Clinical trial NCT03560518
Conditions: Depressive Disorder, Major
Keywords: Depression
Sponsor: Naurex, Inc, an affiliate of Allergan plc
Start date: 2018-06-15; Completion date: 2019-07-08
Enrollment: 439 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the efficacy, safety, and tolerability of 450 milligrams (mg) and 900 milligrams (mg) of Rapastinel, compared to placebo in participants with major depressive disorder (MDD).

Detailed description:

Arms: arm 1: Rapastinel 450 mg (prefilled syringe, weekly intravenous IV administration) arm 2: Rapastinel 900 mg (prefilled syringe, weekly intravenous IV administration) arm 3: Placebo (prefilled syringe, weekly IV administration)
Interventions: intervention 1: Rapastinel intervention 2: Placebo
Intervention descriptions: intervention 1: Rapastinel (prefilled syringe, weekly intravenous IV administration) intervention 2: Placebo (prefilled syringe, weekly IV administration)

Protocol documents:
Prot_001.pdf: 
NCT03560518 
 
Study ID: RAP‐MD‐32 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter Study of Rapastinel 
as Monotherapy in Patients with Major Depressive Disorder 
 
Protocol Date: 10 Apr 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 Monotherapy in Patients with Major Depressive Disorder
RAP-MD-32
(3106-332-008)
IND # 136,870
Original Protocol Date:
10 Apr 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-32
Study Number
RAP-MD-32 (3106-332-008)
Title of Study
A Randomized, Double-blind, Placebo-controlled, 
Multicenter Study of Rapastinel as Monotherapy in Patients 
with Major Depressive Disorder
Study Centers (Country)
Approximately 40 study centers (United States)
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of rapastinel 
as a monotherapy treatment in patients with major 
depressive disorder (MDD)
Methodology
Multicenter, randomized, 6-week, double-blind, 
placebo-controlled, parallel-group study of two doses of 
intravenous (IV) rapastinel (450 mg and 900 mg) vs IV 
placebo (randomized 1:1:1) as monotherapy treatment in 
patients with MDD
Duration of Participation

Up to 2-week screening period

Followed by a 6-week double-blind treatment period

Followed by a 2-week safety follow-up period (for 
patients who do not roll over into the extension study)
Number of Patients
Approximately 690 planned to be enrolled
Diagnosis and Main Criteria for 
Inclusion

Male and female outpatients who are 18 to 75 years of 
age

Meet 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

 
 

Treatment naive (defined as those who have not received 
antidepressant or those who have received antidepressant 
but not meeting adequate dose or duration criteria 
 
in the present episode or inadequate response 
(< 50% reduction in depressive symptoms) to 1 to 3 


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antidepressant therapies [ADTs] given at adequate doses 
(as defined by the ADT package insert) and duration of 
≥ 4 weeks during the present episode 
 
Test Product, Dosage, and Mode 
of Administration

450 mg rapastinel (prefilled syringe, weekly intravenous 
[IV] administration)

900 mg rapastinel (prefilled syringe, weekly IV 
administration)
Reference Therapy, Dosage, and 
Mode of Administration
Placebo (prefilled syringe, weekly IV administration)
Criteria for Evaluation
Primary Endpoint
Change from baseline in MADRS total score at the end of
the double-blind treatment period (end of Week 6)
Key Secondary Endpoint
Change from baseline in MADRS total score at 1 day after 
first dose of treatment
 
 
 
 
 
 


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Statistical Methods
Efficacy analyses will be based on the modified Intent-to-
Treat (mITT) Population, defined as all randomized patients 
who have received randomized investigational product (IP)
and have at least 1 postrandomization assessment of the 
MADRS total score. Safety analyses will be based on the 
Safety Population, defined as all randomized patients who 
received at least 1 dose of randomized IP.
The primary efficacy parameter, change from baseline in 
MADRS total score at the end treatment (end of Week 6), 
will be analyzed using a mixed-effects model for repeated 
measures (MMRM) with treatment group, (pooled) study 
center, visit, and treatment group–by-visit interaction as 
fixed effects and baseline value and baseline-by-visit 
interaction as covariates. An unstructured covariance matrix 
will be used to model the covariance of within-patient 
scores. The key secondary efficacy parameter, change from 
baseline in MADRS total score at 1 day after the first dose of
treatment, will be analyzed using the same MMRM model 
for the primary efficacy parameter. Baseline will be defined 
as the last measurement prior to the first dose of treatment.
All safety parameters will be analyzed using descriptive 
statistics.


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TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS .....................................................................2
3.0
TABLE OF CONTENTS..................................................................................................................7
LIST OF TABLES............................................................................................................................9
LIST OF FIGURES ..........................................................................................................................9
4.0
LIST OF ABBREVIATIONS.........................................................................................................10
5.0
ETHICAL CONSIDERATIONS....................................................................................................13
5.1
Institutional Review Board and Independent Ethics Committee ......................................13
5.2
Ethical Conduct of the Study............................................................................................13
5.3
Patient Information and Informed Consent.......................................................................14
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ......................................15
7.0
INTRODUCTION ..........................................................................................................................16
8.0
STUDY OBJECTIVES...................................................................................................................20
9.0
INVESTIGATIONAL PLAN .........................................................................................................22
9.1
Overall Study Design and Plan: Description ....................................................................22
9.1.1
Screening Period.................................................................................................22
9.1.2
Double-blind Treatment Period..........................................................................22
9.1.3
Safety Follow-up Period.....................................................................................23
9.2
Discussion of Study Design, Including the Choice of Control Groups.............................24
9.3
Selection of Study Population...........................................................................................25
9.3.1
Inclusion Criteria................................................................................................25
9.3.2
Exclusion Criteria...............................................................................................26
9.3.3
Removal of Patients from Therapy or Assessment.............................................30
9.3.3.1
Criteria for Required Removal of Patients from Therapy or 
Assessment.......................................................................................31
9.3.4
Patient Replacement Procedures ........................................................................31
9.4
Treatments ........................................................................................................................31
9.4.1
Treatments Administered ...................................................................................32
9.4.2
Identity of Investigational Products....................................................................33
9.4.3
Handling of Investigational Products .................................................................34
9.4.4
Method of Assigning Patients to Treatment Groups ..........................................34
9.4.5
Selection of Dosages in the Study ......................................................................34
9.4.6
Selection and Timing of Dose for Each Patient..................................................35
9.4.6.1
Screening Period...............................................................................35
9.4.6.2
Double-blind Treatment Period ........................................................35
9.4.6.3
Safety Follow-up Period...................................................................35
9.4.7
Blinding..............................................................................................................35
9.4.8
Unblinding..........................................................................................................36
9.4.9
Prior and Concomitant Therapy .........................................................................36


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9.4.10
Other Restrictions...............................................................................................38
9.4.10.1
Alcohol .............................................................................................38
9.4.10.2
Contraception ...................................................................................38
9.4.11
Monitoring Treatment Compliance ....................................................................39
9.4.12
Treatment After Discontinuation........................................................................39
9.5
Efficacy and Safety Variables...........................................................................................39
9.5.1
Diagnostic and Efficacy Assessments ................................................................39
9.5.1.1
Diagnostic Assessments ...................................................................39
9.5.1.2
Efficacy Assessments .......................................................................40
9.5.1.3
Patient Centricity Assessments.........................................................42
9.5.2
Safety Assessments ............................................................................................42
9.5.2.1
Adverse Events.................................................................................43
9.5.2.2
Immediate Reporting of Serious Adverse Events.............................47
9.5.2.3
Reporting of Pregnancies Occurring During the Study ....................47
9.6
Data Quality Assurance ....................................................................................................65
9.6.1
Data Monitoring .................................................................................................65
9.6.2
Data Recording and Documentation...................................................................65
9.7
Statistical Methods and Determination of Sample Size....................................................66
9.7.1
Analysis Populations ..........................................................................................66
9.7.1.1
Safety Population..............................................................................66
9.7.1.2
Modified Intent-to-Treat Population.................................................66
9.7.1.3
Pharmacokinetic Population.............................................................66
9.7.2
Patient Disposition .............................................................................................67
9.7.3
Demographics and Other Baseline Characteristics.............................................67
9.7.4
Extent of Exposure and Treatment Compliance.................................................67
9.7.4.1
Extent of Exposure ...........................................................................67
9.7.4.2
Prior and Concomitant Medication...................................................67
9.7.4.3
Measurement of Treatment Compliance...........................................68
9.7.5
Efficacy Analyses...............................................................................................68
9.7.5.1
Primary Efficacy Analyses ...............................................................69
9.7.5.2
Key Secondary Efficacy Analysis ....................................................70


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9.7.6
Safety Analyses ..................................................................................................72
9.7.6.1
Adverse Events.................................................................................72
9.7.9
Interim Analysis .................................................................................................76
9.7.10
Determination of Sample Size............................................................................76
9.7.11
Statistical Software.............................................................................................76
9.8
Data and Safety Monitoring Board...................................................................................77
9.9
Changes in the Conduct of the Study or Planned Analyses ..............................................77
9.10
Protocol Deviations ..........................................................................................................78
10.0
STUDY SPONSORSHIP................................................................................................................79
10.1
Study Termination ............................................................................................................79
10.2
Reporting and Publication ................................................................................................79
11.0
INVESTIGATOR OBLIGATIONS................................................................................................80
11.1
Documentation..................................................................................................................80
11.2
Performance......................................................................................................................80
11.3
Use of Investigational Materials.......................................................................................81
11.4
Case Report Forms ...........................................................................................................81
11.5
Retention and Review of Records.....................................................................................81
11.6
Patient Confidentiality......................................................................................................82
12.0
INVESTIGATOR’S STATEMENT ...............................................................................................83
13.0
APPENDICES ................................................................................................................................84
Appendix I.
Elements of Informed Consent...........................................................................84
Appendix II.
Contact Information............................................................................................86
Appendix III.
Concomitant Medications...................................................................................87
Appendix IV.
Scales and Questionnaires ..................................................................................92
14.0
LITERATURE CITED ...................................................................................................................93
LIST OF TABLES
Table 9-1
Contents of Investigational Product Kits ..........................................................................33
LIST OF FIGURES


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LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CI
confidence interval
 
DALYs
disability adjusted life years
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSST
Digit Symbol Substitution Test 
DxV
Diagnostic Validation 
EC
Ethics Committee
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
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


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ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IND
Investigational New Drug (application)
IP
investigational product
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
MMRM
mixed-effect model for repeated measures
NMDAR 
N-methyl-D-aspartate receptor
PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/[RR]½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/[RR]⅓)
SAE
serious adverse event
SAP
Statistical Analysis Plan
 
SD
standard deviation
SIGMA
Structured Interview Guide for the MADRS 
SNRI
selective serotonin and norepinephrine reuptake inhibitor


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SSRI
selective serotonin reuptake inhibitor
T3
triiodothyronine
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid-stimulating hormone
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
United States
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 (if applicable), and amendments (if any) will be 
approved by the IRBs at the study centers in conformance with the US CFR, Title 21, 
Part 56.
Outside the United States
This study will be carried out in full compliance with the guidelines of the independent
ethics committee (EC) and government agencies of each respective country as well as the
European Union Clinical Trial Directive (Directive 2001/20/EC), where applicable.
Before the study begins, the study centers will require approval from an EC and
government agency. During the course of the study, the sponsor or authorized
representative will provide timely and accurate reports to the EC on the progress of the
study, at intervals not exceeding 1 year (or as appropriate) and will notify the EC of
SAEs or other significant safety findings. The study protocol, ICF, information sheet,
advertisements (if applicable), and amendments (if any) will be approved by the EC at 
the study centers in conformance with CFR, Title 21, Part 56, the European Union 
Clinical Trial Directive (Directive 2001/20/EC), and local regulations.
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.


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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 that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements, 
where applicable, and the IRB/EC or study center. 
Each patient will read and sign an ICF and/or other authorization form as per local 
regulations; each patient will be made aware that he or she may withdraw from the study 
at any time.
The ICF contains all the elements of informed consent listed in Appendix I of this 
protocol. Signed copies of the ICF and the HIPAA or other locally applicable form will 
be given to the patient, and both documents will be placed in the investigator’s study 
files.


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INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 40 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/EC (where applicable), 
and completing the electronic case report forms (eCRFs).


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INTRODUCTION
Disease Burden of Major Depressive Disorder
Major depressive disorder (MDD) is a highly disabling, serious condition 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 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 which is a 
leading cause of disability in the world.


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Selective Serotonin Reuptake Inhibitors and Selective Serotonin 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 
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 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 nonpharmacologic treatments including 
psychotherapy and phototherapy, vagus nerve stimulation, transcranial magnetic 
stimulation, and electroconvulsive therapy. 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 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. 


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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 lengthy for patients who are often severely depressed and at a 
high risk for suicide. A drug that could induce a rapid antidepressant effect would 
represent a major advancement for these patients.
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 therapy in MDD. 
Rapastinel as a Novel Approach to Major Depressive Disorder Treatment
The mechanism of action of rapastinel is entirely different from that of first-line 
antidepressants (SSRIs, SNRIs) or adjuvant drugs currently approved for treatment of 
MDD such as 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. 
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 5 mg/kg and 10 mg/kg have 
been shown to produce marked antidepressant effects within 1 day that lasted for 
approximately 1 week or longer in responding patients. These antidepressant effects are 
very similar to ketamine’s effects when administered at a low dose as an infusion. In a 
systematic review and meta-analysis of ketamine and other NMDAR antagonists in the 
treatment of major depression, 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. 


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The purpose of this study is to prospectively confirm that rapastinel, when administered 
at a dose of 450 or 900 mg as a slow bolus IV injection in patients with MDD, is 
significantly superior to placebo in rapidly reducing depressive symptoms. Furthermore, 
the safety and tolerability of rapastinel will be investigated. The study is intended to 
support an application for regulatory approval of rapastinel as monotherapy treatment for 
MDD.


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8.0
STUDY OBJECTIVES
The objectives of this study are to evaluate efficacy, safety, and tolerability of rapastinel 
as a monotherapy treatment in patients with MDD.
Efficacy Objectives

Primary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) versus
placebo and rapastinel (900 mg IV) versus placebo in the treatment of MDD, as 
measured by the change from baseline Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at end of treatment (end of Week 6)

Key secondary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) 
versus placebo and rapastinel (900 mg IV) versus placebo in the treatment of MDD, 
as measured by the change from baseline MADRS total score at 1 day post-first dose
of treatment


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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
3-arm fixed-dose study of weekly IV rapastinel 450 mg, rapastinel 900 mg, and placebo 
in outpatients with a diagnosis of MDD as defined by Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM-5) criteria.
The study will include a total of 10 visits and will be approximately 10 weeks in duration 
(Figure 9.1.3–1): 

Up to 2-week screening period

6-week double-blind treatment period 

2-week safety follow-up period (no treatment) for patients who do not roll over into 
the extension study
Approximately 690 patients are planned to be randomized in the double-blind treatment 
period (230 patients per treatment group). Note that the sponsor may restrict enrollment 
based on patient treatment history to ensure an appropriate balance of patients with an
inadequate response to 1 to 3 ADTs and treatment-naive patients if deemed necessary 
during study conduct.
9.1.1
Screening Period
After providing written consent, patients will enter a screening period of up to 2 weeks, 
prior to Visit 2. Patients will not receive any investigational product (IP) during the 
screening period. Patients will wash out of any ADT and prohibited medications under 
the supervision of the study investigator staff during the screening period. Patients 
meeting the eligibility criteria at the end of Visit 2 (Baseline) will be assigned a treatment 
by the interactive web response system (IWRS) and enter the double-blind treatment 
period.
9.1.2
Double-blind Treatment Period
Patients will be randomized in a ratio of 1:1:1 to 1 of 3 treatment groups: rapastinel 900
mg IV weekly, rapastinel 450 mg IV weekly, or placebo IV weekly. 
During the double-blind treatment period:


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
Patients will have 2 study visits during the first week (treatment day [Visit 2] and 
1 day following the treatment day [Visit 3]). Visits 2 and 3 should be conducted 1 
day apart.  Visit 4 will occur approximately 7 days following Visit 2 with 
subsequent visits occurring at weekly intervals. 

If necessary, study visits, except for those visits specified above as being 
conducted 1 day apart, may be conducted up to 2 days before or after the 
scheduled visits.

All patients who receive IP must complete Visit 9/Early Termination (ET).

Upon completion of the double-blind treatment period, patients may be eligible to 
enter the extension study (RAP-MD-33). Patients who do not enter the extension 
study will enter a 2-week safety follow-up period.
9.1.3
Safety Follow-up Period
Patients who do not roll over into the extension study after completing the double-blind 
treatment period and patients who prematurely discontinue from the study before 
completing 6 weeks of double-blind treatment should enter the 2-week safety follow-up 
period. 
Additional follow-up visits may be scheduled within 30 days, if necessary for safety 
reasons.
A schematic of the study design is presented in Figure 9.1.3–1. The Schedule of 
Evaluations is provided in Section 2.0 and detailed descriptions of each study visit can be 
found in Section 9.5.6.


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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
This multicenter, randomized, placebo-controlled, parallel-group study, with a 6-week 
double-blind treatment period, was designed based on prior studies that established 
rapastinel efficacy and safety in adult patients with MDD. In this study, investigators will 
enroll patients 18 through 75 years of age who meet the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD (American 
Psychiatric Association, 2013). 
 
). The symptoms and severity of MDD will be assessed using the 
MADRS (Section 9.5.1.2.1). 
Study centers will have experience with the study population and will be encouraged to 
apply applicable local guidelines to minimize patient risk or distress. 


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Dose selection information is presented in Section 9.4.5. The planned dosing regimen is 
based on experience from previous rapastinel studies. 
A placebo treatment group is included in the study to comply with worldwide regulatory 
preferences (Laughren, 2001; Gispen-de Wied et al, 2012), since placebo-controlled 
superiority trials have been shown to be conducive to higher quality studies and to 
provide more reliable outcomes (Feifel, 2008; Laughren, 2001; Gispen-de Wied et al, 
2012). Additionally, from a scientific point of view, randomized double-blind 
comparisons versus placebo are needed to permit adequate evaluation of efficacy. 
Comparison to a placebo treatment is also of value for distinguishing disease 
manifestations from adverse reactions of the IP (EMA guidance, 2013). The use of 
placebo in place of the standard therapy should not cause irreversible health problems or 
extreme suffering (depression is recognized by the FDA as a condition in which there is 
substantial improvement and variability in placebo groups) (FDA Guidance for Industry: 
E10, May 2001). 
In Study RAP-MD-32, safety and efficacy assessments are included at every visit to 
determine adequacy of response, safety, and tolerability. In the event of insufficient 
therapeutic response or worsening of the patient’s initial condition, the IP should be 
discontinued and an alternative treatment will then be allowed (Section 9.4.12). An
independent Data and Safety Monitoring Board (DSMB) will evaluate safety data during 
the study (Section 9.8).
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
Criteria to be assessed at Visit 1 (Screening)
1. Written informed consent, obtained from the patient before the initiation of any 
study-specific procedures (Section 5.3) 
2. Male or female outpatients, 18 to 75 (inclusive) years of age at Visit 1
3. Meet 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 (Patients in their first depressive episode may only be enrolled after 
documented discussion with the sponsor representative)  


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6. Treatment naive (defined as those who have not received antidepressant or those who 
have received antidepressant but not meeting adequate dose or duration criteria per
]) in the present
episode or inadequate response (< 50% reduction in depressive symptoms) to 1 to 3 
ADTs given at adequate doses (as defined by the ADT package insert) and duration 
of ≥4 weeks during the present episode as documented using the ATRQ
 
8. If female of childbearing potential, have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test at Visit 1
9. Ability to follow study instructions and likely to complete all required visits
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
Exclusion criteria to be assessed at Screening (Visit 1)
Psychiatric and Treatment-Related Criteria
1. DSM-5–based diagnosis of any disorder other than MDD that was the primary focus 
of treatment within 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:
a.
Schizophrenia spectrum or other psychotic disorder
b. Bipolar or related disorder


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c.
Major neurocognitive disorder 
d. Neurodevelopmental disorder of greater than mild severity or of a 
severity that impacts the patient’s ability to consent, follow study 
directions, or otherwise safely participate in the study
e.
Dissociative disorder
f.
Posttraumatic stress disorder
g. MDD with psychotic features


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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of the study 
visits and procedures. Patients can be prematurely discontinued from the study after 
careful consideration for one of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria)

Pregnancy

Withdrawal of consent 

AE

Lack of efficacy

Protocol deviation

Noncompliance with IP

Lost to follow-up 

Study terminated by sponsor

Study center terminated by sponsor

Other 


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All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at an ET Visit. A final assessment will be defined as 
completion of the evaluations scheduled for all patients at Visit 9. 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 or designee after each premature discontinuation to ensure proper 
characterization of the reason for discontinuation is captured.
9.3.3.1
Criteria for Required Removal of Patients from Therapy or 
Assessment
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

Significant risk, as judged by the investigator, based on the psychiatric interview 
or 

MADRS Item 10 score ≥ 5
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.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.4
TREATMENTS
Patients meeting the eligibility criteria at the end of Visit 2 (Baseline) will be randomized 
in double-blind fashion to 1 of 3 treatment groups: placebo, rapastinel 450 mg, or 
rapastinel 900 mg. 


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9.4.1
Treatments Administered
The IP will only be administered to eligible patients by a medically qualified person as 
per the local state regulations. The range of persons who can administer an IV can be a 
physician, a physician assistant, nurse, or nurse practitioner, etc, depending on the local 
and/or state law.  
IP should be administered after all efficacy and safety assessments with the exception of 
the postdose assessments described below.
The IP will be administered using the 2 provided prefilled syringes in a “slow bolus” 
single injection to an upper extremity vein within approximately 2 to 4 minutes to each 
study patient (approximately 1 to 2 minutes per syringe). The patient should not be 
discharged from the study center until the investigator or medically qualified 
subinvestigator determines that they are medically able to leave the study center
(recommended not less than 15 minutes following administration).
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 state and local regulations/standard of care, to resuscitate a patient in the event of 
a medical emergency.  
At IP administration visits, the patient should not be released from the study center until 
the following are completed:

Postadministration pulse rate and BP 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 release from 
the study center, in the opinion of the investigator (or medically qualified 
subinvestigator)

A physician licensed in the state (investigator or subinvestigator) determines that 
they are medically able to leave the study center and provides written sign-off not 
less than 15 minutes following administration (see IV Administration and 
Evaluation Notes document in Study Reference Manual)


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9.4.2
Identity of Investigational Products
Rapastinel 450 mg IV Prefilled Syringes: 
 
 
Placebo rapastinel IV Prefilled Syringes: 
 
 
 
 
 
 
The table below indicates the kit contents by group: 
Table 9-1
Contents of Investigational Product Kits
Group
Syringe 1
Syringe 2
Placebo
Placebo
Placebo
Rapastinel 450 mg
Rapastinel 450 mg
Placebo
Rapastinel 900 mg
Rapastinel 450 mg
Rapastinel 450 mg
The study center personnel will complete the kit label and attach the tear-off portion to 
the source documents. 
The prefilled syringes will be labeled with the protocol number and kit number. The 
study center personnel will write the PID number on each prefilled syringe associated 
with the kit mentioned above. The prefilled syringe labels will not have a tear-off portion
and will remain on the prefilled syringe.


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


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A 900-mg IV unit dose arm has been included (equivalent to 9.0 mg/kg in a 100-kg 
patient and a dose of 18 mg/kg in a 50-kg patient) to allow for further evaluation of the 
dose-response profile.  This higher dose arm overlaps the dose range that appears 
efficacious in Phase 2 studies and approaches the dose higher than 10 mg/kg at which 
efficacy diminished despite being well tolerated, depending on the body mass of the 
patient.
9.4.6
Selection and Timing of Dose for Each Patient
The IP will be administered IV using the assigned single-use prefilled syringes at 
Visits 2, 4, 5, 6, 7, and 8.
9.4.6.1
Screening Period
At Screening (Visit 1) after written consent is obtained, patients enter a screening period 
of up to 2 weeks. No IP is administered during the screening period.
9.4.6.2
Double-blind Treatment Period
Patients who meet all eligibility criteria at Screening (Visit 1) and who continue to meet 
all the eligibility criteria for participation in the study at the Baseline Visit (Visit 2) will 
be assigned an IP kit number via IWRS at Baseline (Visit 2). Patients will receive the 
first dose of randomized IP that day. The IP kit numbers will also be assigned by IWRS 
at subsequent treatment visits.
Patients will receive rapastinel 450 mg, rapastinel 900 mg, or placebo from a prefilled 
single-dose syringe at Visits 2, 4, 5, 6, 7, and 8. 
9.4.6.3
Safety Follow-up Period 
Patients who complete 6 weeks of randomized treatment may be eligible to enter the 
RAP-MD-33 extension study. If they do not enter RAP-MD-33, they should enter the 
safety follow-up period. Patients who discontinue the study prematurely should enter the 
safety follow-up period. No IP is administered during the safety follow-up period.
9.4.7
Blinding
A list of patient randomization codes will be generated by Statistical Programming and 
implemented by the IWRS vendor (an electronic version will be stored on a secure 
server). This list will identify each patient by randomization number and include the 
patient’s corresponding treatment assignment.


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All study treatments will be provided in identical syringes and cartons to maintain 
masking of the study.
9.4.8
Unblinding
Any unblinding at the study-center level should be done only in an emergency that 
requires identification of the IP for the medical management of the patient. The 
investigator must notify the Study Physician immediately (refer to Appendix II) and a full 
written explanation must be provided if the blind is broken. Before IP is unblinded, every 
attempt should be made to discuss the case with the Study Physician. 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.
In an emergency, the investigator can obtain the treatment assignment of any patient at 
his or her study center through the IWRS. The investigator will access the IWRS to break 
the blind.
9.4.9
Prior and Concomitant Therapy
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. 
Medication history (psychotropic medication history during the previous 5 years [to the 
extent possible] 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
Other Restrictions
9.4.10.1
Alcohol 
It is recommended that patients abstain from alcohol consumption during the study.
9.4.10.2
Contraception
For purposes of this study, females will be considered of childbearing potential unless 
they are naturally postmenopausal or permanently sterilized (ie, hysterectomy). Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any 
other obvious pathological or physiological cause. 
For women of childbearing potential and male partners of women 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), implantable permanent birth control 
device (eg, Essure; note: device must be in place at least 3 months and completed 
confirmation test), vasectomized partner, or complete abstinence for the duration of the 
study (periodic abstinence [such as calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of contraception).
The investigator and each patient will determine the appropriate method of contraception 
for the patient during the participation in the study with consideration for local regulatory 
or IRB/EC requirements.


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See Section 9.5.2.3 for pregnancy reporting procedures.
9.4.11
Monitoring Treatment Compliance
IP compliance during any period will be closely monitored by capturing the date and time 
of each administration of IP. If a scheduled injection does not occur, the sponsor must be 
notified and the reason captured in the eCRF.
9.4.12
Treatment After Discontinuation
Patients whose MDD symptoms worsen or are determined by the investigator not to be 
adequately controlled prior to completing the double-blind treatment period will be 
allowed to discontinue the study and start appropriate treatment at the investigator’s 
discretion. This new treatment will not be provided by the sponsor. 
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9.5.1.1
Diagnostic Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.5.1.2
Efficacy Assessments
The efficacy assessments 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.


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9.5.1.2.1
The Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery and Åsberg, 1979) is a clinician-rated scale. The MADRS 
will be used to assess depressive symptomatology. Patients are rated on 10 items to 
assess feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep 
or appetite, difficulty concentrating, and lack of interest. Each item will be scored on a 7-
point scale. A score of 0 indicates the absence of symptoms, and a score of 6 indicates 
symptoms of maximum severity. 
The MADRS will be evaluated at the timepoints indicated in Schedule of Evaluations 
(Section 2.0) using the Structured Interview Guide for the MADRS (SIGMA) 
methodology (Williams and Kobak, 2008).  At Visit 3 (visit occurring 1 day following IP 
administration), the MADRS will be administered with a look-back timeframe of “since 
last evaluation”.  At all other administrations, the MADRS will be administered with a 
look-back timeframe of 1 week.
9.5.1.2.1.1
 Central Ratings for MADRS
In order to control for possible bias in face-to-face ratings and to obtain a “blinded” 
rating of patient symptom severity and change, blinded expert raters will administer, 
through remote teleconference, the MADRS. The remote (or centralized) raters will be 
blind to the study design, entry criteria, and visit number (except for Screening [Visit 1], 
Baseline [Visit 2], and Visit 3).
The 
 may be observed during the interview by another mental health 
evaluator for quality control purposes. At the study center, the evaluations must be 
conducted in a private room, with the door closed, and a study center representative (eg, 
study coordinator) may be present during the rating session at the discretion of the 
Investigator. Effort should be made to administer the MADRS prior to other efficacy 
assessments where clinically feasible.
 
 
 
 
 
 


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9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care 
professional at every visit and the evaluation must be documented. The procedures 
discussed below will be completed at the designated visits.


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


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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 
poststudy period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least one of the following conditions is met: 1) the event meets the criteria for 
an SAE (see Sections 9.5.2.1.3 and 9.5.2.1.4), and/or 2) the event is judged by the 
investigator to be potentially causally related to IP (Section 9.5.2.1.1).
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.
9.5.2.1.4.1
 Reporting of Safety/Adverse Events
 Raters will complete a safety reporting form (ie, Potential Clinical Events 
Notification Form), including an additional risk assessment form if certain triggers are 
met during their interviews with the patients at the study centers (ie, risk assessment 
forms for suicide, homicide, suspected child abuse, and suspected elder/dependent adult 
abuse). 
 feel morally and ethically obligated to report this information 
to the study center, and the principal Investigator is responsible for follow-up, including 
management of the patient and further reporting as necessary. 
Patients may spontaneously report possible clinical events to the centralized rater during 
an assessment. Possible clinical events as determined by the centralized rater will be 
recorded on a central rater source document and will be forwarded to the study center for 
further evaluation at the conclusion of the assessment. It is the study center’s
responsibility to determine, with further patient questioning, whether this event qualifies 
as an AE or SAE and to adhere to the methods described in Section 9.5.2.1.4 for 
reporting such events to the sponsor. 
If, while conducting the assessment, the centralized rater feels that there is an emergent 
risk to the safety of the patient, or to a third party, the study center will be contacted 
immediately by the centralized rater to intervene in the patient assessment room. The 
central rater shall stay on the teleconference call with the patient until appropriate 
personnel from the study center arrive. Information regarding the assessment shall be 
documented by the central rater and forwarded to the study center where the patient is 
physically present. The principal Investigator at the study center shall be responsible for 
compliance with any state law reporting requirements such as, for example, those 
governing the reporting of child abuse, or any duty to warn third parties of potential 
harmful conduct by the patient.


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9.5.2.2
Immediate Reporting of Serious Adverse Events
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 email 
address or 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 emailed or 
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.
Email or Fax the SAE Form for Clinical Trials to the sponsor.
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 email or fax it to the SAE/Pregnancy email address or fax 
number provided in Section 9.5.2.2, even if no AE has occurred. Pregnancies in female 
partners of male patients occurring during the time frame described above must also be 
reported. 


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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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9.5.3
Investigational Product Concentration Measurements
Sparse PK sampling is optional. For patients who consent, up to 3 blood samples per 
patient will be collected to determine plasma concentrations of rapastinel using a 
validated bioanalytical method.  Samples will be collected from consenting patients at 
Visit 6/Day 21: Sample 1 (collected up to 15 minutes after IP dosing), Sample 2 
(collected 20-30 minutes after IP dosing), and Sample 3 (collected 45 to 60 minutes after 
IP dosing).
Additional information on the collection and handling of samples is detailed in the Lab 
Procedure Manual.


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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.


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After all data have been reviewed and all issues have been resolved, the database will be 
locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, regulatory documents) will be retained at the study center, along with 
adequate source documentation, according to FDA and ICH requirements. All study 
records must be available for inspection by the sponsor, its authorized representatives, the 
FDA, or other health authorities.
 
 
will be captured using paper source.  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 populations will be considered in the statistical analysis of the study, as 
specified in the following subsections.
9.7.1.1
Safety Population
The Safety Population will consist of all randomized patients who received at least 1 dose 
of randomized IP.
9.7.1.2
Modified Intent-to-Treat Population
The modified Intent-to-Treat (mITT) Population will consist of all patients in the Safety 
Population who had at least 1 postbaseline assessment of the MADRS total score. 
9.7.1.3
Pharmacokinetic Population
The PK Population will consist of all patients in the Safety Population with at least 1 
evaluable PK sample.


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9.7.2
Patient Disposition
The number and percentage of patients in the mITT Population will be summarized by 
treatment group.
Screen failures (ie, patients screened but not randomized) and the associated reasons for 
failure to randomize will be tabulated overall for the screened patients. The number and 
percentage of patients who complete the double-blind treatment period, patients who 
prematurely discontinue during the same period and who enter the safety follow-up 
period will be presented for each treatment group and pooled across treatment groups for 
all randomized patients. The reasons for premature discontinuation from the double-blind 
treatment period as recorded on the termination pages of the eCRFs will be summarized 
(number and percentage) by treatment group for all randomized patients.
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters and other baseline characteristics (eg, age, race, ethnicity, sex, 
weight, height, body mass index [BMI]) will be summarized by treatment group for the 
mITT Population. 
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to randomized IP for the Safety Population during the double-blind treatment 
period will be summarized in terms of treatment duration, calculated as the number of 
days from the date of first dose of randomized IP received to the date of the last dose 
received, inclusive. Descriptive statistics (n, mean, SD, minimum, median, and 
maximum) will be presented by treatment group for IP exposure. The total number of IV 
doses actually received by a patient during the double-blind treatment period will be 
summarized by treatment group for the safety population.
9.7.4.2
Prior and Concomitant Medication
Prior medication is defined as any medication taken before the date of the first dose of 
randomized IP. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of randomized IP. 
Both prior and concomitant medication use will be summarized by the number and 
proportion of patients in each treatment group receiving each medication within 
each therapeutic class for the Safety Population. 


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9.7.4.3
Measurement of Treatment Compliance
Dosing compliance for the double-blind treatment period is defined as the total number of 
IV doses actually received by a patient during that period divided by the number of IV 
doses that were expected to be received during the same period multiplied by 100. 
Descriptive statistics for IP compliance will be presented by treatment group for each 
week, as well as for the whole double-blind treatment period of the study for the Safety 
Population.
9.7.5
Efficacy Analyses
All efficacy analyses will be based on the mITT Population, unless stated otherwise. The 
baseline for each specific efficacy endpoint is defined as the last measurement prior to the 
first dose of randomized treatment. All statistical hypothesis tests will be performed at the 
2-sided 5% significance level for main effects. All confidence intervals (CIs) will be 
2-sided 95% CIs, unless stated otherwise. 
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with < 2 patients in ≥ 1 treatment group in the mITT Population. Small centers will 
be pooled to form pseudo-centers so that each treatment group includes ≥ 2 mITT 
patients within the center. Pooling will be done using the following algorithm: 
Based on the number of mITT patients, small centers will be ordered from the largest to 
the smallest, and centers of the same size will be ordered from the largest center code to 
the smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small center is 
formed. The process will be repeated using the small centers left out after the first pass. If 
any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is > 1 smallest pseudo-center, the pseudo-center with the smallest 
center code will be selected. In case the pseudo-center formed by pooling all small 
centers is still a small center, it will be pooled with the smallest non-small center. If there 
is > 1 smallest non-small center, the one with the smallest center code will be selected. 
An additional analysis plan specific to European Medicines Agency will be presented in a 
stand-alone document.  


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9.7.5.1
Primary Efficacy Analyses
The primary efficacy parameter will be the change from baseline in MADRS total score 
at the end of treatment (end of Week 6). The primary parameter will be analyzed using a 
mixed model for repeated measures (MMRM) with terms for treatment, study center, 
visit, baseline, and treatment-by-visit and baseline-by-visit interactions. An unstructured 
covariance matrix will be used to model the covariance of within-patient scores. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
(Kenward et al, 1997). This analysis will only use the observed postbaseline scores 
without imputation of missing values.  The treatment differences for rapastinel 450 mg 
versus placebo and rapastinel 900 mg versus placebo will be estimated and reported 
along with the corresponding 95% CIs and the p-values for superiority testing. 
In the case that the MMRM model with unstructured covariance fails to converge with 
the default algorithm, then the Fisher scoring algorithm will be used to provide better 
initial values of the covariance parameters; if the model still does not converge, a 
simplified model without term for study center will be used to find the initial values of 
the covariance parameters. In the rare event that model still does not converge after using 
those initial values, simplified covariance structures will be used to fit the model in the 
following order: (1) ante-dependence, (2) heterogeneous autoregressive, (3) Toeplitz, and 
(4) compound symmetry.
To assess the robustness of the primary MMRM results to the possible violation of the 
missing-at-random assumption, a sensitivity analysis will be conducted.
The sensitivity analysis will use a pattern-mixture model based on non-future- dependent 
missing-value restrictions (Kenward et al, 2003). The pattern for the pattern-mixture 
model will be defined by the patient’s last visit with observed value. The observed 
MADRS total score at a visit is assumed to have a linear relationship with the patient’s 
prior measurements. The missing values will be imputed under the assumption that the 
distribution of the missing observations differs from the observed only by a shift 
parameter value Δ. The dataset with observed and imputed values will be analyzed using 
the same model as the primary analysis for between-treatment group comparisons at the 
end of the treatment. The imputation of missing values and the analysis will be performed 
20 times and the inference of this sensitivity analysis will be based on the combined 
estimates using the standard multiple imputation technique. The values or Δ will be 
selected as 0 to 8.


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9.7.5.2
Key Secondary Efficacy Analysis
The key secondary efficacy parameter will be the change from baseline in MADRS total 
score at 1 day after first dose of treatment. The key secondary analysis will be analyzed 
using the same MMRM model for the primary efficacy parameter. The treatment 
differences for rapastinel 450 mg versus placebo and rapastinel 900 mg versus placebo 
will be estimated and reported along with the corresponding 95% CIs and the p-values for 
superiority testing.
The following serial gatekeeping procedure will be applied to control the overall type I 
error rate at the 0.05 level for the primary and secondary hypotheses.
Step 1: Rapastinel 450 mg is superior to placebo in MADRS at Week 6.
Step 2: Rapastinel 450 mg is superior to placebo in MADRS at Day 1.
Step 3: Rapastinel 900 mg is superior to placebo in MADRS at Week 6.
Step 4: Rapastinel 900 mg is superior to placebo in MADRS at Day 1.
The above hypotheses will be tested in the specified order. If at any step a test fails, the 
test procedure will stop and no further hypotheses will be tested.


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9.7.6.1
Adverse Events
All AEs will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities.
An AE (classified by preferred term) that occurs during the double-blind treatment period 
will be considered a treatment-emergent adverse event (TEAE) if it was not present 
before the first dose of IP or was present before the date of the first dose of IP and 
increased in severity after the first dose of IP. If more than 1 AE is reported before the 
first dose of IP and coded to the same preferred term, the AE with the greatest severity 
will be used for comparison with the AEs occurring during the double-blind treatment 
period that were also coded to that preferred term. An AE that occurs more than 30 days
after the date of the last dose of IP will not be considered as a TEAE.


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The number and percentage of patients reporting TEAEs in each treatment group will be
tabulated by system organ class and preferred term and further categorized by severity 
and causal relationship to the IP. If more than 1 AE is coded to the same preferred term 
for the same patient, the patient will be counted only once for that preferred term using 
the greatest severity and strictest causality for the summarization by severity and causal 
relationship.
The incidence of common (≥ 2% of patients in any treatment group) TEAEs and AEs 
leading to premature discontinuation of IP will be summarized by preferred term and 
treatment group and sorted by decreasing frequency for the test treatment. 
An SAE that occurred between the date of the first dose of IP and 30 days after the date 
of the last dose of IP, inclusive, will be considered an on-therapy SAE. The number and 
percentage of patients who have on-therapy SAEs will be summarized by preferred term 
and treatment group. In addition, the incidence of on-therapy SAEs that led to death will 
be summarized separately by preferred term for each treatment group.


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9.7.9
Interim Analysis
A blinded sample size reestimation will be conducted after approximately 60% of 
patients have completed the double-blind treatment period. This reestimation will be 
conducted in a blinded manner and will be based upon the observed variability of the 
overall treatment effect during the double-blind treatment period. The detailed procedure 
for blinded sample size reestimation will be described in the SAP. 
9.7.10
Determination of Sample Size
This study will randomize approximately 690 patients to the rapastinel 450 mg, rapastinel 
900 mg, and placebo groups in a 1:1:1 ratio. The primary efficacy endpoint is the change 
from baseline in the MADRS total score at the end of Week 6. Assuming the SD is 10 
points, within-patient correlation is 0.6, and dropout rate over 6 weeks is 20%, adjusting 
for multiple comparisons of 2 rapastinel groups with placebo across the primary and 
secondary endpoints by using the serial gatekeeping procedure (Section 9.7.5.2) a sample 
size of 230 patients per treatment group will provide 90% power to detect a difference of 
3.5 points for a rapastinel dose versus placebo at a 2-sided significance level of 5%.
9.7.11
Statistical Software
Statistical analyses will be performed using 


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9.8
DATA AND SAFETY MONITORING BOARD
The study will be conducted under the supervision of an independent DSMB to be 
chartered to review safety data at predetermined points during the study. The DSMB may 
also decide to meet and review safety data at other time points should it be deemed 
necessary. The DSMB is responsible for the ongoing review of safety data in the clinical 
study and for making recommendations concerning the continuation, modification, and 
termination of the study (FDA Guidance for Clinical Trial Sponsors: Establishment and 
Operation of Clinical Trial Data Monitoring Committees, March 2006; European 
Medicines Agency Guideline on Data Monitoring Committees, 
EMEA/CHMP/EWP/5872/03, July 2005).
All analyses that are required to support the DSMB will be performed by independent
statistician(s) 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/EC and the signature page, signed by the 
investigator, and 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/EC review and approval in jurisdictions where regulatory authorities allow such 
implementation. However, the IRB/EC 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.


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9.10
PROTOCOL DEVIATIONS
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB/EC 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 time points, 
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.
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/EC must be notified within the time period dictated by the IRB/EC
associated with this study. 


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


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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The following must be in place and filed with the sponsor before the start of the study at 
each study center:

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/EC 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/EC, as stated in 
Section 5.1.

A copy of the IRB/EC-approved ICF

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB/EC 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

Participants will be assigned a unique identifier (PID). Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.


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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (RAP-MD-32, dated 10 Apr
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, local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/IEC or study center. 
Signed informed consent will be obtained from each patient participating in a clinical 
research study. This consent must include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA, the 
sponsor, the IRB/EC, 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/EC 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 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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APPENDIX IV.
SCALES AND QUESTIONNAIRES
Please refer to the Study Reference Manual for reference copies of scales and 
questionnaires.


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14.0
LITERATURE CITED
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disorders: DSM-5. Washington, DC: American Psychiatric Association
Ashton AK, Jamerson BD, Weinstein W, et al. Antidepressant-related adverse effects 
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106.doi:10.1016/j.curtheres.2005.04.006.
Boland RJ, Keller MB. Treatment of depression. In: Schatzberg AF, Nemeroff CB, 
editors. Essentials of clinical psychopharmacology. 2nd ed. Arlington, VA: American 
Psychiatric Publishing, Inc.; 2006;p 465-478.
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the 
Clinician Administered Dissociative States Scale (CADSS). J Trauma Stress 
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EMA/CHMP/185423/2010 Rev. 2 previously (CPMP/EWP/518/97, Rev. 1) Committee 
for Medicinal Products for Human Use (CHMP) 30 May 2013 Guideline on clinical 
investigation of medicinal products in the treatment of depression
EMEA/CHMP/EWP/5872/03 Corr, Committee for Medicinal Products for Human Use 
(CHMP) 27 July 2005 Guideline on data monitoring committees
Fava M.  Diagnosis and definition of treatment-resistant depression. Society of Biological 
Psychiatry 2003;53:649-659.
Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. 
Psychiatr Clin North Am. 1996 Jun;19(2):179-200.
FDA Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial 
Data Monitoring Committees, March 2006 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf
FDA Guidance for Industry: Drug Induced Liver Injury- Pre-Marketing Clinical 
Evaluation, July 2009
FDA Guidance for Industry: E10, Choice of Control Group and Related Issues in 
Clinical Trials, May 2001
Feifel D. The use of placebo-controlled clinical trials for the approval of psychiatric 
drugs: Part I—Statistics and the Case for the “Greater Good”. Psychiatry (Edgemont) 
2008;6(3):41–43


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Gispen-de Wied C, Stoyanova V, Yu Y, et al. The placebo arm in clinical studies for 
treatment of Psychiatric Disorders: A Regulatory Dilemma. Eur Neuropsychopharmacol, 
2012;14 June (published ahead of print)
Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in 
the United States: how did it change between 1990 and 2000? J Clin Psychiatry 
2003;64(12):1465-1475.
Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test 
battery, CNS Vital Signs. Arch Clin Neuropsychol. 2006 Oct;21(7):623-643.
Guy W: ECDEU Assessment Manual for Psychopharmacology - Revised, in 
(ed DHEW Publ No ADM 76-338). Rockville, MD, U.S., U.S. Department of Health, 
Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, 1976;pp 218-222
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec;20 (10):1727-1736.
Kalali A. Patient Satisfaction with, and Acceptability of, Atypical Antipsychotics. 
Current Medical Research and Opinion. 1999;15(2): 135-137
Kalali, A.H. Evaluating patient satisfaction: a practical approach. Clear Perspectives 
1999;2(3):18–21.
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika 2003;90(1): 53-71
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997;53:983-997
Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-
III-R psychiatric disorders in the United States: results from the National Comorbidity 
Study. Arch Gen Psychiatry 1994;51:8-19.
Kessler RC, Chiu WJ, Demler O, et al. Prevalence, severity, and comorbidity of 12-
month DSM-IV disorders in the National Comorbidity Survey. Arch Gen Psychiatry 
2005;62(6): 617-627.
Laughren TP. The scientific and ethical basis for placebo-controlled trials in depression 
and schizophrenia: an FDA perspective. Eur Psychiatry. 2001;16(7):418-423
Masand PS. Tolerability and adherence issues in antidepressant therapy. Clin Ther 
2003;25(8):2289-2304.


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McIntyre RS and Donovan C. The human cost of not achieving full remission in 
depression. Can J Psychiatry 2004;49(suppl 1):10S-16S.
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry 1979;134:382-389
Murray CJ, Atkinson C, Bhalla K, et al. The state of US health, 1990-2010: burden of 
diseases, injuries, and risk factors. JAMA 2013;310(6):591-608.
Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA 
antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 
2015;172(10):950-966.
Overall JE and Gorham DR. The brief psychiatric rating scale. Psychological Reports 
1962;10:799-812.
Rosenzweig-Lipson S, Beyer CG, Hughes ZA, et al. Differentiating antidepressants of 
the future: efficacy and safety. Pharmacol Ther 2007;113(1):134-153.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in 
depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J 
Psychiatry 2006;163:1905-1917.
Sheehan DV, Sheehan KH, and Raj BA.  The measurement of disability. International 
Clinical Psychopharmacology 1996;11 (suppl 3):89-95.
Smith DW and Jones KL (1982). Recognizable Patterns of Human Malformation. (3 ed.) 
Philadelphia: Saunders.
Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentations after the failure of 
SSRIs for depression. N Engl J Med 2006;354(12):1243-1252.
Videbech P and Ravnkilde B. Hippocampal volume and depression: a meta-analysis of 
MRI studies. Am J Psychiatry 2004;161:1957-1966.
Williams JA and Kobak KA.  Development and reliability of a structured interview guide 
for the Montgomery-Åsberg Depression Rating Scale (SIGMA). The British Journal of 
Psychiatry 2008;192:52-58.
World Health Organization. Mental health: new understanding, new hope. World Health 
Report 2001

SAP_000.pdf: 
NCT03560518 
 
Study ID: RAP‐MD‐32 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter Study of Rapastinel 
as Monotherapy in Patients with Major Depressive Disorder 
 
Statistical Analysis Plan Amendment 1 Date: 22 May 2019 
 
 
 


Naurex, Inc., an affiliate of Allergan, plc
5 Giralda Farms
Madison, NJ 07940
RAP-MD-32
A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel 
as Monotherapy in Patients with Major Depressive Disorder
STATISTICAL ANALYSIS PLAN AMENDMENT
Original SAP Date: February 12, 2019
Amendment 1 Date: May 22, 2019
Confidentiality Statement
This document is the property of Allergan, plc. and may notin full or partbe passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan, plc.


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1.0
TABLE OF CONTENTS
1.0
TABLE OF CONTENTS..................................................................................................................2
2.0
LIST OF ABBREVIATIONS...........................................................................................................4
3.0
History of change..............................................................................................................................6
4.0
INTRODUCTION ............................................................................................................................7
5.0
OBJECTIVES.................................................................................................................................10
6.0
PATIENT POPULATIONS............................................................................................................12
6.1
Safety Population..............................................................................................................12
6.2
Modified Intent-to-Treat Population.................................................................................12
7.0
PATIENT DISPOSITION ..............................................................................................................13
7.1
Protocol Deviations ..........................................................................................................13
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................14
9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................15
9.1
Extent of Exposure ...........................................................................................................15
9.2
Measurement of Treatment Compliance...........................................................................15
10.0
EFFICACY ANALYSES ...............................................................................................................16
10.1
Primary Efficacy Parameter..............................................................................................16
10.2
Key Secondary Efficacy Parameters.................................................................................17
11.0
SAFETY ANALYSES....................................................................................................................22
11.1
Adverse Events .................................................................................................................22
13.0
INTERIM ANALYSIS ...................................................................................................................30
14.0
DETERMINATION OF SAMPLE SIZE .......................................................................................31
15.0
STATISTICAL SOFTWARE.........................................................................................................32
16.0
DATA HANDLING CONVENTIONS ..........................................................................................33


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16.1
Summary Statistics ...........................................................................................................33
16.3
Repeated or Unscheduled Assessments of Safety Parameters..........................................34
16.4
Missing Severity Assessment for Adverse Events............................................................34
16.5
Missing Causal Relationship to stuDy drug for Adverse Events......................................35
16.6
Missing Date Information for Adverse Events .................................................................35
16.7
Missing Date Information for Prior or Concomitant Medications....................................36
16.7.1
Incomplete Start Date.........................................................................................36
16.7.2
Incomplete Stop Date .........................................................................................37
17.0
REFERENCES ...............................................................................................................................40
18.0
Appendices......................................................................................................................................41
Appendix I.
Reporting Selected Laboratory Parameters in Conventional Unit......................41
Appendix II.
Pattern-Mixture Model Details...........................................................................43
LIST OF TABLES
LIST OF FIGURES
Figure 10-1
Graphical Testing Procedure..................................................................... 18


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2.0
LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
DBTP
double-blind treatment period
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DxV
Diagnostic Validation
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
ET
early termination
ICF
informed consent form
IP
investigational product
LLN
lower limit of normal
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent to treat


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MMRM
mixed-effects model for repeated measures
PCS
potentially clinically significant
PID
patient identification
PK
pharmacokinetic
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
SE
Standard Error
SFUP
Safety Follow-up Period
SI
Le Système International d’Unités (International System of Units)
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal


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3.0
HISTORY OF CHANGE
Section No. 
Section Name
Description
General Notes
The following changes are implemented in the statistical sections of 
protocol amendment 1 (dated May 22, 2019):
1.
The gatekeeping serial testing procedure was replaced by the 
graphical testing procedure to adjust for multiple 
comparisons in the primary and secondary efficacy 
parameters for both rapastinel doses versus placebo. The 
section of “interim analysis” was added based on the 
proposal agreed by the FDA (response dated dd May 2019).
2.
The section of “determination of sample size” was revised to 
reflect the associated changes in the significance level and 
associated power for the final primary efficacy analyses due 
to the addition of interim analysis.
These changes are now implemented in Sections 10.2 (KEY 
SECONDARY EFFICACY PARAMETERS), 13.0 (INTERIM 
ANALYSIS) and 14.0 (DETERMINATION OF SAMPLE SIZE) of 
this SAP amendment.
In addition, other revisions were documented in this history of change 
and implemented in this SAP amendment.
10.2
KEY SECONDARY 
EFFICACY 
PARAMETERS
The gatekeeping testing procedure was replaced by the graphical 
testing procedure to adjust for multiple comparisons in the primary 
and secondary efficacy parameters for both rapastinel doses versus 
placebo.
11.3
VITAL SIGNS
The orthostatic hypotension was specified to be summarized for pre-
dose, post-dose and other visits without IP administration separately 
for the DBTP.
13.0
INTERIM 
ANALYSIS
The blinded sample-size re-estimation was replaced by an unblinded 
interim analysis in order to identify early signs of futility.  
14.0
DETERMINATION 
OF SAMPLE SIZE
The sample size estimation was revised to reflect a reduced 
significance level (from 0.05% to 0.049%) and associated power for 
the final primary efficacy analyses due to the addition of interim 
analysis.
 
 
.
 
 
 
 


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4.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined in the Study RAP-MD-
32 protocol amendment 1 (dated May 22, 2019). Specifications of tables, figures, and 
data listings are contained in a separate document. The SAP for pharmacokinetic, 
pharmacodynamic and/or health economics and outcomes research data (if applicable) 
will be prepared separately.
Study RAP-MD-32 is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study in patients 18 to 75 years of age who meet the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for
major depressive disorder (MDD). The symptoms and severity of MDD will be assessed 
based on their Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical 
. All patients will be treatment naive (defined 
as those who have not received antidepressant, or have received antidepressant but not 
meeting adequate dose or duration criteria per the Antidepressant Treatment Response 
Questionnaire [ATRQ]) in the present episode or inadequate response (<50% reduction in 
depressive symptoms) to 1 to 3 antidepressant therapies (ADTs) given at adequate doses 
for ≥ 4 weeks during the present episode.
The study will include a total of 10 visits and will be approximately 10 weeks in duration:

Up to 2-week screening period

6-week double-blind treatment period

2-week safety follow-up period (no treatment) for patients who do not roll over 
into the extension study
Signed informed consent from the patient or the patient’s legally authorized 
representative will be obtained before any study-related procedures are begun. Patients 
will wash out any previous ADT and/or prohibited medications during the screening 
period. Patients meeting the eligibility criteria at the end of Visit 2 will be randomized in 
a ratio of 1:1:1 to one of the three treatment arms: rapastinel 900 mg IV weekly, 
rapastinel 450 mg IV weekly, or placebo IV weekly. The double-blind treatment period 
(DBTP) starts with the first dose of study treatment. Upon completion of the DBTP, 
patients may be eligible to enter the extension study. Patients who do not enter the 
extension study will enter a 2-week safety follow-up period. Efficacy and safety 
assessments will be conducted at the clinic 1 day following the treatment day in the 1st 
week and at the ends of weeks 1, 2, 3, 4, 5 and 6 of the DBTP. Patients prematurely 
discontinuing from the study, regardless of cause, will be seen for a final evaluation.
The schedule of evaluations for Study RAP-MD-32 is presented in Table 4–1. 


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5.0
OBJECTIVES
The objectives of this study are to evaluate the efficacy, safety, and tolerability of 
rapastinel as monotherapy treatment in patients with MDD.
Efficacy Objectives

Primary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) 
versus placebo and rapastinel (900 mg IV) versus placebo in the treatment of 
MDD, as measured by the change from baseline Montgomery-Åsberg Depression 
Rating Scale (MADRS) total score at end of treatment (end of Week 6)

Key secondary efficacy objective: To evaluate the efficacy of rapastinel (450 mg 
IV) versus placebo and rapastinel (900 mg IV) versus placebo in the treatment of 
MDD, as measured by the change from baseline MADRS total score at 1 day 
post-first dose of treatment


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6.0
PATIENT POPULATIONS
The following populations will be considered in the statistical analysis of the study.
6.1
SAFETY POPULATION
The Safety Population will consist of all randomized patients who received at least 1 dose 
of randomized IP.
6.2
MODIFIED INTENT-TO-TREAT POPULATION
The Modified Intent-to-Treat (mITT) Population will consist of all patients in the Safety 
Population who had at least 1 post-baseline assessment of the MADRS total score.


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7.0
PATIENT DISPOSITION
The number and percentage of patients in the mITT and Safety populations will be 
summarized by treatment group and by study center respectively.
Screen-failure patients (ie, patients screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for all screened patients. The 
number and percentage of patients who complete the DBTP, patients who prematurely 
discontinue from the DBTP and patients who enter the safety follow-up period will be 
presented for each treatment group and pooled across treatment groups for all randomized 
patients. The reasons for premature discontinuation during the DBTP as recorded on the 
disposition pages of the electronic case report forms (eCRFs) will be summarized 
(number and percentage) by treatment group for all randomized patients.
7.1
PROTOCOL DEVIATIONS
Protocol deviations will be defined in Protocol Deviation Requirement Specification, 
including the classification of significance vs. non-significance. The number and 
percentage of patients with significant protocol deviations will be summarized by 
treatment group for all randomized patients. A listing for all significant protocol 
deviations will be provided.


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8.0
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
Demographic parameters (age; race; ethnicity; sex), baseline characteristics (weight; 
height; and body mass index, calculated as weight [kg]/(height [m])2 ) will be 
summarized descriptively by treatment group for the mITT population.
Medical and surgical histories, and psychiatric history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary and summarized by treatment 
group for the Safety Population.  
Prior medication is defined as any medication taken before the date of the first dose of 
randomized IP. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of randomized IP. Concomitant medications started after the last 
visit of the DBTP will not be included in the summaries. If any medication is taken 
before the date of the first dose of randomized IP and continues after initiation of 
randomized IP, it will be considered as both a prior and concomitant medication. The 
World Health Organization (WHO) Drug Dictionary Enhanced will be used to code
medications.
Both prior and concomitant medication use, and previous treatment with psychotropic 
medication will be summarized by treatment group and Anatomical Therapeutic 
Chemical (ATC) code for the Safety Population. 
Nondrug psychiatric treatment will be summarized by treatment group for the Safety 
Population. 


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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
The total number of IV doses actually received by a patient during the double-blind 
treatment period will be summarized by treatment group for the safety population.
IV administration notes including site reaction at placement of IV, reaction to adhesive, 
infusion interruption, failure of administration device, perceptual disturbances or other 
conditions based on mental status assessment are collected. For each item, the number 
and percentage of patients who had a ‘yes’ response will be summarized by treatment 
group and visit for the Safety Population.
Duration of follow-up during the DBTP will be summarized in terms of treatment 
duration, calculated as the number of days from the date of the first dose of randomized 
IP received to the date of the last dose received, inclusive. Descriptive statistics (number 
of patients, mean, SD, median, minimum, and maximum) will be presented by treatment 
group.
9.2
MEASUREMENT OF TREATMENT COMPLIANCE
Dosing compliance for the DBTP is defined as the total number of IV doses actually 
received by a patient during that period divided by the number of IP doses that were 
expected to be received during the period, multiplied by 100, regardless if a patient 
discontinued from the study. The number of expected doses for a patient is defined as the 
number of the days from the first dose to the exit visit divided by 7 and rounded up the 
next integer with the upper limit of 6. 


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10.0
EFFICACY ANALYSES
All efficacy analyses will be based on the mITT Population, unless stated otherwise. The 
baseline for each specific efficacy endpoint is defined as the last non-missing 
measurement prior to the first dose of randomized IP. All statistical hypothesis tests will 
be performed at the 2-sided significance level of 5% for main effects. All confidence 
intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise.
For efficacy analyses in which pooled study center is a factor, a small center will be 
defined as a center with < 2 patients in ≥ 1 treatment group in the mITT Population. 
Small centers will be pooled to form pseudo-centers so that each treatment group 
includes ≥ 2 mITT patients within the center. Pooling will be done using the following 
algorithm: 
Based on the number of mITT patients, small centers will be ordered from the largest to 
the smallest, and centers of the same size will be ordered from the largest center code to 
the smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small center is 
formed. The process will be repeated using the small centers left out after the first pass. If 
any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is > 1 smallest pseudo-center, the pseudo-center with the smallest 
center code will be selected. In case the pseudo-center formed by pooling all small 
centers is still a small center, it will be pooled with the smallest non-small center. If there 
is > 1 smallest non-small center, the one with the smallest center code will be selected.
The efficacy analyses using the mITT population will be performed based on the 
treatment to which the patient is randomized regardless of the actual treatment received. 
The efficacy analyses of MADRS assessments will be based on the rater-administered 
MADRS.
10.1
PRIMARY EFFICACY PARAMETER
The primary efficacy parameter will be the change from baseline in MADRS total score 
at the end of treatment (end of Week 6). The MADRS contains 10 items that assess 
depression, with scores for each item ranging from 0 (absence of symptoms) to 6 
(symptoms of maximum severity). The MADRS total score is the sum of the 10 
individual items.  If more than 2 items are missing, the total score will be set to missing.  
If there are multiple assessments of MADRS total score for the same day visit of a 
patient, only the last assessment will be used in the analysis.


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The primary parameter will be analyzed using a mixed model for repeated measures 
(MMRM) with terms for treatment, pooled study center, visit (Day 1 visit and the weekly 
visits from Week 1 to Week 6), baseline, and treatment-by-visit and baseline-by-visit 
interactions. An unstructured covariance matrix will be used to model the covariance of 
within-patient scores. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom (Kenward et al, 1997). This analysis will only use the 
observed postbaseline scores without imputation of missing values. The treatment 
differences for rapastinel 450 mg versus placebo and rapastinel 900 mg versus placebo 
will be estimated and reported along with the corresponding 95% CIs and p-values.
In the case that the MMRM model with unstructured covariance fails to converge with 
the default algorithm, then the Fisher scoring algorithm will be used to provide better 
initial values of the covariance parameters; if the model still does not converge, a 
simplified model without the factor of the pooled study center will be used to find the 
initial values of the covariance parameters. In the rare event that model still does not 
converge after using those initial values, simplified covariance structures will be used to 
fit the model in the following order until the model converges: (1) ante-dependence, (2) 
heterogeneous autoregressive, (3) Toeplitz, and (4) compound symmetry. 
To assess the robustness of the primary MMRM results to the possible violation of the 
missing-at-random assumption, a sensitivity analysis will be conducted.
The sensitivity analysis will use a pattern-mixture model based on non-future dependent 
missing value restrictions (Kenward et al, 2003). The pattern for the pattern-mixture 
model will be defined by the patient’s last visit with observed value. The observed 
MADRS total score at a visit is assumed to have a linear relationship with the patient’s 
prior measurements. The missing values will be imputed under the assumption that the 
distribution of the missing observations differs from the observed only by a shift 
parameter value Δ. The dataset with observed and imputed values will be analyzed using 
the same model as the primary analysis for between-treatment group comparisons at the 
end of the treatment. The imputation of missing values and the analysis will be performed 
20 times and the inference of this sensitivity analysis will be based on the combined 
estimates using the standard multiple imputation technique. The values of Δ will be 
selected as 0 to 8.
10.2
KEY SECONDARY EFFICACY PARAMETERS
The key secondary efficacy parameter will be the change from baseline in MADRS total 
score at 1 day after first dose of randomized IP. The key secondary efficacy parameter
will be analyzed in the same MMRM model for the primary efficacy parameter. The 
treatment differences for rapastinel 450 mg versus placebo and rapastinel 900 mg versus 
placebo will be estimated and reported along with the corresponding 95% CIs and p-
values.


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Let H1 and H2 represent the treatment effect comparing rapastinel 450 mg versus 
placebo and rapastinel 900 mg versus placebo in regards to the primary efficacy 
parameter of change from baseline in MADRS total score at end of treatment (end of 
Week 6), respectively; and let H3 and H4 represent the treatment effect comparing 
rapastinel 450 mg versus placebo and rapastinel 900 mg versus placebo in regards to the 
secondary efficacy parameter of change from baseline in MADRS total score at 1 day 
after first dose of treatment.  The graphical procedure displayed in Figure 10-1 will be 
employed to control the overall familywise error rate at α = 0.049.  
Figure 10-1
Graphical Testing Procedure
Specifically, H1 and H2 will be tested at α = 0.0245 separately. If H1 is rejected, H3 will 
then be tested at α = 0.0245. If H2 is rejected, H4 will then be tested at α = 0.0245. If H3 
is rejected but H2 is not rejected, H2 will be further tested at α = 0.049. If H2 is rejected 
at α = 0.049, H4 will be further tested at α = 0.049. Similarly, if H4 is rejected but H1 is 
not rejected, H1 will be further tested at α = 0.049. If H1 is rejected at α = 0.049, H3 will 
be further tested at α = 0.049.


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.
11.1
ADVERSE EVENTS
Adverse events will be coded using the Medical Dictionary for Regulatory Activities and 
summarized separately for the DBTP and SFUP.
An AE (classified by preferred term) will be considered a treatment-emergent adverse 
event (TEAE) during the DBTP if it was present after the first dose of IP, or was present 
before the date of the first dose of IP and increased in severity or became serious after the
first dose of IP. If more than 1 AE was reported before the first dose of IP and coded to 
the same preferred term, the AE with the greatest severity will be used for comparison 
with the AEs occurring during the DBTP or safety follow-up period. For patients who 
complete this study and enters the RAP-MD-33 study, an AE that occurs on or after the 
last day of the DBTP will not be considered as a TEAE. For patients who do not enter the 
RAP-MD-33 study, an AE that occurs more than 30 days after the date of the last dose of 
IP will not be considered as a TEAE. 
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term, and further categorized by severity
and causal relationship to the IP. If more than 1 AE is coded to the same preferred term 
for the same patient, the patient will be counted only once for that preferred term using 
the greatest severity and strictest causality for the summarization by severity and causal 
relationship.
The incidence of common (≥2% of patients in any treatment group) TEAEs will be 
summarized by preferred term and treatment group and sorted by decreasing frequency 
for the test treatment.
Overall summaries of AEs will be provided on a per-patient basis for categories of all 
TEAEs, treatment-related TEAEs, death, Treatment-emergent serious AEs (TESAEs), 
and TEAEs leading to study discontinuation.


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13.0
INTERIM ANALYSIS
An unblinded interim analysis will be conducted in order to identify early signs of
futility.  Separate Statistical Analysis Group and Data Review Committee will be 
established to conduct the unblinded interim analysis, review the unblinded results, and 
make recommendations regarding the continuation of the study.  In order to maintain the 
scientific reliability of possible final results and guard from introducing any potential bias 
into the conduct of the study and/or analysis of its results, individuals in these 2 groups 
will not be involved in any operational aspect of the study.  Additionally, to adjust for 
multiple comparison issues caused by having several looks at the data, the Bonferroni 
method will be applied to split the overall Type I Error between the interim and final 
analysis (α = 0.001 and 0.049 two-sided, respectively) in order to further protect the 
integrity of the study.  Further details of the unblinded interim analysis, in particular, its 
scope, the processes put in place to maintain study integrity, team structures, and 
responsibilities, are documented in the Data Review Committee Charter.


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14.0
DETERMINATION OF SAMPLE SIZE
This study initially planned to randomize approximately 690 patients to the rapastinel 
450 mg, rapastinel 900 mg, and placebo groups in a 1:1:1 ratio. The primary efficacy 
endpoint is the change from baseline in the MADRS total score at the end of Week 6. 
Assuming the SD is 10 points, within-patient correlation is 0.6, and dropout rate over 6 
weeks is 20%, a sample size of 230 patients per treatment group will provide 91% power 
to detect a difference of 3.5 points for each rapastinel dose versus placebo at a 2-sided 
significance level of 4.9% originally adjusting for multiple comparisons of 2 rapastinel 
groups with placebo across the primary and secondary endpoints by using a graphical 
testing procedure.


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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 


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16.0
DATA HANDLING CONVENTIONS
16.1
SUMMARY STATISTICS
The following statistical summaries will be presented for each type of data.  Further 
details are specified in the tables, figures, and listings shells.
-
Continuous variables will be summarized by descriptive statistics (number of 
patients, mean, standard deviation (SD), median, Q1 and Q3, minimum, and 
maximum values). 
-
Categorical variables will be summarized by frequency distributions (counts and 
percentages).
-
Time-to-event data will be summarized by showing the number of patients, 
number of patients experiencing the event of interest, estimates of the median, 1st
quartile and 3rd quartile using the Kaplan Meier estimate as well as a 95% CI for 
the median
16.2
VISIT TIME WINDOWS
Table 16.2-1 presents the visits assigned for efficacy and safety analyses and the 
corresponding range of treatment days (window) during which an actual visit may occur.
Table 16.2–1.
Visit Time Windows
Derived Visit
Target Day
Analysis Visit Window
Baseline
<= Day 0 a and before the first study IP
Double Blind Treatment Period (DBTP)
Post First 
Study IPc
Day 0
Post the first study IP on Day 0
Day 1
Day 1
Day 1
Day 7
Day 7
Start: Day 2 
End: the Day 7 dosing (Visit 4) date or Day 10 (if no Day 7 dosing)b
Week 2
Day 14
Start: 1 day after the Day 7 window ends 
End: the Week 2 (Visit 5) dosing date or Day 17 (if no Week 2 dosing)b
Week 3
Day 21
Start: 1 day after the Week 2 window ends 
End: the Week 3 (Visit 6) dosing date or Day 24 (if no Week 3 dosing) b
Week 4
Day 28
Start: 1 day after the Week 3 window ends 
End: the Week 4 (Visit 7) dosing date or Day 31 (if no Week 4 dosing)b


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Table 16.2–1.
Visit Time Windows
Week 5
Day 35
Start: 1 day after the Week 4 window ends
End: the Week 5 (Visit 8) dosing date or Day 38 (if no Week 5 dosing)b
Week 6
Day 42
Start: 1 day after the Week 5 window ends 
End: End of DBTP (the study exit date of DBTP)
Safety Follow-up Period (SFP)
Week 8
Day 56
Within the safety follow-up phase
    End of SFP: Final or termination visit during SFP
a Day 0 is the date of the first dose of study treatment; baseline is defined as the last non-missing observations prior to 
first dose of study treatment. 
b Dosing visit is the nominal visit reported in CRF. A patient is scheduled to receive the 1st dose on day 0, the 2nd 
dose at week 1, and will be weekly administered until week 5. If a patient skipped a scheduled re-treatment dosing at 
a week, the dosing date will be treated as missing for that week.
 
If a patient has 2 or more non-missing assessment within the same window, the 
assessment closest to the target day will be used for analysis; if the 2 closet assessments 
are equidistant to the target day, the later one will be used for analysis.
16.3
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a patient has repeated assessments before the start of the first treatment, the results 
from the final non-missing assessment made prior to the start of the study treatment will
be used as baseline. If end-of-study assessments are repeated or if unscheduled visits 
occur, the last non-missing postbaseline assessment will be used as the end-of-study 
assessment for generating summary statistics. However, all postbaseline assessments will 
be used for PCS value determinations, and all assessments will be presented in the data 
listings.
16.4
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of study 
treatment, an intensity of mild will be assigned. If severity is missing for an AE that 
started on or after the date of the first dose of study treatment, an intensity of severe will 
be assigned. The imputed values for severity assessment will be used for the incidence 
summary; the values will be shown as missing in the data listings.


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16.5
MISSING CAUSAL RELATIONSHIP TO STUDY DRUG FOR 
ADVERSE EVENTS
If the causal relationship to the study treatment is missing for an AE that started on or 
after the date of the first dose of study treatment, a causality of yes will be assigned. The 
imputed values for causal relationship to study treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings.
16.6
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (i.e., partly missing).
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
treatment, the month and day of the first dose of study treatment will be assigned to 
the missing fields

If the year of the incomplete start date is before the year of the first dose of study 
treatment, December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of study 
treatment, January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and year 
of the first dose of study treatment, the day of the first dose of study treatment will be 
assigned to the missing day

If either the year of the incomplete start date is before the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of study treatment, the last 
day of the month will be assigned to the missing day

If either the year of the incomplete start date is after the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is after the month of the date of the first dose of study treatment, the first 
day of the month will be assigned to the missing day


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If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following 
algorithm will be used to impute the start date:

If the stop date is after the date of the first dose of study treatment, the date of the first 
dose of study treatment will be assigned to the missing start date

If the stop date is before the date of the first dose of study treatment, the stop date will 
be assigned to the missing start date
16.7
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS
For prior or concomitant medications, incomplete (ie, partly missing) start dates and/or 
stop dates will be imputed. When the start date and the stop date are both incomplete for 
a patient, the start date will be imputed first.  
16.7.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, the start date will be imputed 
using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
treatment, the month and day of the first dose of study treatment will be assigned to 
the missing fields

If the year of the incomplete start date is before the year of the first dose of study 
treatment, December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of study 
treatment, January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure


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Missing day only

If the month and year of the incomplete start date are the same as the month and year 
of the first dose of study treatment, the day of the first dose of study treatment will be 
assigned to the missing day

If either the year of the incomplete start date is before the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of study treatment, the last 
day of the month will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first 
dose of study treatment or if both years are the same but the month of the incomplete 
start date is after the month of the date of the first dose of study treatment, the first 
day of the month will be assigned to the missing day
16.7.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the date of the last dose of study 
treatment is missing, impute it as descripted in Section 16.4. If the imputed stop date is 
before the start date (imputed or nonimputed start date), the imputed stop date will be 
equal to the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study 
treatment, the month and day of the last dose of study treatment will be assigned to 
the missing fields

If the year of the incomplete stop date is before the year of the last dose of study 
treatment, December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of study 
treatment, January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure


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Missing day only

If the month and year of the incomplete stop date are the same as the month and year 
of the last dose of study treatment, the day of the last dose of study treatment will be 
assigned to the missing day

If either the year of the incomplete stop date is before the year of the date of the last 
dose of study treatment or if both years are the same but the month of the incomplete 
stop date is before the month of the date of the last dose of study treatment, the last 
day of the month will be assigned to the missing day

If either the year of the incomplete stop date is after the year of the date of the last 
dose of study treatment or if both years are the same but the month of the incomplete 
stop date is after the month of the date of the last dose of study treatment, the first day 
of the month will be assigned to the missing day


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17.0
REFERENCES
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika 2003; 90(1): 53-71.
Kenward MG and Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997; 53: 983–997.


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