 5  ye ars,  ≥3 5  t o < 5 0  years,  a n d ≥5 0  years ) 
• Se x  
• Et h nicit y  
• Race  
Baseli ne  s u bj ect c har act eristi cs  i ncl u de: 
• Hei g ht  ( meas ure d at scree ni n g, c m) 
• Wei g ht  ( prese nt e d i n kil o gra ms)  
• B o d y  mass  i n de x ( B MI; k g/ m 2) 
• H A M -D 1 7  sc ore c o nti n u o us  a n d cate g oric al (re missi o n [ H A M-D 1 7  ≤7],  mil d  ill ness 
( H A M-D 1 7  fr o m 8  t o 1 8),  a n d m o derate  t o se vere ill ness [ H A M D 1 7  ≥1 9])  
• S H A P S  sc ore 
• D A R S  sc ore 
• M A D R S  sc ore 
• C GI -S  sc ore 
• Use  of  c o nc o mit a nt a nti de pressa nt  m e dic ati o n(s)  ( yes, n o)  
• Use  of  selecti v e ser ot o ni n re u pt a ke i n hi bit or ( S S RI) ( yes, n o)  
• Use  of  b u pr o pi o n  ( yes, n o)  
 
 
6. 5.    
Me dic al  Hist or y  
Me dical hist or y dat a will b e s u m marize d descri pti v el y f or t he F A S, b y tre at m e nt gr o u p a n d 
o verall. Me dical hist or y data will b e c o de d usi n g Me d D R A. T he me dic al hist or y d ata will be 
s u m mariz e d wit h  fre q ue n cies a n d  perc e nta g es  of  s u bjects wit h  at l east o n e  me dic al  hist or y  ite m, 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 1  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
a n d s u bject fr e q ue nci es a n d perc e nta g es acc or di n g t o t he S yste m Or ga n Cl ass ( S O C) a n d 
Preferre d  T er m  ( P T) le vels. T he  t a ble will  be  s ort e d al p ha beticall y  b y  S O C  a n d t he n, wit hi n  a 
S O C, b y P T.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 2  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
7.    
E F FI C A C Y  
T he effi cac y e n d p oi nts a n d pl a n ne d a n al ysis met h o ds are descri be d bel o w. U nless ot her wise 
s pecifie d, t he F ull  A nal ysis  Set  will  be  use d  f or t h e pri mar y  a nal yses  of  all effic ac y  e n d p oi nts. 
Descri pti ve st atistics will b e prese nte d b y treat me nt gr o u p acc or di n g t o t he st u d y visit.  
C o nti n u o us sec o n dar y efficac y e n d p oi nts will be a n al yze d usi n g a si mil ar A N C O V A m o del as 
descri be d  f or t he pri mar y  e n d p oi nt;  cate g ori cal  a n d or di nal  se c o n dar y e n d p oi nts  will  be  a n al yz e d 
usi n g t he C oc hra n -Ma ntel -Hae nsz el ( C M H) C hi -s q uare test a dj uste d f or ill ness se verit y 
(stratifi cati o n fact or) a n d use of c o nc o mit a nt a nti de pressa nt me di cati o n(s) at ti me of 
ra n d o mizati o n. 
7. 1.    
M ulti ple  C o m p aris o ns  a n d  M ulti plicit y  A dj ust me nt  
P -val ues  will n ot  be  a dj uste d  f or m ulti plicit y  a n d s h o ul d be  c o nsi dere d  n o mi nal p -val ues.  
7. 2.    
I nteri m A n al ysis  
T here  is n o  pla n ne d  i nt eri m a n al ysis  i n t his st u d y. 
7. 3.    
St atistic al  H y p ot hesis  a n d  Esti m a n d  
7. 3. 1.  
St atistic al  H y p ot hesis  
T he  n ull  h y p ot h esis  f or t he pri mar y  e n d p oi nt is t hat t he mea n  c ha n g e i n D A R S  fr o m baseli ne  t o 
Da y 5 7 i n t he pl ace b o gr o u p is greater t ha n or e q u al t o t hat i n t he N BI -1 0 6 5 8 4 6 gr o u p. T he 
alter n ati v e h y p ot hesis  is t hat t he m ea n c ha n g e i n D A R S fr o m baseli ne t o Da y 5 7 i n t h e  pla ce b o 
gr o u p is less t ha n t hat i n t h e N BI -1 0 6 5 8 4 6 gr o u p.  
T he  n ull  h y p ot h esis  t o be  t este d is: 
H 0: µ1 ≥ µ 2  
T he  alter nati ve h y p ot hesis  is: 
H 1: µ 1  <  µ 2  
w here  µ 1  is t he mea n  c h a n ge i n D A R S  fr o m baseli ne  t o Da y  5 7  i n t he plac e b o  gr o u p,  a n d µ 2  is 
t he me a n c ha n g e i n D A R S fr o m baseli ne t o Da y 5 7 i n t he N BI-1 0 6 5 8 4 6 gr o u p.  
7. 3. 2.  
Esti m a n d  
C o nsiste nt  wit h  t he I nter nati o nal C o u ncil  f or Har m o nizati o n  of  Te c h nic al  R e q uire m e nts  f or 
P har mace utic als f or H u ma n Use (I C H) E 9 A d de n d u m, t he 4 attri b utes of t he esti m a n d i n 
c o nj u ncti o n wit h t h e pri m ar y e n d p oi nt are:  
• P o p ulati o n:  
− S u bjects  wit h  a dia g n osis  of  M D D  w h o  ha ve  bee n  tre ate d wit h  a nti de pressa nt 
me dic ati o n(s) a n d w h o c o nti n ue t o h a ve a n h e d o nia as defi ne d b y t he st u d y 
i ncl usi o n/ e xcl usi o n crit eria ( Secti o n 5 of t h e pr ot oc ol). 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 3  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
• E n d p oi nts:  
−  C ha n ge fr o m  baseli ne  i n t h e D A R S  sc ore at Da y  5 7.  
• I nterc urre nt e ve nts: 
− S u bjects  w h o disc o nti n ue  st u d y tre at m e nt pr e mat urel y or ma ke c ha n g es  t o t heir 
bac k gr o u n d  me dicati o ns  will  c o nti n u e t o be  f oll o we d per  pr ot oc ol,  t heref or e t he 
treat me nt p olic y str ate g y will be use d t o a d dress i nterc urre nt e v e nts. 
• S u m mar y  meas ures:  
− Differe nce  of  mea ns  i n c ha n ge fr o m b aseli n e  i n t he D A R S  sc ore at Da y  5 7 
bet wee n N BI -1 0 6 5 8 4 6 a n d pl ace b o.  
All  a vaila bl e assess me nts  u p  t o Da y  5 7  will  be  use d,  re gar dless of  occ urre n ce  of  i nterc urre nt 
e ve nts. 
7. 4.    
Pri m ar y  Effic ac y  E n d p oi nt  
T he D A R S is a d y na mic sc ale t hat meas ures desire, m oti vati o n, eff ort a n d c o ns u m mat or y 
pleas ure a cr oss he d o nic d o mai ns. T he D A R S is a self -re p ort q uesti o n n aire t hat m eas ures 
a n he d o nia acr oss 4 d o mai ns: h o b bies/ pasti mes, f o o d/ dri n ks, s ocial a cti viti es, a n d se ns or y 
e x perie n ces.  T h e  D A R S  is rate d o n  a fi v e-p oi nt  Li kert  scal e fr o m 0  ( n ot at all) t o 4  ( ver y m u c h), 
hi g her  val ues  i n dic ati n g less a n he d o nia.  All  it e ms are s u m me d u p  t o a t ot al sc ore i n t he r a n ge of 
0 t o 6 8.  
Descri pti ve  statistics will b e  prese nte d  b y  tre at m e nt gr o u p  f or t he D A R S  t otal sc ore o bser ve d 
val ues,  a n d  c ha n g es  fr o m b aseli ne  at  ea c h visit.  T he  pri mar y  e n d p oi nt will  be  a n al yze d  usi n g 
t he F ull A nal ysis Set b y c o m pari n g N BI-1 0 6 5 8 4 6 a n d place b o usi n g a n A nal ysis of 
C o varia nc e ( A N C O V A) m o del. T he m o del will i n cl u de treat me nt gr o u p, ill ness se verit y 
(stratifi cati o n fact or), use of c o nc o mita nt a nti de press a nt me dicati o n(s) at ti m e of 
ra n d o miz ati o n ([ie, yes vs n o], c o vari ate), a n d baseli ne D A R S sc ore (c o variate). 
 
S u bjects w h o are missi n g D A R S sc ore at Da y 5 7 will ha ve t h eir data i m p ute d t hr o u g h a 
m ulti ple i m p utati o n ( MI) pr oce d ure. Missi n g data will be i m p ute d f or s u bj ects i n t he N BI 
1 0 6 5 8 4 6 treat me nt gr o u p usi n g r etrie v e d dat a (i.e., o bser ve d data fr o m s u bjects w h o 
disc o nti n ue d  st u d y dr u g)  i n t hat sa m e tre at m e nt gr o u p,  pr o vi de d  t h ere is s uffici e nt r etrie v e d 
data. Ot her wise, missi n g dat a will b e i m p ute d usi n g o bser ve d data fr o m s u bjects i n t he 
place b o treat me nt gr o u p. F or s u bje cts i n t h e pla ce b o treat me nt gr o u p, missi n g dat a will b e 
i m p ute d usi n g o bser v e d dat a fr o m s u bjects i n t he pla ce b o tre at m e nt gr o u p. T he d etails of 
i m p utati o n m et h o d ar e descri be d b el o w:  
 
Ste p  1:  F or  s u bjects wit h  i nt er mitte nt missi n g  val ues,  a m o n ot o n e  missi n g ness  patter n  will  be 
ge nerat e d b y i m p uti n g f or t he i nter mitte nt missi n g v al ues usi n g t he Mar k o v C h ai n M o nte 
Carl o ( M C M C) met h o d, w hic h ass u mes a m ulti variate n or mal distri b uti o n a m o n g all 
varia bl es i ncl u d e d i n t h e i m p utati o n m o del. T he MI pr oce d ure usi n g S A S ® s oft ware will be 
e m pl o ye d f or  t his p ur p ose  a n d t his  first MI ste p is pl a n ne d t o be r e peat e d 1 0 0 ti mes, cre ati n g 
se veral differe nt  datasets wit h  a m o n ot o ne  missi n g  d ata  str uct ure. T he i m p ut ati o n is b ase d  o n 
t he missi n g at ra n d o m ( M A R) ass u m pti o n, i.e., t h e missi n g data are ass u me d t o f oll o w t h e 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 4  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
sa me m o del  as  t he ot her  s u bjects i n t heir res pecti ve treat m e nt ar m. 
 
T he  f oll o wi n g S A S ®  s oft ware c o de will  be  use d  t o g e nerat e  t he m o n ot o n e  missi n g  data 
patter n:  
 
 
 
 
 
Ste p 2: T he r e mai ni n g missi n g data will be i m p ut e d usi n g a met h o d f or m o n ot o ne 
missi n g ness base d o n missi n g n ot at ra n d o m ass u m pti o n ( M N A R). T he traje ct ories of t h e 
s u bjects i n t h e N BI-1 0 6 5 8 4 6 treat me nt gr o u p are ass u me d t o f oll o w t he retrie ve d s u bjects 
fr o m t he sa m e gr o u p after t he disc o nti n uati o n, pr o vi de d t here is s ufficie nt retri e ve d data (t h e 
rati o of retrie v e d data p oi nts t o t h e missi n g data p oi nts is greater t ha n 9 t o 1[ Lee, H u ber, 
2 0 2 1]). Ot her wise, t he tr aject ories of t h e s u bjects are ass u me d t o f oll o w t h e pla ce b o gr o u p 
after t h e disc o nti n uati o n (i.e., c o ntr ol gr o u p -base d ass u m pti o n).  T h us, f or ea c h create d 
dataset  wit h  a  m o n ot o ne  missi n g  dat a  patter n,  t h e MI  pr oce d ure  usi n g  S A S ®  s oft ware will  be 
e m pl o ye d t o i m p ute missi n g D A R S t otal sc ore val ues base d o n a se q ue nti al pr oce d ur e 
reflecti n g t h e m o n ot o n e missi n g data patter n. S u bje cts wit h t he first missi n g val u e occ urri n g 
at Da y 2 9 will h a ve t h eir missi n g Da y 2 9 val ue re pla ce d b y a n i m p ute d v al ue fr o m a 
re gressi o n m o del wit h tre at me nt gr o u p, ill ness se verit y, use of c o nc o mita nt a nti de pressa nt 
me dic ati o n(s) at ti me of ra n d o mizati o n, a n d b aseli n e D A R S t otal sc ore as e x pl a nat or y 
varia bl es. I n t he ne xt ste p, s u bjects wit h t heir Da y 5 7 val ue missi n g will ha v e t heir missi n g 
Da y 5 7 val ue re place d b y a n i m p ute d val ue fr o m a re gressi o n m o del wit h treat me nt gr o u p, 
t he baseli ne val ue, a n d t h e Da y 2 9 val u e as e x pl a nat or y varia bl es. 
 
A n  e xa m pl e of  S A S ®  s oft ware c o de  is pr o vi de d  bel o w  t o perf or m  t he i m p ut ati o n wit h  t he 
M N A R ass u m pti o n:  
 
 
 
 
 
 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 5  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
 
 
 
Ste p 3: T he i m p ut e d dat asets ge nerate d wit h t he a p pr oac h descri b e d a b o ve c o ntai n o nl y 
n o n‑ m issi n g val ues a n d are use d as i n p ut i n t he m o d el f or t he pri mar y a nal ysis aft er c ha n g e 
fr o m baseli n e val u es ha ve bee n cal c ulate d at Da ys 2 9 a n d 5 7. A nal ysis of c o vari a nce m o d el 
descri be d f or t h e pri mar y a nal ysis will t h us be r u n o n eac h of t h e 1 0 0 ge nerate d i m p ute d 
datasets  a n d  t he differ e nce  bet we e n  t h e tr eat me nt gr o u ps  at Da y  5 7  will  be  esti mate d.  Fi n all y, 
t he MI A N A L Y Z E pr oce d ure usi n g S A S ® s oft ware will be a p plie d t o c o m bi ne t h e res ults 
fr o m t hese a n al yses t o deri ve a n o ver all esti m ate of t he treat me nt differe n ce at Da y 5 7. I n 
a d diti o n t o t he esti m ates, c orres p o n di n g o ne si de d 9 0 % CIs a n d p -val ues will b e calc ulate d.  
A n  e xa m ple of  S A S ®  s oft ware c o de is pr o vi de d bel o w:  
 
 
 
 
 
C o m paris o n of N BI -1 0 6 5 8 4 6 vs. place b o at ea c h visit will be p erf or me d b y c o nstr ucti n g 
li near c o ntrasts ( or e q ui vale nt pr o gra m mi n g c o d e) f or differe nces bet wee n tr eat me nt gr o u p 
least-s q uares ( L S) m ea ns. T he L S m ea ns a n d diff ere nces i n L S me a ns will be pr ese nte d i n 
s u m mar y ta bles, al o n g wit h t he ass ociate d 9 0 % c o nfi de nce i nter vals.  T he tre at m e nt 
differe nc e  f or t he pri mar y  e n d p oi nt ( Da y 5 7)  f or N BI -1 0 6 5 8 4 6  vs  plac e b o  will  b e  c o nsi d ere d 
statisti call y si g nifi ca nt if t he o n e-si de d n o mi n al p-val ue is < 0. 1.  N o mi nal p -val u es f or 
c o m pari n g treat me nt gr o u ps at t he i n di vi d u al p ost bas eli ne visits will als o be re p orte d i n t he 
s u m mar y ta bles. 
A n  e xa m ple of t he  S A S ®  s oft ware c o de f or t h e A N C O V A  m o del is  pr o vi de d bel o w:  
 
 
 
 
 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 6  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
 
 
 
T o  c o n vert t h e t w o-si de d p -val u es  i nt o o ne -si de d p -v al ue,  if t he tre at m e nt differe n ce  f or N BI - 
1 0 6 5 8 4 6 vs place b o is i n t he p ositi ve dir ecti o n, t he o ne -si de d p-val u e e q uals half of t he t w o - 
si de d p-val ue; if t h e treat me nt differ e nce f or N BI -1 0 6 5 8 4 6 vs place b o is i n t he ne g ati v e 
directi o n, t he o n e -si de d p-val u e e q uals o ne mi n us half of t he t w o - si de d p-v al ue.  
 
S u b gr o u p a nal yses f or t he pri mar y effi cac y e n d p oi nt will be perf or me d f or fact ors defi ne d i n 
Secti o n  7. 6. 7  usi n g  a n A N C O V A  m o del,  w hic h  will  be  si milar t o t he m o del  descri be d  a b o ve f or t he 
pri mar y e n d p oi nt a nal ysis, i ncl u di n g a d diti o n al fi x e d fact ors f or t he s u b gr o u p vari a ble a n d t he 
i ntera cti o n b et wee n t h e tre at m e nt gr o u p a n d s u b gr o u p varia bl e. N o mi nal t w o -si de d p-val ues f or 
c o m pari n g treat me nt gr o u ps a n d t he ass ociate d 9 5 % c o nfi de nce i nter v als will be re p orte d i n  
s u m mar y ta bles a n d a f orest pl ot, a n d p-val ues f or t he i nteracti o n ter m bet wee n tre at me nt gr o u ps a n d 
eac h s u b gr o u p varia bl e will be prese nte d. T his st u d y was n ot desi g ne d t o d ete ct tre at m e nt 
differe nc es wit h hi g h statisti cal p o wer wit hi n s u b gr o u ps. N o f or mal statistical testi n g will b e 
c o n d ucte d f or s u b gr o u p a nal yses; p -val u es are n o mi nal a n d i nte n de d t o be i nter pret e d i n a 
descri pti v e ma n n er.  
7. 4. 1.  
Se nsiti vit y  A n al ysis  of  Pri m ar y  Effi c ac y  V ari a ble  
T he  f oll o wi n g se nsiti vit y a n al ysis  will  be  p erf or me d  f or t he pri mar y  e n d p oi nt t o e x pl ore  t he 
r o b ust ness of i nfere nces fr o m t h e mai n esti mat or: 
• Ti p pi n g  p oi nt  a nal ysis  ( M N A R): T he  ti p pi n g p oi nt  ass u m pti o n  will  be  use d,  i.e., after 
t he first visit wit h missi n g data, t he tr aje ct ories of t h e s u bjects i n t he N BI-1 0 6 5 8 4 6 
gr o u p are ass u me d t o b e w orse b y a n a m o u nt of d elt a. After t he MI, as defi n e d 
pre vi o usl y, a n a m o u nt of delta will be a d d e d t o e ac h i m p ute d v al ue at Da y 5 7 i n t he 
N BI -1 0 6 5 8 4 6 gr o u p. S uccessi vel y hars her deltas will be i m p ose d o n t he i m p ute d 
val ues i n t h e N BI -1 0 6 5 8 4 6 gr o u p, starti n g wit h a D A R S t otal sc ore de crease 
( w orse ni n g) of -1. T he delta is f urt her d ecre ase d i n t he ste ps of 1 (ie, -1, -2, -3, …) 
u ntil t h e statistic al si g nifica n ce is l ost, ie, u ntil t he p -val ue be c o mes ≥0. 1. F or t h e 
c o ntr ol gr o u p, t h e MI usi n g M A R ass u m pti o n will b e use d.  
7. 4. 2.  
S u p ple me nt ar y  A n al ysis  of  Pri m ar y  Effic a c y  V ari a ble  
T he  f oll o wi n g s u p ple m e ntar y a nal yses  will b e  perf or me d f or t he  pri mar y  effic ac y  e n d p oi nt: 
• C o m plet ers  a nal ysis  usi n g  all s u bj ects i n t h e Efficac y  A nal ysis  Set  wit h  n o n -missi n g 
data f or t h e pri m ar y e n d p oi nt at t h e Da y 5 7 visit  
• C O VI D -1 9  i m pact a n al ysis  e xcl u di n g  all s u bj ects w h o  disc o nti n ue d  st u d y tr eat me nt 
d osi n g pre mat ur el y d ue t o C O VI D -1 9.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 7  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
7. 5.    
Sec o n d ar y  Effic ac y  E n d p oi nts  
7. 5. 1.  
 C h a n ge  i n t ot al M A D R S  sc ore fr o m b aseli ne  t o D a y  5 7  i n s u bjects wit h 
m o der ate or hi g her se v erit y de pressi o n  
T he  M A D R S  is a 1 0 -ite m dia g n ostic  q u esti o n naire  t h at ps yc hi atrists  use  t o meas ure  t he se verit y 
of de pressi ve e pis o des i n s u bj ects wit h m o o d dis or ders. Hi g her M A D R S sc ores i n dicat e m ore 
se vere de pressi o n, a n d e ac h ite m yiel ds a sc or e of 0 t o 6. 
 
T he M A D R S t otal sc ore will be c alc ul ate d as t he s u m of t he 1 0 i n di vi d ual it e m sc ores, w hic h 
ra n ges fr o m 0  t o 6 0.  If m ore  t ha n t w o i n di vi d ual ite ms are missi n g,  t he M A D R S  t otal sc ore will 
n ot be calc ul ate d a n d will be left as missi n g. If less t ha n or e q ual t o t w o i n di vi d ual ite m sc ores 
are missi n g, t h e missi n g ite m sc or es will be i m p ut e d b y t he me a n of all ot her a v ail a ble ite m 
sc ores, or t he ma xi m u m p ossi bl e val u es f or t he missi n g res p o nses, w hic he ver is s maller, t o 
calc ulat e t he M A D R S t otal sc ore.  
Descri pti ve  st atistics will  be  prese nt e d  b y  treat me nt gr o u p  f or o bser ve d  t otal M A D R S  sc ore, a n d 
c ha n ges fr o m baseli ne at ea c h visit will be pr ese nte d b y treat me nt gr o u p f or s u bj ects wit h 
m o derat e or hi g her se verit y  de pressi o n, w hic h is defi ne d as baseli n e H A M -D 1 7 sc ore ≥1 9.  T he 
c ha n ges fr o m baseli ne t o Da y  5 7 will be a n al yz e d usi n g A N C O V A.  T he A N C O V A m o del will 
be si mil ar t o t h e m o del descri be d a b o ve f or t h e pri m ar y e n d p oi nt a nal ysis.  
7. 5. 2.  
C h a n ge  i n C GI-S  sc ore fr o m b aseli ne  t o D a y  5 7  
T he  Cli ni cal Gl o bal I m pressi o n - Se verit y  ( C GI-S) uses  a 7 -p oi nt Li kert scale t o rat e t he  se verit y 
of t he s u bject’s ill n ess at t he ti m e of assess me nt, rel ati ve t o t he cli ni cia n’s past e x perie n ce wit h 
s u bjects w h o  ha v e  t he sa me dia g n osis.  C o nsi deri n g  t otal cli nical e x p erie n ce,  a s u bject is assesse d 
o n se verit y of m e ntal ill ness at t h e ti me of rati n g as 1 = n or mal, n ot at all ill; 2 = b or d erli n e 
me ntall y ill; 3 = mil dl y ill; 4 = m o d erat el y ill; 5 = mar ke dl y ill; 6 =se verel y ill; a n d 7 = e xtre mel y ill.  
N u m ber  a n d p erce nta ge  of  s u bj ects b y  C GI -S  cate g ories  will  be  s u m mari ze d b y  tre at m e nt gr o u p 
a n d visit. I n a d diti o n, t he s hift ta bl e f or C GI -S cate g ories fr o m baseli ne t o Da y 5 7 will be 
prese nte d.  
7. 6.    
Ot her  Effic ac y  E n d p oi nts  
7. 6. 1.  
 
 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 8  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
7. 6. 2.  
 
 
7. 6. 3.  
 
 
7. 6. 4.  
 
 
7. 6. 5.  
 
 
7. 6. 6.  
 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
2 9  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
 
7. 6. 7.  
E x a mi n ati o n  of  s u b gr o u ps 
T he  f oll o wi n g s u b gr o u ps will be  use d  t o e xa mi ne c o nsiste nc y  of  effect f or t h e pri mar y  effi cac y 
e n d p oi nt: 
• De m o gra p hics  ( a ge gr o u ps  [< 3 5  ye ars,  ≥3 5  t o < 5 0  years,  a n d ≥5 0  years ], se x, a n d race) 
• Baseli ne H A M -D 1 7 sc ore  ( ≤ 7 vs. 8  t o 1 8 vs.  ≥1 9 ) 
• Baseli ne  H A M -D 1 7  sc ore ( < 2 2 vs.  ≥2 2 ) 
• Baseli ne  t otal M A D R S  sc ore ( ≤ 2 3 vs.  2 4  t o 2 7 vs. ≥2 8)  
• Baseli ne  M A D R S Ite m  8 sc ore  ( ≤3 vs.  ≥4)  
• Baseli ne D A R S  sc ore ( < 3 3t h vs. 3 3t h -6 6t h  vs.  > 6 6t h ce ntile) 
• Baseli ne  S H A P S  sc ore ( < 4 1 vs. ≥4 1 ) 
• Use  of  a nti de pressa nts  at b aseli n e ( Yes vs.  N o)  
• Use  of  selecti v e ser ot o ni n re u pta k e i n hi bit or ( S S RI) ( yes, n o)  
• Use  of  b u pr o pi o n  ( yes, n o)  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 0  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
8.    
P H A R M A C O KI N E TI C S  
T he  P K  e n d p oi nt  is pl as ma  c o nce ntrati o ns  f or N BI -1 0 6 5 8 4 6  after a  si n gle d ose  a n d  at  stea d y 
state. 
8. 1.    
C o nce ntr ati o ns  of  N BI -1 0 6 5 8 4 6  
T he plas m a c o nc e ntrati o ns of N BI -1 0 6 5 8 4 6 a n d met a b olit es, if a p pr o pri ate will be s u m mariz e d 
wit h descri pti ve statisti cs, w hic h will i ncl u d e t he c o efficie nt of vari ati o n ( C V [ %]), ge o m etri c 
mea n,  a n d ge o metric  C V  ( %) i n a d diti o n  t o t he d escri pti ve  statistics descri be d  i n Secti o n  5. 1, b y 
sa m pli n g ti me p oi nt ( pre d ose, 0. 5-2 h o ur, a n d 2 -3 6 h o ur)  a n d t he st u d y visit base d o n t h e P K 
a nal ysis set.  C o nc e ntrati o ns bel o w t h e l o wer li mit of q ua ntifi cati o n will b e set e q ual t o z er o f or 
all pl as ma c o n ce ntrati o n s u m maries.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 1  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
9.    
S A F E T Y  
T he safet y o bjecti ve of t h e st u d y is t o c h aracteri ze t h e safet y pr ofile of N BI -1 0 6 5 8 4 6 as 
meas ure d b y  T E A Es  a n d S A Es, vital si g ns, cli nic al l a b orat or y  t ests, E C G, me di cati o ns, a n d 
safet y scales. All o ut p uts f or safet y e n d p oi nts will b e base d o n t he Safet y  A nal ysis Set. T he 
a nal ysis of t he saf et y  dat a will b e base d o n descri pti v e statistics a n d prese nte d b y  tre at m e nt 
gr o u p a n d t he st u d y visit u nless ot her wise n ote d. Saf et y dat a will n ot be s u bje ct t o a n y 
i m p utati o n a n d will  be  s u m m arize d o n  a n o bser ve d  c ase basis.  N o  f or mal h y p ot hesis -testi n g 
a nal ysis of safet y d ata will be perf or me d.  
9. 1.    
St u d y  Tre at me nt  D osi n g  a n d  C o m pli a nce  
T he  d urati o n  of  e x p os ure t o  ra n d o mize d st u d y tr eat m e nt will be  calc ulat e d as: l ast  d ose  date  –  
first d ose  date  + 1.  
D urati o n of e x p os ure will be s u m m arize d wit h descri pti ve statisti cs b y treat me nt gr o u p. 
T he  perce nta ge  of  st u d y dr u g  c o m pli a nce will  be  defi ne d  as ( n u m ber of  ta blets dis pe nse d  –  
n u m ber  of  ta blets ret ur ne d) / 8  x  1 0 0 %.  
Assess me nt  of  c o m plia nce will  be  s u m mari ze d as n u m ber  a n d perce nta ge  of  s u bjects recei vi n g 
< 8 0 %,  8 0 % -1 2 0 %,  a n d > 1 2 0 %  of prescri be d  st u d y tr eat me nt. 
9. 2.    
Pri or  a n d  C o nc o mit a nt  Me dic ati o ns  
Pri or  me di cati o n  is defi ne d  as  a n y n o n -st u d y me di cati o n  ta ke n bef ore  t he first d ose  of  st u d y 
treat me nt. 
C o nc o mit a nt  me di cati o n is defi n e d as  a n y n o n -st u d y me dic ati o n t hat is starte d: 
• Bef ore  t he d ate  of  first a d mi nistrati o n  of  st u d y treat m e nt a n d  o n g oi n g  t hr o u g h o ut t h e 
st u d y or e n ds o n/after t he date of first a d mi nistr ati o n of st u d y treat me nt.  
• O n/after  t he d ate  of  fist a d mi nistrati o n  of  st u d y tre at me nt a n d is o n g oi n g  or  e n ds  d uri n g 
t he c o urse of st u d y. 
Me dicati o ns  wit h  a start date  bef ore  t h e first d ose  of  st u d y treat m e nt a n d a n e n d  dat e  after t he 
first d ose of st u d y treat me nt ( or o n g oi n g) will be cl assifie d as “ b ot h pri or a n d c o nc o mit a nt 
me dicati o n”.  
T he n u m ber a n d perce nta ge of p ati e nts ta ki n g pri or a n d c o nc o mita nt me di cati o ns will be 
ta b ulate d b y  W H O  Dr u g  Dicti o n ar y  A nat o mi cal  T her a pe uti c  C he mical  ( A T C) Le vel  3  cate g or y 
or Le vel 2 if t her e is n ot a n a p plic a ble Le vel 3 cate g or y, a n d preferre d na mes usi n g t he Saf et y 
A nal ysis Set.  S u bjects will be c o u nte d o nl y o n ce f or eac h A T C or preferr e d na m e if t h e y ha ve 
m ulti ple re c or ds of t he sa me A T C or pr eferre d n a me i n t he data base. T he ta ble will be s orte d 
al p ha betic all y b y A T C class a n d t he n, wit hi n a n A T C class, b y preferre d na mes.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 2  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
9. 3.    
A d verse  E ve nts  
A d verse  e ve nts  ar e re c or de d i n t h e e C R F. Eac h  A E  will  be  c o de d  t o S O C  a n d P T  usi n g 
Me d D R A.  
A treat m e nt -e mer ge nt a d verse e v e nt ( T E A E) is a n A E t hat o cc urs aft er t he i niti ati o n of 
ra n d o miz e d st u d y treat m e nt d osi n g.  I n vesti g at ors will  be  as ke d t o res p o n d “ Yes” or  “ N o” o n  t he 
e C R F as  t o w het her  t he A E  start e d after t he s u bj ect t o o k t he first d ose  of  st u d y dr u g. A n  A E  wit h 
a res p o nse of “ Yes” will be classifi e d as a T E A E. If t he i n vesti g at or’s res p o nse is missi n g, t h e n 
t he tre at m e nt e mer ge nt st at us will b e deri v e d base d o n t he A E o nset date a n d ti m e relati ve t o t he 
date a n d ti m e of t he s u bj ect’s first d ose of st u d y dr u g. If t he A E o nset date a n d ti me are 
u n k n o w n,  it will  be  ass u me d  t hat t he A E  is a T E A E. If  t he A E  o nset  ti me is u n k n o w n  b ut  t he A E 
o nset date is t he sa m e date as t he first d ose of st u d y dr u g, it will b e ass u me d t h at t h e A E is a 
T E A E.  
T he  fre q ue n c y t a bles will  i ncl u d e t he n u m b er  a n d per ce nta g e  of  u ni q u e  s u bje cts e x perie nci n g 
eac h e v e nt at least o n ce d uri n g t he st u d y. U nless ot h er wise s pecifi e d, s u m mar y ta bles will 
i ncl u de e ve nts wit h a start date o n or after t h e dat e of t he first d ose of ra n d o miz e d st u d y 
treat me nt a n d u p t o t h e last d ose of st u d y treat me nt + 1 0 da ys. 
T w o  versi o ns  of t he  pri mar y  T E A E fr e q ue nc y  ta bl es will  be  prese nte d b y  tr eat m e nt gr o u p:  
• Fre q ue n c y of T E A Es b y S O C a n d P T, wit h S O Cs s orte d al p h a beticall y a n d P Ts 
wit hi n  e ac h S O C  s orte d b y  decr easi n g  fre q ue n c y ( n u m ber of  u ni q u e  s u bje cts) i n t he 
acti v e tre at me nt gr o u p.  
• Fre q ue n c y  of  T E A Es  b y  P T,  wit h  P T  s orte d b y  decreasi n g  fre q ue nc y ( n u m ber of 
u ni q ue s u bjects) i n t he acti ve tre at m e nt gr o u p.  
S u m mar y ta bles of se vere T E A Es will be pr ese nte d b y treat me nt gr o u p. T he n u m ber a n d 
perce nt a ge  of  s u bjects wit h  a  se vere T E A E  will  be  pr ese nte d  b y  P T  wit hi n  S O C  ( prese nte d i n t h e 
sa me met h o d as t he pri mar y T E A E ta ble). T he first li ne of t he t a ble will dis pl a y  t he n u m b er a n d 
perce nt a ge of s u bjects wit h at least o n e se vere T E A E.  
A n  A E  o ver vie w  s u m mar y ta bl e will  be  pr o vi de d  w hic h  s u m m ariz es t he n u m ber  a n d p erce nta ge 
of s u bjects wit h a n y T E A E, a n y T E A E le a di n g t o st u d y treat me nt disc o nti n u ati o n, a n y seri o us 
T E A E, a n d a n y T E A E l ea di n g t o d eat h. T he s u m m ar y ta ble will als o i ncl u d e t he ma xi m u m 
T E A E se verit y ( mil d, m o derate, se ver e) re p ort e d f or eac h s u bje ct.  
I n a d diti o n, ta bl es will be pr o vi de d f or n o n-tre at m e nt e mer ge nt A Es ( A E start dat es after last 
d ose date + 1 0 da ys) se par atel y.  T hese t a bles will be s u m mariz e d b y tre at me nt gr o u p a n d 
prese nte d  b y  P T  wit hi n  S O C,  wit h  S O Cs  s orte d al p ha beti call y  a n d P Ts  wit hi n  eac h S O C  s orte d 
b y decreasi n g fre q u e nc y ( n u m b er of u ni q ue s u bj ects) i n t he a cti v e gr o u p.  
9. 3. 1.  
A d verse  E ve nts  Le a di n g  t o Disc o nti n u ati o n  of  St u d y  Tre at me nt  
S u m mar y ta bles of T E A Es l ea di n g t o disc o nti n uati o n of st u d y treat me nt will be pr ese nte d b y 
treat me nt gr o u p.  T he  n u m ber  a n d per ce nt a ge  of  s u bj ects wit h  a T E A E  l ea di n g t o st u d y tre at m e nt 
disc o nti n uati o n will be prese nte d b y P T wit hi n S O C ( prese nte d i n t he sa m e met h o d as t he 
pri mar y T E A E ta ble). M ore t ha n o n e A E ca n c o ntri b ute t o st u d y tr eat me nt disc o nti n u ati o n p er  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 3  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
s u bject. T he  first li ne of  t he ta bl e will  dis pla y  t he n u m ber  a n d perc e nta g e  of  s u bjects wit h  at le ast 
o ne T E A E l ea di n g t o st u d y treat me nt disc o nti n uati o n.  
A listi n g of T E A Es l ea di n g t o st u d y tre at m e nt disc o nti n uati o n will b e pr o vi de d w hi c h i ncl u des 
s u bject I D, tre at m e nt gr o u p, last treat me nt rec ei ve d pri or t o t he o nset ti me of t h e T E A E(s) 
lea di n g t o disc o nti n uati o n,  st u d y da y  of  t h e disc o nti n uati o n,  a n d ot h er  rel e va nt i nf or m ati o n fr o m 
t he A E e C R F. N ote t h at “last tr eat me nt re cei v e d pri or t o t he o nset ti m e of t he T E A E[s] lea di n g 
t o disc o nti n u ati o n ” refl ects t he act u al d ose l e vel r ecei ve d pri or t o t he A E. 
9. 3. 2.  
De at hs  a n d  Ot her  Seri o us  A d verse  E ve nts  
S u m mar y  t a bles of  Tre at m e nt -e mer ge nt S A Es  a n d d e at hs  will  be  prese nte d  b y  tre at m e nt gr o u p. 
T he ta bles will i ncl u d e t he fre q u e nc y of S A Es prese nte d b y P T wit hi n S O C ( prese nt e d i n t h e 
sa me met h o d as t he pri mar y T E A E ta ble).  
Se parate listi n gs of S A Es a n d fat al T E A Es will als o be pr o vi de d. E ac h listi n g will i ncl u de 
s u bject I D, treat me nt gr o u p,  last tr eat m e nt rec ei ve d pri or  t o t he o nset  ti me of  t h e S A E  or  fatal 
T E A E,  st u d y da y  of  t h e S A E  or  fatal T E A E,  a n d a n y a d diti o n al r ele v a nt i nf or mati o n fr o m t h e 
A E e C R F.  
9. 4.    
L a b or at or y  S afet y  P ar a meters  
T he he m at ol o g y a n d cli nical c he mistr y will be s u m m arize d wit h descri pti ve statistics b y 
treat me nt at  baseli ne  a n d at  ea c h sc he d ule d p ost b aseli ne  visit  t hr o u g h f oll o w-u p  visit  ( Da y 1 0 6). 
B ot h o bser ve d val u es a n d c ha n ges fr o m b aseli n e will be s u m mari ze d b y tr eat m e nt gr o u p.  
S hift  ta bles fr o m baseli ne  t o Da y  5 7  will  be  pr ese nte d  f or sele cte d cli nic al la b or at or y vari a bles 
base d o n t he ref ere nce r a n ge -base d cat e g ories of “ L o w,” “ N or mal,” or “ Hi g h. ” A cli nical 
la b orat or y v aria ble val u e will b e assi g ne d t o o n e of t hese t hree cate g ories ac c or di n g t o t he 
refere nce r a n ges pr o vi de d b y t he c e ntral cli nic al la b orat or y. T he s hift ta ble will ha ve r o ws 
reflecti n g t h e refere n ce ra n g e cate g or y at baseli ne, a n d c ol u m ns refl ecti n g t he ref ere nc e ra n ge 
cate g or y o n Da y 5 7. A “ T otal ” r o w a n d “ T otal ” c ol u m n will als o be i ncl u de d. T h e n u m ber of 
s u bjects i n e ac h s hift cate g or y will be dis pla ye d i n t h e ta bl e.  
T he  s hift ta ble will  b e  prese nte d  b y  tr eat me nt gr o u p  f or t he f oll o wi n g cli nic al  la b orat or y 
varia bles:  
• as partat e a mi n otr a nsferase  ( A S T), 
• ala ni n e a mi n otr a nsferase  ( A L T), 
• al kali ne p h os p hatase ( A L P), 
• ga m ma -gl uta m yl  tr a nsferase ( G G T), 
• t otal bilir u bi n,  
• creati ne ki nase,  
• creati ni ne, 
• bl o o d  urea  nitr o ge n  ( B U N), 
• w hite  bl o o d  cell c o u nt, 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 4  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
• a bs ol ute ne utr o p hil  c o u nt, 
• he m o gl o bi n,  
• platelet  c o u nt, 
Re peat cli nical la b orat or y sa m pl es ma y be c oll ect e d at a n y ti me d uri n g t his st u d y d ue t o eit her 
missi n g or a b n or mal res ults. T h e ge neral r ule f or s u m mari zi n g t h ese dat a is t o i n cl u de t h e 
ori gi nal sa m ple r es ults i n s u m m ar y ta bles. E xce pti o ns t o t his r ule is t h at if t here are missi n g 
res ults fr o m t he ori gi n al  la b sa m pl es at scre e ni n g, t h e res ults of  a re peat scree ni n g sa m ple will  be 
s u bstit ute d f or t h e missi n g res ults i n s u m mar y ta bl es. 
9. 5.    
Vit al  Si g ns  
T he vit al si g ns dat a, i ncl u di n g ort h ost ati c s yst olic a n d diast oli c bl o o d press ure (c alc ul ate d as 
sta n di n g val ue  mi n us  s u pi ne v al ue),  ort h ostatic  heart  rate, res pirat or y rat e (rec or de d o nl y  s u pi n e), 
a n d b o d y te m p erat ur e, will be s u m mari ze d wit h d escri pti ve st atistics b y tre at m e nt gr o u p at 
baseli ne a n d at eac h sc he d ule d p ost baseli ne visit t hr o u g h f oll o w -u p visit. B ot h o bser v e d val u es 
a n d c ha n ges fr o m b aseli ne will be s u m mari ze d.  
9. 6.    
B o d y  Wei g ht  
T he  b o d y  wei g ht  dat a  (i n u nits  of  kil o gra ms)  will  be  s u m mariz e d wit h  descri pti ve  statistics b y 
treat me nt gr o u p at baseli ne a n d at e ac h sc he d ule d p ost baseli ne visit t hr o u g h f oll o w-u p visit.  
O bser ve d  val ues  a n d a bs ol ut e a n d perce nt c ha n ges  fr o m baseli ne  will  b e  s u m marize d. 
9. 7.    
Electr oc ar di o gr a m  ( E C G) 
T he tri plic ate v al ues of t he q u a ntitati ve E C G varia bl es ( heart rate, P R i nt er val, Q R S d urati o n, 
Q T  i nter val, a n d c orr ect e d  Q T  i nter val usi n g  Fri d ericia’s  f or m ula [ Q Tc F]) meas ure d  at e ac h visit 
will be  a ver a ge d f or  t he p ur p ose of a n al ysis. F or t he  cate g orical E C G i nter pr etati o n varia ble (t he 
i n vesti gat or’s assess me nt of t he E C G as “ N or mal”, “ A b n or mal, n ot Cli nic all y Si g nific a nt”, or 
“ A b n or mal,  Cli nicall y  Si g nifica nt ”),  w hic h  is als o re p orte d i n tri plicate, t h e val u e t hat r e prese nts 
t he greatest de gre e of a b n or m alit y will b e use d i n all s u m mar y ta bles. If less t ha n 3 v al ues are 
rec or de d at a n assess me nt,  t he n t h e a vera ge/ greatest  a b n or malit y  of  t he a vaila bl e val ue(s)  will  be 
use d.  
T he  q ua ntitati ve  E C G  vari a bles  will  b e  s u m m ariz e d wit h  descri pti ve  statistics b y  treat me nt gr o u p 
at baseli ne a n d at ea c h sc he d ul e d p ost baseli ne visit t hr o u g h f oll o w -u p visit. B ot h o bser v e d  
val ues a n d c h a n ges fr o m baseli ne will be s u m m ariz e d. Fre q ue n c y  c o u nts a n d perc e nta ges f or t h e 
E C G i nter pretati o n varia ble c ate g ories will b e s u m m arize d at ea c h sc he d ul e d visit.  
Cate g ori cal s u m mari es will be prese nte d f or t h e Q Tc F i nt er val d ata. F or t h ese s u m maries, a 
s u bject’s hi g hest  r e p orte d p ost baseli ne  val ue  (i n cl u di n g val ues  re p ort e d at u nsc he d ule d  visits) 
will be use d t o d eter mi ne i n w hic h cate g or y(s) t he s u bject will be c o u nte d. T he a ver a ge d 
tri pli cat e val u es will be use d w he n deter mi ni n g e ac h s u bject’s hi g hest r e p orte d v al ues. 
T w o  cat e g oric al s u m mari es will  be  pr ese nte d  f or t he Q Tc F  i nter vals. F or  t h e first s u m mar y, t he 
n u m ber a n d per ce nta g e of s u bjects i n ea c h tre at m e nt gr o u p w h ose hi g hest re p orte d Q Tc F 
p ost baseli ne v al ue meets t he f oll o wi n g t hres h ol ds will be s u m m ariz e d:  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 5  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
• Greater  t h a n 4 5 0  msec  
• Greater  t h a n 4 8 0  msec  
• Greater  t h a n 5 0 0  msec  
T he  sec o n d cate g orical s u m m ar y will  dis pl a y  t he n u m ber  a n d perc e nta g e  of  s u bjects i n ea c h 
treat me nt gr o u p w h ose lar g est Q Tc F i ncre ase fr o m t heir baseli ne val ue me ets t he f oll o wi n g 
t hres h ol ds: 
• Greater  t h a n 3 0  msec  
• Greater  t h a n 6 0  msec  
9. 8.    
Ot her  S afet y  E n d p oi nts  
9. 8. 1.  
C ol u m bi a -S uici de  Se verit y  R ati n g  Sc ale  ( C-S S R S)  
T he C ol u m bia -S uici de Se verit y Rati n g Scale ( C -S S R S) is a meas ure of s uici dal i deati o n a n d 
be ha vi or. T h ere are v ersi o ns of t he q uesti o n nair e desi g ne d f or use at scr ee ni n g 
( Baseli ne/ Scree ni n g versi o n) a n d at baseli ne a n d visits t hr o u g h o ut t he st u d y ( Si n ce L ast Visit 
versi o n).  S u bject  res p o nses of  “ yes” t o o ne  or  m ore  s cree ni n g q uesti o ns  will  pr o m pt  a d diti o nal 
q uesti o ns t hat e val u ate fre q u e nc y a n d i nte nsit y of s ui ci dal i deati o n a n d/ or be ha vi or.  
T he  C -S S R S  data will  be prese nt e d i n t h e  f oll o wi n g s u m maries: 
• Scree ni n g  ( Baseli ne/ Scr ee ni n g versi o n)  
• Baseli ne  ( Da y 1)  a n d p ost baseli ne  assess me nt ( Si nc e Last  Visit  versi o n)  
 
T he C -S S R S s u m mar y  will dis pl a y  t he n u m ber a n d p erce nt a ge of s u bjects w h o re p ort “ Yes” t o 
s pecific C -S S R S  ite ms or  cat e g ories  of  ite ms ( a c ate g or y  is assi g ne d a “ Yes” val ue  if a “ Yes” is 
re p orte d f or a n y ite m i n t he cat e g or y). T hese C -S S R S ite ms a n d c ate g ories are as f oll o ws:  
• S uici dal  I deati o n Ite ms 
( 1)   
Wis h t o  be dea d  
( 2)   
N o n -s pecific acti ve  s uici d al t h o u g hts 
( 3)   
Acti ve  s uici d al i de ati o n wit h  a n y m et h o ds  ( n ot pla n)  wit h o ut  i nte nt t o act 
( 4)   
Acti ve  s uici d al i de ati o n wit h  s o me i nt e nt t o a ct, wit h o ut  s pecific pla n  
( 5)   
Acti ve  s ui ci dal i deati o n wit h  s pecific pl a n  a n d i nte nt 
• S uici dal  I de ati o n Cat e g or y:  A n y  of  ite ms ( 1) t hr o u g h ( 5) 
• S uici dal  Be ha vi or  Ite ms 
( 6)   
Pre parat or y  a cts  or  be ha vi or  
( 7)   
A b orte d  atte m pt 
( 8)   
I nterr u pte d atte m pt  
( 9)   
N o n -fatal s uici de atte m pt 


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 6  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
( 1 0) 
C o m plet e d  s uici de 
• S uici dal  Be h a vi or  Cate g or y: A n y  of  it e ms ( 6) t hr o u g h ( 1 0) 
• S uici dal I d eati o n  or  Be ha vi or  Cat e g or y:  A n y  of  ite ms ( 1) t hr o u g h ( 1 0) 
F or t he “all p ost baseli ne assess me nts” s u m mar y, ea c h s u bject’s C -S S R S res p o nses f or all 
p ost baseli ne  assess me nts  d uri n g  t he st u d y will  be  e val uate d,  a n d  a “ Yes” res p o nse f or a n y 
assess me nt will be c o nsi dere d as a “ Yes” f or t he s u bj ect.  
I n a d diti o n t o t he s u m mari es descri be d a b o v e, s hift t a bles c o m p ari n g p ost baseli ne s uici dal 
i deati o n sc ores t o baseli ne  sc or es will  b e  prese nt e d.  T he  s hift ta bl e sc ores are defi n e d  as t he 
f oll o wi n g: 
0  =  N o  s uici dal i deati o n 
1  =  Wis h  t o be dea d  
2  =  N o n -s pecific acti ve s uici d al t h o u g hts 
3  =  Acti ve  s uici d al i d eati o n wit h  a n y met h o ds  ( n ot pl a n)  wit h o ut  i nte nt t o act 
4  =  Acti ve  s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut s pecifi c pla n  
5  =  Acti ve  s uici dal i d eati o n wit h s pecific pla n  a n d  i nte nt 
T he  s hift ta bles will dis pl a y t he n u m ber a n d perce nta ge  of s u bjects wit hi n eac h cell of a  6 x 6 
ta ble f or eac h tre at m e nt gr o u p, wit h t he  r o ws re prese nti n g t he b aseli ne sc ore a n d t h e c ol u m ns 
re prese nti n g t h e m a xi m u m  sc ore r ec or de d acr oss  all p ost baseli ne  assess me nts  (i ncl u di n g b ot h 
sc he d ule d a n d u nsc h e d ule d  visits).  S u bje cts  missi n g  eit her a baseli n e  sc ore or  all p ost b aseli n e 
sc ores will a p pe ar i n t h e a d diti o nal “ missi n g” c ol u m n/r o w i n t he t a ble.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
3 7  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
1 0.    
P E R F O R M A N C E  Q U A LI FI C A TI O N  O F  S A S ®  P R O G R A M S  
T he a nal ysis a n d s u m mar y of d ata fr o m t his st u d y will be perf or me d usi n g S A S ® 9. 4 ( or a later 
release if a vaila bl e). All S A S ® pr o gra ms use d i n t he pr o d ucti o n of statisti cal a nal yses, ta bles, 
listi n gs, a n d fi g ur es descri be d i n t his S A P will u n der g o perf or ma nc e q ualificati o n ( verific ati o n 
t hat t he pr o gr a m  pr o d u ces  t h e i nte n de d o ut p ut)  i n acc or da nce wit h  de part me nt  sta n d ar d o per ati n g 
pr oce d ures. T he perf or ma nc e q ualific ati o n ma y i n cl u de i n de pe n d e nt pr o gra m mi n g a n d/ or peer 
re vie w of t he S A S ® l o g files. I n a d diti o n, t a bles, fi g ures, listi n gs, a n d statisti cal a nal ysis o ut p ut 
will be i n d e pe n de ntl y re vie we d f or c o m plet e ness a n d acc ura c y.  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
 
 
Ne ur ocri ne Bi os cie nces, I nc.  
St u d y  N BI -1 0 6 5 8 4 6 -M D D 2 0 2 0 
Statistical  A nal ysis  Pla n  
 
1 6 A u g ust 2 0 2 3  
 
1 1.    
R E F E R E N C E S  
E ur o pea n  Me di ci nes  A ge nc y.  P oi nts  t o C o nsi der  o n  I m plic ati o ns of  C or o na vir us  Disease 
( C O VI D-1 9) o n Met h o d ol o gical As pects of O n g oi n g Cli nic al Trials. Marc h 2 0 2 0.  
Healt h  C a na da.  Ma na ge me nt  of  Cli nical  Trials  D uri n g  t he C O VI D -1 9  Pa n de mic:  N otice  t o 
Cli nic al Trial S p o ns ors. Ma y 2 0 2 1.  
Lee  J H, H u ber  J C Jr. E v al uati o n  of  M ulti ple  I m p ut ati o n wit h  Lar ge  Pr o p orti o ns  of  Missi n g  Data: 
H o w M uc h Is T o o M uc h? Ira n J P u blic Healt h. 2 0 2 1 J ul; 5 0( 7): 1 3 7 2 -1 3 8 0.  
U nite d  States  F o o d  a n d Dr u g  A d mi nistrati o n.  C o n d u ct  of  Cli nic al  Trials  of  Me dical  Pr o d ucts 
D uri n g t he C O VI D -1 9 P u blic Healt h E mer ge n c y. G ui da nce f or I n d ustr y, I n vesti gat ors, a n d 
I nstit uti o n al Re vie w B oar ds. Marc h 2 0 2 0, u p date d Ja n uar y 2 0 2 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 8  


D oc u me nt N u m ber: V V -T M F -5 4 2 4 0   
Versi o n: 1. 0   
Stat us: A p pr o ve d  
T his  d oc u me nt c o p y  was retrie ve d  fr o m t he s yste m b y  
o n 0 3 N o v 2 0 2 3.  
E ns ure t his is t he m ost c urre nt versi o n (e. g., A p pr o ve d) pri or t o refere nci n g. 
Na me:  
R ole: Bi ostatistics  
Date of si g nat ure: 1 6 -A u g -2 0 2 3 2 2: 5 1: 3 7 G M T + 0 0 0 0  
Re as o n f or si g ni n g: A p pr o ve d  
Na me:  
R ole: Cli nic al De vel o p me nt  
Date of si g nat ure: 2 3 -A u g -2 0 2 3 1 8: 0 8: 4 2 G M T + 0 0 0 0  
Re as o n f or si g ni n g: A p pr o ve d  
Na me:  
R ole: Bi ostatistics  
Date of si g nat ure: 2 3 -A u g -2 0 2 3 1 8: 4 2: 0 8 G M T + 0 0 0 0  
Re as o n f or si g ni n g: A p pr o ve d  
Si g nat ure Pa ge f or V V -T M F -5 4 2 4 0 v 1. 0  
Si g nat ure Pa ge f or V V -T M F -5 4 2 4 0 v 1. 0