Clinical trial NCT02943564
Conditions: Depressive Disorder, Major
Sponsor: Naurex, Inc, an affiliate of Allergan plc
Start date: 2016-11-01; Completion date: 2018-12-18
Enrollment: 658 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, and tolerability of two doses of rapastinel, 225 milligrams (mg) and 450 mg, compared to placebo adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who have a partial response to ADT.

Detailed description:

Arms: arm 1: Rapastinel 225 milligram (mg) weekly intravenous (IV) injections. Each participant will continue to take the same dose of antidepressant therapy the participant was receiving prior to entering this study throughout treatment. arm 2: Rapastinel 450 mg weekly IV injections. Each participant will continue to take the same dose of antidepressant therapy the participant was receiving prior to entering this study throughout treatment. arm 3: Placebo-matching rapastinel weekly IV injections. Each participant will continue to take the same dose of antidepressant therapy the participant was receiving prior to entering this study throughout treatment.
Interventions: intervention 1: Rapastinel intervention 2: Placebo
Intervention descriptions: intervention 1: Rapastinel pre-filled syringes for weekly IV injections. intervention 2: Placebo-matching rapastinel pre-filled syringes for weekly IV injections.

Protocol documents:
Prot_000.pdf: 
NCT02943564 
 
Study ID: RAP‐MD‐02 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter Study of Rapastinel as Adjunctive 
Therapy in Major Depressive Disorder 
 
Protocol Amendment 2: 10 Dec 2018 
 
 
 


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TITLE PAGE
Naurex, Inc, an indirect subsidiary of Allergan, plc.
5 Giralda Farms
Madison, NJ 07940
A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel 
as Adjunctive Therapy in Major Depressive Disorder
RAP-MD-02
IND # 107, 974
Original Protocol Date:
20 May 2016
Amendment 1:
10 Oct 2016
Amendment 2:
10 Dec 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-02
Study Number
RAP-MD-02
Title of Study
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study of Rapastinel as Adjunctive Therapy in Major Depressive 
Disorder
Study Centers (Country)
Approximately 50 study centers (United States)
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of rapastinel 
adjunctive to antidepressant therapy (ADT) in patients with 
major depressive disorder (MDD) who have a partial response 
to ADT
Methodology
Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, 3-week study in patients with MDD who have a 
partial response to ongoing ADT. 
Number of Patients
Approximately 630 planned to be enrolled 
Diagnosis and 
Main Criteria for Inclusion

Male and female outpatients who are 18 to 65 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
 

Have no more than partial response (< 50% improvement) 
to ongoing treatment with a protocol-allowed ADT (
 
 
 
 
 
 
 
 
 
Test Product, Dosage, and 
Mode of Administration
Rapastinel (225 mg, 450 mg weekly intravenous [IV] 
administration) adjunctive to ongoing ADT, prefilled syringe


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Duration of Treatment
Up to 14 days of screening and washout period, followed by a 
3-week double-blind treatment period, followed by a 1-week 
safety follow-up period
Reference Therapy, Dosage, 
and Mode of Administration
Placebo adjunctive to ongoing ADT, weekly IV administration, 
prefilled syringe
Criteria for Evaluation
Primary Endpoint
Change from baseline in MADRS total score at end of study.
Key Secondary Endpoint
Change from baseline in MADRS total score at 1 day after the 
first dose of randomized treatment.
Additional Endpoints
 
 
 
 
 
 
 
 
 
Safety Measures
Adverse event (AE) recording, clinical laboratory measures, 
vital sign parameters, electrocardiograms (ECGs), and physical 
 
 
 
 


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Statistical Methods
The primary efficacy parameter will be the change from 
baseline in MADRS total score at end of study. The primary 
analysis will be performed using a mixed-effects model for
repeated measures (MMRM) with terms for treatment, pooled
study center, visit, and treatment-by-visit interaction as the 
fixed effects, and baseline MADRS total score, and baseline 
MADRS total score-by-visit as covariates. The key secondary 
efficacy parameter, change from baseline in MADRS total score 
1 day after randomized treatment will be analyzed using the 
same MMRM model as was used for the primary efficacy 
parameter. An unstructured covariance matrix will be used to 
model the covariance of within-patient scores.  Baseline will be 
defined as the last measurement prior to the first dose of 
double-blind treatment. To control the overall type I error rate 
for both the primary and key secondary endpoint, a sequential 
testing procedure will be implemented.
All safety parameters will be analyzed using descriptive 
statistics. Safety analyses will be based on the Safety 
Population, defined as all randomized patients who receive at 
least 1 dose of randomized treatment. Efficacy analyses will be 
based on the modified Intent-to-Treat (mITT) Population, 
defined as all patients who are randomized and receive at least 
1 dose of treatment and have at least 1 postrandomization 
assessment of the MADRS total score.


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TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
2.0
SYNOPSIS AND 
.....................................................................2
3.0
Table of Contents..............................................................................................................................8
3.1
List of Figures...................................................................................................................10
4.0
LIST OF ABBREVIATIONS.........................................................................................................11
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 ..........................................13
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ......................................14
7.0
INTRODUCTION ..........................................................................................................................15
8.0
STUDY OBJECTIVES...................................................................................................................19
9.0
INVESTIGATIONAL PLAN .........................................................................................................21
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION.........................................21
9.1.1
Screening Period.................................................................................................21
9.1.2
Double-blind Treatment Period..........................................................................21
9.1.3
Safety Follow-up Period.....................................................................................22
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUPS ..........................................................................................................................23
9.3
SELECTION OF STUDY POPULATION ......................................................................24
9.3.1
Inclusion Criteria................................................................................................24
9.3.2
Exclusion Criteria...............................................................................................25
9.3.3
Removal of Patients from Therapy or Assessment.............................................29
9.3.4
Patient Replacement Procedures ........................................................................30
9.4
TREATMENTS................................................................................................................30
9.4.1
Background Antidepressant Therapy .................................................................30
9.4.2
Treatments Administered ...................................................................................31
9.4.3
Identity of Investigational Products....................................................................32
9.4.4
Handling of Investigational Products .................................................................33
9.4.5
Method of Assigning Patients to Treatment Groups ..........................................33
9.4.6
Selection of Dosages in the Study ......................................................................33
9.4.7
Selection and Timing of Dose for Each Patient..................................................34
9.4.8
Blinding..............................................................................................................34
9.4.9
Unblinding..........................................................................................................35
9.4.10
Prior and Concomitant Therapy .........................................................................35
9.4.11
Other Restrictions...............................................................................................37
9.4.12
Monitoring Treatment Compliance ....................................................................38
9.4.13
Treatment After Discontinuation........................................................................38
9.5
EFFICACY AND SAFETY VARIABLES ......................................................................38


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9.5.1
Diagnostic and Efficacy Assessments ................................................................38
9.5.2
Safety Assessments ............................................................................................40
9.5.6
Schedule of Assessments....................................................................................52
9.6
DATA QUALITY ASSURANCE....................................................................................60
9.6.1
Data Monitoring .................................................................................................60
9.6.2
Data Recording and Documentation...................................................................60
9.7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .................61
9.7.1
Analysis Populations ..........................................................................................61
9.7.2
Patient Disposition .............................................................................................62
9.7.3
Demographics and Other Baseline Characteristics.............................................62
9.7.4
Extent of Exposure and Treatment Compliance.................................................62
9.7.5
Efficacy Analyses...............................................................................................63
9.7.8
Interim Analysis .................................................................................................70
9.7.9
Determination of Sample Size............................................................................71
9.7.10
Computer Methods.............................................................................................71
9.8
DATA AND SAFETY MONITORING BOARD ............................................................71
9.9
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES.........72
9.10
PROTOCOL DEVIATIONS ............................................................................................72
10.0
STUDY SPONSORSHIP................................................................................................................73
10.1
STUDY TERMINATION ................................................................................................73
10.2
REPORTING AND PUBLICATION...............................................................................73
11.0
INVESTIGATOR OBLIGATIONS................................................................................................74
11.1
DOCUMENTATION .......................................................................................................74
11.2
PERFORMANCE.............................................................................................................74
11.3
USE OF INVESTIGATIONAL MATERIALS................................................................75
11.4
CASE REPORT FORMS .................................................................................................75
11.5
RETENTION AND REVIEW OF RECORDS ................................................................75
11.6
PATIENT CONFIDENTIALITY.....................................................................................76
12.0
INVESTIGATOR’S STATEMENT ...............................................................................................77
13.0
APPENDICES ................................................................................................................................78
APPENDIX I 
ELEMENTS OF INFORMED CONSENT ...............................................................79
APPENDIX II 
CONTACT INFORMATION ...................................................................................81
 
 
 
 


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14.0
LITERATURE CITED .................................................................................................................111
3.1
LIST OF FIGURES


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LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CI
confidence interval
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSST
Digit Symbol Substitution Test
DxV
Diagnostic Validation Questionnaire
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
ECT
electroconvulsive therapy
EDC
electronic data capture
ET
early termination
FDA
Food and Drug Administration
FR
Federal Register
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation 


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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-Asberg Depression Rating Scale
MDD
major depressive disorder
mITT
modified Intent-to-Treat
MMRM
mixed-effects model for repeated measures
NMDAR 
N-methyl-D-aspartate receptor
PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/[RR]½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/[RR]⅓)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCID
Structured Clinical Interview for Diagnostic Statistic Manual of Mental Health 
Disorders, Fifth Edition
SD
standard deviation
SDMT
Symbol Digit Modealities Test
SNRI
selective serotonin and norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal


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


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INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 50 study centers in the United States.
The Investigator is responsible for ensuring that the investigation is conducted according 
to the signed Investigator statement, the investigational plan, GCP guidelines, and 
applicable regulations; for protecting the rights, safety, and welfare of patients under the 
Investigator’s care; and for the control of investigational products under investigation. An 
investigator shall obtain the informed consent for each patient prior to the patient
enrolling in the study and/or prior to participating in any study-related activity.
The Investigator at each study center must meet his or her obligations to the patients, 
ethics committee, Sponsor, and regulatory authorities by maintaining oversight and 
control of the study’s conduct and the study staff. It is the responsibility of the 
Investigator to ensure that any and all delegated duties be assigned to qualified staff by 
education, experience, and licensure (in accordance with local regulations) and that the 
Investigator oversight is documented and assessment of staff capabilities and 
performance is consistent with the study investigational plan. The Investigator at each 
study center will be responsible for the management of the study, including maintaining 
the study file and the patient records, corresponding with the IRB, and completing the 
electronic case report forms (eCRFs).


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INTRODUCTION
Disease Burden of Major Depressive Disorder
Major depressive disorder (MDD) is a highly disabling, serious condition 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.
Selective Serotonin Reuptake Inhibitors and Selective Serotonin and Norepinephrine 
Reuptake Inhibitors in Major Depressive Disorder
Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and 
norepinephrine reuptake inhibitors (SNRIs) currently represent the first line of treatment 
of depression in the United States. Unfortunately, a large number of patients do not 
experience therapeutic benefit from these first-line agents (Rosenzweig-Lipson et al, 
2007). Lack of sufficient response to adequate treatment remains a critical problem in the 
management of patients with MDD. Up to two thirds of patients treated with first-line 
antidepressant monotherapy do not reach full remission, and as many as a third become 
treatment resistant (Fava and Davidson, 1996; Trivedi et al, 2006). Not achieving 
remission has been shown to be predictive of poorer psychosocial functioning, higher 
rates of relapse, and higher rates of rehospitalization (McIntyre and O’Donovan, 2004). 


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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 (ECT). Clearly, there remains a critically 
important unmet medical need for this patient population.
Existing antidepressants have a number of limitations, leading to considerable unmet 
medical need in the effective treatment of MDD, with up to 50% of patients with MDD
having an inadequate response or failing current antidepressant therapy (ADT). Currently 
available first-line antidepressants (SSRIs, SNRIs) typically take 3 to 4 weeks or more of 
continuous daily dosing to relieve symptoms of MDD and are associated with side effects 
related to their pharmacological mechanisms of action (sexual dysfunction, weight gain, 
jitteriness, sleep disturbances), which are further associated with poor patient compliance 
(Masand 2003, Ashton et al, 2005).  Patients often experience undesirable side effects 
before they experience an improvement in depressive symptoms, which could lead to 
premature discontinuation of therapy. Taken together, these factors define significant 
areas for improvement of ADT. 
Patients vary greatly in their response to antidepressants and it is not possible to reliably 
predict whether an individual patient will respond to a given antidepressant. This leads to 
clinicians often using a trial-and-error approach to identify an effective antidepressant. 
Due to the gradual development of the full therapeutic effect of currently available 
antidepressants, each antidepressant needs to be administered for 4 weeks or longer in 
order to determine the individual therapeutic benefit, making the process of finding an 
effective antidepressant a lengthy process for patients who are often severely depressed 
and at a high risk for suicide. Clearly a drug that could induce a rapid antidepressant 
effect would represent a major advancement for these patients.
Atypical Antipsychotics as Adjunctive Therapy in Major Depressive Disorder
The available treatments for adjunctive therapy in MDD also have substantial safety and 
efficacy limitations. The drugs currently approved for use as adjunctive therapy to 
antidepressants for the treatment of MDD—namely, the atypical antipsychotics Abilify®
(aripiprazole), Seroquel XR® (quetiapine fumarate), and Rexulti® (brexpiprazole)—are 
associated with significant adverse reactions, as well as a number of serious warnings and 
precautions. Originally developed for the treatment of psychotic disorders, these drugs 
share a number of clinically relevant adverse effects based on their mechanisms of action. 


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As all current antipsychotic agents modulate central dopaminergic systems, they all carry 
a risk of extrapyramidal symptoms such as muscular rigidity, acute dystonia, as well as 
akathisia, which is a particularly relevant adverse event (AE) that complicates clinical 
management in a significant number of treated individuals, as high as 45% 
(Sachdev, 1995). In addition, these compounds are associated with a risk of neuroleptic 
malignant syndrome and tardive dyskinesia. Depending on their individual 
pharmacological profile, antipsychotics also carry a risk for metabolic changes including 
hyperglycemia/diabetes mellitus, dyslipidemia and body weight gain; blood dyskrasias 
such as leucopenia, neutropenia, and agranulocytosis; orthostatic hypotension; cognitive 
and motor impairment; cataracts; and insomnia (Abilify, 2014; Seroquel, 2013; 
Rexulti, 2015). The range of clinically relevant side effects with antipsychotics has to be 
balanced carefully against the potential for therapeutic benefits in patients with major 
depression. In this context it is important to highlight that for the approved atypical 
antipsychotics the full therapeutic benefit required several weeks of daily adjunctive 
dosing to become apparent, and in many subjects adverse effects occurred substantially 
earlier than the mood-alleviating effects of these drugs. 
Furthermore, the drugs currently approved for adjunctive treatment of MDD also have 
limited efficacy. The pivotal studies for Abilify, the atypical antipsychotic most 
commonly used for adjunctive treatment of MDD, showed a delayed onset of effect 
(1-2 weeks), a modest magnitude of effect (effect sizes were 0.35-0.39 after 6 weeks of 
repeat dosing) and modest rates of response and remission after 6 weeks of repeat dosing 
(response rates were 32-34% and remission rates were 25-26%) (Berman et al, 2007; 
Marcus et al, 2008). 
Clearly, there is a substantial need for the development of novel treatments with a better 
safety/tolerability profile and a faster onset of full therapeutic benefit. Rapastinel has 
initially shown substantially improved safety/tolerability as well as promising efficacy, in 
both speed of onset and overall magnitude, for adjunctive therapy in MDD. 
Rapastinel as a Novel Approach to Major Depressive Disorder Treatment
The mechanism of action of rapastinel is entirely different from that of atypical 
antipsychotics. Rapastinel is an N-methyl-D-aspartate receptor (NMDAR) modulator
with a novel and complex pharmacological mechanism of action, acting as a nonselective 
agent at NR2 subunits and displaying properties as a functional partial agonist in a 
number of pharmacological assays. 
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. 


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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. 
The purpose of this study is to prospectively confirm that rapastinel, when administered 
as an adjunctive treatment at doses of 225 and 450 mg as a short IV infusion 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 adjunctive 
treatment for MDD.


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8.0
STUDY OBJECTIVES
The objectives of this study are to evaluate the efficacy, safety, and tolerability of 
rapastinel adjunctive to ongoing ADT in patients with MDD who have a partial response 
to ADT.
Efficacy Objectives

Primary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV, 225 mg 
IV) versus placebo in the treatment of MDD as an adjunct to ongoing ADT, as 
measured by the change from baseline to end of study in the Montgomery-Asberg 
Depression Rating Scale (MADRS) total score

Key secondary efficacy objective:  To evaluate the efficacy of rapastinel (450 mg IV, 
225 mg IV) versus placebo in the treatment of MDD as an adjunct to ongoing ADT, 
as measured by the change from baseline in the MADRS total score 1 day after 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-week study in patients with MDD who have a partial response to ADT. The study will 
include a total of 12 visits and will be approximately 4 to 6 weeks in duration
(Figure 9.1-1): 

Up to 2-week screening period 

3-week double-blind treatment period 

1-week safety follow-up period (for patients who do not enter the RAP-MD-04 
maintenance study)
9.1.1
Screening Period
After providing written consent, patients will enter a screening period of up to 14 days.
The screening/washout period will be up to 2 weeks prior to Visit 2. Screening 
procedures may be conducted on up to 2 separate dates where necessary to accommodate 
patient and study center schedule; however, every effort should be made to conduct all 
procedures as early as possible in the screening period and the rater-administered 
MADRS and computer-administered MADRS must be collected on the same date.  
Patients will not receive any investigational product (IP) during the screening period but 
must continue their background ADT at the same dose. 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
Approximately 630 patients are planned for enrollment in the double-blind treatment 
period (350 placebo patients, 350 rapastinel 225 mg patients, and 350 rapastinel 450 mg 
patients). Patients will be randomized in a ratio of 1:1:1 to 1 of 3 treatment groups: 
rapastinel 225 mg IV weekly, rapastinel 450 mg IV weekly, or placebo IV administration 
(all adjunctive to ongoing ADT).


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During the double-blind treatment period, patients have 3 study visits per week. The 
visits will occur in the following pattern: treatment day, 1 day following the treatment 
day, 4 days following the treatment day, and 7 days following the treatment day (which is 
the next treatment day). If necessary, study visits may be conducted up to 2 days before 
or after the scheduled visits with the exception of visits which are 24 hours apart
(eg, Visits 2 and 3 must be conducted 1 day apart; similarly, Visits 5 and 6 as well as 
Visits 8 and 9 must be conducted 1 day apart). All patients who receive IP must complete 
Visit 11. Upon completion of the double-blind treatment period, patients are eligible to 
enter the RAP-MD-04 maintenance study.  Patients who do not enter RAP-MD-04 will 
enter a 1-week safety follow-up period.
9.1.3
Safety Follow-up Period
Patients who do not enter the RAP-MD-04 maintenance study upon completing the 
double-blind treatment period and patients who prematurely discontinue from the study 
before completing 3 weeks of double-blind treatment should enter the 1-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 9.1-1. The Schedule of 
Evaluations is presented in Section 2.0. 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 3-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 65 years of age who meet the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD
(American Psychiatric Association, 2013). The MDD diagnosis will be confirmed using 
the Modified Structured Clinical Interview for Diagnostic Statistic Manual of Mental 
Health Disorders, Fifth Edition (SCID). The symptoms and severity of MDD will be 
assessed using the MADRS (Section 9.5.1.2.1). 


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Study centers will have experience with the study population and will be encouraged to 
apply available guidelines to minimize patient risk or distress. 
Dose selection information is presented in Section 9.4.6. 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 to 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-02, safety and efficacy assessments are included during 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 9.4.13). An 
independent Data and Safety Monitoring Board (DSMB) will evaluate safety data during 
the study (Section 9.8).
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
1. Written informed consent, obtained from the patient before the initiation of any 
study-specific procedures (Section 5.3) 
2. Male or female outpatients, 18 to 65 years of age
3. Meet DSM-5 criteria for MDD (based on confirmation from the modified SCID, 
with a current major depressive episode of at least 8 weeks and not exceeding 
18 months in duration at Visit 1
 


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5. Have no more than partial response (< 50% improvement) to ongoing treatment 
with a protocol-allowed ADT
 
 
 
 
 
 
 
 
 
 
7. If female of childbearing potential, have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test
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
c.
Major neurocognitive disorder 


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


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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of the study 
visits and procedures. Patients can be prematurely discontinued from the study after 
careful consideration for one of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria or pregnancy)

Pregnancy

Withdrawal of consent 

AE
o
Any patient may be withdrawn due to AE at the discretion of the 
Investigator
o
Any patient who meets any of the following criteria at any point during 
the study must be withdrawn from participation, due to AEs related to 
suicide:
a) A suicide attempt
In the event that a patient is withdrawn for a suicide-related AE, the patient should be 
referred for additional treatment or hospitalization, as clinically indicated, in addition 
to withdrawing the patient from the study.

Lack of efficacy

Protocol violation

Noncompliance with IP

Noncompliance with ADT


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
Lost to follow-up

Study terminated by Sponsor

Study center terminated by Sponsor

Other 
All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for a final assessment at an Early Termination (ET) Visit. A final 
assessment will be defined as completion of the evaluations scheduled for all patients at 
Visit 11. All patients discontinuing the study prematurely should enter the 1-week safety 
follow-up period.
Patients who discontinue from the study and do not return to the study center for final 
assessments must be requested in writing to return to the study center for a final 
assessment. A copy of the letter, together with the source documentation, will be kept in 
the Investigator’s files. The reason for premature discontinuation from the study will be 
recorded on the Study Termination Page of the eCRF. Study center staff will be contacted 
by the Sponsor after each premature discontinuation to ensure proper characterization of 
the reason for discontinuation is captured.
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 225 mg, or 
rapastinel 450 mg. 
9.4.1
Background Antidepressant Therapy
Patients must enter the study while having no more than partial response (< 50% 
improvement) to ongoing treatment with a protocol-allowed ADT
 
 
 
 
 
 
 
 
. 


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Upon entry into the study at Screening (Visit 1), the dosage of the ADT must be held 
constant at a dose allowed in the respective label through Visit 11/ET. If a patient 
experiences an AE, intercurrent illness, or symptoms of intolerance, he or she will be 
permitted to stop taking the ADT for a maximum of 3 consecutive days at the discretion 
of the Investigator. No other alterations in the ADT dose regimen are allowed. If an ADT 
dose change is required during the study, the patient should be discontinued from the 
study.
Background ADT medication compliance will also be closely monitored. Patients should 
be questioned to determine if there were any missed doses or changes in dose at Visits 2, 
5, 8, and 11. Every effort should be made to have patients bring their background ADT to
Visits 5, 8, and 11 for verification of patient-reported compliance by pill count (to the 
extent possible).
9.4.2
Treatments Administered
The IP will only be administered to eligible patients by a medically qualified person as 
per the local state regulations. The range of persons who can administer an IV can be a 
physician, a physician assistant, nurse, or nurse practitioner, etc, depending on the local 
and/or state law.  
IP should be administered after all efficacy and safety assessments with the exception of 
the post-dose assessments described below. IP will be administered in a “slow bolus” 
injection to each study patient in an upper extremity vein within approximately 1 to 2 
minutes. 
During IP administration and until completion of postadministration assessments a 
licensed physician must be immediately available and in close proximity to the patient(s) 
to attend to medical emergencies.  The study center must have the capabilities, in 
accordance with the applicable country, local, and/or state regulations and standard of 
care, to resuscitate a patient in the event of a medical emergency.  
The patient should not be discharged from the study center until the following are 
completed:

Postadministration vital sign measures (approximately 15 minutes after 
administration)

Patient is clinically assessed and determined to not be at increased risk of 
suicidality in the opinion of the Investigator (or medically qualified 
subinvestigator)


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
Patient is assessed for mental status and is determined to be free of perceptual 
disturbances or other conditions that would deem them not ready for discharge 
from the study center, in the opinion of the Investigator (or medically qualified 
subinvestigator)

A physician licensed in the state (Investigator or subinvestigator) determines that 
they are medically able to leave the study center and provides written sign-off not 
less than 15 minutes following administration (see IV Administration and 
Discharge Notes document in Program Reference Manual)
9.4.3
Identity of Investigational Products
Rapastinel 450 mg IV Prefilled Syringes: 
 
 
Rapastinel 225 mg IV Prefilled Syringes: 
 
 
Placebo rapastinel IV Prefilled Syringes: prefilled single-dose syringes for injection
containing 3 mL of normal saline.
 
 
 
 
The study center personnel will complete the kit label and attach the tear-off portion to 
the source documents.
The prefilled syringe will be labeled with the protocol number and kit number. The study 
center personnel will write the PID number on the prefilled syringe associated with the 
kit mentioned above. The prefilled syringe will not have a tear off and will remain on the 
prefilled syringe.


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9.4.4
Handling of Investigational Products
The IP must be stored in a secure area and administered only to patients entered into the 
clinical study, at no cost to the patient, in accordance with the conditions specified in this 
protocol.
 
 
 Study centers must report any temperature excursions as 
described in the Study Reference Manual or contact the Sponsor or its designee for 
further instructions.
At the end of the study, all IP must be accounted for. In addition, at the end of the study, 
all unused IP should be returned to the Sponsor or the local distributor at the address 
provided in the Study Reference Manual.
9.4.5
Method of Assigning Patients to Treatment Groups
After a patient signs the ICF at Screening (Visit 1), study personnel will register the 
patient in the IWRS, and the system will assign the patient a sequential PID. 
 
 
 
 
 
 
The IP will be labeled with medication kit numbers. The IWRS will provide the study 
center with the specific medication kit number(s) for each randomized patient at the time 
of randomization.  Study centers will dispense IP according to the IWRS instructions. 
Study centers will also log onto the IWRS at subsequent visits to obtain a study 
medication kit number for dispensing IP. Study centers will receive the IWRS 
confirmation notifications for each transaction.  All notifications are to be maintained 
with the study source documents.
9.4.6
Selection of Dosages in the Study
Doses of rapastinel 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.


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A 450-mg unit dose is expected to be appropriate for most patients as this represents a 
dose of 4.5 mg/kg in a 100 kg patient and a 9 mg/kg dose in a 50 kg patient. The 225-mg 
unit dose has been included in this study for purposes of characterizing the minimum 
effective dose.
9.4.7
Selection and Timing of Dose for Each Patient
The IP will be administered IV using the assigned single-use prefilled syringes at Visits 
2, 5, and 8.
9.4.7.1
Screening Period
At Screening (Visit 1) after written consent is obtained, patients enter a screening period 
of up to 14 days. No IP is administered during the screening period, however, patients 
must continue their background ADT at a stable dose.
9.4.7.2
Double-blind Treatment Period
Patients who meet all eligibility criteria at Screening (Visit 1) and who continue to meet 
all the eligibility criteria for participation in the study at the Baseline Visit (Visit 2) will 
be assigned an IP kit number via IWRS at Baseline (Visit 2). Patients will receive the 
first dose of IP that day. IP kit numbers will also be assigned by IWRS at subsequent 
treatment visits (ie, Visits 5 and 8).
Patients will receive either rapastinel 450 mg, rapastinel 225 mg, or placebo from a 
prefilled single-dose syringe at Visits 2, 5, and 8.
9.4.7.3
Safety Follow-up Period
Patients who complete 3 weeks of randomized treatment are eligible to enter the 
RAP-MD-04 maintenance study.  If they do not enter RAP-MD-04, 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 and 
patients’ background ADT may be modified as deemed appropriate by the Investigator.
9.4.8
Blinding
A list of patient randomization codes will be generated by Statistical Programming and 
implemented by the IWRS vendor (an electronic version will be stored on a secure 
server). This list will identify each patient by randomization number and include the 
patient’s corresponding treatment assignment.


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All study treatments will be provided in identical syringes and cartons to maintain 
masking of the study.
9.4.9
Unblinding
Any unblinding at the study center level should be done only in an emergency that 
requires for the IP to be identified for the medical management of the patient. The 
Investigator must notify the Study Physician immediately (refer to Appendix II) and a 
full written explanation must be provided if the blind is broken. Before IP is unblinded, 
every attempt should be made to discuss the case with the Study Physician. Breaking the 
code at the study center will immediately disqualify the patient from further participation 
in the study.
Treatment codes may be broken by Global Drug Safety for regulatory reporting purposes. 
In such cases, the study staff will be kept blinded and the patient will not need to be 
disqualified from the study.
For IWRS Unblinding
In an emergency, the Investigator can obtain the treatment assignment of any patient at 
his or her study center through the IWRS. The Investigator will access the IWRS to break 
the blind and record the unblinding in the eCRF.
9.4.10
Prior and Concomitant Therapy
A list of example medications that are allowed and not allowed as concomitant 
medications for either episodic or chronic use is provided in Appendix III. Medication 
history (psychotropic medication history during the previous 5 years and all other 
medications during the past 12 months) will be recorded at Screening (Visit 1) in the 
eCRF. Thereafter, any changes in concomitant medications or any new medications 
added will be recorded in the eCRF. 
 
 


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9.4.11
Other Restrictions
9.4.11.1
Alcohol 
It is recommended that patients abstain from alcohol consumption during the study.
9.4.11.2
Contraception
For purposes of this study, females will be considered of childbearing potential unless 
they are naturally postmenopausal or permanently sterilized (ie, hysterectomy). Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any 
other obvious pathological or physiological cause.  
For women of childbearing potential and male partners of childbearing potential who 
may participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable: hormonal contraceptives (ie, oral, patch, injection, 
implant), male condom with intravaginal spermicide, diaphragm or cervical cap with 
spermicide, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral 
tubal ligation, bilateral salpingectomy), vasectomized partner, or sexual abstinence.
The Investigator and each patient will determine the appropriate method of contraception 
for the patient during the participation in the study.
See Section 9.5.2.3 for pregnancy reporting procedures.


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9.4.12
Monitoring Treatment Compliance
IP compliance during any period will be closely monitored by capturing the date and time 
of each injection of IP. If a scheduled injection does not occur, the Sponsor must be 
notified and the reason captured in the eCRF.
Background ADT compliance will also be closely monitored. Patients should be 
questioned to determine if there were any missed doses or changes in dose at Visits 2, 5, 
8, and 11. Every effort should be made to have patients bring their background ADT to
Visits 5, 8, and 11 for verification of patient-reported compliance by pill count (to the 
extent possible). Missed doses or other changes in the dose of ADT and the reason should 
be captured in the eCRF.
9.4.13
Treatment After Discontinuation
Patients whose MDD symptoms worsen or are determined by the Investigator not to be 
adequately controlled prior to completing the 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. Patients who initiate 
a new treatment must be discontinued from the study.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9.5.1.1
Diagnostic Assessments
The SCID will be administered during the screening interviews by a psychiatrist, doctoral 
level clinical psychologist, or other clinician who has extensive professional training and 
experience in the diagnosis of mental illness and who meets the training requirements and 
qualifications standards set by the Sponsor and rater training vendor.
Patients will complete a computer-administered Diagnostic Validation (DxV) assessment 
at the Screening visit prior to the rater-administered SCID, on a tablet computer provided 
to the study center. The DxV will collect data about the patients’ history relative to 
lifelong history of MDD. The patient’s diagnostic information, based on the responses to 
the computerized interview, will be reviewed by the independent clinical reviewers team 
appointed by the Sponsor, and any uncertainty raised by the patient’s responses on the 
diagnostic interview will be discussed with the Investigator/study center clinician in order 
to establish confidence in the diagnosis. Patients for whom diagnostic agreement between 
the Investigator/study center clinician and the rater vendor clinician cannot be reached, 
may not be appropriate for study participation.


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9.5.1.2
Efficacy Assessments
The efficacy assessments (MADRS
) will be administered by a psychiatrist,
doctoral level clinical psychologist, or other clinician who has extensive professional 
training and experience in the diagnosis of mental illness and who meets the training 
requirements and qualifications standards set by the Sponsor and rater training vendor.
9.5.1.2.1
The Montgomery-Asberg 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. 
9.5.1.2.1.1
MedAvante 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] 
and Baseline [Visit 2]).
The MedAvante rater 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. Every effort should be made to administer the MADRS prior to other 
assessments.


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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.
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


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Please note that medical procedures scheduled prior to consenting, but occurring during 
the study should not be captured as AEs, but should be listed in the medical history if 
related to a pre-existing condition.
9.5.2.1.1
Causality Assessment
For each AE, the Investigator must provide an assessment of causal relationship to the IP. 
The causality assessment must be recorded on the appropriate AE reporting page of the 
patient’s eCRF. Causal relationship must be assessed by answering the following 
question:
Is there a reasonable possibility the IP caused the event?
Yes:
There is evidence to suggest a causal relationship between the IP and AE, ie:
○
There is a reasonable temporal relationship between the IP and the event, and/or
○
The event is unlikely to be attributed to underlying/concurrent disease or other 
factors, and/or
○
Positive dechallenge and/or rechallenge exist
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:


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Mild:
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort, but poses no significant or permanent risk of harm to 
the research participant.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
9.5.2.1.3
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

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.


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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
In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify study center personnel of any AEs occurring during the 30-day 
poststudy period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least one of the following conditions is met: 1) the event meets the criteria for 
an SAE (see Sections 9.5.2.1.3 and 9.5.2.1.4), and/or 2) the event is judged by the 
Investigator to be potentially causally related to IP.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the IP. If a follow-up visit is deemed necessary for 
appropriate safety surveillance, it will take place within 30 days of the final 
protocol-defined study visit.
9.5.2.1.4.1
MedAvante Reporting of Safety/Adverse Events
MedAvante 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). MedAvante Raters 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. 


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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 9.5.2.1.3 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.
9.5.2.2
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the Sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study center personnel must report the event to Global Drug Safety on the SAE Form for 
Clinical Trials. The Study Physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE.
The study center must transmit the SAE Form for Clinical Trials to the SAE fax number 
shown below. Even if an initial report is made by telephone, the SAE Form for Clinical 
Trials completed with all available details must still be faxed within 24 hours of 
knowledge of the event at the study center.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.


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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.
9.5.2.3
Reporting of Pregnancies Occurring During the Study
Study center personnel must report every pregnancy from the time the patient signs the 
ICF until 30 days after the last dose of IP. Within 24 hours of learning of the pregnancy, 
the study center personnel must report the event to Global Drug Safety on the Clinical 
Trial Pregnancy Form and fax it to the SAE/Pregnancy fax number provided in 
Section 9.5.2.2, even if no AE has occurred. Pregnancies in female partners of male 
patients occurring during the time frame described above must also be reported. 
Any pregnancy of a patient treated with IP (or in female partners of male patients 
occurring during the time frame described above) must be followed to term and the 
outcome reported by completing a follow-up Clinical Trial Pregnancy Form. If the 
pregnancy is associated with an SAE (eg, if the mother is hospitalized for hemorrhage), a 
separate SAE Form for Clinical Trials must be filed as described in Section 9.5.2.2 with 
the appropriate serious criterion (eg, hospitalization) indicated in addition to the 
pregnancy form.


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9.5.6
Schedule of Assessments
The schedule of study procedures and assessments is tabulated by visit in the Schedule of 
Evaluations in Section 2.0. The descriptions of the procedures to be performed at each 
visit are provided in the following sections.
Upon providing written informed consent, patients enter a screening period of up to 
14 days.  Following the screening period, patients enter the 3-week, double-blind 
treatment period.  During the double-blind treatment period, patients have 3 study visits 
per week. The visits occur in the following pattern: treatment day, 1 day following the 
treatment day, 4 days following the treatment day, and 7 days following the treatment day 
(which is the next treatment day). If necessary, study visits may be conducted up to 
2 days before or after the scheduled visits with the exception of visits which are 24 hours 
apart (ie, Visits 2 and 3 must be conducted 1 day apart; similarly, Visits 5 and 6 as well 
as Visits 8 and 9 must be conducted 1 day apart).  Upon completion of the double-blind 
treatment period, patients are eligible to enter the RAP-MD-04 maintenance study or 
enter a 1-week safety follow-up period.
 
 
 
 


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9.5.6.13
Unscheduled Visits
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
Investigator. Additional examinations may be performed as necessary to ensure the safety 
and well-being of the patients during the study.
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.
 
 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
Three populations will be considered in the statistical analysis of the study, as specified 
in the following subsections.
9.7.1.1
Enrolled Population
The Enrolled Population will consist of all patients who sign informed consent, receive a
patient identification (PID) number, and enter into screening.
9.7.1.2
Safety Population
The Safety Population will consist of all patients who receive at least 1 dose of 
randomized IP.
9.7.1.3
Modified Intent-to-Treat Population
The modified Intent-to-Treat (mITT) Population will consist of all patients who are 
randomized, receive at least 1 dose of IP and have at least 1 postbaseline assessment of 
the MADRS total score.


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9.7.2
Patient Disposition
The number and percentage of patients in the Enrolled, Safety, and mITT populations
will be summarized by treatment group and study center.
Screen-failure patients (ie, patients screened but not included in the Enrolled 
Population) and the associated reasons for failure to randomize will be tabulated overall 
for all screened patients. 
The number and percentage of patients in the mITT Population who complete the 
double-blind treatment period and of patients who prematurely discontinue during the 
same period will be presented for each treatment group and pooled across treatment 
groups. The reasons for premature discontinuation during the double-blind treatment 
period as recorded on the disposition pages of the eCRFs will be summarized by 
treatment group for the mITT Population. 
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (eg, age, race, ethnicity, sex, weight, height, body mass index 
[BMI]) and other baseline characteristics will be summarized by treatment group for the 
Safety and mITT populations. 
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Patients in the Safety Population will be categorized by the number of IP doses 
received. The number and percentage of patients in each category will be summarized 
by treatment group.
Prior medication is defined as any medication taken before the date of the first dose of 
randomized IP. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of randomized IP.
Both prior and concomitant medication use will be summarized by the number and 
proportion of patients in each treatment group receiving each medication within 
each therapeutic class for the Safety Population. Multiple medication use by a patient will 
only be counted once.


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IV administration notes including site reaction at placement of IV, reaction to 
adhesive, infusion interruption, failure of administration device, increase in suicidality 
based on clinical evaluation, and perceptual disturbance based on mental status 
assessment are collected. For each item, the number and percentage of patients who 
had a ‘yes’ response will be summarized by treatment group and visit for the Safety 
Population. The number and percentage of patients taking each qualifying ADT will be 
summarized by treatment group for the mITT Population. Mean daily dose for each 
qualifying ADT will be summarized using descriptive statistics (number of patients, 
mean, standard deviation [SD], median, Q1, Q3, minimum, and maximum) by treatment 
group for the mITT Population.
9.7.4.2
Measurement of Treatment Compliance
Dosing compliance for the background ADT during a specified period is defined as the 
total daily dose administered to a patient during that period divided by the total daily 
dose prescribed during the same period multiplied by 100, as captured in the eCRF.
Descriptive statistics for ADT compliance will be presented for each ADT and overall by 
treatment group for the mITT 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. Details of the pooling algorithm will be provided in the 
Statistical Analysis Plan (SAP).


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9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter will be the change from baseline in MADRS total score 
at end of study. The primary analysis will be performed using a mixed-effects model for 
repeated measures (MMRM) with treatment group, pooled study center, visit and 
randomized treatment-by-visit interaction as the fixed effects, and baseline MADRS 
total score and baseline MADRS total score-by-visit interaction as covariates. An 
unstructured covariance matrix will be used to model the covariance of within-patient 
scores. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom (Kenward et al, 1997; Kenward et al, 2003). The treatment 
difference for rapastinel doses versus placebo will be estimated and reported along with 
the corresponding 95% CI and nominal p-value.
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 the 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 using a pattern-mixture model 
based on non-future dependent missing value restrictions (Kenward et al, 2003) will be 
performed. 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 missing 
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 multiple 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.
9.7.5.2
Key Secondary Efficacy Parameter
The key secondary efficacy parameter will be the change from baseline to 1 day after the 
first dose of treatment in MADRS total score. This parameter will be analyzed using the 
same MMRM as will be used for the primary efficacy parameter.  The treatment 
difference for rapastinel versus placebo will be estimated and reported along with the 
corresponding 95% CI and nominal p-value.


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A sequential testing procedure will be used to control the overall type I error rate at 
5% for the comparisons of treatment difference in the following order:

Rapastinel 450 mg versus placebo - primary efficacy parameter

Rapastinel 450 mg versus placebo - key secondary efficacy parameter

Rapastinel 225 mg versus placebo - primary efficacy parameter

Rapastinel 225 mg versus placebo - key secondary efficacy parameter
 
 
 
 
 


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9.7.6.1
Adverse Events
AEs will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities.


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An AE (classified by preferred term) will be considered a treatment-emergent adverse 
event (TEAE) if it was not present before the first dose of IP or was present before the 
date of the first dose of IP and increased in severity after the first dose of IP. An AE that 
becomes serious after the date of first dose of IP will also be considered as a TEAE.
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.
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.
A serious adverse event (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 a treatment-
emergent SAE (TESAE). The number and percentage of patients who have TESAEs will 
be summarized by preferred term and treatment group. In addition, the incidence of 
TESAEs that lead to death will be summarized separately by preferred term for each 
treatment group.
Overall summaries of AEs will be provided on a per-patient basis for categories of all 
TEAEs, treatment-related TEAEs, TESAEs, and TEAEs leading to study 
discontinuation.
 
 
 


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.
9.7.8
Interim Analysis
At the time of preparation for Protocol Amendment 2, a blinded interim analysis 
was performed as part of data quality review as the study was progressing. In this 
review, it was observed that the SD for the primary and secondary endpoints were 
substantially lower than the originally assumed values for sample size calculations. 
The observed SDs in the blinded reviews of this study and other ongoing acute 
studies at the same time (RAP-MD-02 and RAP-MD-03) were taken into 
consideration for revising the estimate of the sample size as proposed in the next 
section (Section 9.7.9 Determination of Sample Size).


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9.7.9
Determination of Sample Size
The originally proposed primary efficacy variable is the change from baseline in the 
MADRS total score at 1 day after the first dose of treatment.  The study was planned to 
randomize 1050 patients assuming SD of 10 points, which provides 99% power to 
detect a difference of 3.25 points in MADRS total score between at least 1 of the 2 
rapastinel dose groups and placebo at a 2-sided significance level of 0.05.   
While the study was ongoing, the primary efficacy variable was revised to be the 
change from baseline in MADRS score at the last visit, Day 21, as recommended by the 
FDA, EMA, and PDMA, and included in Amendment 2 of the protocol. At the same 
time of Amendment 2, a blinded data review was conducted for Studies RAP-MD-01, 
RAP-MD-02, and RAP-MD-03. The pooled SD for the 3 studies were 7.4, 8.0, and 8.7, 
respectively, all smaller than the originally assumed 10 points. Sample size was re-
calculated using 8.7 as the common SD. The calculation used MMRM model with 
simulations; it also assumed correlation of 0.5 between the repeated measures and an 
overall dropout rate of 15%. To have 90% power, the total sample size required is 540 
patients. However, the study had already enrolled more than 590 patients with less than 
5% of overall dropout rate, surpassing the re-estimated sample size of 540 patients.  
The study enrollment will be halted as soon as operationally feasible. The final sample 
size expected is approximately 630 patients (210 patients per treatment group).
9.7.10
Computer Methods
Statistical analyses will be performed using version 9.3 (or newer) of SAS.
9.8
DATA AND SAFETY MONITORING BOARD
The study will be conducted under the supervision of an independent DSMB to be 
chartered to review safety data at predetermined points during the study. The DSMB may 
also decide to meet and review safety data at other timepoints should it be deemed 
necessary. The DSMB is responsible for the ongoing review of safety data in the clinical 
study and for making recommendations concerning the continuation, modification, and 
termination of the study (FDA Guidance for Clinical Trial Sponsors: Establishment and 
Operation of Clinical Trial Data Monitoring Committees, March 2006).
All analyses that are required to support the DSMB will be performed by an independent 
unblinded statistician not otherwise involved in the study.  Details of the DSMB 
membership, meeting schedule, and data review and analysis will be documented in the 
DSMB Charter.


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9.9
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the Investigator in writing by the 
Sponsor. No protocol amendment may be implemented (with the exceptions noted below) 
before it has been approved by the IRB, and the signature page, signed by the 
Investigator, has been received by the Sponsor. If the protocol is amended to eliminate or 
reduce the risk to patients, the amendment may be implemented before IRB review and 
approval. However, the IRB must be informed in writing of such an amendment, and 
approval must be obtained within reasonable time limits. 
9.10
PROTOCOL DEVIATIONS 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the Investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB approval or favorable opinion of an appropriate 
amendment and that does not have a major impact on the patient’s rights, safety, or 
well-being, or on the integrity and authenticity of the study data. Deviations may include, 
but are not limited to, departure from inclusion/exclusion criteria, dosing, duration of 
treatment, failure to perform the required assessments at specified timepoints, scheduling 
of visits not in accordance with specifications, or patient safety. Deviating from the 
protocol is permitted only if absolutely necessary for the safety or clinical management of 
the patients and must immediately be reported to the Sponsor.
A significant important protocol deviation is a form of protocol deviation that has a 
major impact on the patient’s rights, safety, or well-being, or on the integrity and 
authenticity of the study data. Important protocol deviations must be reported to the 
Sponsor within 24 hours, if possible. The IRB must be notified within the time period 
dictated by the IRB associated with this study. 


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


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


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


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


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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (RAP-MD-02, Amendment 
2, dated 10 Dec 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


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APPENDIX I
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained for each patient participating in a clinical research study. This consent must 
include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence).

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA, the 
Sponsor, the IRB, or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the Investigator as the 
contact. The guidance of the IRB may be required.)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled

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


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
The expected circumstances for which the patient’s participation may be terminated 
by the Investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of permission, providing consent for the patient to participate (eg, “I 
agree to participate . . .”)

A place for the patient’s signature and date of signing of the ICF 

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient.


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


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14.0
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Report 2001

SAP_001.pdf: 
NCT02943564 
 
Study ID: RAP‐MD‐02 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter Study of Rapastinel as Adjunctive 
Therapy in Major Depressive Disorder 
 
Statistical Analysis Plan: 25 Jan 2019