A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel as Adjunctive Therapy in the Prevention of Relapse in Patients With Major Depressive Disorder
Phase: PHASE3
Conditions: Depressive Disorder, Major
Sponsor: Naurex, Inc, an affiliate of Allergan plc

NCT02951988 
 
Study ID: RAP‐MD‐04 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter Study of Rapastinel as Adjunctive 
Therapy in the Prevention of Relapse in Patients With Major Depressive Disorder 
 
Protocol Amendment 2: 06 Nov 2018 
 
 
 

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TITLE PAGE
Naurex, Inc, an indirect subsidiary of Allergan, plc
5 Giralda Farms
Madison, NJ 07940
A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel 
as Adjunctive Therapy in the Prevention of Relapse in Patients with Major 
Depressive Disorder
RAP-MD-04
IND # 107, 974
Original Protocol Date:
04 May 2016
Amendment 1:
29 Sep 2016
Amendment 2:
06 Nov 2018
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-04
Title of Study
A Randomized, Double-blind, Placebo-controlled, 
Multicenter Study of Rapastinel as Adjunctive Therapy in the 
Prevention of Relapse in Patients with Major Depressive 
Disorder
Study Centers (Country)
Approximately 105 to 110 study centers (United States)
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of rapastinel 
relative to placebo in the prevention of relapse in patients 
with major depressive disorder (MDD)
Methodology
This study comprises the following periods:

An 8- to 16-week, open-label treatment period (OLTP) 
during which patients will receive 450 mg intravenous 
(IV) rapastinel once weekly adjunctive to ongoing 
antidepressant therapy (ADT) to identify stable 
responders. Individual treatment duration in the period 
will be at least 8 weeks and up to 16 weeks to 
accommodate variability among patients and adequately 
identify stable responders (patients treated for a 
minimum of 8 weeks and meet response criteria for at 
least 6 weeks)

A 26- to 104-week, double-blind randomized-withdrawal 
period during which stable responders from the 
open-label period will be randomized (1:1:1) to 1 of 
3 double-blind treatment arms: 
o
Weekly adjunctive IV administration of 450 mg 
rapastinel
o
Adjunctive IV administration of 450 mg 
rapastinel once every 2 weeks
o
Weekly adjunctive IV administration of placebo
Individual double-blind treatment period (DBTP) durations 
will vary with a minimum duration of 26 weeks and a 
maximum duration of 104 weeks (the study ends when all 
randomized patients have either met relapse criteria, early 
terminated for other reasons, or completed 26 weeks of the 
double-blind treatment period [DBTP]).
Upon completion of the DBTP, patients will be eligible to 
enroll in the open-label safety extension study, RAP-MD-06.  
The last visit in the DBTP will become the first visit of Study 
RAP-MD-06 for such patients.  Patients who do not enroll in 
RAP-MD-06 will enter a 2-week safety follow-up period.

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Number of Patients
Approximately 1500 planned to be enrolled in the OLTP; 
approximately 600 planned to be randomized during the 
DBTP
Diagnosis and 
Main Criteria for Inclusion
Patients who completed lead-in studies RAP-MD-01, 
RAP-MD-02, and RAP-MD-03 (rollover patients) are 
considered to have met inclusion criteria for diagnosis, 
severity, and prior ADT response and are not required to 
meet these criteria upon entry into RAP-MD-04.
De novo patients may be considered for enrollment if 
enrollment of rollover patients does not meet targeted 
projections. Entry criteria for de novo patients are as follows:

Male and female outpatients, ages 18 to 65 years, 
who meet the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) criteria for 
MDD with a current major depressive episode of at 
least 8 weeks and not exceeding 18 months in 
duration at Visit 1
 
 

Have no more than partial response (< 50% 
improvement) to ongoing treatment with a protocol-
allowed ADT (
 
 
 
 
 
 
 
 
 
 
 
Test Product, Dosage, and Mode 
of Administration
During the OLTP: Rapastinel 450 mg IV administered 
weekly as adjunctive to ongoing ADT.
During the DBTP: Rapastinel 450 mg IV administered 
weekly or administered once every 2 weeks (IV placebo will 
be given on alternating weeks to patients randomized to this 
once-every-2-weeks rapastinel group) 

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Duration of Treatment
An 8- to 16-week open-label period; a variable double-blind 
period with a minimum duration of 26 weeks and a maximum 
duration of 104 weeks (the study ends when all randomized 
patients have either met relapse criteria, early terminated for 
other reasons, or completed 26 weeks of the DBTP); and a 
2-week safety follow-up period
Reference Therapy, Dosage, and 
Mode of Administration
IV administration of placebo as adjunctive to ongoing ADT, 
weekly 
Criteria for Evaluation
Primary Efficacy Endpoint
Time to first relapse during the first 52 weeks of the DBTP, 
defined as the number of days from the randomization date to 
the relapse date. Relapse during the DBTP is defined as 
meeting 1 or more of the following criteria within 52 weeks 
of randomization:
o
MADRS total score ≥ 18 at 2 consecutive visits, or
o
A ≥ 2 increase in Clinical Global Impressions-
Severity (CGI-S) score compared with that obtained 
at randomization, or
o
Risk of suicide as determined by the Investigator, or
o
Need for hospitalization due to worsening of 
depression as determined by the Investigator, or
o
Need for alternative treatment of depressive 
symptoms as determined by the Investigator
Secondary Efficacy Endpoint
Time to first relapse during the entire DBTP, defined as the 
number of days from the randomization date to the relapse 
date. Relapse during the DBTP is defined as meeting 1 or 
more of the following criteria: 
o
MADRS total score ≥ 18 at 2 consecutive visits, or
o
A ≥ 2 increase in CGI-S score compared with that 
obtained at randomization, or
o
Risk of suicide as determined by the Investigator, or
o
Need for hospitalization due to worsening of 
depression as determined by the Investigator, or
o
Need for alternative treatment of depressive 
symptoms as determined by the Investigator
 

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Statistical Methods
The primary and secondary efficacy analyses will compare 
the time to relapse between placebo and rapastinel groups in 
the respective time-frame (within the first 52 weeks of the 
DBTP for the primary endpoint and during the entire DBTP 
for the secondary endpoint) using the log-rank test using the 
Double-blind modified Intent-To-Treat (mITT) Population. 
Estimates of the hazard ratio and 95% confidence intervals 
will be based on the Cox proportional hazards model with 
treatment group as an explanatory variable. The cumulative 
distribution function of time to relapse will be characterized 
by the Kaplan-Meier curves.
All safety parameters will be analyzed descriptively for the 
Open-label Safety Population and the Double-blind Safety 
Population.
The Open-label Safety Population will consist of all patients 
who signed the informed consent form (ICF) if they 
participated in the lead-in studies, and all de novo patients 
who signed the ICF and underwent OLTP Screening Visit 
procedures and receive at least 1 dose of open-label 
rapastinel during the OLTP of the study.
The Double-blind Safety Population will consist of all  
patients in the Open-label Safety Population who are
randomized to a treatment group during the DBTP of the 
study and receive at least 1 dose of IP during the DBTP.
The Open-label ITT population will consist of all patients in 
the Open-label Safety Population who have at least 1 
postbaseline assessment of the MADRS during the OLTP of 
the study.
The Double-blind mITT Population will consist of all 
patients in the Double-blind Safety Population.

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3.0
TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS .....................................................................2
3.0
Table of Contents............................................................................................................................14
List of Figures.................................................................................................................................16
4.0
LIST OF ABBREVIATIONS.........................................................................................................17
5.0
ETHICAL CONSIDERATIONS....................................................................................................19
5.1
Institutional Review Board and INDEPENDENT Ethics Committee ..............................19
5.2
Ethical Conduct of the Study............................................................................................19
5.3
Patient Information and Informed Consent.......................................................................19
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ......................................20
7.0
INTRODUCTION ..........................................................................................................................21
7.1
Disease Burden of Major Depressive Disorder.................................................................21
7.2
Selective Serotonin Reuptake Inhibitors and Selective Serotonin and Norepinephrine 
Reuptake Inhibitors in Major Depressive Disorder ..........................................................21
7.3
Atypical Antipsychotics as Adjunctive Therapy in Major Depressive Disorder ..............22
7.4
Rapastinel as a Novel Approach to the Treatment of Major Depressive Disorder ...........23
8.0
STUDY OBJECTIVES...................................................................................................................25
9.0
INVESTIGATIONAL PLAN .........................................................................................................27
9.1
Overall Study Design and Plan: Description ....................................................................27
9.1.1
Screening Period ................................................................................................29
9.1.2
Open-Label Treatment Period ............................................................................30
9.1.3
Double-blind Treatment Period..........................................................................30
9.1.4
Safety Follow-up Period.....................................................................................31
9.2
Discussion of Study Design, Including the Choice of Control Groups.............................31
9.3
Selection of Study Population...........................................................................................32
9.3.1
Inclusion Criteria................................................................................................32
9.3.2
Exclusion Criteria...............................................................................................33
9.3.3
Removal of Patients from Therapy or Assessment.............................................37
9.3.4
Patient Replacement Procedures ........................................................................39
9.4
Treatments ........................................................................................................................39
9.4.1
Background Antidepressant Therapy .................................................................39
9.4.2
Treatments Administered ...................................................................................40
9.4.3
Identity of Investigational Product .....................................................................40
9.4.4
Handling of Investigational Product...................................................................41
9.4.5
Method of Assigning Patients to Treatment Groups ..........................................42
9.4.6
Selection of Dosages in the Study ......................................................................42
9.4.7
Selection and Timing of Dose for Each Patient..................................................43
9.4.8
Blinding..............................................................................................................44
9.4.9
Unblinding..........................................................................................................44
9.4.10
Prior and Concomitant Therapy .........................................................................44
9.4.11
Other Restrictions...............................................................................................46

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9.4.12
Monitoring Treatment Compliance ....................................................................47
9.4.13
Treatment After Discontinuation........................................................................47
9.5
Efficacy and Safety Variables...........................................................................................47
9.5.1
Diagnostic and Efficacy Assessments ................................................................47
9.5.2
Safety Assessments ............................................................................................48
9.5.5
Schedule of Assessments....................................................................................60
9.6
Data Quality Assurance ....................................................................................................90
9.6.1
Data Monitoring .................................................................................................90
9.6.2
Data Recording and Documentation...................................................................90
9.7
Statistical Methods and Determination of Sample Size....................................................91
9.7.1
Analysis Populations ..........................................................................................91
9.7.2
Patient Disposition .............................................................................................92
9.7.3
Demographics and Other Baseline Characteristics.............................................92
9.7.4
Extent of Exposure and Treatment Compliance.................................................93
9.7.5
Efficacy Analyses...............................................................................................94
9.7.6
Safety Analyses ..................................................................................................97
9.7.9
Interim Analysis ...............................................................................................102
9.7.10
Determination of Sample Size..........................................................................102
9.7.11
Computer Methods...........................................................................................102
9.8
Data and Safety Monitoring Board.................................................................................103
9.9
Changes in the Conduct of the Study or Planned Analyses ............................................103
9.10
Protocol Deviations and Violations ................................................................................103
10.0
STUDY SPONSORSHIP..............................................................................................................105
10.1
Study Termination ..........................................................................................................105
10.2
Reporting and Publication ..............................................................................................105
11.0
INVESTIGATOR OBLIGATIONS..............................................................................................106
11.1
Documentation................................................................................................................106
11.2
Performance....................................................................................................................106
11.3
Use of Investigational Materials.....................................................................................107
11.4
Case Report Forms .........................................................................................................107
11.5
Retention and Review of Records...................................................................................107
11.6
Patient Confidentiality....................................................................................................108
12.0
INVESTIGATOR’S STATEMENT .............................................................................................109
13.0
APPENDICES ..............................................................................................................................110
Appendix I.
Elements of Informed Consent.........................................................................110
Appendix II.
Contact Information..........................................................................................112

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14.0
LITERATURE CITED .................................................................................................................147
LIST OF FIGURES

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4.0
LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
β-hCG
human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CI
confidence interval
DALY
disability-adjusted life-year
DBTP
double-blind treatment period
DSMB
Data Safety Monitoring Board
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSST
Digit Symbol Substitution Test 
ECG
electrocardiogram, electrocardiographic
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
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

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IRB
institutional review board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
major depressive disorder
mITT
modified Intent-to-Treat
NEAE
newly emergent adverse event
NMDAR
N-methyl-D-aspartate receptor
OLTP
open-label treatment period
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 deviation
SDMT
Symbol Digit Modalities Test
SNRI
serotonin norepinephrine reuptake inhibitor
SOC
system organ class
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious 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 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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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 105 to 110 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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7.0
INTRODUCTION
7.1
DISEASE BURDEN OF MAJOR DEPRESSIVE DISORDER 
Major depressive disorder (MDD) is a highly disabling, serious condition which 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 a 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 (DALYs) associated with 
suicide and 4 million of the DALYs 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 and a leading 
cause of disability in the world.
7.2
SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND 
SELECTIVE SEROTONIN AND NOREPINEPHRINE 
REUPTAKE INHIBITORS IN MAJOR DEPRESSIVE 
DISORDER
Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and 
norepinephrine reuptake inhibitors (SNRIs) currently represent the first line of treatment 
of depression in the United States. Unfortunately, a large number of patients do not 
experience therapeutic benefit from these first-line agents (Rosenzweig-Lipson et al, 
2007). Lack of sufficient response to adequate treatment remains a critical problem in the 
management of patients with MDD. Up to two-thirds of patients treated with first-line 

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antidepressant monotherapy do not reach full remission, and as many as a third become 
treatment resistant (Fava and Davidson, 1996; Trivedi et al, 2006). Not achieving 
remission has been shown to be predictive of poorer psychosocial functioning, higher 
rates of relapse, and higher rates of rehospitalization (McIntyre and O’Donovan, 2004). 
The results of the STAR*D study suggest that with successive failures of treatment, 
patients are less and less likely to respond to subsequent treatment, and those who do 
respond are more likely to relapse (Rush et al, 2006). Present strategies available to treat 
patients who do not respond to first-line antidepressant monotherapy include switching of 
antidepressant (either within or between classes); combination therapy in which multiple 
antidepressants are used simultaneously; augmentation of ongoing antidepressant 
monotherapy with adjunctive use of drugs such as mood stabilizers or atypical 
antipsychotics (Boland and Keller, 2006); and the use of nonpharmacologic treatments 
including psychotherapy and phototherapy, vagus nerve stimulation, transcranial 
magnetic stimulation, and electroconvulsive therapy (ECT). Clearly, there remains a 
critically important unmet medical need for this patient population.
Existing antidepressants have a number of limitations, leading to considerable unmet 
medical need in the effective treatment of MDD, with up to 50% of patients with MDD 
having an inadequate response to or failing current antidepressant therapy (ADT). 
Currently available first-line antidepressants (SSRIs, SNRIs) typically take 3 to 4 weeks 
or more of continuous daily dosing to relieve symptoms of MDD and are associated with 
side effects related to their pharmacological mechanisms of action (sexual dysfunction, 
weight gain, jitteriness, sleep disturbances), which are further associated with poor 
patient compliance (Masand, 2003; Ashton et al, 2005). Patients often experience 
undesirable side effects before they experience an improvement in depressive symptoms, 
which could lead to premature discontinuation of therapy. Taken together, these factors 
define significant areas for improvement of ADT. 
Patients vary greatly in their response to antidepressants and it is not possible to reliably 
predict whether an individual patient will respond to a given antidepressant. This leads to 
clinicians often using a trial-and-error approach to identify an effective antidepressant. 
Due to the gradual development of the full therapeutic effect of currently available 
antidepressants, each antidepressant needs to be administered for 4 weeks or longer in 
order to determine the individual therapeutic benefit, making the process of finding an 
effective antidepressant a lengthy process for patients who are often severely depressed 
and at a high risk for suicide. Clearly a drug that could induce a rapid antidepressant 
effect would represent a major advancement for these patients.
7.3
ATYPICAL ANTIPSYCHOTICS AS ADJUNCTIVE THERAPY 
IN MAJOR DEPRESSIVE DISORDER
The available treatments for adjunctive therapy in MDD also have substantial safety and 
efficacy limitations. The drugs currently approved for use as adjunctive therapy to 

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antidepressants for the treatment of MDD—namely, the atypical antipsychotics Abilify®
(aripiprazole), Seroquel XR® (quetiapine fumarate), and Rexulti® (brexpiprazole)—are 
associated with significant adverse reactions, as well as a number of serious warnings and 
precautions. Originally developed for the treatment of psychotic disorders, these drugs 
share a number of clinically relevant adverse effects based on their mechanisms of action.
As all current antipsychotic agents modulate central dopaminergic systems, they all carry 
a risk of extrapyramidal symptoms such as muscular rigidity, acute dystonia, as well as 
akathisia, which is a particularly relevant adverse event (AE) that complicates clinical 
management in a significant number of treated individuals, as high as 45% 
(Sachdev, 1995). In addition, these compounds are associated with a risk of neuroleptic 
malignant syndrome and tardive dyskinesia. Depending on their individual 
pharmacological profile, antipsychotics also carry a risk for metabolic changes including 
hyperglycemia/diabetes mellitus, dyslipidemia and body weight gain; blood dyskrasias 
such as leucopenia, neutropenia, and agranulocytosis; orthostatic hypotension; cognitive 
and motor impairment; cataracts; and insomnia (Abilify, 2014; Seroquel, 2013; 
Rexulti, 2015). The range of clinically relevant side effects with antipsychotics has to be 
balanced carefully against the potential for therapeutic benefits in patients with major 
depression. In this context, it is important to highlight that for the approved atypical 
antipsychotics, the full therapeutic benefit required several weeks of daily adjunctive 
dosing to become apparent, and in many patients, adverse effects occurred substantially 
earlier than the mood-alleviating effects of these drugs. 
Furthermore, the drugs currently approved for adjunctive treatment of MDD also have 
limited efficacy. The pivotal studies for Abilify, the atypical antipsychotic most 
commonly used for adjunctive treatment of MDD, showed a delayed onset of effect 
(1-2 weeks), a modest magnitude of effect (effect sizes were 0.35-0.39 after 6 weeks of 
repeat dosing), and modest rates of response and remission after 6 weeks of repeat dosing 
(response rates were 32%-34% and remission rates were 25%-26%) (Berman et al, 2007; 
Marcus et al, 2008). 
Clearly, there is a substantial need for the development of novel treatments with a better 
safety/tolerability profile and a faster onset of full therapeutic benefit. Rapastinel has 
initially shown substantially improved safety/tolerability as well as promising efficacy, in 
both speed of onset and overall magnitude, for adjunctive therapy in MDD. 
7.4
RAPASTINEL AS A NOVEL APPROACH TO THE 
TREATMENT OF MAJOR DEPRESSIVE DISORDER
The mechanism of action of rapastinel is entirely different from that of atypical 
antipsychotics. 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. 

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Rapastinel has demonstrated antidepressant properties in relevant animal models, 
displays cognitive enhancing properties in treated animals, and facilitates 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 available as an intravenous (IV) formulation only. In 2 Phase 2 clinical 
studies in patients with MDD, single IV doses of rapastinel at 5 mg/kg and10 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 those of ketamine 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, a single infusion of ketamine produced a rapid, yet 
transient antidepressant effect, accompanied by brief psychotomimetic and dissociative 
effects (Newport et al, 2015). 
The available Phase 1 and 2 data demonstrated a favorable safety and tolerability profile 
of rapastinel. In contrast to ketamine, rapastinel has not shown a high likelihood to induce 
psychotomimetic or dissociative effects in humans so far. 
As rapastinel constitutes a fundamentally novel approach to the treatment of depression, 
the best practice for the long-term use of rapastinel, particularly as an adjunctive 
treatment, is not comprehensively characterized at this time. The purpose of this study is 
to evaluate the safety, tolerability, and efficacy of rapastinel, administered as an IV 
injection at a dose of 450 mg weekly or 450 mg once every 2 weeks, as an adjunctive 
treatment to ongoing ADT in patients with MDD. Specifically, this study is designed to 
assess whether rapastinel is superior to placebo in maintaining clinical response in 
stabilized patients. The data gathered in this study are expected to provide substantial 
empirical evidence to address several questions with regard to the durability of treatment 
effect following acute and long-term treatment, the safety and tolerability of long-term 
treatment, and the effect of varying the treatment frequency after initial stabilization. This 
study is intended to support an application for regulatory approval of rapastinel as an 
adjunctive treatment for MDD.

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8.0
STUDY OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of rapastinel 
relative to placebo in the prevention of relapse in patients with MDD.
Efficacy Objectives

Primary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV weekly 
or once every 2 weeks) versus placebo in the maintenance treatment of MDD as an 
adjunctive treatment to ongoing ADT, as measured by time to relapse during the first 
52 weeks of the double-blind treatment period (DBTP)

Secondary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV 
weekly or once every 2 weeks) versus placebo in the maintenance treatment of MDD 
as an adjunctive treatment to ongoing ADT, as measured by time to relapse during the
DBTP
 
 
 
 
 
 
 
 
 
 

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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
Study RAP-MD-04 is a multicenter, double-blind, randomized, placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and tolerability of rapastinel as
long-term maintenance treatment for patients with MDD who either completed 1 of the 
rapastinel lead-in studies (RAP-MD-01, RAP-MD-02, or RAP-MD-03) or who are de 
novo patients (patients who did not participate in one of the lead-in studies). Enrollment 
of de novo patients may be considered at some study centers if enrollment of rollover 
patients does not meet targeted projections and will not be allowed unless specified in an 
official communication from the Sponsor.
The study will be conducted in the following periods:

A screening period of up to 14 days (for de novo patients only)

An 8- to 16-week open-label treatment period (OLTP)

A randomized DBTP of at least 26 weeks (and up to 104 weeks)

A 2-week safety follow-up period (for patients who do not enter the RAP-MD-06 
extension study only)
Individual treatment durations will vary, as patients enrolled early in the study will be 
allowed to continue double-blind treatment until a relapse occurs or the study is 
terminated. The maximum duration of the study will be 104 weeks (the study ends when 
all randomized patients have either met relapse criteria, early terminated for other 
reasons, or completed 26 weeks of the DBTP).
Figure 9.1–1 and Figure 9.1–2 provide study design schematics for rollover and de novo
patients, respectively. The schedules of evaluations for the OLTP and DBTP are 
presented in Section 2.0. Detailed descriptions of the procedures conducted at each study 
visit can be found in Section 9.5.5.

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9.1.1
Screening Period
The screening period will occur up to 2 weeks prior to Visit 2:

For completers of 1 of the lead-in studies RAP-MD-01, RAP-MD-02, or RAP-MD-03
(rollover patients), the final/Early Termination (ET) visit of the lead-in study will 
serve as the Screening Visit/Visit 1 for RAP-MD-04. Rollover patients will receive 
the first dose of open-label investigational product (IP) (ie, rapastinel 450 mg IV) at 
Visit 1 of the OLTP to ensure continuity of treatment.

Upon providing written informed consent, de novo patients will enter a screening 
period of up to 14 days.  Screening procedures may be conducted on up to 2 separate 
dates where necessary to accommodate patient and study center schedule; however, 
every effort should be made to conduct all procedures as early as possible in the 
screening period and the rater-administered MADRS and computer-administered 
MADRS must be collected on the same date. Following the screening period, patients 
enter the 8- to 16-week OLTP.  

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All patients will maintain usage of their background ADT throughout participation in the 
study (see Section 9.4.10.1).
9.1.2
Open-Label Treatment Period
Approximately 1500 patients are planned for enrollment in the OLTP to achieve 
600 randomized patients in the DBTP. When 600 patients are randomized into the DBTP, 
enrollment in the OLTP will be closed.
The OLTP consists of weekly visits for at least 8 weeks (and up to 16 weeks). During this 
period, patients will be treated with weekly IV injections of 450 mg rapastinel in addition 
to the continued unchanged ADT. The purpose of this period is to identify stable 
responders who will be eligible for the randomized-withdrawal period.
A patient will be considered a stable responder upon achieving both:

MADRS total score ≤ 12 with no more than 1 modest MADRS excursion 
(MADRS > 12 but ≤ 16) during 6 consecutive weeks, and  

MADRS total score ≤ 12 for 2 consecutive visits prior to randomization
Stability criteria may be met at any point from Study Week 7 to Study Week 15 for 
rollover patients and at any point from Study Week 8 to Study Week 16 for de novo
patients.  
Patients who do not meet stability criteria within these timeframes will undergo the End-
of-Treatment/Early Termination assessments (Visit 122/Week 104/ET) at their last OLTP 
visit and will exit the study.  Such patients are eligible to enroll in the Open-label Safety 
Extension study RAP-MD-06. The last visit in End-of-Treatment/Early Termination 
(Visit 122/Week 104/ET) will be the first visit of the Study RAP-MD-06 for such 
patients.  
Patients who discontinue from RAP-MD-04 and do not enroll in RAP-MD-06 will enter a 
2-week safety follow-up period.
9.1.3
Double-blind Treatment Period
Approximately 600 patients are planned for randomization in the DBTP. 
Upon meeting stability criteria, patients will enter the DBTP. Each patient entering the 
DBTP will be randomized 1:1:1 to either adjunctive weekly IV administration of 450 mg 
rapastinel, adjunctive IV administration of 450 mg rapastinel once every 2 weeks (with 
weekly IV administration of placebo to maintain blinding of the overall treatment 
regimen), or weekly IV administration of placebo.  

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Patients will be monitored for relapse events defined as meeting any of the following 
criteria:

MADRS total score ≥ 18 at 2 consecutive MADRS assessments

≥ 2 increase in CGI-S score compared with that obtained at randomization

Risk of suicide as determined by the Investigator

Need for hospitalization due to worsening of depression as determined by the 
Investigator

Need for alternative treatment (including dose increase of background ADT) of 
depressive symptoms as determined by the Investigator 
Upon meeting any of the relapse criteria at any visit in the DBTP, the patient will be 
considered a completer and the Visit 122/ET Visit procedures should be conducted. 
Each randomized patient will be treated until relapse criteria are met or until he/she has 
completed a minimum of 26 weeks of double-blind treatment.  Individual treatment 
durations will vary, as patients enrolled early in the study will be allowed to continue 
double-blind treatment until a relapse occurs or up to a maximum of 104 weeks of 
double-blind treatment.  The study will be terminated when all randomized patients have 
either met relapse criteria, early terminated for other reasons, or completed 26 weeks of 
the DBTP.
Upon completion of the DBTP, patients will be eligible to enroll in the open-label safety 
extension study, RAP-MD-06.  The last visit in the DBTP will become the first visit of 
Study RAP-MD-06 for such patients.  Patients who do not enroll in Study RAP-MD-06
will enter a 2-week safety follow-up period.
9.1.4
Safety Follow-up Period
All patients who complete or discontinue from the OLTP or the DBTP and who do not 
enroll in Study RAP-MD-06 will enter a 2-week safety follow-up period. 
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
The placebo-controlled withdrawal design is considered standard to demonstrate 
effectiveness of long-term maintenance treatment. 

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The 8- to 16-week OLTP was designed to ensure sustained response following continued 
adjunctive rapastinel treatment. The double-blind design is included to minimize 
systematic bias resulting from the scale raters, patient, or Investigator knowing the 
treatment being administered. Randomization at the beginning of the DBTP is expected 
to minimize patient selection bias and increase baseline comparability of the 3 treatment 
groups. 
The use of placebo control is critical to the study design both to understand the safety 
findings of the drug and to ensure that efficacy results can be interpreted. In this study, 
the placebo control is used during the DBTP to demonstrate the reemergence of MDD
symptoms upon withdrawal of rapastinel compared with patients who continue adjunctive 
rapastinel treatment. Patients who continue adjunctive rapastinel treatment should 
maintain improvement in their MDD symptoms, whereas those who switch to placebo 
should have a return of MDD symptoms. 
The variable duration of the DBTP with a maximum of 104 weeks and a minimum of 
26 weeks was selected to provide sufficient time to demonstrate MDD relapse upon 
withdrawal of rapastinel. 
The 2-week safety follow-up period allows continued patient monitoring after the IP has 
been discontinued. 
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
Note: For rollover patients who completed one of the lead-in studies (RAP-MD-01, 
RAP-MD-02, or RAP-MD-03), medical, psychiatric, and medication histories from Visit 
1 of the lead-in study will be used. In addition, Inclusion Criteria Nos. 2 to 5 are not 
applicable to rollover patients.
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
2. Male or female outpatients who are 18 to 65 years of age
3. Meet DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) 
criteria for MDD based on Structured Clinical Interview for Diagnostic Statistic 
Manual of Mental Health Disorders, Fifth Edition (SCID), with a current major 
depressive episode of at least 8 weeks and not exceeding 18 months in duration at 
Visit 1

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5. Have no more than partial response (< 50% improvement) to ongoing treatment with 
a protocol-allowed ADT 
 
 
 
 
 
 
 
 
 
7. If female of childbearing potential, have a negative serum β-human chorionic
gonadotropin (β-hCG) pregnancy test at Screening (Visit 1). Because Visit 1 
pregnancy test results will not be available on the day of Visit 1, rollover patients can 
be discontinued at Visit 2 if Visit 1 pregnancy test is positive.
8. Ability to follow study instructions and likely to complete all required visits
9.3.2
Exclusion Criteria
Note: For rollover patients who completed one of the lead-in studies (RAP-MD-01, 
RAP-MD-02, or RAP-MD-03), medical, psychiatric, and medication histories from 
Visit 1 of the lead-in study will be used (Exclusion Criteria Nos. 1-8, 12-14, 17, 21-25, 
and 27). Because Visit 1 clinical laboratory or ECG results will not be available on the 
day of Visit 1, if there are any safety concerns related to Visit 1 clinical laboratory or 
ECG results, patients can be discontinued at Visit 2.
Patients who meet any of the following criteria will not be eligible to participate in the 
study.

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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 6 months before Visit 1. Comorbid generalized anxiety disorder, 
social anxiety disorder, or specific phobias are acceptable provided they play a 
secondary role in the balance of symptoms and are not the primary driver of treatment 
decisions. 
2. Lifetime history of meeting DSM-5 criteria for:
○
Schizophrenia spectrum or other psychotic disorder
○
Bipolar or related disorder
○
Major neurocognitive disorder 
○
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
○
Dissociative disorder
○
Posttraumatic stress disorder
○
MDD with psychotic features
 
 
 
 
 

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9. Suicide risk, as determined by meeting any of the following criteria:
 

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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 one of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria)

Pregnancy

Withdrawal of consent 

AE

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o
Any patient may be withdrawn due to AE at the discretion of the Investigator
o
Any patient who meets any of the following criteria at any point during the 
study must be withdrawn from participation, due to AEs related to suicide:

A suicide attempt
 
In the event that a patient is withdrawn for a suicide-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 (applicable only to patients in the OLTP)

Protocol violation

Noncompliance with IP

Noncompliance with ADT

Lost to follow-up 

Study terminated by Sponsor

Study center terminated by Sponsor

Other 
All patients who prematurely discontinue from the OLTP or DBTP, 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 122. All patients 
discontinuing the study prematurely should enter the 2-week safety follow-up period.
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.

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9.3.4
Patient Replacement Procedures
Patients who prematurely discontinue treatment during the OLTP or DBTP will not be 
replaced.
9.4
TREATMENTS
During the OLTP, all eligible patients will receive open-label, once-weekly IV rapastinel 
450 mg. Patients who meet eligibility criteria at the end of the OLTP will be randomized 
in a double-blind fashion to 1 of 3 treatment groups: once-weekly IV placebo, 
once-weekly IV rapastinel 450 mg, or IV rapastinel 450 mg once every 2 weeks. 
9.4.1
Background Antidepressant Therapy
De novo patients must enter the study while having no more than partial response (< 50% 
improvement) to ongoing treatment with a protocol-allowed ADT
 
 
 
 
 
 
 
 
Patients entering from lead-in studies RAP-MD-01, RAP-MD-02, or RAP-MD-03 will 
have already fulfilled this requirement but must continue their background ADT as 
described below.
Upon entry into the study at Screening/Visit 1, the dosage of the ADT must be held 
constant at a dose in accordance with the respective label throughout participation in 
RAP-MD-04. If a patient experiences an AE, intercurrent illness, or symptoms of 
intolerance, he or she will be permitted to stop taking the ADT for a maximum of 
5 consecutive days at the discretion of the Investigator. No other alterations in the ADT 
dose regimen are allowed. If an ADT dose change is required during the study, the 
patient should be discontinued from the study.
Background ADT medication compliance will also be closely monitored. Compliance 
will be based on patient report. Every effort should be made to have patients bring their 
background ADT to each study visit for verification of patient-reported compliance by 
pill count (to the extent possible).

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9.4.2
Treatments Administered
During the OLTP and DBTP, 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 postadministration 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 applicable country, local, and/or state regulations and standard of care, to 
resuscitate a patient in the event of a medical emergency.  
The patient should not be discharged from the study center until the following are 
completed:

Postadministration vital sign measures (approximately 15 minutes after 
administration)

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 discharge 
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)
9.4.3
Identity of Investigational Product
The following IP will be administered intravenously during this study:

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
Rapastinel 450 mg IV Prefilled Syringes: 
 

Placebo rapastinel IV Prefilled Syringes:
 
 
 
 
 
 
 
In addition to contents identified for double-blind IP described above, open-label IP will 
also present the lot number.
The study center personnel will complete the kit label and attach the tear-off portion from 
the kit label to the source documents.
The prefilled syringe will be labeled with 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.
9.4.4
Handling of Investigational Product 
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.

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9.4.5
Method of Assigning Patients to Treatment Groups
After a patient signs the consent at Screening (Visit 1), study personnel will register the 
patient in the interactive web response system (IWRS) which will assign the patient a 
sequential PID number. 
All rollover patients will be identified using the same PID that was assigned by the IWRS 
in the lead-in study. 
 
 
 
 
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 onto the IWRS at subsequent visits to obtain a study 
medication kit number for dispensing IP.  Study centers will receive the IWRS 
confirmation notifications for each transaction.  All notifications are to be maintained 
with the study source documents.
9.4.6
Selection of Dosages in the Study
A rapastinel dose of 450 mg was chosen for this study was based on results from 2 Phase 
2 studies of patients with MDD in which single IV doses of rapastinel 5 mg/kg and 
10 mg/kg demonstrated marked antidepressant effects within 1 day that lasted for 
approximately 1 week or longer in responding patients. The 450 mg IV dose is expected 
to provide an appropriate dose for most patients based upon the Phase 2 study results.
The use of a single-unit dose is intended to aid in the simplicity of administration and 
avoid dosing errors.
This study assesses both weekly and once-every-2-weeks dosing regimens. While the 
GLYX13-C-202 study also assessed the effect of weekly and once-every-2-weeks
administration after initial stabilization, and found no differences, the comparison was 
only carried out for 6 weeks in that study. Assessing a less frequent dosing regimen over 
this more substantial time period of 26 weeks to 2 years is expected to yield a better 
understanding of the long-term efficacy and safety characteristics of rapastinel treatment 
and allow proper guidance to physicians regarding treatment beyond initial stabilization.

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9.4.7
Selection and Timing of Dose for Each Patient
The IP will be administered IV at each weekly visit. Patients in the 450 mg once-every-2-
weeks treatment arm will receive placebo on intervening weeks to maintain the blinding 
of the overall treatment regimen.
9.4.7.1
Screening Period
For rollover patients enrolling from one of the lead-in studies, the final visit from the 
lead-in study will serve as Visit 1 in this study. Rollover patients will receive open-label 
treatment at Visit 1 to ensure continuity of treatment.
At Visit 1, after written consent is obtained, de novo patients will enter a screening period
of up to 14 days before entering the OLTP. No IP will be administered to de novo 
patients during the screening period. However, de novo patients must continue their 
background ADT at a stable dose.
9.4.7.2
Open-label Treatment Period
All rollover patients will have received open-label rapastinel at Visit 1 of the OLTP. At 
Baseline/Visit 2 of the OLTP, additional eligibility criteria will be reviewed for all 
patients.  Rollover and de novo patients who meet the Baseline/Visit 2 eligibility criteria 
will receive open-label IP from Baseline/Visit 2 through open-label Visit 18/Week 16. 
Open-label dosing will continue for patients who do not meet stability criteria at 
open-label Visits 10-18 (Weeks 8-16).
9.4.7.3
Double-blind Treatment Period
Patients will be randomized in a 1:1:1 ratio to receive either weekly IV rapastinel 
450 mg, IV rapastinel 450 mg once every 2 weeks, or IV placebo at DBTP Visits 18-121
(Weeks 1-103 for de novo patients and Weeks 0-103 for rollover patients).
After all DBTP Baseline/Visit 18 assessments are completed for patients who meet 
stability criteria, eligible patients will be randomized into the DBTP. The IWRS will 
assign an IP kit number during the DBTP Baseline visit and at all subsequent DBTP 
visits. Patients will receive the first dose of double-blind IP at the DBTP Baseline Visit.
9.4.7.4
Safety Follow-up Period
Patients who complete the DBTP or patients who prematurely discontinue from the study 
should enter the 2-week safety follow-up period. No IP is administered during the safety 
follow-up period. Patients’ background ADT may be modified as deemed appropriate by 
the Investigator.

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9.4.8
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.
9.4.9
Unblinding
Any unblinding at the study center level should be done only in an emergency that 
requires the IP to be identified for the medical management of the patient. The 
Investigator must notify the Study Physician immediately (refer to Appendix II) and a 
full written explanation must be provided if the blind is broken. Before the IP is 
unblinded, every attempt should be made to discuss the case with the Study 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 and record the unblinding in the eCRF.
9.4.10
Prior and Concomitant Therapy
A list of example medications that are allowed and not allowed as concomitant 
medications for either episodic or chronic use is provided in Appendix III.
For de novo patients, medication history (psychotropic medication history during the 
previous 5 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.

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9.4.10.1
Permitted Medications/Treatments
 
 
 
 
 
 
 
 
 
 
 
 

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9
2
 
 
 
 
 
 
 
9.4.11
Other Restrictions
9.4.11.1
Alcohol
It is recommended that patients abstain from alcohol consumption during the study.
9.4.11.2
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.
9.4.12
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 must be captured in the eCRF.
Background ADT compliance will also be closely monitored. Background ADT 
medication compliance will be based on patient report. Every effort should be made to 
have patients bring their background ADT to each study visit for verification of patient-
reported compliance by pill-count (to the extent possible).  Missed doses or other changes 
in the dose of ADT and the reason should be captured in the eCRF.
9.4.13
Treatment After Discontinuation
Patients whose MDD 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. Patients who initiate a new treatment must be 
discontinued from the study.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9.5.1.1
Diagnostic Assessments
The SCID will be administered during the screening interviews 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. 

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9.5.1.2
Efficacy Assessments
All efficacy assessments (MADRS and CGI-S) 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 during the past week. 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. This instrument will be administered by an 
experienced rater meeting the training requirements and qualifications set by the 
rater-training vendor.    
At each visit with a MADRS assessment, the rater-administered MADRS interview will 
be audio recorded; a computer-administered MADRS interview will also be completed 
by patients. The computer-administered interview will involve a series of probe and 
follow-up questions with multiple-choice response options. At the screening visit of the 
OLTP, for de novo patients only, the computer administered MADRS will be conducted 
prior to the rater-administered MADRS. At all other visits, the rater-administered 
MADRS will be conducted first.
9.5.1.2.2
The Clinical Global Impressions-Severity 
The CGI-S (Guy, 1976) is a clinician-rated scale used to rate the severity of the patient’s 
current state of mental illness compared with a patient population with MDD. The patient 
will be rated on a scale from 1 to 7 with 1 indicating a “normal, not at all ill” and 7
indicating “among the most extremely ill patients.” The CGI-S will be administered by 
the Investigator or by a subinvestigator with extensive professional training and 
experience in assessing mental illness and qualifications standards established by the 
Sponsor and rater training vendor.
9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately-trained healthcare 
professional at every visit and the evaluation must be documented. The procedures 
discussed below will be completed at designated visits.

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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).
For the purpose of the study center’s data collection responsibilities, any untoward event 
that was reported from the time the ICF was signed 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 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 
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
The event is unlikely to be attributed to underlying/concurrent 
disease or other factors, and/or

Positive dechallenge and/or rechallenge exist
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

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
Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

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.
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

Document the outcome of the AE

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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 
post-study period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. They are also to be recorded in 
the eCRF if at least one of the following conditions are met: 1) those that meet the criteria 
for an SAE (see Sections 9.5.2.1.3 and 9.5.2.1.4), and/or 2) those 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 
Special 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 Global Drug Safety 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 stated 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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9.5.5
Schedule of Assessments
The schedule of study procedures and assessments is tabulated by visit in the Schedule of 
Evaluations in Section 2.0. The descriptions of the procedures to be performed at each 
visit are provided in the following sections.
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9.5.5.5
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, and 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.
 
 
 may be captured 
using an electronic source tablet-based system. 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. 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
The following analysis populations will be considered in the statistical analysis of the 
study.
9.7.1.1
Open-label Safety Population
The Open-label Safety Population will consist of all patients who signed the ICF if they 
participated in the lead-in studies, and all de novo patients who signed the ICF and 
underwent OLTP Screening Visit procedures and receive at least 1 dose of open-label 
rapastinel during the OLTP of the study.
9.7.1.2
Open-label Intent-to-Treat Population
The Open-label Intent-to-Treat (Open-label ITT) Population will consist of all patients in 
the Open-label Safety Population who have at least 1 postbaseline assessment of the
MADRS during the OLTP of the study.

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9.7.1.3
Double-Blind Safety Population
The Double-blind Safety Population will consist of all patients in the Open-label Safety 
Population who are randomized to a treatment group during the DBTP of the study 
and receive at least 1 dose of IP during the DBTP.
9.7.1.4
Double-Blind Modified Intent-to-Treat Population
The Double-blind modified Intent-to-Treat (Double-blind mITT) Population will consist 
of all patients in the Double-blind Safety Population.
9.7.2
Patient Disposition
The number of patients in the Open-label Safety, and Open-label ITT Populations will be 
summarized overall by study center. The number of patients in the Double-blind Safety 
and Double-blind mITT Populations will be summarized overall, by treatment group and 
study center.
For de novo enrolled patients, screen failures (ie, patients who were screened but not 
included in the Open-label Safety Population) and the associated reasons for failure will 
be tabulated overall.
The number and percentage of patients who entered the OLTP, who prematurely 
discontinued from the OLTP, who completed the OLTP, who met or did not meet the 
criteria to enter the DBTP at the end of the OLTP, and who entered the DBTP will be 
summarized overall and by reasons for premature discontinuation for the Open-label 
Safety Population. Similarly, the number and percentage of patients who completed the 
DBTP and who prematurely discontinued from the DBTP will be summarized overall, by 
double-blind treatment group, and by reasons for premature discontinuation for the 
Double-blind Safety Population.
9.7.3
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 for the Open-label Safety 
Population and by treatment group for the Double-blind mITT population. 

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9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to open-label rapastinel for the Open-label Safety Population during the OLTP
will be summarized for treatment duration, calculated as the number of days from the 
date of the first dose of open-label rapastinel taken to the date of the last dose taken 
during the OLTP, inclusive. Descriptive statistics (number of patients, mean, SD, 
minimum, median, and maximum) will be presented.
Exposure to double-blind IP for the Double-blind 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 (number of patients, mean, SD, minimum, 
median, and maximum) will be presented by treatment group.
Prior medication is defined as any medication started before the date of first dose of 
open-label IP. Concomitant medication during the OLTP is defined as any medication 
taken on or after the date of the first dose of open-label IP during the OLTP. Concomitant 
medication during the DBTP will be defined as any medication taken on or after the date 
of the first dose of double-blind IP.
The use of prior medication will be summarized by the number and percentage of patients 
receiving each medication within each therapeutic class for the Open-label Safety 
Population. The use of concomitant medications during the OLTP will be summarized by 
the number and percentage of patients receiving each medication within each therapeutic 
class for the Open-label Safety Population. The use of concomitant medications during 
the DBTP will be summarized by treatment group by the number and percentage of 
patients receiving each medication within each therapeutic class for the Double-blind 
Safety Population. Multiple use of the same medication by a patient will only be counted 
once.
The number and percentage of patients taking each qualifying ADT in the OLTP will be 
summarized for the Open-label ITT Population; the number and percentage of patients 
taking each qualifying ADT in the DBTP will be summarized by double-blind treatment 
group for the Double-Blind mITT Population. Mean daily dose and duration of previous 
treatment with each qualifying ADT will be summarized using descriptive statistics 
(number of patients, mean, SD, median, minimum, and maximum) for the OLTP and by 
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9.7.4.2
Measurement of Treatment Compliance
Dosing compliance for a specified period will be 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. The total number of IV 
doses actually taken during a specific time period is calculated as the sum of IV doses 
taken during that period as obtained from the study medication record. The number of IV 
doses expected to be taken for a specific treatment period will be the number of weeks in 
that period. 
Descriptive statistics for open-label IP compliance will be presented for the OLTP for the 
Open-label Safety Population. Descriptive statistics for double-blind IP compliance will 
be presented by treatment group for the DBTP for the Double-blind Safety Population.
Dosing compliance for the background ADT during a specified period is defined as the 
doses actually taken by a patient during that period divided by the doses expected to be 
taken during the same period multiplied by 100. Descriptive statistics for ADT 
compliance during the OLTP will be presented for each ADT for the Open-label ITT
Population. Descriptive statistics for ADT compliance during the DBTP will be presented 
for each ADT by the double-blind treatment group for the Double-blind mITT
Population.
9.7.5
Efficacy Analyses
All efficacy analyses for the OLTP will be performed using the Open-label ITT 
Population. All efficacy analyses for the DBTP will be performed using the Double-blind 
mITT Population. For rollover patients, the baseline of the lead-in study will be used as 
the baseline for the OLTP.  The last nonmissing assessment before the first dose of 
Double-blind IP will be used as the baseline for the DBTP. For de novo patients, the last 
measurement before the first dose of open-label IP will be used as baseline. All statistical 
tests will be 2-sided hypothesis tests performed at the 5% level of significance and all 
confidence intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise.
9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter is the time to first relapse during the first 52 weeks of the 
DBTP, defined as the number of days from the randomization date to the relapse date
during the first 52 weeks of the DBTP. Relapse during the DBTP is defined as meeting 
any of the following criteria:

MADRS total score ≥ 18 at 2 consecutive visits

≥ 2 increase in CGI-S score compared with that obtained at randomization

Risk of suicide as determined by the Investigator

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Need for hospitalization due to worsening of depression as determined by the 
Investigator

Need for alternative treatment of depressive symptoms as determined by the 
Investigator 
For patients who did not meet the above relapse criteria during the first 52 weeks of the 
DBTP, the time to relapse will be censored at the time of completion or discontinuation 
from the study, or 52 weeks, whichever is earlier.
The primary efficacy analysis will compare the time to relapse between placebo and 
rapastinel treatment groups using the log-rank test. Estimates of the hazard ratio and 95% 
CI will be based on the Cox proportional hazards model with treatment group as an 
explanatory variable. The cumulative distribution function of time to relapse will be 
characterized by the Kaplan-Meier curves.
Three sensitivity analyses will be performed to assess the robustness of the primary 
analysis results to the possible violation of the noninformative censoring assumption. 
The first sensitivity analysis assumes that patients who discontinued without meeting 
any of the relapse criteria during the DBTP relapsed instead of being censored. The 
second sensitivity analysis will be based on the delta-adjusted method examined by 
Zhao et al. (2014). The third sensitivity analysis is an extension of the placebo-based 
pattern mixture model proposed by Lu (2014, 2015). The placebo-based pattern 
mixture model assumes that patients who discontinued from the rapastinel treatment 
groups would have disease progression after discontinuation similar to that of placebo. 
The extended placebo-based pattern mixture model uses a sensitivity parameter to 
characterize the gradual deviation from the noninformative censoring underlying the 
primary analysis toward the informative censoring underlying the placebo-based 
pattern mixture model.
9.7.5.2
Secondary Efficacy Parameter
The secondary efficacy parameter is the time to first relapse during the entire DBTP, 
defined as the number of days from the randomization date to the relapse date during the 
entire DBTP. For patients who did not meet the relapse criteria during the DBTP, their 
time to relapse will be censored at the time of completion or discontinuation from the 
study.
The same analysis methods for the primary endpoint will be applied to the secondary 
endpoint.
In order to control the overall Type I error rate for the primary and secondary 
hypotheses, the following sequential testing procedure will be implemented in the 
following order:

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1) The comparison of time to relapse during the first 52 weeks between rapastinel 
450 mg weekly and placebo
2) The comparison of time to relapse during the entire DBTP between rapastinel 
450 mg weekly and placebo,
3) The comparison of time to relapse during the first 52 weeks between rapastinel 
450 mg biweekly and placebo
4) The comparison of time to relapse during the entire DBTP between rapastinel 
450 mg biweekly and placebo
Each of the 4 hypothesis tests above will be implemented at the 2-sided 0.05 
significance level.  A given hypothesis test will be carried out only when each of the 
preceding hypothesis tests have concluded rejection of the null hypothesis at the 0.05 
significance level. In the event a given hypothesis test fails to reject its null hypothesis 
at the 0.05 significance level, the conclusion for the subsequent hypotheses not tested is 
to not reject their respective null hypotheses. This testing strategy will control the 
overall Type I error rate at 0.05 significance level.
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9.7.6.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities.
For rollover patients, an AE (classified by preferred term) that occurs during the OLTP or 
thereafter will be considered a treatment-emergent adverse event (TEAE) if it was not 
present before the date of the first dose of IP in the lead-in study or was present before 
the first dose of IP in the lead-in study and increased in severity during the OLTP or 
thereafter. If more than 1 AE is reported before the date of the first dose of IP in the lead-
in study and coded to the same preferred term, the AE with the greatest severity will be 
used as the benchmark for comparison with the AEs occurring during the OLTP or 
thereafter that were also coded to that preferred term. An AE that becomes serious 
during the OLTP or thereafter will also be considered as a TEAE.
For de novo patients, an AE (classified by preferred term) that occurs during the OLTP or 
thereafter will be considered a TEAE if it was not present before the date of the first dose 
of open-label IP or was present before the date of the first dose of open-label IP and 
increased in severity during the OLTP or thereafter. If more than 1 AE is reported before 
the date of the first dose of open-label IP and coded to the same preferred term, the AE 
with the greatest severity will be used as the benchmark for comparison with the AEs 
occurring during the OLTP or thereafter that were also coded to that preferred term. An 
AE that becomes serious during the OLTP or thereafter will also be considered as a 
TEAE.
An AE that occurs more than 30 days after the date of the last dose of IP will not be 
counted as a TEAE.

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An AE (classified by preferred term) that occurs during the DBTP of the study will be 
considered a newly emergent adverse event (NEAE) if the AE was not present before the 
first dose of the double-blind IP or it was present before the first dose of the double-blind 
IP and increased in severity during the DBTP. If more than 1 AE is reported before the 
first dose of the double-blind IP and coded to the same preferred term, the AE with the 
greatest severity will be used as the benchmark for comparison with the AEs occurring 
during the DBTP that were also coded to that preferred term. An AE that becomes 
serious during the DBTP will also be considered as an NEAE for the DBTP.  An AE 
that occurs more than 30 days after the date of the last dose of IP will not be counted as a 
NEAE.
The number and percentage of patients reporting TEAEs during the OLTP will be 
tabulated by SOC and preferred term.. The number and percentage of patients in each 
treatment group reporting TEAEs and NEAEs during the DBTP will be tabulated by SOC 
and preferred term; by SOC, preferred term, and severity; and by SOC, preferred term, 
and causal relationship to the IP. If more than 1 AE is coded to the same preferred term 
for the same patient during the same treatment period, the patient will be counted only 
once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by causal relationship to the IP.
The incidence of common (≥ 2% of patients in any treatment group) TEAEs and NEAEs 
during the DBTP will be summarized by preferred term and treatment group and will be 
sorted by decreasing frequency for the weekly rapastinel group. 
An SAE that occurred between the date of the first dose of the open-label IP and 30 days 
after the date of the last dose of IP, inclusive, will be considered a treatment-emergent
SAE (TESAE). The number and percentage of patients who had TESAEs during the 
OLTP will be summarized by preferred term and sorted by decreasing frequency. The 
number and percentage of patients who had TESAEs during the DBTP will be 
summarized by treatment group and preferred term and will be sorted by decreasing 
frequency for the weekly rapastinel group.
The number and percentage of patients who had fatal TESAEs during the OLTP will be 
summarized by preferred term and sorted by decreasing frequency. The number and 
percentage of patients who had fatal TESAEs during the DBTP will be summarized by 
treatment group and preferred term and sorted by decreasing frequency for the weekly 
rapastinel group.
The incidence of TEAEs leading to premature discontinuation of IP during the OLTP
will be summarized by preferred term and will be sorted by decreasing frequency. The 
incidence of TEAEs leading to premature discontinuation of IP during the DBTP will be 
summarized by preferred term and treatment group and will be sorted by decreasing 
frequency for the weekly rapastinel group.

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Listings will be presented for all patients with SAEs, patients with AEs leading to 
discontinuation, and patients who died (if any).
9
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9.7.9
Interim Analysis
No interim analysis is planned for this study.
9.7.10
Determination of Sample Size
The sample size and power calculations are based on the analysis of time to relapse 
during the first 52 weeks of the DBTP. Assuming a relapse rate of 19% per 26 weeks in 
the placebo group and a dropout rate of 20% per 26 weeks in all treatment groups, the 
sample size of 200 per group will have 90% power to detect a hazard ratio of 0.475 for a
rapastinel treatment versus placebo at a 0.05 significance level. To achieve this number 
of randomized patients, approximately 1500 patients need to be enrolled in this study if 
40% of patients are qualified for randomization.
9.7.11
Computer Methods
Statistical analyses will be performed using version 9.3 (or newer) of SAS on a 
Linux operating system.

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9.8
DATA AND SAFETY MONITORING BOARD
The study will be conducted under the supervision of an independent Data and Safety 
Monitoring Board (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 the 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. 
If unclarities arise with regard to interpretation or conduct of the approved protocol 
during the conduct of the study, the sponsor will provide guidance in the form of a 
protocol clarification letter.  Such guidance will be used to clarify only within the 
bounds of the approved protocol.
9.10
PROTOCOL DEVIATIONS AND VIOLATIONS
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.

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A significant 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. 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, Inc, an affiliate 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 
Procedures 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-04, 
Amendment 2, dated 06 Nov 2018) 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 for 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 
which the patient is otherwise entitled

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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 of 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
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