Clinical trial NCT03352453
Conditions: Depressive Disorder, Major
Sponsor: Naurex, Inc, an affiliate of Allergan plc
Start date: 2017-12-15; Completion date: 2019-06-21
Enrollment: 138 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the efficacy, safety, and tolerability of 450 milligrams (mg) of Rapastinel, compared to placebo in adult patients with major depressive disorder (MDD) who are at imminent risk of suicide.

Detailed description:

Arms: arm 1: Rapastinel 450 milligram (mg) weekly intravenous (IV) injections. arm 2: Placebo-matching rapastinel weekly IV injections.
Interventions: intervention 1: Rapastinel intervention 2: Placebo
Intervention descriptions: intervention 1: Rapastinel pre-filled syringes for weekly IV injections. intervention 2: Placebo-matching rapastinel pre-filled syringes for weekly IV injections.

Protocol documents:
Prot_001.pdf: 
NCT03352453 
 
Study ID: RAP‐MD‐20 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter, Efficacy and Safety Study of 
Rapastinel for Rapid Treatment of Symptoms of Depression and Suicidality in Adult Patients with Major 
Depressive Disorder 
 
Protocol Date: 26 Sept 2017 
 
 
 


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TITLE PAGE
Naurex, an indirect subsidiary of Allergan, plc.
Madison, NJ 07940
A Randomized, Double-blind, Placebo-controlled, Multicenter, Efficacy and Safety 
Study of Rapastinel for Rapid Treatment of Symptoms of Depression and 
Suicidality in Adult Patients with Major Depressive Disorder
Study #RAP-MD-20
(3106-201-008)
IND #136,789
Original Protocol Date:
26 Sep 2017
Confidentiality Statement
This document is the property of Allergan, plc and may not—in full or part—be passed 
on, reproduced, published, distributed, or submitted to any regulatory authority without 
the express written permission of Allergan, plc.


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SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study RAP-MD-20
Study Number
RAP-MD-20 (3106-201-008)
Title of Study
A Randomized, Double-blind, Placebo-controlled, 
Multicenter, Efficacy and Safety Study of Rapastinel for 
Rapid Treatment of Symptoms of Depression and Suicidality 
in Adult Patients with Major Depressive Disorder
Study Centers (Country)
Approximately 20-30 study centers (United States)
Development Phase
2
Objective
To evaluate the efficacy, safety, and tolerability of rapastinel
as a rapid treatment of symptoms of depression and 
suicidality in adult patients with major depressive disorder 
(MDD) who are at imminent risk of suicide
Study Design
Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, 4-week, study in patients with MDD 
experiencing suicidality.
Total study participation will be approximately 5 to 6 weeks 
in duration and will include the following periods: 

Up to 5-day screening period 

4-week double-blind treatment period (DBTP)

1-week safety follow-up period 
Patients are generally expected to remain in an inpatient 
setting through at least the completion of assessments 
conducted 4 days after the initial dose of investigational 
product (IP). During participation in the study, patients may 
be treated per local standard of care (SOC) with limited 
restrictions and IP will be administered in addition to SOC 
treatments.
Number of Patients
Approximately 300 planned to be enrolled
Diagnosis and Main Criteria for 
Inclusion
Inclusion:

Male or female outpatients, 18 to 65 years of age

Meet Diagnostic and Statistical Manual of Mental 
Disorders – Fifth Edition (DSM-5) criteria for MDD
 

Have current, ongoing suicidality (ideation or behavior)
of sufficient severity to warrant hospitalization based on 
the judgment of the investigator and at least one of the 
following:


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Exclusion:

DSM-5–based diagnosis of any disorder other than 
MDD that was the primary focus of treatment within 
1 month before Visit 1

Have known lifetime history or currently meet DSM-5 
criteria for:
o
Schizophrenia spectrum or other psychotic 
disorder
o
Bipolar or related disorder
o
Major neurocognitive disorder 
o
Neurodevelopmental disorder of greater than 
mild severity or of a severity that impacts the 
patient’s ability to consent, follow study 
directions, or otherwise safely participate in the 
study 
o
Dissociative disorder
o
Posttraumatic stress disorder
o
MDD with psychotic features

DSM-5–based diagnosis of borderline personality 
disorder or any other personality disorder of sufficient 
severity to interfere with participation in this study in the 
opinion of the investigator
Test Product, Dosage, and Mode 
of Administration
Rapastinel (450 mg weekly intravenous [IV] administration), 
prefilled syringe
Duration of Treatment
Up to 5-day screening period, followed by a 4-week DBTP, 
followed by a 1-week safety follow-up period
Reference Therapy, Dosage, and 
Mode of Administration
Placebo, weekly IV administration, prefilled syringe 


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Criteria for Evaluation
Primary Endpoint
Change from baseline in MADRS total score at 1 day after 
first dose of IP
Key Secondary Endpoint
Change from baseline in S-STS total score at 1 day after first 
dose of IP
 
 
 
 
 
 
Statistical Methods
The primary and key secondary efficacy parameters will be 
analyzed using analysis of covariance (ANCOVA) models
with terms for treatment, study center, and baseline. Baseline 
will be defined as the last measurement prior to the first dose 
of treatment.
All safety parameters will be analyzed using descriptive 
statistics. Safety analyses will be based on the Safety 
Population, defined as all randomized patients who receive
at least 1 dose of randomized IP. Efficacy analyses will be 
based on the Intent-to-Treat (ITT) Population, defined as all 
patients in the Safety Population with at least 1 post-
randomization assessment of the MADRS total score.


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TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS .....................................................................2
3.0
TABLE OF CONTENTS..................................................................................................................7
LIST OF FIGURES ..........................................................................................................................9
4.0
LIST OF ABBREVIATIONS.........................................................................................................10
5.0
ETHICAL CONSIDERATIONS....................................................................................................12
5.1
Institutional Review Board and Independent Ethics Committee ......................................12
5.2
Ethical Conduct of the Study............................................................................................12
5.3
Patient Information and Informed Consent.......................................................................12
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ......................................13
7.0
INTRODUCTION ..........................................................................................................................14
8.0
STUDY OBJECTIVES...................................................................................................................17
9.0
INVESTIGATIONAL PLAN .........................................................................................................20
9.1
Overall Study Design and Plan: Description ....................................................................20
9.1.1
Screening Period.................................................................................................20
9.1.2
Double-blind Treatment Period..........................................................................20
9.1.3
Safety Follow-up Period.....................................................................................22
9.2
Discussion of Study Design, Including the Choice of Control Groups.............................23
9.3
Selection of Study Population...........................................................................................24
9.3.1
Inclusion Criteria................................................................................................24
9.3.2
Exclusion Criteria...............................................................................................26
9.3.3
Removal of Patients from Therapy or Assessment.............................................29
9.3.4
Patient Replacement Procedures ........................................................................30
9.4
Treatments ........................................................................................................................30
9.4.1
Treatments Administered ...................................................................................30
9.4.2
Identity of Investigational Products....................................................................31
9.4.3
Handling of Investigational Products .................................................................32
9.4.4
Method of Assigning Patients to Treatment Groups ..........................................32
9.4.5
Selection of Dosages in the Study ......................................................................32
9.4.6
Selection and Timing of Dose for Each Patient..................................................33
9.4.6.1
Screening Period...............................................................................33
9.4.6.2
Double-blind Treatment Period ........................................................33
9.4.6.3
Safety Follow-up Period...................................................................33
9.4.7
Blinding..............................................................................................................33
9.4.8
Unblinding..........................................................................................................34
9.4.9
Prior and Concomitant Therapy .........................................................................34
9.4.10
Other Restrictions...............................................................................................36
9.4.10.1
Alcohol .............................................................................................36
9.4.10.2
Contraception ...................................................................................36


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9.4.11
Monitoring Treatment Compliance ....................................................................37
9.4.12
Treatment After Discontinuation........................................................................37
9.5
Efficacy and Safety Variables...........................................................................................37
9.5.1
Diagnostic and Efficacy Assessments ................................................................37
9.5.1.1
Diagnostic Assessments ...................................................................37
9.5.1.2
Efficacy Assessments .......................................................................38
9.5.2
Safety Assessments ............................................................................................39
9.5.2.1
Adverse Events.................................................................................39
9.5.2.2
Immediate Reporting of Serious Adverse Events and Events of 
Interest..............................................................................................43
9.5.2.3
Reporting of Pregnancies Occurring During the Study ....................44
9.6
Data Quality Assurance ....................................................................................................59
9.6.1
Data Monitoring .................................................................................................59
9.6.2
Data Recording and Documentation...................................................................59
9.7
Statistical Methods and Determination of Sample Size....................................................60
9.7.1
Analysis Populations ..........................................................................................60
9.7.1.1
Screened Population .........................................................................60
9.7.1.2
Randomized Population....................................................................60
9.7.1.3
Safety Population..............................................................................60
9.7.1.4
Intent-to-Treat Population ................................................................61
9.7.2
Patient Disposition .............................................................................................61
9.7.3
Demographics and Other Baseline Characteristics.............................................61
9.7.4
Extent of Exposure and Treatment Compliance.................................................61
9.7.4.1
Extent of Exposure ...........................................................................61
9.7.4.2
Measurement of Treatment Compliance...........................................62
9.7.5
Efficacy Analyses...............................................................................................62
9.7.5.1
Primary Efficacy Parameter..............................................................62
9.7.5.2
Key Secondary Efficacy Parameter ..................................................63
9.7.6
Safety Analyses ..................................................................................................66
9.7.6.1
Adverse Events.................................................................................66


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9.7.8
Interim Analysis .................................................................................................69
9.7.9
Determination of Sample Size............................................................................70
9.7.10
Computer Methods.............................................................................................70
9.8
Data and Safety Monitoring Board...................................................................................70
9.9
Changes in the Conduct of the Study or Planned Analyses ..............................................70
9.10
Protocol Deviations ..........................................................................................................71
10.0
STUDY SPONSORSHIP................................................................................................................72
10.1
Study Termination ............................................................................................................72
10.2
Reporting and Publication ................................................................................................72
11.0
INVESTIGATOR OBLIGATIONS................................................................................................73
11.1
Documentation..................................................................................................................73
11.2
Performance......................................................................................................................73
11.3
Use of Investigational Materials.......................................................................................74
11.4
Case Report Forms ...........................................................................................................74
11.5
Retention and Review of Records.....................................................................................74
11.6
Patient Confidentiality......................................................................................................75
12.0
INVESTIGATOR’S STATEMENT ...............................................................................................76
13.0
APPENDICES ................................................................................................................................77
Appendix I.
Elements of Informed Consent...........................................................................77
Appendix II.
Contact Information............................................................................................79
14.0
LITERATURE CITED .................................................................................................................100
LIST OF FIGURES


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
β-hCG
serum β-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
DBTP
double-blind treatment period
DSMB
Data Safety Monitoring Board
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
eCRF
electronic case report form
ECT
electroconvulsive therapy
EDC
electronic data capture
ET
early termination
FDA
Food and Drug Administration
FR
Federal Register
GCP
good clinical practice
h
hours
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation 
IND
Investigational New Drug (application)
IP
investigational product
IRB
Institutional Review Board
ITT
Intent-to-Treat


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IV
intravenous
IWRS
interactive web response system
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
major depressive disorder
 
MMRM
mixed-effects model for repeated measures
NMDAR
N-methyl-D-aspartate receptor 
PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/[RR]½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/[RR]⅓)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SOC
standard of care
SIGMA
Structured Interview Guide for the MADRS
S-STS
Sheehan - Suicidality Tracking Scale
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal


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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the investigator. A copy of the approval letter will be supplied to the 
Sponsor, along with a roster of IRB members or the US Department of Health and 
Human Services general assurance number. During the course of the study, the 
investigator will provide timely and accurate reports to the IRB on the progress of the 
study, at intervals not exceeding 1 year (or as appropriate), and will notify the IRB of 
serious adverse events (SAEs) or other significant safety findings. The study protocol, 
informed consent form (ICF), information sheet advertisements, and amendments (if any) 
will be approved by the IRBs at the study centers in conformance with the US CFR, Title 
21, Part 56.
5.2
ETHICAL CONDUCT OF THE STUDY
This clinical study will be conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki.
This clinical study will comply with the ICH Guidance on General Considerations for 
Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP (ICH-E6; 62 FR 25692, 
09 May 1997), as well as Part 312 of the US CFR.
5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the study and before participating in any study 
procedures, each patient must provide written informed consent in compliance with 21 
CFR, Parts 50 and 312 and give HIPAA authorization. 
Each patient will read and sign an ICF and/or other authorization form as per local 
regulations; each patient will be made aware that he or she may withdraw from the study 
at any time.
The ICF contains all the elements of informed consent listed in Appendix I of this 
protocol. Signed copies of the ICF and the HIPAA or other locally applicable form will 
be given to the patient, and both documents will be placed in the Investigator’s study 
files.


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INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 20 to 30 study centers in the United States.
The investigator is responsible for ensuring that the investigation is conducted according 
to the signed investigator statement, the investigational plan, GCP guidelines, and 
applicable regulations; for protecting the rights, safety, and welfare of patients under the 
investigator’s care; and for the control of investigational products under investigation. An 
investigator shall obtain the informed consent for each patient prior to the patient 
enrolling in the study and/or prior to participating in any study-related activity. 
The investigator at each study center must meet his or her obligations to the patients, 
ethics committee, sponsor, and regulatory authorities by maintaining oversight and 
control of the study’s conduct and the study staff. It is the responsibility of the 
investigator to ensure that any and all delegated duties be assigned to qualified staff by 
education, experience, and licensure (in accordance with local regulations) and that the 
investigator oversight is documented and assessment of staff capabilities and 
performance is consistent with the study investigational plan. The investigator at each 
study center will be responsible for the management of the study, including maintaining 
the study file and the patient records, corresponding with the IRB, and completing the 
electronic case report forms (eCRFs).


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INTRODUCTION
Disease Burden of Major Depressive Disorder
Major depressive disorder (MDD) is a highly disabling, serious condition that is 
associated with significant morbidity and mortality. MDD manifests as a major 
depressive episode (which may be singular or recurrent) in which the affected individual 
experiences 1) depressed mood, or 2) loss of interest or pleasure (as well as other 
symptoms) for most of the day, nearly every day, for at least 2 weeks. MDD affects 
approximately 14.8 million American adults, or about 6.7% of the US population 
18 years of age and older, in a given year (Kessler et al, 2005). Worldwide, about 15% of 
the adult population is at lifetime risk of developing MDD (Kessler et al, 1994).
Depression may cause serious, long-lasting symptoms and often disrupts a person’s 
ability to perform routine tasks. In 2000, unipolar depressive disorders were by far the 
leading cause (11.9%) of worldwide years of life lived with disability (World Health 
Organization, 2001), and the total economic burden of treating depression in the United 
States was $83.1 billion, with workplace costs, including missed days and lack of 
productivity due to illness, accounting for most of the total economic burden (62%). 
Other economic burdens in 2000 included $26.1 billion (31%) for treatment costs and 
$5.4 billion (7%) for suicide-related costs (Greenberg et al, 2003). 
MDD is a leading cause of disability in the United States (Murray et al, 2013). Moreover, 
MDD is known to be a significant risk factor for suicide and ischemic heart disease, as it 
accounted for 16 million of the disability adjusted life years associated with suicide and 
4 million of the disability adjusted life years associated with ischemic heart disease. 
Research has shown that untreated depression has both a functional (social and work 
role) as well as a neuroanatomical (hippocampal shrinkage) effect on the patient 
(Videbech and Ravnkilde, 2004). Given the disease burden and link to suicidality as well 
as increased mortality with other comorbid conditions, MDD is a serious and life-
threatening condition that is a leading cause of disability in the world.


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Disease Burden of Suicidality
Suicidality is a complex multifactorial public health problem with far-reaching 
consequences for individuals and families, as well as significant impacts on society at 
large.  Suicide is the 10th leading cause of death in the United States, and each year over 
40,000 die by suicide in the United States (Centers for Disease Control and Prevention. 
2017).  It is estimated that suicide costs the United States $51 billion annually (Centers 
for Disease Control and Prevention, 2010).  Approximately 7% of the US population 
knew someone who died by suicide during the past 12 months (Berman, 2011) and these 
survivors are deeply impacted psychologically (Brent, 2010).  Suicide rates have 
increased from 1999 through 2014 with greater increases since 2006, indicating that the 
impact of suicide is growing over time (Curtin et al, 2016).  Suicidal ideation and 
behavior is a common comorbidity across the spectrum of mental health disorders 
although it is strikingly associated with mood disorders, particularly MDD.  Depression is 
the psychiatric diagnosis most commonly associated with suicide and approximately 2% 
to 9% of patients with a lifetime diagnosis of depression die of suicide (Bostwick and 
Pankratz, 2000; Nock et al, 2010).
Rationale for Rapastinel as a Rapid Treatment of Symptoms of Depression and 
Suicidality in MDD
Rapastinel is an N-methyl-D-aspartate receptor (NMDAR) modulator with a novel and 
complex pharmacological mechanism of action, acting as a nonselective agent at NR2 
subunits and displaying properties as a functional partial agonist in a number of 
pharmacological assays. Rapastinel demonstrated antidepressant properties in relevant 
animal models, displayed cognitive enhancing properties in treated animals, and 
facilitated hippocampal long-term potentiation of synaptic transmission in preclinical 
models. In contrast to ketamine, no signal of abuse liability was detected in informative 
animal models. Rapastinel is hypothesized to produce its long-lasting antidepressant 
effects via triggering NMDAR-dependent processes that lead to increased sensitivity to 
LTP that persist for up to 2 weeks (Burgdorf et al, 2015).
In 2 Phase 2 clinical studies in patients with MDD, single intravenous (IV) doses of 
rapastinel 5 mg/kg and 10 mg/kg have been shown to produce marked antidepressant 
effects within 1 day that lasted for approximately 1 week or longer in responding 
patients. These antidepressant effects are very similar to ketamine’s effects when 
administered at a low dose as an infusion.  In a systematic review and meta-analysis of 
ketamine and other NMDAR antagonists in the treatment of major depression, ketamine 
produced a rapid, yet transient, antidepressant effect, accompanied by brief 
psychotomimetic and dissociative effects. However, rapastinel significantly reduced 
depressive symptoms with a much lower propensity for psychotomimetic or dissociative 
effects (Newport et al, 2015).


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Naurex, Inc initially developed rapastinel as a treatment for patients with MDD who 
manifest a serious and common aspect of the disease: inadequate response to existing 
antidepressant therapy. In Phase 2 studies, single doses of 5 or 10 mg/kg showed rapid 
antidepressant effects, with a large effect detected after 1 day.  Repeated doses 
demonstrated a rapid, sustained antidepressant effect and were well tolerated with 
adjunctive treatment in patients with partial responses to their antidepressants. To date, 
rapastinel has been shown to be safe and well tolerated and the observed safety of 
rapastinel is significantly better than that of NMDAR antagonists, which induce 
psychotomimetic side effects and have abuse/diversion potential.  Rapastinel showed a 
low propensity to induce psychotomimetic side effects or effects that might predict abuse 
potential.  The available clinical data also suggest that rapastinel is not associated with
the serious metabolic and extrapyramidal side effects seen with the atypical 
antipsychotics currently approved for adjunctive treatment of MDD.
The efficacy of rapastinel is consistent with that observed in several other studies 
utilizing NMDAR modulators (such as ketamine).  Such NMDAR modulating drugs are 
increasingly being recognized as having potential as treatments for suicidality (Griffiths 
et al, 2014; Reinstatler and Youssef, 2015; Price and Matthew, 2015). Multiple small 
studies have been undertaken with ketamine (Burger et al, 2016; De Gioannis et al, 2014; 
Lee et al, 2015) and esketamine has entered late stage clinical trials (NCT03039192; 
NCT03097133) targeting suicidality after promising proof-of-concept results (Canuso et 
al, 2016a; Canuso et al, 2016b).  Of interest are recent indicators that the anti-suicidality 
effects of ketamine may be due at least in part to procognitive effects (Price et al, 2009; 
Price et al, 2014).  Preclinical data indicate that rapastinel has strong procognitive effects 
which has led to suggestions from experts that the study of rapastinel for suicidality is 
warranted (Lee et al, 2016).  The rapid onset of efficacy and favorable safety profile seen 
with rapastinel provide a compelling rationale for evaluating its potential for rapid 
treatment of symptoms of depression and suicidality in MDD.
The purpose of this study is to prospectively confirm that rapastinel, when administered 
along with standard of care (SOC) at a dose of 450 mg as a short IV infusion in adult 
patients with MDD who are at imminent risk of suicide, is significantly superior to 
placebo in rapidly reducing symptoms of depression and suicidality. Furthermore, the 
safety and tolerability of rapastinel will be investigated. The study is intended to support 
an application for regulatory approval of rapastinel as a rapid treatment for symptoms of 
depression and suicidality in adult patients with MDD at imminent risk of suicide.


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8.0
STUDY OBJECTIVES
The objectives of this study are to evaluate the efficacy, safety, and tolerability of rapastinel as 
a rapid treatment of symptoms of depression and suicidality in adult patients with MDD
who are at imminent risk of suicide.
Efficacy Objectives

Primary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) versus
placebo as a rapid treatment of MDD symptoms in adult patients with MDD who are 
at imminent risk of suicide, as measured by the change from baseline Montgomery-
Asberg Depression Rating Scale (MADRS) total score at 1 day post-first dose of 
treatment 

Key secondary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) 
versus placebo as a rapid treatment of suicidality symptoms in adult patients with
MDD who are at imminent risk of suicide, as measured by the change from baseline
on the Sheehan-Suicidality Tracking Scale (S-STS) total score at 1 day post-first dose
of treatment
 
 
 
 
 
 
 
 
 
 


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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
4-week, fixed-dose study comparing rapastinel with placebo in patients with a diagnosis 
of in patients with MDD defined by DSM-5 criteria. The study will be approximately 5 to 
6 weeks in duration and will include the following periods (Figure 9.1.3-1): 

Approximately 5-day screening period

4-week double-blind treatment period (DBTP)

1-week safety follow-up period 
Approximately 300 patients are planned to be randomized in the DBTP (150 patients per 
treatment group).
A schematic of the study design is presented in Figure 9.1.3-1. The Schedule of 
Evaluations is provided in Section 2.0 and detailed descriptions of each study visit can be 
found in Section 9.5.5.
9.1.1
Screening Period
Consent and screening procedures are to be conducted in an inpatient setting for 
suicidality (see Inclusion Criterion #3).  After providing written consent, patients will 
enter a screening period of no more than 5 days. Every effort should be made to conduct 
all procedures as early as possible in the Screening.  Patients will not receive any 
investigational product (IP) during the screening period. Treatment for suicidality should 
proceed per local SOC with limited restrictions (Section 9.4.9.1).  
Efforts should be made to minimize the length of the Screening Period and proceed to 
randomization or screen failure as rapidly as clinically reasonable. Patients meeting the 
eligibility criteria at Assessment/Visit 2 (Baseline) will be assigned a treatment by the 
interactive web response system (IWRS) and enter the DBTP.  
9.1.2
Double-blind Treatment Period
Patients will be randomized in a ratio of 1:1 to 1 of 2 treatment groups: rapastinel 450 mg 
IV weekly injection or placebo IV weekly injection. During participation in the study, 
patients may be treated per local SOC with limited restrictions (see Section 9.4.9.1) and 
IP will be administered in addition to SOC treatments.


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There will be 4 study visits during the first week of the DBTP:

Visit 2: Baseline IP dosing
Note: If Baseline is ≤ 1 day since Screening assessments were conducted, specified 
Baseline assessments do not need to be repeated and Screening assessments will count as 
Baseline (see Section 9.5.5.2 for details).  

Visit 3: 4 hours following the baseline IP dosing

Visit 4: 1 day following the baseline IP dosing

Visit 5: 4 days following the baseline IP dosing
There will be 2 study visits during the second week of the DBTP: 

Visit 6: 7 days following Visit 2

Visit 7: 1 day following Visit 6
There will be 3 weekly study visits during the remainder of the DBTP: 

Visit 8: 14 days following Visit 2

Visit 9: 21 days following Visit 2 

Visit 10: 28 days following Visit 2 
If necessary, study visits may be conducted up to 2 days before or after the scheduled 
visits except for Assessment/Visit 3 (which must be conducted approximately 4 hours 
after Visit 2), Visit 4 (which must be conducted 1 day after Visit 2), and Visit 7 (which 
must be conducted 1 day after Visit 6). All patients who receive IP must complete 
Visit 10 or Early Termination (ET) Visit. 
Generally, it is expected that patients will remain in an inpatient setting until 
approximately 4 days after IP is administered (Visit 5), although this may be adjusted at 
the investigator’s discretion to be shorter or longer to accommodate local SOC based 
upon the patient’s clinical condition.  Patients who require hospitalization for greater than 
14 days (Visit 8) after initial dose of IP should be evaluated regarding other potential 
treatment options and appropriateness of continuing in the study.
Upon completion of the DBTP, patients will enter a 1-week safety follow-up period.


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9.1.3
Safety Follow-up Period
Patients completing the DBTP and patients who prematurely discontinue from the study 
before completing 4 weeks of double-blind treatment should enter the 1-week safety 
follow-up period. 
Additional follow-up visits may be scheduled within 30 days of last dose of IP or last 
study visit, if necessary for safety reasons.


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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
This multicenter, randomized, placebo-controlled, parallel-group study with a 4-week 
DBTP, was designed based on prior studies that established rapastinel efficacy and safety 
in adult patients with MDD as well as consideration of the sponsor’s participation in and 
recommendations from a recent International Society for CNS Clinical Trials and 
Methodology Consensus Meeting (Chappell et al, 2017).  The design was further 
developed with the aid of an advisory board conducted on 24 Apr 2017 with participation 
from several recognized experts in the study of suicidality. In this study, investigators 
will enroll patients 18 through 65 years of age who meet the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD (American 
Psychiatric Association, 2013). The MDD diagnosis will be confirmed using the Mini 
International Neuropsychiatric Inventory (MINI). The symptoms and severity of MDD 
will be assessed using the MADRS (Section 9.5.1.2.1). The symptoms and severity of 
suicidality will be assessed using the S-STS (Section 9.5.1.2.2).
Allergan has carefully considered the overall study design and setting in light of the 
unique requirements of conducting a clinical trial in this at-risk population. Study centers 
will have experience with the study population and will be encouraged to apply available 
guidelines to minimize patient risk or distress. Because patients will enter the study with 
symptoms of acute suicidality, the study is a partially inpatient design with a required 
initial period of hospitalization of flexible duration intended to accommodate the 
variability of SOC across study centers while ensuring that patients receive appropriate 
monitoring. Patients may enter the study once being admitted to an inpatient setting after 
initially presenting at an emergency room setting or via referral from an outpatient 
healthcare provider, such as a psychiatric private practice or clinic. Generally, it is 
expected that patients will remain in an inpatient setting until approximately 4 days after 
IP is administered, although this may be adjusted at the investigator’s discretion to be 
shorter or longer to accommodate local SOC based upon the patient’s clinical condition.  
Patients who require hospitalization for greater than 14 days after initial dose of IP should 
be evaluated regarding other potential treatment options and appropriateness of 
continuing in the study.
Dose selection information is presented in Section 9.4.5. The planned dosing regimen is 
based on experience from previous rapastinel studies. 


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A placebo treatment group is included in the study to comply with worldwide regulatory 
preferences (Laughren, 2001; Gispen-de Wied et al, 2012), since placebo-controlled 
superiority trials have been shown to be conducive to higher-quality studies and to 
provide more reliable outcomes (Feifel, 2008; Laughren, 2001; Gispen-de Wied et al, 
2012). Additionally, from a scientific point of view, randomized double-blind 
comparisons versus placebo are needed to permit adequate evaluation of efficacy. 
Comparison to a placebo treatment is also of value for distinguishing disease 
manifestations from adverse reactions to the IP (EMA guidance, 2013). At present, there 
is no approved pharmacologic therapy as an acute intervention for treatment of symptoms 
of suicidality and depression.  However, patients who present with imminent risk of 
suicide require careful assessment, monitoring, and are typically treated with 
pharmacologic agents based upon their primary diagnosis and comorbidities (Jacobs et al, 
2010).  For this reason, the IP will be given in addition to standard therapy. The use of 
placebo given in addition to standard therapy should not cause irreversible health 
problems or extreme suffering (depression is recognized by the FDA as a condition in 
which there is substantial improvement and variability in placebo groups) (FDA 
Guidance for Industry: E10, May 2001). 
Safety and efficacy assessments are included at every visit to determine adequacy of 
response, safety, and tolerability. In the event of insufficient therapeutic response or 
worsening of the patient’s initial condition, the IP should be discontinued and an 
alternative treatment will then be allowed (Section 9.4.12). An independent Data and 
Safety Monitoring Board (DSMB) will evaluate safety data during the study 
(Section 9.8).
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
1. Written informed consent, obtained from the patient before the initiation of any 
study-specific procedures (Section 5.3) 
2. Male or female outpatients, 18 to 65 years of age
3. Have current, ongoing suicidal ideation or behavior of sufficient severity to warrant 
hospitalization based on the judgment of the investigator and at least one of the 
following:
 


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5. Meet DSM-5 criteria for MDD
 with a current 
major depressive episode of at least 4 weeks and not exceeding 24 months in duration 
at Visit 1)
 
 
 
 
 
 
8. If female of childbearing potential, have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test (local laboratory results may be used for 
purposes of inclusion)
9. Ability to follow study instructions and likely to complete all required visits


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9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study.
Exclusion criteria to be assessed at Screening (Visit 1)
Psychiatric and Treatment-Related Criteria
1. DSM-5–based diagnosis of any disorder other than MDD that was the primary focus
of treatment within 1 month before Visit 1. Some comorbid conditions (eg,
generalized anxiety disorder, social anxiety disorder, or specific phobias) are 
acceptable provided they play a secondary role in the balance of symptoms, are not 
the primary driver of treatment decisions, and are not excluded in other criteria
2. Have known lifetime history or currently meet DSM-5 criteria for:
a.
Schizophrenia spectrum or other psychotic disorder
b. Bipolar or related disorder
c.
Major neurocognitive disorder
d. Neurodevelopmental disorder of greater than mild severity or of a
severity that impacts the patient’s ability to consent, follow study
directions, or otherwise safely participate in the study
e.
Dissociative disorder
f.
Posttraumatic stress disorder
g. MDD with psychotic features


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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of the study 
visits and procedures. Patients can be prematurely discontinued from the study after 
careful consideration for 1 of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria)

Pregnancy

Withdrawal of consent 

AE
o
Any patient who meets any of the following criteria at any point during the 
study must be withdrawn from participation due to suicidality-related AE:
a) A treatment-emergent suicide attempt, interrupted attempt, or aborted 
attempt
b) Significant increase in suicide risk, requiring removal from study as 
judged by the investigator, based on all available information such as
the psychiatric interview or information collected in the study 
assessments
Note: In the event that a patient is withdrawn for a suicidality-related AE, the patient 
should be referred for additional treatment or hospitalization, as clinically indicated, in 
addition to withdrawing the patient from the study.

Lack of efficacy

Protocol deviation

Lost to follow-up 

Study terminated by sponsor

Study center terminated by sponsor

Other 
All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at an ET Visit. A final assessment will be defined as 
completion of the evaluations scheduled for all patients at Visit 10. All patients 
discontinuing the study prematurely should enter the 1-week safety follow-up period.


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Patients who discontinue from the study and do not return to the study center for final 
assessments must be requested in writing to return to the study center for a final 
assessment. A copy of the letter, together with the source documentation, will be kept in 
the investigator’s files. The reason for premature discontinuation from the study will be 
recorded on the Study Termination Page of the eCRF. Study center staff will be contacted 
by the sponsor after each premature discontinuation to ensure proper characterization of 
the reason for discontinuation is captured.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.4
TREATMENTS
Patients meeting the eligibility criteria at the end of Visit 2 (Baseline) will be randomized 
in double-blind fashion to 1 of 2 treatment groups: placebo or rapastinel 450 mg weekly. 
The treatments will be given in a double-blind fashion.  The study treatments are to be 
given in addition to local SOC treatment with limited restrictions as described in 
Section 9.4.9.1.
9.4.1
Treatments Administered
The IP will only be administered to eligible patients by a medically qualified person as 
per the local state regulations. The range of persons who can administer an IV can be a 
physician, a physician assistant, nurse, or nurse practitioner, etc, depending on the local 
and/or state law.  
IP should be administered after all efficacy and safety assessments with the exception of 
the post-dose assessments described below. IP will be administered in a “slow bolus” 
injection to each study patient in an upper extremity vein within approximately 1 to 
2 minutes. 
During IP administration and until completion of post-administration assessments a 
licensed physician must be immediately available and in close proximity to the patient(s) 
to attend to medical emergencies.  The facility must have the capabilities, in accordance 
with the state and local regulations/SOC, to resuscitate a patient in the event of a medical 
emergency.  
At IP administration visits conducted on an outpatient basis after hospital discharge, the 
patient should not be released from the study center until the following are completed:

Postadministration vital sign measures (approximately 15 minutes after 
administration)


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
Patient is clinically assessed and determined to not be at increased risk of 
suicidality in the opinion of the investigator (or medically qualified 
subinvestigator)

Patient is assessed for mental status and is determined to be free of perceptual 
disturbances or other conditions that would deem them not ready for release from 
the study center, in the opinion of the investigator (or medically qualified 
subinvestigator)

A physician licensed in the state (investigator or subinvestigator) determines that 
they are medically able to leave the study center and provides written sign-off not 
less than 15 minutes following administration (see IV Administration and 
Discharge Notes document in Program Reference Manual)
9.4.2
Identity of Investigational Products
Rapastinel 450 mg IV Prefilled Syringes: 
 
 
Placebo rapastinel IV Prefilled Syringes: 
 
 
 
 
The study center personnel will complete the kit label and attach the tear-off portion to 
the source documents. 
The prefilled syringe will be labeled with the protocol number and kit number. The study 
center personnel will write the PID number on the prefilled syringe associated with the 
kit mentioned above. The prefilled syringe will not have a tear off and will remain on the 
prefilled syringe.


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9.4.3
Handling of Investigational Products
The IP must be stored in a secure area and administered only to patients entered into the 
clinical study, at no cost to the patient, in accordance with the conditions specified in this 
protocol.
 
 
Study centers must report any temperature 
excursions as described in the Study Reference Manual or contact the sponsor or its 
designee for further instructions. 
At the end of the study, all IP must be accounted for. In addition, at the end of the study, 
all unused IP should be returned to the sponsor or the local distributor at the address 
provided in the Study Reference Manual.
9.4.4
Method of Assigning Patients to Treatment Groups
After a patient signs the ICF at Screening (Visit 1), study personnel will register the 
patient in the IWRS, and the system will assign the patient a sequential PID. 
 
 
 
 
 
 
The IP will be labeled with medication kit numbers. The IWRS will provide the study 
center with the specific medication kit number(s) for each randomized patient at the time 
of randomization. Study centers will dispense IP according to the IWRS instructions. 
Study centers will also log on to the IWRS at subsequent visits to obtain a study 
medication kit number for dispensing the IP. Study centers will receive the IWRS 
confirmation notifications for each transaction. All notifications are to be maintained with 
the study source documents.
9.4.5
Selection of Dosages in the Study
The dose of rapastinel in this study was selected based on 2 Phase 2 clinical studies in 
patients with MDD, in which single IV doses of rapastinel 5 mg/kg and 10 mg/kg were
shown to produce marked antidepressant effects within 1 day that lasted approximately
1 week or longer in responding patients.
A 450-mg unit dose is expected to be appropriate for most patients as this represents a 
dose of 4.5 mg/kg in a 100-kg patient and a dose of 9 mg/kg in a 50-kg patient.


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9.4.6
Selection and Timing of Dose for Each Patient
The IP will be administered IV using the assigned single-use prefilled syringes at 
Visits 2, 6, 8, and 9.
9.4.6.1
Screening Period
At Screening (Visit 1) after written consent is obtained, patients enter a screening period 
of up to 5 days. No IP is administered during the screening period.
9.4.6.2
Double-blind Treatment Period
Patients who meet all eligibility criteria at Screening (Visit 1) and who continue to meet 
all the eligibility criteria for participation in the study at the Baseline Visit (Visit 2) will 
be assigned an IP kit number via IWRS at Baseline (Visit 2). Patients will receive the 
first dose of IP that day. The IP kit numbers will also be assigned by IWRS at subsequent 
treatment visits (ie, Visits 6, 8, and 9).
Patients will receive either rapastinel 450 mg or placebo from a prefilled single-dose 
syringe at Visits 2, 6, 8, and 9. 
9.4.6.3
Safety Follow-up Period 
Patients who complete 4 weeks of randomized treatment and those who discontinue the 
study prematurely should enter the safety follow-up period. No IP is administered during 
the safety follow-up period and patients may be treated as deemed appropriate by the 
investigator.
9.4.7
Blinding
A list of patient randomization codes will be generated by Statistical Programming and 
implemented by the IWRS vendor (an electronic version will be stored on a secure 
server). This list will identify each patient by randomization number and include the 
patient’s corresponding treatment assignment.
All study treatments will be provided in identical syringes and cartons to maintain 
masking of the study.


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9.4.8
Unblinding
Any unblinding at the study center level should be done only in an emergency that 
requires identification of the IP for the medical management of the patient. The 
investigator must notify the Medical Safety Physician immediately (refer to Appendix II) 
and a full written explanation must be provided if the blind is broken. Before IP is 
unblinded, every attempt should be made to discuss the case with the study physician or 
Medical Safety Physician. Breaking the code at the study center will immediately 
disqualify the patient from further participation in the study.
Treatment codes may be broken by Global Drug Safety for regulatory reporting purposes. 
In such cases, the study staff will be kept blinded and the patient will not need to be 
disqualified from the study.
For IWRS Unblinding
In an emergency, the investigator can obtain the treatment assignment of any patient at 
his or her study center through the IWRS. The investigator will access the IWRS to break 
the blind.
9.4.9
Prior and Concomitant Therapy
Medication history (psychotropic medication history during the previous 2 years and all 
other medications during the past 12 months) will be recorded at Screening (Visit 1) in 
the eCRF. Thereafter, any changes in concomitant medications or any new medications 
added will be recorded in the eCRF.
9.4.9.1
Permitted Medications/Treatments
 
 
 
 
 
 
 


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9
2
 
 
 
 
 
 
 
 
9.4.10
Other Restrictions
9.4.10.1
Alcohol 
It is recommended that patients abstain from alcohol consumption during the study.
9.4.10.2
Contraception
For purposes of this study, females will be considered of childbearing potential unless 
they are naturally postmenopausal or permanently sterilized (ie, hysterectomy). Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any 
other obvious pathological or physiological cause. 


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For women of childbearing potential and male partners of childbearing potential who 
may participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable: hormonal contraceptives (ie, oral, patch, injection, 
implant), male condom with intravaginal spermicide, diaphragm or cervical cap with 
spermicide, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral 
tubal ligation, bilateral salpingectomy), vasectomized partner, or sexual abstinence.
The investigator and each patient will determine the appropriate method of contraception 
for the patient during the participation in the study.
See Section 9.5.2.3 for pregnancy reporting procedures.
9.4.11
Monitoring Treatment Compliance
IP compliance during any period will be closely monitored by capturing the date and time 
of each injection of IP. If a scheduled injection does not occur, the sponsor must be 
notified and the reason captured in the eCRF.
9.4.12
Treatment After Discontinuation
Patients whose MDD or suicidality symptoms worsen or are determined by the 
investigator not to be adequately controlled prior to completing the DBTP will be 
allowed to discontinue the study and start appropriate treatment at the investigator’s 
discretion. This new treatment will not be provided by the sponsor. 
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9.5.1.1
Diagnostic Assessments
 
 


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9.5.1.2
Efficacy Assessments
The efficacy assessments (MADRS and S-STS) will be administered by a psychiatrist, 
doctoral-level clinical psychologist, or other clinician who has extensive professional 
training and experience in the diagnosis of mental illness and who meets the training 
requirements and qualifications standards set by the sponsor and rater training vendor.
9.5.1.2.1
The Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery and Åsberg, 1979) is a clinician-rated scale. The MADRS 
will be used to assess depressive symptomatology. Patients are rated on 10 items to 
assess feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep 
or appetite, difficulty concentrating, and lack of interest. Each item will be scored on a 
7-point scale. A score of 0 indicates the absence of symptoms, and a score of 6 indicates 
symptoms of maximum severity.
The MADRS will be evaluated at the timepoints indicated in Schedule of Evaluations 
(Section 2.0) using the Structured Interview Guide for the MADRS (SIGMA) 
methodology (Williams and Koback 2008).  At Screening (Visit 1) and Baseline (Visit 2) 
the MADRS will be administered with a look-back timeframe of 1 week.  At all other 
administrations, the MADRS will be administered with a look-back timeframe of “since 
last evaluation”.
9.5.1.2.2
Sheehan - Suicidality Tracking Scale 
The Sheehan - Suicidality Tracking Scale (S-STS) (Sheehan et al, 2014a; Sheehan et al, 
2014b) is a patient-report informed, clinician-rated scale used to rate the severity of both 
suicidal ideation and behavior.  The scale is compatible with the FDA categories for 
prospective assessment of suicidal ideation and behavior (FDA, 2012).  Developed for 
use as both a safety and efficacy outcome measure in research and in clinical settings, the 
scale is sensitive enough to detect an efficacy signal in conventional sample sizes used in 
clinical trials.  Each administration of the S-STS will include the patient- and clinician-
rated “Global Severity of Suicide Impulses, Thoughts, and Behaviors” items extracted 
from the Sheehan - Suicidality Tracking Scale: Clinically Meaningful Change Measures 
(S-STS CMCM) (Sheehan et al, 2014b).    


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The S-STS will be evaluated at the timepoints indicated in the Schedule of Evaluations
(Section 2.0). At Screening (Visit 1) and Baseline (Visit 2) the S-STS will be 
administered with a look-back timeframe of 1 week.  At all other administrations, the 
S-STS will be administered with a look-back timeframe of “since last evaluation”.
9.5.1.2.3
Clinician’s Assessment of Readiness for Hospital Discharge  
The clinician’s assessment of readiness for hospital discharge will capture the date of 
readiness for discharge based solely on clinical factors associated with the patient’s initial 
hospitalization for acute suicidality, regardless of whether actual discharge occurred on 
that date. The assessment should reflect the date upon which the patient has clinically 
improved to the extent that they would be eligible for discharge without consideration of 
protocol requirements, social factors, or other reasons that may prevent the actual 
discharge from occurring on that date.  This assessment will be administered by a 
psychiatrist or other clinician who has extensive professional training and experience in 
the diagnosis of mental illness and is authorized to make decisions regarding 
hospitalization and discharge of patients.
9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care 
professional at every visit and the evaluation must be documented. The procedures 
discussed below will be completed at the designated visits.
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A).


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For the purpose of the study center’s data collection responsibilities, any untoward event 
that was reported from the time the patient signed the ICF until 30 days after the final 
protocol-defined study visit or the last known dose of IP (if the final visit does not occur)
is to be considered an AE.
Examples of AEs are as follows:

Changes in the general condition of the patient

Subjective symptoms offered by or elicited from the patient

Objective signs observed by the investigator or other study center personnel

All diseases that occur after signing informed consent, including any change in 
severity or frequency of pre-existing disease

All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study schedule
Please note that medical procedures scheduled prior to consenting, but occurring during 
the study should not be captured as AEs, but should be listed in the medical history if 
related to a pre-existing condition.
9.5.2.1.1
Causality Assessment
For each AE, the investigator must provide an assessment of causal relationship to the IP. 
The causality assessment must be recorded on the appropriate AE reporting page of the 
patient’s eCRF. Causal relationship must be assessed by answering the following 
question:
Is there a reasonable possibility the IP caused the event?
Yes:
There is evidence to suggest a causal relationship between the IP and AE, ie: 

There is a reasonable temporal relationship between the IP and the event, 
and/or 

The event is unlikely to be attributed to underlying/concurrent disease or other 
factors, and/or

Positive dechallenge and/or rechallenge exist


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No:
There is no evidence to suggest a causal relationship between the IP and AE, 
ie:

There is no reasonable temporal relationship between the IP and the event, or

The patient did not take the IP, or

The event is likely to be attributed to underlying/concurrent disease or other 
factors, or

The event is commonly occurring in the (study) population independent of IP
exposure
9.5.2.1.2
Severity Assessment
The investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. Severity,
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 9.5.2.1.3). Severity will be 
assessed according to the following scale:
Mild:
A type of 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:
A type of 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 participant.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
9.5.2.1.3
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization


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
Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in patient hospitalization, or the 
development of IP dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (eg, elective procedures for pre-existing conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.
Any postbaseline worsening (as opposed to lack of improvement) of symptoms of 
suicidal ideation or behavior that is clinically significant based on the judgment of the 
investigator should be captured as an SAE.
Any extension of hospitalization beyond 14 days postbaseline for symptoms of suicidal 
ideation, behavior, or depression (eg, lack of improvement over 14 days), excluding other 
reasons such as placement issues, should be captured as an SAE.
9.5.2.1.4
Reporting Adverse Events and Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study center personnel will 
record all pertinent information in the patient’s eCRF. 
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF 
whether or not they are considered causally related to the IP.
For every AE, the investigator must:

Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as 
the severity and casual relationship

Document all actions taken with regard to the IP

Detail any other treatment measures taken for the AE


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
Document the outcome of the AE
In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify study center personnel of any AEs occurring during the 30-day 
poststudy period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least one of the following conditions is met: 1) the event meets the criteria for 
an SAE (see Sections 9.5.2.1.3 and 9.5.2.1.4), and/or 2) the event is judged by the 
investigator to be potentially causally related to IP.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the IP. If a follow-up visit is deemed necessary for 
appropriate safety surveillance, it will take place within 30 days of the final 
protocol-defined study visit.
9.5.2.2
Immediate Reporting of Serious Adverse Events and Events of 
Interest
The sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study center personnel must report the event to the sponsor on the SAE Form for Clinical 
Trials. The study physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The study center must transmit the SAE Form for Clinical Trials to the SAE fax number 
shown below. Even if an initial report is made by telephone, the SAE Form for Clinical 
Trials completed with all available details must still be faxed within 24 hours of 
knowledge of the event at the study center.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs are to be followed by 
the study staff until resolution or until the SAE is deemed stable. The sponsor may 
contact the study center to solicit additional information or follow up on the event.


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9.5.2.3
Reporting of Pregnancies Occurring During the Study
Study center personnel must report every pregnancy from the time the patient signs the 
ICF until 30 days after the last dose of IP. Within 24 hours of learning of the pregnancy, 
the study center personnel must report the event to Global Drug Safety on the Clinical 
Trial Pregnancy Form and fax it to the SAE/Pregnancy fax number provided in 
Section 9.5.2.2, even if no AE has occurred. Pregnancies in female partners of male 
patients occurring during the time frame described above must also be reported. 
Any pregnancy of a patient treated with IP (or in female partners of male patients 
occurring during the time frame described above) must be followed to term and the 
outcome reported by completing a follow-up Clinical Trial Pregnancy Form. If the 
pregnancy is associated with an SAE (eg, if the mother is hospitalized for hemorrhage), a 
separate SAE Form for Clinical Trials must be filed as described in Section 9.5.2.2, with 
the appropriate serious criterion (eg, hospitalization) indicated in addition to the 
pregnancy form.
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9.5.4
Health Economic and Outcomes Research Assessments
Health outcomes will not be assessed in this study.
 
 


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9.5.5.12
Unscheduled Visits
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator. Additional examinations may be performed as necessary to ensure the safety 
and well-being of the patients during the study.


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9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the study, a representative of the sponsor will meet with the 
investigator and the study center staff to review the procedures to be followed during the 
study. Electronic data capture (EDC) functionality training is provided via 
computer-based training to train investigators and authorized designees on recording the 
data in the eCRFs using the EDC system. After the first patient is enrolled, the sponsor
representative, a Regional Site Manager or designee, will periodically monitor the 
progress of the study by conducting on-site visits. This Regional Site Manager or 
designee will review query statuses remotely, possibly warranting more frequent 
communication and/or study center visits with the investigator and the study center staff. 
The investigator will make available to the Regional Site Manager or designee source 
documents (written notes and electronic medical records, if used), signed consent forms, 
and all other study-related documents. The investigator and the study center staff will be 
responsible for data entry of patient data into the eCRFs via the EDC system, resolving 
data queries generated via the EDC system, and providing missing or corrected data. The 
investigator or designee will be responsible for approving all changes performed on the 
data, and endorsing the patient data within the EDC system. This approval method will 
include applying an electronic signature linked to a uniquely assigned username and 
password that together will represent a traditional handwritten signature used in the past.
9.6.2
Data Recording and Documentation
Data collection will involve the use of the EDC system, to which only authorized 
personnel will have access. Patient’s data are to be entered into the EDC system by the 
investigator or designee using their assigned EDC user account. After data entry into the 
EDC system by the investigator or designee, a combination of manual and programmatic 
edit checks will be used to review the data for completeness, logic, and adherence to 
study protocol. As a result of these edit checks, data monitoring, and reviews, queries 
may be electronically issued to the study center and should be answered electronically via 
the EDC system.
Each query will carry identifying information (assigned username, date, and time) to 
assist the sponsor and the investigator on the origin of the data clarification request and 
the response provided by the investigator. All data changes made to the patient’s data via 
a data query will be approved by the investigator prior to final database lock.
After all data have been reviewed and all issues have been resolved, the database will be 
locked.


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All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, regulatory documents) will be retained at the study center, along with 
adequate source documentation, according to FDA and ICH requirements. All study 
records must be available for inspection by the sponsor, its authorized representatives, the 
FDA, or other health authorities.
Source documents will be used at the study centers and may include a patient’s medical 
record, hospital charts, clinic charts, the investigator’s patient study files, as well as the 
results of diagnostic tests such as laboratory tests, ECGs, etc. 
 
 will be captured using an electronic source 
tablet-based system, with paper source to be used only as a backup if it is not possible to 
use the tablet-based system. A centralized clinical laboratory will be used for the analysis 
of all blood samples. Additional information on the collection and handling of samples is 
detailed in the Lab Procedure Manual.
9.7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
9.7.1
Analysis Populations
Four populations will be considered in the statistical analysis of the study, as specified in 
the following subsections.
9.7.1.1
Screened Population
The Screened Population will consist of all patients who sign informed consent and 
receive a PID number.
9.7.1.2
Randomized Population
The Randomized Population will consist of all patients in the Screened Population who 
are randomized to a treatment group in the study.
9.7.1.3
Safety Population
The Safety Population will consist of all patients in the Randomized Population who took 
at least 1 dose of randomized IP.


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9.7.1.4
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who had at least 1 postbaseline assessment of the MADRS total score. 
9.7.2
Patient Disposition
The number and percentage of patients in the Randomized, Safety, and ITT populations
will be summarized by treatment group and study center; the Screened Population will 
only be summarized overall and by study center.
Screen failures (ie, patients screened but not randomized) and the associated reasons for 
failure to randomize will be tabulated overall for the Screened Population. The number 
and percentage of patients who complete the DBTP, patients who prematurely 
discontinue during the same period and who enter the safety follow-up period will be 
presented for each treatment group and pooled across treatment groups for the 
Randomized Population. The reasons for premature discontinuation from the DBTP as 
recorded on the termination pages of the eCRFs will be summarized (number and 
percentage) by treatment group for the Randomized Population.
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (eg, age, race, ethnicity, sex, weight, height, body mass index 
[BMI]) and other baseline characteristics will be summarized by treatment group for the 
Safety and ITT populations. 
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
The number and percent of patients who received 1, 2, 3, and 4 randomized IV doses will 
be summarized by treatment group for the Safety Population.
Prior medication is defined as any medication taken before the date of the first dose of 
randomized IP. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of randomized IP. 
Both prior and concomitant medication use will be summarized by the number and 
proportion of patients in each treatment group receiving each medication within 
each therapeutic class for the Safety Population. Multiple medication use by a patient will 
only be counted once.


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9.7.4.2
Measurement of Treatment Compliance
Dosing compliance for a specified period is defined as the total number of IV doses 
actually taken by a patient during that period divided by the number of IV doses that were 
expected to be taken during the same period multiplied by 100. Descriptive statistics for 
IP compliance will be presented by treatment group for each week, as well as for the 
whole DBTP of the study for the Safety Population.
9.7.5
Efficacy Analyses
All efficacy analyses will be based on the ITT Population, unless stated otherwise. The 
baseline for each specific efficacy endpoint is defined as the last measurement prior to the 
first dose of randomized treatment. All statistical hypothesis tests will be performed at the 
2-sided 5% significance level for main effects. All confidence intervals (CIs) will be 
2-sided 95% CIs, unless stated otherwise. 
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with < 2 patients in ≥ 1 treatment group in the ITT Population. Small centers will 
be pooled to form pseudo-centers so that each treatment group includes ≥ 2 ITT patients 
within the center. Pooling will be done using the following algorithm: 
Based on the number of ITT patients, small centers will be ordered from the largest to the 
smallest, and centers of the same size will be ordered from the largest center code to the 
smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small center is 
formed. The process will be repeated using the small centers left out after the first pass. If 
any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is > 1 smallest pseudo-center, the pseudo-center with the smallest 
center code will be selected. In case the pseudo-center formed by pooling all small 
centers is still a small center, it will be pooled with the smallest non-small center. If there 
is > 1 smallest non-small center, the one with the smallest center code will be selected.
9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter will be the change from baseline in MADRS total score 
at 1 day after first dose of treatment. The primary analysis will be performed using an 
analysis of covariance (ANCOVA) model with terms for treatment, study center, and 
baseline MADRS total score. The analysis will be performed based on postbaseline 
scores using only the observed cases without imputation of missing values. The treatment 
difference for rapastinel versus placebo will be estimated and reported along with the 
corresponding 95% CI and the p-value for superiority testing.


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9.7.5.2
Key Secondary Efficacy Parameter
The key secondary efficacy parameter will be the change from baseline in S-STS total 
score at 1 day after first dose of treatment. The same statistical method for the primary 
efficacy parameter will be used for the key secondary efficacy parameter with baseline S-
STS total score as the covariant in the ANCOVA model.
To control the overall type I error rate for multiple comparisons of rapastinel with 
placebo for primary and key secondary endpoints, Hochberg testing procedure will be 
implemented. 
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9.7.6.1
Adverse Events
All AEs will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities.
An AE (classified by preferred term) will be considered a treatment-emergent adverse 
event (TEAE) if it was not present before the first dose of IP or was present before the 
date of the first dose of IP and increased in severity after the first dose of IP. If more than 
1 AE is reported before the first dose of IP and coded to the same preferred term, the AE 
with the greatest severity will be used for comparison with the AEs occurring during the 
DBTP that were also coded to that preferred term. An AE that occurs more than 30 days
after the date of the last dose of IP will not be considered as a TEAE.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term and further categorized by severity 
and causal relationship to the IP. If more than 1 AE is coded to the same preferred term 
for the same patient, the patient will be counted only once for that preferred term using 
the greatest severity and strictest causality for the summarization by severity and causal 
relationship.


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The distribution of TEAEs by severity and relationship to the IP will be summarized by 
treatment group. 
An AE that occurs more than 30 days after the date of the last dose of IP will not be 
summarized.
The incidence of common (≥ 2% of patients in any treatment group) TEAEs and AEs 
leading to premature discontinuation of IP will be summarized by preferred term and 
treatment group and sorted by decreasing frequency for the test treatment. 
An SAE that occurred between the date of the first dose of IP and 30 days after the date 
of the last dose of IP, inclusive, will be considered an on-therapy SAE. The number and 
percentage of patients who have on-therapy SAEs will be summarized by preferred term 
and treatment group. In addition, the incidence of on-therapy SAEs that led to death will 
be summarized separately by preferred term for each treatment group.
Listings will be presented for patients with SAEs, patients with AEs leading to 
discontinuation, and patients who die (if any). All patients with SAEs, including SAEs 
reported during the screening period and the safety follow-up period, and patients 
discontinuing because of AEs occurring before the start of IP will be included in these 
listings.
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9.7.7
Health Economics and Outcomes Research Analyses
Not applicable.
9.7.8
Interim Analysis
No interim analysis is planned for this study.


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9.7.9
Determination of Sample Size
This study will randomize approximately 300 patients to the rapastinel 450 mg and 
placebo groups in a 1:1 ratio. The primary efficacy endpoint is the change from baseline 
in the MADRS total score at 1 day after the first dose of treatment. Assuming the SD is 
10 points, a sample size of 150 patients per treatment group will provide 90% power to 
detect a difference of 3.76 points for a rapastinel dose versus placebo at a 2-sided 
significance level of 5%.
9.7.10
Computer Methods
Statistical analyses will be performed using version 
 
.
9.8
DATA AND SAFETY MONITORING BOARD
The study will be conducted under the supervision of an independent DSMB to be 
chartered to review safety data at predetermined points during the study. The DSMB may 
also decide to meet and review safety data at other timepoints should it be deemed 
necessary. The DSMB is responsible for the ongoing review of safety data in the clinical 
study and for making recommendations concerning the continuation, modification, and 
termination of the study (FDA Guidance for Clinical Trial Sponsors: Establishment and 
Operation of Clinical Trial Data Monitoring Committees, March 2006).
All analyses that are required to support the DSMB will be performed by an independent
unblinded statistician not otherwise involved in the study. Details of the DSMB 
membership, meeting schedule, and data review and analysis will be documented in the 
DSMB Charter.
9.9
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the investigator in writing by the 
sponsor. No protocol amendment may be implemented (with the exceptions noted below) 
before it has been approved by the IRB, and the signature page, signed by the 
investigator, has been received by the sponsor. If the protocol is amended to eliminate or 
reduce the risk to patients, the amendment may be implemented before IRB review and 
approval. However, the IRB must be informed in writing of such an amendment, and 
approval must be obtained within reasonable time limits. 


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9.10
PROTOCOL DEVIATIONS
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB approval or favorable opinion of an appropriate 
amendment and that does not have a major impact on the patient’s rights, safety, or well-
being, or on the integrity and authenticity of the study data. Deviations may include, but 
are not limited to, departure from inclusion/exclusion criteria, dosing, duration of 
treatment, failure to perform the required assessments at specified timepoints, scheduling 
of visits not in accordance with specifications, or patient safety. Deviating from the 
protocol is permitted only if absolutely necessary for the safety or clinical management of 
the patients and must immediately be reported to the sponsor.
An important protocol deviation is a form of protocol deviation that has a major impact 
on the patient’s rights, safety, or well-being, or on the integrity and authenticity of the 
study data. Important protocol deviations must be reported to the sponsor within 
24 hours, if possible. The IRB must be notified within the time period dictated by the IRB 
associated with this study. 


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10.0
STUDY SPONSORSHIP
This study is sponsored by Naurex, an indirect subsidiary of Allergan, plc. 
10.1
STUDY TERMINATION
The sponsor reserves the right to terminate the study in its entirety or at a specific study 
center before study completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this study are the property of the sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
Publication of the results by the investigator will be subject to mutual agreement between 
the investigator and the sponsor and will follow the sponsor’s Standard Operating 
Procedure on publications.


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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The investigator must provide the following to the sponsor before the start of the study:

A completed and signed Form FDA 1572. If, during the course of the study, any 
changes are made that are not reflected on Form FDA 1572, a new Form FDA 1572 
must be completed and returned to the sponsor for submission to the FDA.

A fully executed contract

The curricula vitae for the investigator and all subinvestigators listed on Form FDA 
1572, including a copy of each physician’s license

A copy of the original IRB approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent modifications must be 
submitted and approved by the IRB, as stated in Section 5.1.

A copy of the IRB-approved ICF

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB members or the US Department of Health and Human Services 
general assurance number

A copy of the laboratory certifications and reference ranges

The Investigator’s Statement page in this protocol. signed and dated by the 
investigator

Financial disclosure agreement completed and signed by the investigator and all 
subinvestigators listed on Form FDA 1572. The investigator and all subinvestigators 
will provide an updated financial disclosure agreement to the sponsor 1 year after the 
completion of the study.
11.2
PERFORMANCE
The investigator must demonstrate reasonable efforts to obtain qualified patients for the 
study.


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11.3
USE OF INVESTIGATIONAL MATERIALS
The investigator will acknowledge that the IP supplies are investigational and as such 
must be used strictly in accordance with the protocol and only under the supervision of 
the investigator or subinvestigators listed on Form FDA 1572. The IP must be stored in a 
secured place and must be locked. At study initiation, a representative from the sponsor
will inventory the IP at the study center. The investigator must maintain adequate records 
documenting the receipt and disposition of all study supplies. The sponsor will supply 
forms on which to record the date the IP was received and a dispensing record in which 
to record each patient’s use. All unused IP must be returned to the sponsor. 
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by the 
sponsor through the EDC system. The investigator is responsible for verifying that all 
data entries in the eCRFs are accurate and correct by electronically signing the completed 
eCRF casebook submitted to the sponsor. The investigator must maintain and retain 
accurate documentation that supports the information entered into the EDC system for 
source document verification and possible regulatory inspection.
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents, consent forms, regulatory documents, clinical laboratory results, calibration 
logs, or reports (including, but not limited to, all local and central laboratory results and 
ECG reports), and medication inventory records in all formats (including, but not limited 
to, written, electronic, magnetic, and optical records, and scans, x-rays, and ECGs) must 
be retained by the investigator for a period of at least 15 years after study completion 
unless local regulations or institutional policies require a longer retention period or 
otherwise notified in writing by the sponsor. 
No study records shall be destroyed without notifying the sponsor and providing the 
sponsor the opportunity to arrange long-term storage for such study records or 
authorizing in writing the destruction of records after the required retention period.
The investigator must permit access to any documentation relating to the study upon 
request of the sponsor or applicable regulatory authorities. If the investigator for the study 
retires, relocates, or for other reasons withdraws from the responsibility of keeping the 
study records, custody must be transferred to a suitable alternate custodian employee of 
the institution or to a suitably qualified and responsible third party. The sponsor must be 
notified in writing of the name and address of the new custodian in advance of the 
transfer.


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11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by initials and PID number. Patients’ names are 
not to be transmitted to the sponsor. The investigator will keep a master patient list on 
which the PID number and the full name, address, and telephone number of each patient
are listed.


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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (RAP-MD-20 [3106-201-
008]) and with all applicable government regulations and good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name


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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study. This consent must 
include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA, the 
sponsor, the IRB, or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the investigator as the 
contact. The guidance of the IRB may be required.)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of permission, providing consent for the patient to participate (eg, “I 
agree to participate . . .”)

A place for the patient’s signature and date of signing the ICF

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient.


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APPENDIX II.
CONTACT INFORMATION 
Contact information for the sponsor personnel is maintained in the Study Reference 
Manual.


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14.0
LITERATURE CITED
American Psychiatric Association (2013). Diagnostic and statistical manual of mental 
disorders: DSM-5. Washington, DC: American Psychiatric Association.
Berman, AL. Estimating the population of survivors of suicide: Seeking an evidence 
base. Suicide and Life-Threatening Behavior 2011;41:110-116.
Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J 
Psychiatry 2000;157:1925-1932.
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the 
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Report 2001.

SAP_000.pdf: 
NCT03352453 
 
Study ID: RAP‐MD‐20 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter, Efficacy and Safety Study of 
Rapastinel for Rapid Treatment of Symptoms of Depression and Suicidality in Adult Patients with Major 
Depressive Disorder 
 
Statistical Analysis Plan: 20 May 2019 
 
 
 


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Naurex Inc., an indirect subsidiary of Allergan, plc
5 Giralda Farms 
Madison, NJ 07940
RAP-MD-20
A Randomized, Double-blind, Placebo-controlled, Multicenter, Efficacy and Safety 
Study of Rapastinel for Rapid Treatment of Symptoms of Depression and 
Suicidality in Adult Patients with Major Depressive Disorder 
STATISTICAL ANALYSIS PLAN
Version 1.0: 20 May 2019
Confidentiality Statement
This document is the property of Allergan, plc. and may notin full or partbe passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, plc.


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
LIST OF IN-TEXT TABLES..........................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................4
1.0
LIST OF ABBREVIATIONS...........................................................................................................5
2.0
INTRODUCTION ............................................................................................................................7
4.0
STUDY OBJECTIVES...................................................................................................................11
5.0
ANALYSIS POPULATIONS.........................................................................................................14
5.1
Randomized Population....................................................................................................14
5.2
Safety Population..............................................................................................................14
5.3
Modified Intent-to-Treat Population.................................................................................14
6.0
PATIENT DISPOSITION ..............................................................................................................15
6.1
Protocol Deviations ..........................................................................................................15
7.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................16
8.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................17
8.1
Extent of Exposure ...........................................................................................................17
8.2
Measurement of Treatment Compliance...........................................................................17
8.3
Weight-Adjusted Dose of Rapastinel................................................................................17
9.0
EFFICACY ANALYSES ...............................................................................................................18
9.1
Primary Efficacy Analysis................................................................................................18
9.2
Secondary Efficacy Analysis............................................................................................19
10.0
SAFETY ANALYSES....................................................................................................................24
10.1
Adverse Events .................................................................................................................24
11.0
DETERMINATION OF SAMPLE SIZE .......................................................................................31


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12.0
STATISTICAL SOFTWARE.........................................................................................................32
13.0
STATISTICAL AND DATA HANDLING CONVENTIONS.......................................................33
13.1
Summary Statistics ...........................................................................................................33
13.2
Visit Windows ..................................................................................................................33
13.3
Derived Efficacy and Safety Variables.............................................................................34
13.4
Repeated or Unscheduled Assessments of Safety Parameters..........................................34
13.5
Missing Severity Assessment for Adverse Events............................................................34
13.6
Missing Causal Relationship to Study drug for Adverse Events ......................................35
13.7
Missing Date Information for Adverse Events .................................................................35
13.8
Missing Date Information for Prior or Concomitant Medications....................................36
13.8.1
Incomplete Start Date.........................................................................................36
13.8.2
Incomplete Stop Date .........................................................................................37
14.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................40
15.0
REFERENCES ...............................................................................................................................41
16.0
17.0
HISTORY OF CHANGES .............................................................................................................48


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LIST OF IN-TEXT TABLES
LIST OF IN-TEXT FIGURES
Figure 9.2-1.
Graphical Testing Procedure .....................................................................................20


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1.0
LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
BPM
beats per minute
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
DBTP
double-blind treatment period
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
ET
early termination
IP
investigational product
IV
intravenous
IWRS
interactive web response system
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
Major Depressive Disorder
MMRM
mixed-effects model for repeated measures


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PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard déviation
SFU
safety follow-up
SI
Le Système International d’Unités (International System of Units)
SOC
standard of care
S-STS
Sheehan-Suicidality Tracking Scale
TBL
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal 


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2.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined and/or specified in the 
final protocol amendment 2 of RAP-MD-20 (version dated 20 MAY 2019). 
Specifications of tables, figures, and data listings are contained in a separate document.
RAP-MD-20 is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, 4-week, fixed-dose study comparing rapastinel with placebo in patients 
with MDD experiencing suicidality. The study will be approximately 5 to 6 weeks in 
duration and will include the following periods: 

Approximately 5-day screening period 

4-week double-blind treatment period (DBTP)

1-week safety follow-up period 
Approximately 300 patients are planned to be randomized in the DBTP (150 patients per 
treatment group).
A schematic of the study design is presented in Figure 3–1. The Schedule of Evaluations 
is provided in Section 3.0.
Patients will be randomized in a ratio of 1:1 to 1 of 2 treatment groups in DBTP: 
rapastinel 450 mg IV weekly injection or placebo IV weekly injection. During 
participation in the study, patients may be treated per local SOC with limited restrictions
and IP will be administered in addition to SOC treatments.
Patients completing the DBTP and patients who prematurely discontinue from the study 
before completing 4 weeks of double-blind treatment should enter the 1-week safety 
follow-up period. 
Additional follow-up visits may be scheduled within 30 days of last dose of IP or last 
study visit, if necessary for safety reasons.


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4.0
STUDY OBJECTIVES
The objectives of this study are to evaluate the efficacy, safety and tolerability of 
rapastinel as a rapid treatment of symptoms of depression and suicidality in adult patients 
with MDD who are at imminent risk of suicide.
Primary Efficacy Objectives

To evaluate the efficacy of rapastinel (450 mg IV) versus placebo as a rapid treatment 
of MDD symptoms in adult patients with MDD who are at imminent risk of suicide, 
as measured by the change from baseline Montgomery-Asberg Depression Rating 
Scale (MADRS) total score at 1 day after first dose of investigational product (IP)

To evaluate the efficacy of rapastinel (450 mg IV) versus placebo as a rapid treatment 
of suicidality symptoms in adult patients with MDD who are at imminent risk of 
suicide, as measured by the change from baseline on the Sheehan-Suicidality 
Tracking Scale (S-STS) total score at 1 day after first dose of IP
Key Secondary Efficacy Objectives:

To evaluate the efficacy of rapastinel (450 mg IV) versus placebo in the treatment of 
MDD symptoms, as measured by change from baseline MADRS at 28 Days after first 
dose of IP.

To evaluate the efficacy of rapastinel (450 mg IV) versus placebo in the treatment of 
suicidality symptoms, as measured by the change from baseline on the S-STS total 
score at 28 Days after first dose of IP.


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S
:
 
 
 
 
 


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5.0
ANALYSIS POPULATIONS
The following populations will be considered in the statistical analysis of the study.
5.1
Randomized Population
The Randomized Population will consist of all screened patients who are randomized to a 
treatment group in the study.
5.2
Safety Population
The Safety Population will consist of all patients in the Randomized Population who took 
at least 1 dose of randomized IP.
5.3
Modified Intent-to-Treat Population
The modified Intent-to-Treat (mITT) Population will consist of all patients in the Safety 
Population who had at least 1 postbaseline assessment of the MADRS total score or 
S-STS total score. 


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6.0
PATIENT DISPOSITION
The number of patients in the Randomized, Safety, and mITT populations will be 
summarized by treatment group and study center.
Screen failures (ie, patients screened but not randomized) and the associated reasons for
failure to randomize will be tabulated overall for all screened patients. 
The number and percentage of patients who complete the DBTP, patients who 
prematurely discontinue during the same period and who enter the safety follow-up 
period will be presented for each treatment group and pooled across treatment groups for 
the randomized population. The reasons for premature discontinuation from the DBTP as 
recorded on the disposition pages of the eCRFs will be summarized (number and 
percentage) by treatment group for the randomized population.
6.1
Protocol Deviations
Protocol deviations will be defined in Protocol Deviation Requirement Specification, 
including significance classification. The number and percentage of patients with 
significant protocol deviations will be summarized by treatment group for the 
Randomized Population. A listing of all significant protocol deviations will be provided.


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7.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (eg, age, race, ethnicity, sex, weight, height, body mass index) 
and other baseline characteristics will be summarized overall and by treatment group for 
the mITT Population. 
Medical and surgical history, psychiatric history, previous treatment with psychotropic 
medication, and nondrug psychiatric treatment will be summarized by treatment group 
for the Safety Population.
Prior medication is defined as any medication taken before the date of the first dose of
randomized IP. Concomitant medication is defined as any medication taken on or after
the date of the first dose of randomized IP.
Both prior and concomitant medication use will be summarized by the number and
proportion of patients in each treatment group receiving each medication within
each therapeutic class for the Safety Population. Multiple medication use of the same 
therapeutic class by a patient will only be counted once.
The World Health Organization (WHO) Drug Dictionary Enhanced will be used to 
classify prior and concomitant medications by therapeutic class and drug name. 


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8.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
8.1
Extent of Exposure
The number and percentage of patients who received 1, 2, 3, and 4 randomized IV doses 
will be summarized by treatment group for the Safety Population. IV administration notes 
including site reaction at placement of IV, reaction to adhesive, infusion interruption, 
failure of administration device, increase in suicidality based on clinical evaluation, and 
perceptual disturbance based on mental status assessment are collected. For each item, 
the number and percentage of patients who had a ‘yes’ response will be summarized by 
treatment group and visit for the Safety Population.
Exposure to the IP for the Safety Population during the DBTP will be summarized for 
treatment duration, calculated as the number of days from the date of the first dose of 
double-blind IP taken to the date of the last dose taken during the DBTP, inclusive. 
Descriptive statistics will be presented by treatment group.
8.2
Measurement of Treatment Compliance
Dosing compliance is defined as the total number of IV doses actually taken by a patient 
during the DBTP divided by the number of IV doses that were expected to be taken 
during the DBTP multiplied by 100. Descriptive statistics for IP compliance will be 
presented by treatment group for each week for the Safety Population.
8.3
Weight-Adjusted Dose of Rapastinel
The dose of rapastinel will be divided by patient baseline weight and summarized 
descriptively by treatment group for the Safety Population.


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9.0
EFFICACY ANALYSES
All efficacy analyses will be based on the mITT Population, unless stated otherwise. The 
baseline for each specific efficacy endpoint is defined as the last non-missing 
measurement prior to the first dose of randomized treatment during DBTP.
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with < 2 patients in ≥ 1 treatment group in the mITT Population. Small centers will 
be pooled to form pseudo-centers so that each treatment group includes ≥ 2 mITT 
patients within the center. Pooling will be done using the following algorithm: 
Based on the number of mITT patients, small centers will be ordered from the largest to 
the smallest, and centers of the same size will be ordered from the largest center code to 
the smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small center is 
formed. The process will be repeated using the small centers left out after the first pass. If 
any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is > 1 smallest pseudo-center, the pseudo-center with the smallest 
center code will be selected. In case the pseudo-center formed by pooling all small 
centers is still a small center, it will be pooled with the smallest non-small center. If there 
is > 1 smallest non-small center, the one with the smallest center code will be selected.
These pseudo-centers will be used for all efficacy analyses when the model is adjusted 
for study center. The efficacy analyses using the mITT Population will be performed 
based on the treatment to which the patient is randomized regardless of the actual 
treatment received.
The efficacy analyses of MADRS assessments will be based on the rater-administered 
MADRS. The MADRS total score is the sum of the 10 individual items. If more than
2 items are missing, then the total score will be set to missing. If there are multiple 
assessments of MADRS total score for the same nominal visit of a participant, only the 
last assessment will be used in the analysis.
The efficacy analyses using the mITT population will be performed based on the 
treatment to which the patient is randomized regardless of the actual treatment received. 
9.1
Primary Efficacy Analysis
The primary efficacy parameters will be the change from baseline in MADRS total score 
and the change from baseline in S-STS total score at 1 day after first dose of treatment. 
The primary analysis for both primary efficacy parameters will be performed using 
analysis of covariance (ANCOVA) models with terms for treatment, study center, and 
baseline. The analysis will be performed based on postbaseline scores using only the 
observed cases without imputation of missing values. The treatment difference for 
rapastinel versus placebo will be estimated and reported along with the corresponding 
95% CI and the p-value for superiority testing.


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9.2
Secondary Efficacy Analysis
The two key secondary efficacy parameters are:

Change from baseline in MADRS total score at 28 days after first dose of treatment

Change from baseline in S-STS total score at 28 days after first dose of treatment
Analysis of change from baseline in MADRS total scores and change from baseline in 
S-STS total score will be performed using mixed-effects model for repeated measures 
(MMRM) with terms for treatment, study center, visit, baseline, and treatment-by-visit 
and baseline-by-visit interactions. An unstructured covariance matrix will be used to 
model the covariance of within-patient scores. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom (Kenward et al, 1997). The 
treatment difference for rapastinel versus placebo at selected timepoints will be estimated 
and reported along with the corresponding 95% CI and the p-value for superiority testing.
In the case that the MMRM with unstructured covariance fails to converge with the 
default algorithm, then the Fisher scoring algorithm will be used to provide better initial 
values of the covariance parameters; if the model still does not converge, a simplified 
model without term for study center will be used to find the initial values of the 
covariance parameters. In the rare event that model still does not converge after using 
those initial values, simplified covariance structures will be used to fit the model in the 
following order: (1) ante-dependence, (2) heterogeneous autoregressive, (3) Toeplitz, and 
(4) compound symmetry. If MMRM still fails to converge, by visit ANCOVA model 
similar to the primary efficacy analysis will be used for the analysis.
Let H1 and H2 represent the treatment effect comparisons of rapastinel with placebo in 
regards to the primary efficacy parameters of change from baseline in MADRS total 
score and change from baseline in S-STS total score at 1 day after first dose of treatment, 
respectively; and let H3 and H4 represent the treatment effect comparisons of rapastinel 
with placebo in regards to the secondary efficacy parameters of change from baseline in 
MADRS total score and change from baseline in S-STS total score at 28 days after first 
dose of treatment. The graphical procedure displayed in Figure 9.2-1 will be employed to 
control the overall familywise error rate at α=0.049. 


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Figure 9.2-1.
Graphical Testing Procedure
Specifically, H1 and H2 will be tested at a=0.0245 separately. If H1 is rejected, H3 will 
then be tested at a=0.0245. If H2 is rejected, H4 will then be tested at a=0.0245. If H3 is 
rejected but H2 is not rejected, H2 will be further tested at a=0.049. If H2 is rejected at 
a=0.049, H4 will be further tested at a=0.049. Similarly, if H4 is rejected but H1 is not 
rejected, H1 will be further tested at a=0.049. If H1 is rejected at a=0.049, H3 will be 
further tested at a=0.049.
 
 
 
 
 
 
 


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10.1
Adverse Events
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities and reported separately for DBTP and Safety 
Follow-up (SFU).
An AE (classified by preferred term) will be considered a treatment-emergent adverse 
event (TEAE) if it was not present before the first dose of DB IP or was present before 
the date of the first dose of DB IP and increased in severity after the first dose of DB IP. 
An AE that becomes serious after the date of the first dose of DB IP will also be 
considered as TEAE. If more than 1 AE was reported before the first dose of DB IP and 
coded to the same preferred term, the AE with the greatest severity will be used for 
comparison with the AEs occurring during each study period analyzed. An AE that 
occurred more than 30 days after the date of the last dose of DB IP will not be considered 
as a TEAE.
The number and percentage of patients reporting TEAEs and TEAEs leading to study 
discontinuation in each treatment group will be tabulated by system organ class and 
preferred term and further categorized by severity and causal relationship to the IP. If 
more than 1 AE is coded to the same preferred term for the same patient, the patient will 
be counted only once for that preferred term using the greatest severity and strictest 
causality for the summarization by severity and causal relationship.
The incidence of common (≥ 2% of patients in any treatment group) TEAEs will be
summarized by preferred term and treatment group and sorted by decreasing frequency 
for the test treatment.
A serious adverse event (SAE) that occurred between the date of the first dose of DB IP 
and 30 days after the date of the last dose of DB IP, inclusive, will be considered a 
treatment-emergent SAE (TESAE). The number and percentage of patients who have 
TESAEs will be summarized by preferred term and treatment group. 


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Listings will be presented for patients with SAEs, patients with AEs leading to
discontinuation, and patients who die (if any). All patients with SAEs, including SAEs 
reported during the screening period and the SFU, and patients discontinuing because of 
AEs occurring before the start of IP will be included in these listings.
 
 
 
 
 
 
 
 
 
 
 
 


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10.6
Interim Analysis
An unblinded interim analysis will be conducted to identify early signs of futility. An 
internal, but separate, fire-walled Statistical Analysis Group and Data Review Committee 
will be established to conduct the unblinded interim analysis, review the unblinded 
results and make recommendations regarding the continuation of the study. To maintain 
the scientific reliability of statistical analyses after the final database lock, preserve the 
integrity of study conduct, and guard from introducing any potential bias into the conduct 
of the study and/or analysis of its results, individuals in these two groups will not be 
involved in any operational aspects of the trial. Additionally, to adjust for multiple 
comparison issues caused by having several looks at the data, the Bonferroni method will 
be applied to split the overall Type I Error between the interim and final analysis 
(α = 0.001 and 0.049 2-sided, respectively) to further protect the integrity of the study. 
Further details of the unblinded interim analysis, in particular its scope, the processes put 
in place to maintain study validity, team structures, and responsibilities, are documented 
within a separate Data Review Committee Charter.


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11.0
DETERMINATION OF SAMPLE SIZE
This study will randomize approximately 300 patients to the rapastinel 450 mg and 
placebo groups in a 1:1 ratio. The sample size is determined based on the primary 
efficacy endpoint of the change from baseline in the MADRS total score at 1 day after the 
first dose of treatment. Assuming the SD of the change from baseline in the MADRS 
total score is 10 points, a sample size of 150 patients per treatment group will provide 
about 90% power to detect a difference of 3.76 points for a rapastinel dose versus placebo 
at a 2-sided significance level of 4.9%.
With respect to S-STS total score, 150 patients per arm will provide approximately 
88% power for a treatment difference of 4 between rapastinel 450 mg and placebo and 
estimated standard deviation of 11 based on the blinded analysis in April 2019 at a 
2-sided significance level of 4.9%.


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STATISTICAL SOFTWARE
Statistical analyses will be performed using 
.


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STATISTICAL AND DATA HANDLING CONVENTIONS
13.1
Summary Statistics
The following statistical summaries will be presented for each type of data. Further 
details are specified in the tables, figures, and listings shells.
-
Continuous variables will be summarized by descriptive statistics (number of 
patients, mean, standard deviation (SD), median, minimum, and maximum 
values). 
-
Categorical variables will be summarized by frequency distributions (counts and 
percentages).
-
Time-to-event data will be summarized by showing the number of patients, 
number of patients experiencing the event of interest, estimates of the median, 
1st quartile and 3rd quartile using the Kaplan Meier estimate as well as a 95% CI 
for the median.
13.2
Visit Windows
Table 13.2–1 presents the visits assigned for efficacy and safety analyses and the 
corresponding range of treatment days (window) during which an actual visit may occur.
Table 13.2–1.
Visit Windows
Analysis Visit
Target Date
Analysis Window (Based on Date)
Day 0 (Baseline)
IndexAa
Last record on or before IndexAa
Hour 4
IndexAa
(IndexAa, 6 hours after IndexAa]
Day 1
IndexAa+1
(6 hours after IndexAa, IndexAa+1]
Day 4
IndexAa+4
[IndexAa+2, IndexBb-1]
Day 7
IndexBb
IndexBb
Day 8
IndexBb+1
[IndexBb+1, IndexCc-1]
Day 14
IndexCc
[IndexCc, IndexDd-1]
Day 21
IndexDd
[IndexDd, IndexDd+3]
Day 28
IndexDd+7
[IndexDd+4, day of final double-blind visit or
early-termination visit occurring after IndexDd+3]
Day 35
IndexDd+14
Within the safety follow-up phase
a
IndexA: Date of the first dose
b
IndexB: Date of the second dose or IndexA+7 if the second dose was not administered


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c
IndexC: Date of the third dose or IndexB+7 if the third dose was not administered or IndexA+14 if both the 
second and the third dose were not administered
d
IndexD: Date of the fourth dose or IndexC+7 if the fourth dose was not administered or IndexB+14 if both the 
third and the fourth dose were not administered or IndexA+21 if the second, third and fourth dose were not 
administered
e
, the visit windows for Days 0 and 7 will be extended to cover the next dosing 
day (IndexB and IndexC, respectively); the visit window for Day 21 will be IndexD to the last double-blind visit, 
inclusively.
If a patient has 2 or more non-missing assessments within the same window, the 
assessment closest to the target day will be used for analysis; if there are 2 closest 
assessments with the same number of days from the scheduled day, the later one will be 
used for analysis.
13.3
Derived Efficacy and Safety Variables
The total score of each variable including MADRS, 
 at a particular 
visit will be calculated using (sum of nonmissing items) × (total number of items) / 
(number of non-missing items) only if the number of missing items is less than the 
specified number for each variable. Otherwise, the total score will be set to missing. 
Specifically, if more than 2 items are missing for MADRS, then the total score will be set 
to missing; 
 
 
Derivation of S-STS total score is detailed in Appendix II.
13.4
Repeated or Unscheduled Assessments of Safety Parameters
If a patient has repeated assessments before the start of the first treatment, the results 
from the last non-missing assessment made prior to the start of the IP will be used as 
baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
non-missing postbaseline assessment will be used as the end-of-study assessment for 
generating summary statistics. However, all postbaseline assessments will be used for 
PCS value determinations, and all assessments will be presented in the data listings.
13.5
Missing Severity Assessment for Adverse Events
If severity is missing for an AE that started before the date of the first dose of IP, an
intensity of mild will be assigned. If severity is missing for an AE that started on or after 
the date of the first dose of IP, an intensity of severe will be assigned. The imputed values 
for severity assessment will be used for the incidence summary; the values will be shown 
as missing in the data listings.


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13.6
Missing Causal Relationship to Study drug for Adverse Events
If the causal relationship to the IP is missing for an AE that started on or after the date of 
the first dose of IP, a causality of yes will be assigned. The imputed values for causal 
relationship to IP will be used for the incidence summary; the values will be shown as
missing in the data listings.
13.7
Missing Date Information for Adverse Events
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (i.e., partly missing).
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of IP, 
the month and day of the first dose of IP will be assigned to the missing fields.

If the year of the incomplete start date is before the year of the first dose of IP, 
December 31 will be assigned to the missing fields.

If the year of the incomplete start date is after the year of the first dose of IP, 
January 1 will be assigned to the missing fields.
Missing month only

If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year 
of the first dose of IP, the day of the first dose of IP will be assigned to the missing
day.

If either the year of the incomplete start date is before the year of the date of the first 
dose of IP or if both years are the same, but the month of the incomplete start date is 
before the month of the date of the first dose of IP, the last day of the month will be 
assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first 
dose of IP or if both years are the same, but the month of the incomplete start date is 
after the month of the date of the first dose of IP, the first day of the month will be 
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If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following 
algorithm will be used to impute the start date:

If the stop date is after the date of the first dose of IP, the date of the first dose of IP
will be assigned to the missing start date.

If the stop date is before the date of the first dose of IP, the stop date will be assigned 
to the missing start date.
13.8
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, including background ADT, incomplete 
(i.e., partially missing) start dates and/or stop dates will be imputed. When the start date 
and the stop date are both incomplete for a patient, the start date will be imputed first. If 
the stop date is complete and the imputed start date is after the stop date, the start date 
will be imputed using the stop date. If the imputed stop date is before the start date 
(imputed or non-imputed start date), the start date will be the imputed stop date. 
13.8.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of IP, 
the month and day of the first dose of IP will be assigned to the missing fields.

If the year of the incomplete start date is before the year of the first dose of IP, 
December 31 will be assigned to the missing fields.

If the year of the incomplete start date is after the year of the first dose of IP, 
January 1 will be assigned to the missing fields.
Missing month only

If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure.


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Missing day only

If the month and year of the incomplete start date are the same as the month and year 
of the first dose of IP, the day of the first dose of IP will be assigned to the missing 
day.

If either the year of the incomplete start date is before the year of the date of the first 
dose of IP or if both years are the same, but the month of the incomplete start date is 
before the month of the date of the first dose of IP, the last day of the month will be 
assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first 
dose of IP or if both years are the same, but the month of the incomplete start date is 
after the month of the date of the first dose of IP, the first day of the month will be 
assigned to the missing day.
13.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the imputed stop date is before 
the start date (imputed or non-imputed start date), the imputed stop date will be equal to 
the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of IP, 
the month and day of the last dose of IP will be assigned to the missing fields.

If the year of the incomplete stop date is before the year of the last dose of IP, 
December 31 will be assigned to the missing fields.

If the year of the incomplete stop date is after the year of the last dose of IP, 
January 1 will be assigned to the missing fields.
Missing month only

If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure.
Missing day only

If the month and year of the incomplete stop date are the same as the month and year 
of the last dose of IP, the day of the last dose of IP will be assigned to the missing 
day.


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
If either the year of the incomplete stop date is before the year of the date of the last 
dose of IP or if both years are the same, but the month of the incomplete stop date is 
before the month of the date of the last dose of IP, the last day of the month will be 
assigned to the missing day.

If either the year of the incomplete stop date is after the year of the date of the last 
dose of IP or if both years are the same, but the month of the incomplete stop date is 
after the month of the date of the last dose of IP, the first day of the month will be 
assigned to the missing day.
 
 
 
 
 


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14.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
There are no changes to the analyses specified in the final protocol Amendment 2
(version dated 20 MAY 2019). 


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15.0
REFERENCES
Cohen J. Statistical power analysis for the behavioral sciences. 2nd edition. New York: 
Academic Press; 1988.
Coric V, Stock EG, Pultz J, et al. Sheehan Suicidality Tracking Scale (Sheehan - STS): 
preliminary results from a multicenter clinical trial in generalized anxiety disorder. 
Psychiatry 2009; 6(1):26-31.
Kenward MG and Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997; 53: 983–997.
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality 
of life: the remarkable universality of half a standard deviation. Med Care 
2003;41(5):582-92.
SAS Institute Inc. SAS/STAT User’s Guide, Version 9.3. Cary, NC: SAS Institute Inc; 
2004.
Sheehan DV, Alphs LD, Mao L, et al. Comparative validation of the S-STS, the
ISST-Plus, and the C–SSRS for assessing the suicidal thinking and behavior. FDA 2012 
Suicidality Categories. Innovations in Clinical Neuroscience 2014a;11(9-10):32-46.
Sheehan DV, Giddens JM, Sheehan IS. Status update on the Sheehan Suicidality 
Tracking Scale (S-STS) 2014. Innov Clin Neurosci. 2014b;11(9–10):93–140.


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17.0
HISTORY OF CHANGES
Date
Section
Description