An Open-label, Long-term Safety Study of Rapastinel as Adjunctive Therapy in Patients With Major Depressive Disorder
Phase: PHASE3
Conditions: Depressive Disorder, Major
Sponsor: Naurex, Inc, an affiliate of Allergan plc

NCT03002077 
 
Study ID: RAP-MD-06 
 
 
 
Title: An Open-label, Long-term Safety Study of Rapastinel as Adjunctive Therapy in Patients With 
Major Depressive Disorder 
 
 
Protocol Date: 07 Jun 2016 
 

1.0
TITLE PAGE
Naurex, Inc, an affiliate of Allergan, plc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
An Open-label, Long-term Safety Study of Rapastinel as Adjunctive Therapy in
Patients with Major Depressive Disorder
RAP-MD-06
IND # 107,974
Original Protocol Date:
07 Jun 2016
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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2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study RAP-MD-06
Title of Study
An Open-label, Long-term Safety Study of Rapastinel as Adjunctive Therapy in 
Patients with Major Depressive Disorder
Study Centers (Country)
Approximately 105 to 110 study centers (United States)
Development Phase
3
Objective
To evaluate the long-term safety and tolerability of rapastinel as an adjunctive to 
antidepressant therapy (ADT) in patients with major depressive disorder (MDD)
Methodology
Multicenter, open-label, long-term study in adult patients with a primary 
diagnosis of MDD.
For patients enrolling from RAP-MD-04, the final visit from that study (ie, 
Visit 122) will serve as Visit 1 in RAP-MD-06 and, after obtaining informed 
consent, open-label rapastinel will be administered at Visit 1 to ensure 
continuity of treatment. 
The enrollment of patients who did not participate in RAP-MD-04 (identified as 
de novo enrollment patients) may be allowed at select study centers at the 
discretion of the Sponsor in the event that overall program enrollment indicates 
such de novo enrollment is necessary.  Should de novo patients be enrolled with 
Sponsor approval, such patients will include adult patients with MDD who have 
no more than a partial response (defined as < 50% improvement) to ongoing 
ADT treatment in the current episode. Upon written informed consent, de novo
enrollment patients will enter a screening period of up to 14 days.  
Following the screening period, all patients will enter the 52-week Open-label
Treatment Period (OLTP).  The OLTP consists of weekly or biweekly (once 
every 2 weeks, based on Investigator discretion) visits for up to 52 weeks. 
Upon completion of the OLTP, patients will enter a 2-week safety follow-up 
period.
Number of Patients
Approximately 500 patients are expected to enter the OLTP. The study will be 
terminated when 100 patients have completed the 52-week OLTP.
Diagnosis and 
Main Criteria for Inclusion
The following are requirements for entry into the study (patients entering from 
RAP-MD-04 are considered to have met inclusion criteria for diagnosis, 
severity, and prior ADT response, and are not required to meet these criteria 
upon entry into RAP-MD-06):

Male or female outpatients, ages 18 to 65 years who meet Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for 
MDD based on Structured Clinical Interview for Diagnostic Statistic 
Manual of Mental Health Disorders, Fifth Edition (SCID), with a current 
major depressive episode of at least 8 weeks and not exceeding 18 months 
in duration at Visit 1

Have no more  than partial response (< 50% improvement) to ongoing 
treatment with a protocol-allowed ADT (
 
 
 
 
 
 
 
 
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Test Product, Dosage, and Mode of 
Administration
Rapastinel 450 mg given intravenously (IV) either weekly or biweekly, per 
Investigator discretion, as adjunctive to ongoing ADT during the OLTP.
Duration of Treatment
For patients enrolling into RAP-MD-06 from RAP-MD-04 there will be a 
1-week screening period, up to 52 weeks of open-label rapastinel as adjunctive 
treatment to ongoing ADT, and a 2-week safety follow-up period. 
Should de novo patients be enrolled at a later date, there will be a screening 
period of up to 2 weeks, up to 52 weeks of open-label rapastinel as adjunctive 
treatment to ongoing ADT, and a 2-week safety follow-up period.
Reference Therapy, Dosage, and 
Mode of Administration
None
Criteria for Evaluation
Safety Measures

Adverse event (AE) recording, clinical laboratory measures, vital sign 
parameters, electrocardiograms (ECGs), and physical examinations

Measure of psychotomimetic effects: Brief Psychiatric Rating Scale 
Positive Symptoms subscale (BPRS+)

Measure of dissociative effects: Clinician Administered Dissociative States 
Scale (CADSS)
Pharmacokinetic Analysis
None
Pharmacogenetic Analysis
None
Statistical Methods
Descriptive statistics will be presented for all efficacy and safety parameters. No 
inferential statistical analyses will be performed.
All safety parameters will be summarized for the Safety Population, defined as 
all patients who receive at least 1 dose of investigational product (IP) in this 
study.
 
 
 
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3.0 OVERALL TABLE OF CONTENTS 
 
 
Page
1.0 TITLE PAGE ..............................................................................................
 
2.0 SYNOPSIS AND SCHEDULE OF EVALUATIONS ...............................
 
3.0 OVERALL TABLE OF CONTENTS ........................................................
 
3.1 LIST OF IN-TEXT FIGURES.................................................................
 
4.0 LIST OF ABBREVIATIONS .....................................................................
 
5.0 ETHICAL CONSIDERATIONS ................................................................
 
5.1 INSTITUTIONAL REVIEW BOARD ...................................................
 
5.2 ETHICAL CONDUCT OF THE STUDY ...............................................
 
5.3 PATIENT INFORMATION AND INFORMED CONSENT .................
 
6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................
 
7.0 INTRODUCTION ......................................................................................
 
8.0 STUDY OBJECTIVES ...............................................................................
 
9.0 INVESTIGATIONAL PLAN .....................................................................
 
9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ...............
 
9.1.1 Screening ...........................................................................................
 
9.1.2 Open-label Treatment Period ............................................................
 
9.1.3 Safety Follow-up Period....................................................................
 
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS .............................................................................
 
9.3 SELECTION OF STUDY POPULATION .............................................
 
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9.3.1 Inclusion Criteria ...............................................................................
 
9.3.2 Exclusion Criteria ..............................................................................
 
9.3.3 Removal of Patients from Therapy or Assessment ...........................
 
9.3.4 Patient Replacement Procedures .......................................................
 
9.4 TREATMENTS .......................................................................................
 
9.4.1 Background Antidepressant Therapy ................................................
 
9.4.2 Treatments Administered ..................................................................
 
9.4.3 Identity of Investigational Product ....................................................
 
9.4.4 Handling of Investigational Product .................................................
 
9.4.5 Method of Assigning Patients to Treatment Groups .........................
 
9.4.6 Selection of Dosages in the Study .....................................................
 
9.4.7 Selection and Timing of Dose for Each Patient ................................
 
9.4.7.1 Screening Period .........................................................................
 
9.4.7.2 Open-label Treatment Period ......................................................
 
9.4.7.3 Safety Follow-up Period .............................................................
 
9.4.8 Blinding .............................................................................................
 
9.4.9 Unblinding .........................................................................................
 
9.4.10 Prior and Concomitant Therapy ......................................................
 
 
 
9.4.11 Other Restrictions ............................................................................
 
9.4.11.1 Alcohol ......................................................................................
 
9.4.11.2 Contraception ............................................................................
 
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9.4.12 Monitoring Treatment Compliance .................................................
 
9.4.13 Treatment After Discontinuation ....................................................
 
9.5 EFFICACY AND SAFETY VARIABLES .............................................
 
9.5.1 Diagnostic and Efficacy Assessments ...............................................
 
9.5.1.1 Diagnostic Assessments ..............................................................
 
 
 
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9.5.2 Safety Assessments ...........................................................................
 
9.5.2.1 Adverse Events ...........................................................................
 
9.5.2.1.1 Causality Assessment ...........................................................
 
9.5.2.1.2 Severity Assessment .............................................................
 
9.5.2.1.3 Serious Adverse Events ........................................................
 
9.5.2.1.4 Reporting Adverse Events and Serious Adverse Events ......
 
9.5.2.2 Immediate Reporting of Serious Adverse Events and Events 
of Special Interest ...................................................................................
 
9.5.2.3 Reporting of Pregnancies Occurring During the Study ..............
 
9.5.2.4 Potential Hy’s Law Cases ...........................................................
 
9.5.2.5 Clinical Laboratory Determinations ...........................................
 
9.5.2.6 Vital Signs ...................................................................................
 
9.5.2.7 Electrocardiograms .....................................................................
 
 
 
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9.5.2.8.3 Brief Psychiatric Rating Scale - Positive Symptoms 
Subscale ...............................................................................................
 
9.5.2.8.4 Clinician Administered Dissociative States Scale ................
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.6.9 Unscheduled Visits .....................................................................
 
9.6 DATA QUALITY ASSURANCE...........................................................
 
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9.6.1 Data Monitoring ................................................................................
 
9.6.2 Data Recording and Documentation .................................................
 
9.7 STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..............................................................................................
 
9.7.1 Analysis Populations .........................................................................
 
9.7.1.1 Screened Population ....................................................................
 
9.7.1.2 Safety Population ........................................................................
 
9.7.1.3 Intent-to-Treat Population ...........................................................
 
9.7.2 Patient Disposition ............................................................................
 
9.7.3 Demographics and Other Baseline Characteristics ...........................
 
9.7.4 Extent of Exposure and Treatment Compliance ...............................
 
9.7.4.1 Extent of Exposure ......................................................................
 
9.7.4.2 Measurement of Treatment Compliance .....................................
 
 
9.7.6 Safety Analyses .................................................................................
 
9.7.6.1 Adverse Events ...........................................................................
 
9.7.6.2 Clinical Laboratory Parameters ..................................................
 
9.7.6.3 Vital Signs ...................................................................................
 
9.7.6.4 Electrocardiogram .......................................................................
 
9.7.6.5 Other Safety Parameters .............................................................
 
 
9.7.8 Interim Analysis ................................................................................
 
9.7.9 Determination of Sample Size ...........................................................
 
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9.7.10 Computer Methods ..........................................................................
 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ..................................................................................................
 
9.9 PROTOCOL DEVIATIONS ...................................................................
 
10.0 STUDY SPONSORSHIP..........................................................................
 
10.1 STUDY TERMINATION .....................................................................
 
10.2 REPORTING AND PUBLICATION ...................................................
 
11.0 INVESTIGATOR OBLIGATIONS .........................................................
 
11.1 DOCUMENTATION ............................................................................
 
11.2 PERFORMANCE ..................................................................................
 
11.3 USE OF INVESTIGATIONAL MATERIALS ....................................
 
11.4 CASE REPORT FORMS ......................................................................
 
11.5 RETENTION AND REVIEW OF RECORDS .....................................
 
11.6 PATIENT CONFIDENTIALITY..........................................................
 
12.0 INVESTIGATOR’S STATEMENT .........................................................
 
13.0 APPENDICES ..........................................................................................
 
APPENDIX I. ELEMENTS OF INFORMED CONSENT ...........................
 
APPENDIX II. CONTACT INFORMATION ..............................................
 
 
APPENDIX IV. ANTIDEPRESSANT TREATMENT RESPONSE 
 
 
 
 
 
 
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14.0 LITERATURE CITED .............................................................................
 
 
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3.1 LIST OF IN-TEXT FIGURES 
 
 
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Figure 9.1-1. Study Design ............................................................................
 
 
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4.0
LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
BPRS+
Brief Psychiatric Rating Scale – Positive Symptoms Subscale
CADSS
Clinician Administered Dissociative States Scale
CFR
Code of Federal Regulations
DALY
disability-adjusted life-year
DBTP
double-blind treatment period
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSST
Digit Symbol Substitution Test
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
ECT
electroconvulsive therapy
EDC
electronic data capture
ET
early termination
FDA
Food and Drug Administration
FR
Federal Register
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus
ICF
informed consent form
 
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ICH
International Conference on Harmonisation 
IND
Investigational New Drug (application)
IP
investigational product
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous(ly)
IWRS
interactive web response system
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
major depressive disorder
NEAE
newly emergent adverse event
NMDAR
N-methyl-D-aspartate receptor
OLTP
open-label treatment period
PCS
potentially clinically significant
PID
patient identification
PRN
as needed
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
SDC
Symbol Digit Coding
SDMT
Symbol Digit Modalities Test
SNRI
selective serotonin and norepinephrine reuptake inhibitor
SOC
system organ class
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal
 
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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD
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 the US CFR, Part 312.
5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the study and before participating in any study 
procedures, each patient must provide written informed consent (in compliance with 
21 CFR, Parts 50 and 312) and HIPAA authorization. 
Each patient will read and sign an ICF and/or other authorization form as per local 
regulations; each patient will be made aware that he or she may withdraw from the study 
at any time.
The ICF contains all the elements of informed consent listed in Appendix I of this 
protocol. Signed copies of the ICF and the HIPAA or other locally applicable form will 
be given to the patient, and both documents will be placed in the Investigator’s study 
files.
 
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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 105 to 110 study centers in the United 
States.
The Investigator is responsible for ensuring that the investigation is conducted according 
to the signed Investigator statement, the investigational plan, GCP guidelines, and 
applicable regulations; for protecting the rights, safety, and welfare of patients under the 
Investigator’s care; and for the control of investigational products under investigation. An 
investigator shall obtain the informed consent for each patient prior to the patient 
enrolling in the study and/or prior to participating in any study-related activity. 
The Investigator at each study center must meet his or her obligations to the patients, 
ethics committee, Sponsor, and regulatory authorities by maintaining oversight and 
control of the study’s conduct and the study staff. It is the responsibility of the 
Investigator to ensure that any and all delegated duties be assigned to qualified staff by 
education, experience, and licensure (in accordance with local regulations) and that the 
Investigator oversight is documented and assessment of staff capabilities and 
performance is consistent with the study investigational plan. The Investigator at each 
study center will be responsible for the management of the study, including maintaining 
the study file and the patient records, corresponding with the IRB, and completing the 
electronic case report forms (eCRFs).
 
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7.0
INTRODUCTION
Disease Burden of Major Depressive Disorder
Major depressive disorder (MDD) is a highly disabling, serious condition which is 
associated with significant morbidity and mortality. MDD manifests as a major 
depressive episode (which may be singular or recurrent) in which the affected individual 
experiences 1) depressed mood, or 2) loss of interest or pleasure (as well as other 
symptoms) for most of the day, nearly every day, for at least 2 weeks. MDD affects 
approximately 14.8 million American adults, or about 6.7% of the US population 
18 years of age and older, in a given year (Kessler et al, 2005). Worldwide, about 15% of 
the adult population is at lifetime risk of developing MDD (Kessler et al, 1994). 
Depression may cause serious, long-lasting symptoms and often disrupts a person’s 
ability to perform routine tasks. In 2000, unipolar depressive disorders were by far the 
leading cause (11.9%) of worldwide years of life lived with disability 
(World Health Organization, 2001), and the total economic burden of treating depression 
in the United States was $83.1 billion, with workplace costs, including missed days and 
lack of productivity due to illness, accounting for most of the total economic burden 
(62%). Other economic burdens in 2000 included $26.1 billion (31%) for treatment costs 
and $5.4 billion (7%) for suicide-related costs 
(Greenberg et al, 2003). 
MDD is a leading cause of disability in the United States (Murray et al, 2013). Moreover, 
MDD is known to be a significant risk factor for suicide and ischemic heart disease, as it 
accounted for 16 million of the disability-adjusted life-years (DALYs) associated with 
suicide and 4 million of the DALYs associated with ischemic heart disease. Research has 
shown that untreated depression has both a functional (social and work role) as well as a 
neuroanatomical (hippocampal shrinkage) effect on the patient (Videbech and Ravnkilde, 
2004). Given the disease burden and link to suicidality as well as increased mortality with 
other comorbid conditions, MDD is a serious and life-threatening condition which is a 
leading cause of disability in the world.
 
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Selective Serotonin Reuptake Inhibitors and Selective Serotonin 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). 
The results of the STAR*D study suggest that with successive failures of treatment, 
patients are less and less likely to respond to subsequent treatment, and those who do 
respond are more likely to relapse (Rush et al, 2006). Present strategies available to treat 
patients who do not respond to first-line antidepressant monotherapy include switching of 
antidepressant (either within or between classes); combination therapy in which multiple 
antidepressants are used simultaneously; augmentation of ongoing antidepressant 
monotherapy with adjunctive use of drugs such as mood stabilizers or atypical 
antipsychotics (Boland and Keller, 2006); and the use of nonpharmacologic treatments 
including psychotherapy and phototherapy, vagus nerve stimulation, transcranial 
magnetic stimulation, and electroconvulsive therapy (ECT). 
Existing antidepressants have a number of limitations, leading to considerable unmet 
medical need in the effective treatment of MDD, with up to 50% of patients with MDD 
having an inadequate response or failing current antidepressant therapy (ADT). Currently 
available first-line antidepressants (SSRIs, SNRIs) typically take 3 to 4 weeks or more of 
continuous daily dosing to relieve symptoms of MDD and are associated with side effects 
related to their pharmacological mechanisms of action (sexual dysfunction, weight gain, 
jitteriness, sleep disturbances), which are further associated with poor patient compliance 
(Masand 2003, Ashton et al, 2005). Patients often experience undesirable side effects 
before they experience an improvement in depressive symptoms, which could lead to 
premature discontinuation of therapy. Taken together, these factors define significant 
areas for improvement of ADT. 
 
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Patients vary greatly in their response to antidepressants and it is not possible to reliably 
predict whether an individual patient will respond to a given antidepressant. This leads to 
clinicians often using a trial-and-error approach to identify an effective antidepressant. 
Due to the gradual development of the full therapeutic effect of currently available 
antidepressants, each antidepressant needs to be administered for 4 weeks or longer in 
order to determine the individual therapeutic benefit, making the process of finding an 
effective antidepressant 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. 
As all current antipsychotic agents modulate central dopaminergic systems, they all carry 
a risk of extrapyramidal symptoms such as muscular rigidity, acute dystonia, as well as 
akathisia, which is a particularly relevant adverse event (AE) that complicates clinical 
management in a significant number of treated individuals, as high as 45% 
(Sachdev, 1995). In addition, these compounds are associated with a risk of neuroleptic 
malignant syndrome and tardive dyskinesia. Depending on their individual 
pharmacological profile, antipsychotics also carry a risk for metabolic changes including 
hyperglycemia/diabetes mellitus, dyslipidemia and body weight gain; blood dyskrasias 
such as leucopenia, neutropenia, and agranulocytosis; orthostatic hypotension; cognitive 
and motor impairment; cataracts; and insomnia (Abilify, 2014; Seroquel, 2013; 
Rexulti, 2015). The range of clinically relevant side effects with antipsychotics has to be 
balanced carefully against the potential for therapeutic benefits in patients with major 
depression. In this context, it is important to highlight that for the approved atypical 
antipsychotics the full therapeutic benefit required several weeks of daily adjunctive 
dosing to become apparent, and in many patients, adverse effects occurred substantially 
earlier than the mood-alleviating effects of these drugs. 
Furthermore, the drugs currently approved for adjunctive treatment of MDD also have 
limited efficacy. The pivotal studies for Abilify, the atypical antipsychotic most 
commonly used for adjunctive treatment of MDD, showed a delayed onset of effect 
(1-2 weeks), a modest magnitude of effect (effect sizes were 0.35-0.39 after 6 weeks of 
repeat dosing) and modest rates of response and remission after 6 weeks of repeat dosing 
(response rates were 32-34% and remission rates were 25-26%) (Berman et al, 2007; 
Marcus et al, 2008). 
 
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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 Treatment of Major Depressive Disorder
The mechanism of action of rapastinel is entirely different from that of atypical 
antipsychotics. Rapastinel is an N-methyl-D-aspartate receptor (NMDAR) modulator 
with a novel and complex pharmacological mechanism of action, acting as a nonselective 
agent at NR2 subunits and displaying properties as a functional partial agonist in a 
number of pharmacological assays.  
Rapastinel has demonstrated antidepressant properties in relevant animal models, 
displays cognitive enhancing properties in treated animals, and facilitates hippocampal 
long-term potentiation of synaptic transmission in preclinical models. In contrast to 
ketamine, no signal of abuse liability was detected in informative animal models. 
Rapastinel is available as an intravenous (IV) formulation only. In two 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 assess the safety and tolerability of rapastinel when 
administered open-label as an adjunctive treatment at a dose of 450 mg as a short IV 
infusion in patients with MDD.  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 objective of this study is to evaluate the long-term safety and tolerability of 
rapastinel as adjunctive to ADT in patients with MDD.
Safety Objectives

To evaluate the safety and tolerability of rapastinel (450 mg IV weekly or once every 
2 weeks [biweekly]) as an adjunct to ongoing ADT, as evaluated by AEs, clinical 
laboratory measures, ECGs, vital signs, 
 

To evaluate the psychotomimetic effects of rapastinel (450 mg IV weekly or once 
every 2 weeks) as an adjunct to ongoing ADT, as measured by the change from 
baseline in BPRS+ at all postdose evaluations

To evaluate the dissociative effects of rapastinel (450 mg IV weekly or once every 
2 weeks) as an adjunct to ongoing ADT, as measured by the change from baseline in 
CADSS at all postdose evaluations
 
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
Study RAP-MD-06 is a multicenter, open-label study to evaluate the long-term safety and 
tolerability of rapastinel as adjunctive therapy to ADT in adult patients with MDD who 
either completed the RAP-MD-04 Double-blind Treatment Period (DBTP) at Visit 122
(Week 104, ET) or who do not meet criteria to be randomized into the DBTP of
RAP-MD-04 and are therefore discontinued from that study.  The enrollment of patients 
who did not participate in RAP-MD-04 (identified as de novo enrollment patients) may 
be considered at some study centers if enrollment of rollover patients does not meet 
targeted projections and will not be allowed unless specified in an official communication 
from the Sponsor.
The study will be conducted in the following periods:

Up to 2-week screening period

Up to 52-week OLTP

2-week safety follow-up period
The study is planned to be terminated when 100 patients have completed the 52-week 
OLTP. The actual sample size is expected to be larger than 100 patients and some 
patients will have less than 52 weeks of open-label treatment (as many as 500 patients are 
expected to enter the OLTP of Study RAP-MD-06).
Figure 9.1-1 provides the study design schematic. The schedule of evaluations is 
presented in Section 2.0, and detailed descriptions of the procedures conducted at each 
study visit can be found in Section 9.5.
 
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9.1.1
Screening
The screening period will occur up to 2 weeks prior to Visit 2:

For patients enrolling from Study RAP-MD-04, the final visit from that study (Visit 
122 [Week 104, ET]) will serve as Visit 1 in RAP-MD-06. These rollover patients
will receive the first dose of open-label investigational product (IP) (ie, rapastinel 
450 mg IV) at Visit 1 to ensure continuity of treatment. 

Upon providing written informed consent, de novo patients will enter a screening 
period of up to 14 days. De novo patients will not receive any IP during the screening 
period but must continue their background ADT at the same dose and wash out of 
prohibited medications (Appendix III). De novo patients meeting the eligibility 
criteria at the end of Visit 2 (Baseline) will be assigned a treatment by IWRS and 
enter the OLTP.
 
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All patients will maintain usage of their ADT throughout participation in the study 
(see Section 9.4.10.1).
9.1.2
Open-label Treatment Period
Approximately 500 patients are planned for enrollment in the OLTP; all patients will 
receive open-label rapastinel at 450 mg IV (adjunctive to ADT), either weekly or once 
every 2 weeks, based upon the Investigator’s discretion. Patients will skip odd-numbered 
visits if being treated on a biweekly basis). The once-every-2-weeks schedule can only be 
initiated on even-numbered visits in order to maintain the appropriate visit schedule. 
Patients who are on a once-every-2-weeks schedule can be transitioned back to weekly 
visits at any visit.
Upon completion of the OLTP at Visit 54 (Week 52, ET), patients will enter a 2-week 
safety follow-up period and will return to the clinic at Visit 55 (Week 54). The maximum 
duration of the study will be 56 weeks.
The study will be terminated when 100 patients have completed the 52-week OLTP.
9.1.3
Safety Follow-up Period
All patients who complete or discontinue from the OLTP should enter the 2-week safety 
follow-up period.
Additional follow-up visits may be scheduled within 30 days, if necessary, for safety 
reasons.
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
The 52-week, open-label study was designed to assess long-term safety following 
continued adjunctive rapastinel treatment in adult patients with MDD. In this study, 
investigators will enroll patients who completed Study RAP-MD-04 or, as needed, 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 
Montgomery-Åsberg Depression Rating Scale (MADRS) (Section 9.5.1.2.1). 
Study centers will have experience with the study population and will be encouraged to 
apply available guidelines to minimize patient risk or distress.
 
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Dose selection information is presented in Section 9.4.6. The planned dosing regimen is 
based on experience from previous rapastinel studies.
The 2-week safety follow-up period allows continued patient monitoring after IP has 
been discontinued.
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
Note: For rollover patients who completed the lead-in study (RAP-MD-04), medical, 
psychiatric, and medication histories from Visit 1 of RAP-MD-04 will be used. For such 
patients, Inclusion Criteria 2, 4, 5, and 6 are not applicable based on participation in 
RAP-MD-04.
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 who are 18 to 65 years of age
3. For rollover patients from RAP-MD-04, completion of Study RAP-MD-04 
(either OLTP or DBTP) with continued ADT treatment
4. 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
 
6. Have no more than partial response (< 50% improvement) to ongoing treatment 
with a protocol-allowed ADT 
 
 
 
 
 
 
 
 
 
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8. If female of childbearing potential, have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test at Screening (Visit 1). Because Visit 1 
pregnancy test results will not be available on the day of Visit 1, rollover patients 
can be discontinued at Visit 2 if Visit 1 pregnancy test is positive.
9.3.2
Exclusion Criteria
Note: For rollover patients who completed the lead-in study (RAP-MD-04), medical, 
psychiatric, and medication histories from Visit 1 of the lead-in study will be used
(Exclusion Criteria Nos. 1-8, 12-14, 17, 21-25, and 27). Because Visit 1 clinical 
laboratory or ECG results will not be available on the day of Visit 1, if there are any 
safety concerns related to Visit 1 clinical laboratory or ECG results, patients can be 
discontinued at Visit 2.
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
Exclusion criteria to be assessed at Screening (Visit 1)
Psychiatric and Treatment-Related Criteria:
1. DSM-5-based diagnosis of any disorder other than MDD that was the primary 
focus of treatment within 6 months before Visit 1. Comorbid generalized anxiety 
disorder, social anxiety disorder, or specific phobias are acceptable provided they 
play a secondary role in the balance of symptoms and are not the primary driver 
of treatment decisions. 
2. Lifetime history of meeting DSM-5 criteria for:
○
Schizophrenia spectrum or other psychotic disorder
○
Bipolar or related disorder
○
Major neurocognitive disorder 
○
Neurodevelopmental disorder of greater than mild severity or of a severity 
that impacts the patient's ability to consent, follow study directions, or 
otherwise safely participate in the study
○
Dissociative disorder
 
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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:
 
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
Screen failure (failure to meet inclusion/exclusion criteria)

Pregnancy

Withdrawal of consent

AE

Lack of efficacy

Protocol violation

Noncompliance with IP

Noncompliance with ADT

Lost to follow-up

Study terminated by Sponsor

Study center terminated by Sponsor

Other
All patients who prematurely discontinue from the study, regardless of cause, should be 
seen for a final assessment at an ET Visit. A final assessment will be defined as 
completion of the evaluations scheduled for all patients at Visit 54 (Week 52). All 
patients discontinuing the study prematurely should enter the 2-week safety follow-up 
period.
Patients who discontinue from the study and do not return to the study center for final 
assessments must be requested in writing to return to the study center for a final 
assessment. A copy of the letter, together with the source documentation, will be kept in 
the Investigator’s files. The reason for premature discontinuation from the study will be 
recorded on the Study Termination Page of the eCRF. Study center staff will be contacted 
by the Sponsor after each premature discontinuation to ensure proper characterization of 
the reason for discontinuation is captured.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
 
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9.4
TREATMENTS
During the OLTP, all eligible patients will receive open-label, once-weekly or once every 
2 weeks (biweekly, at Investigator’s discretion) IV rapastinel 450 mg. Patients receiving 
biweekly treatment will skip all odd-numbered visits on the Schedule of Evaluations 
(Section 2.0).
9.4.1
Background Antidepressant Therapy
De novo patients must enter the study while having no more than partial response (< 50% 
improvement) to ongoing treatment with a protocol-allowed ADT
 
 
 
 
 
 
 
 
Patients entering from Study RAP-MD-04 will have already fulfilled this requirement but 
must continue their background ADT as described below.
Upon entry into the study at Screening/Visit 1, the dosage of the ADT must be held 
constant at a dose in accordance with the respective label throughout participation in 
RAP-MD-06. If a patient experiences an AE, intercurrent illness, or symptoms of 
intolerance, he or she will be permitted to stop taking the ADT for a maximum of 
5 consecutive days at the discretion of the Investigator. No other alterations in the ADT 
dose regimen are allowed. If an ADT dose change is required during the study, the 
patient should be discontinued from the study.
Background ADT medication compliance will also be closely monitored. Compliance 
will be based on patient report. Every effort should be made to have patients bring their 
background ADT to each study visit for verification of patient-reported compliance by 
pill count (to the extent possible).
 
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9.4.2
Treatments Administered
The IP will only be administered to eligible patients under the supervision of the 
Investigator or identified subinvestigators or other assigned personnel authorized to 
administer IV drugs.  IP will be administered in a “slow bolus” injection to an upper 
extremity vein within approximately 1 to 2 minutes to each study patient. The patient 
should not be discharged from the study center until the Investigator or medically 
qualified subinvestigator determines that the patient is medically able to leave the study 
center (recommended not less than 15 minutes following administration).
9.4.3
Identity of Investigational Product
Rapastinel 450 mg IV Prefilled Syringes:
 
.
 
 
 
 
 
 
The study center personnel will complete the kit label and attach the tear-off portion from 
the kit label to the source documents.
The prefilled syringe will be labeled with 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 the label will 
remain on the prefilled syringe.
9.4.4
Handling of Investigational Product
The IP must be stored in a secure area and administered only to patients entered into the 
clinical study, at no cost to the patient, in accordance with the conditions specified in this 
protocol.
 
 
 
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At the end of the study, all IP must be accounted for. In addition, at the end of the study, 
all unused IP and empty IP packages should be returned to the Sponsor or the local 
distributor at the address provided in the Study Reference Manual.
9.4.5
Method of Assigning Patients to Treatment Groups
Patients enrolling from RAP-MD-04 will keep the same PID number that was assigned in 
that study. 
For de novo patients (new patients who did not participate in RAP-MD-04), 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 number. 
 
 
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 patient.  Study centers will 
dispense IP according to the IWRS instructions.  Study centers will also log onto the 
IWRS at subsequent visits to obtain a study medication kit number for dispensing IP. 
Study centers will receive the IWRS confirmation notifications for each transaction. All 
notifications are to be maintained with the study source documents.
9.4.6
Selection of Dosages in the Study
A rapastinel dose of 450 mg was chosen for this study based on results from 2 Phase 2 
clinical studies of 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. The 450-mg IV dose is expected 
to provide an appropriate dose for most patients based upon the Phase 2 study results. 
The use of a single-unit dose is intended to aid in the simplicity of administration and 
avoid dosing errors.
RAP-MD-04 also assessed both weekly and biweekly dosing regimens. While the 
GLYX13-C-202 study also assessed the effect of weekly and biweekly administration 
after initial stabilization, and found no differences, the comparison was only carried out 
for 6 weeks in that study. Assessing a less frequent dosing regimen over the more 
substantial time period of 26 weeks to 2 years in RAP-MD-04 followed by an additional 
52 weeks of treatment in RAP-MD-06 is expected to yield a better understanding of the 
long-term safety characteristics of rapastinel treatment and allow proper guidance to 
physicians regarding treatment beyond initial stabilization.
 
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9.4.7
Selection and Timing of Dose for Each Patient
The IP will be administered IV using the assigned single-use prefilled syringes either 
weekly or biweekly based on the discretion of the Investigator, per the Schedule of 
Evaluations (Section 2.0). A patient may be switched between weekly and biweekly 
treatment at any time during the OLTP. For patients on a biweekly schedule, only 
odd-numbered visits during the OLTP may be skipped.
9.4.7.1
Screening Period
For patients enrolling from RAP-MD-04, the final visit from that study (Visit 122
[Week 104, ET]) will serve as Visit 1 in this study, after written consent is obtained. 
Rollover patients will receive open-label IP at Visit 1 to ensure continuity of treatment.
For de novo patients, at Visit 1, after written consent is obtained, patients will enter a 
screening period of up to 14 days. No IP is administered to de novo patients during the 
screening period; however, patients must continue their background ADT at a stable 
dose. During this time de novo patients will wash out of prohibited medications, per 
Appendix III.
9.4.7.2
Open-label Treatment Period
Patients enrolling from RAP-MD-04 who meet all eligibility criteria at Screening 
(Visit 1) will receive IP at Visit 1, and patients who continue to meet all the eligibility 
criteria for participation in the study at Baseline (Visit 2) will continue to receive IP 
during the OLTP.
De novo 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 Baseline (Visit 2) will be 
assigned an IP kit number via IWRS at Visit 2.
All eligible patients will receive rapastinel 450 mg IV from a prefilled single-dose 
syringe at Visits 2 through Visit 53 (Week 51).
9.4.7.3
Safety Follow-up Period
Patients who complete the OLTP or patients who prematurely discontinue from the study 
should enter the 2-week safety follow-up period, returning to the clinic for Visit 55 
(Week 54). No IP is administered during the safety follow-up period.  Patients’ 
background ADT may be modified as deemed appropriate by the Investigator.
9.4.8
Blinding
Not applicable
 
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9.4.9
Unblinding
Not applicable
9.4.10
Prior and Concomitant Therapy
A list of example medications that are allowed and not allowed as concomitant 
medications for either episodic or chronic use is provided in Appendix III. 
For de novo patients, medication history (psychotropic medication history during the 
previous 5 years and all other medications during the past 12 months) will be recorded at 
Screening (Visit 1) in the eCRF. Thereafter, any changes in concomitant medications or 
any new medications added will be recorded in the eCRF.
9
1
 
 
 
 
 
 
 
 
 
 
 
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9
2
 
 
 
 
 
.
9.4.11
Other Restrictions
9.4.11.1
Alcohol
It is recommended that patients abstain from alcohol consumption during the study.
9.4.11.2
Contraception
For purposes of this study, females will be considered of childbearing potential unless 
they are naturally postmenopausal or permanently sterilized (ie, hysterectomy).  Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any 
other obvious pathological or physiological cause.  
 
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For women of childbearing potential who may participate in the study, the following 
methods of contraception, if properly used, are generally considered reliable: hormonal 
contraceptives (ie, oral, patch, injection, implant), male condom with intravaginal 
spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring, 
intrauterine device, surgical sterilization (bilateral tubal ligation, bilateral salpingectomy), 
vasectomized partner, or sexual abstinence.
The Investigator and each patient will determine the appropriate method of contraception 
for the patient during the participation in the study.
See Section 9.5.2.3 for pregnancy reporting procedures.
9.4.12
Monitoring Treatment Compliance
IP compliance during any period will be closely monitored by capturing the date and time 
of each injection of IP.  If a scheduled injection does not occur, the Sponsor must be 
notified and the reason captured in the eCRF.
Background ADT compliance will also be closely monitored. Background ADT 
medication compliance will be based on patient report. Every effort should be made to 
have patients bring their background ADT to each study visit for verification of 
patient-reported compliance by pill count (to the extent possible).  Missed doses or other 
changes in the dose of ADT and the reason should be captured in the eCRF.
9.4.13
Treatment After Discontinuation
Patients whose MDD symptoms worsen or are determined by the Investigator not to be 
adequately controlled prior to completing the OLTP will be allowed to discontinue the 
study and start appropriate treatment at the Investigator’s discretion. This new treatment 
will not be provided by the Sponsor. Patients who initiate a new treatment must be 
discontinued from the study.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9.5.1.1
Diagnostic Assessments
The SCID will be administered during the screening interviews by a psychiatrist, doctoral 
level clinical psychologist, or other clinician who has extensive professional training and 
experience in the diagnosis of mental illness and who meets the training requirements and 
qualifications standards set by the Sponsor and rater training vendor.
 
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9
2
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately-trained healthcare 
professional at every visit and the evaluation must be documented. The procedures 
discussed in the following sections will be completed at the designated visits.
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A).
 
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For the purpose of the study center’s data collection responsibilities, any untoward event 
that was reported from the time the patient signed the ICF until 30 days after the final 
protocol-defined study visit or the last known dose of IP (if the final visit does not occur) 
is to be considered an AE.
Examples of AEs are as follows:

Changes in the general condition of the patient

Subjective symptoms offered by or elicited from the patient

Objective signs observed by the Investigator or other study center personnel

All diseases that occur after signing informed consent, including any change in 
severity or frequency of pre-existing disease

All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study schedule
Please note that medical procedures scheduled prior to consenting, but occurring during 
the study should not be captured as AEs, but should be listed in the medical history if 
related to a pre-existing condition.
9.5.2.1.1
Causality Assessment
For each AE, the Investigator must provide an assessment of causal relationship to the IP. 
The causality assessment must be recorded on the appropriate AE reporting page of the 
patient’s eCRF. Causal relationship must be assessed by answering the following 
question:
Is there a reasonable possibility the IP caused the event?
Yes:
There is evidence to suggest a causal relationship between the IP and AE, ie:
○
There is a reasonable temporal relationship between the IP and the event, and/or 
○
The event is unlikely to be attributed to underlying/concurrent disease or other 
factors, and/or
○
Positive dechallenge and/or rechallenge exist
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
 
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○
The patient did not take the IP, or
○
The event is likely to be attributed to underlying/concurrent disease or other 
factors, or
○
The event is commonly occurring in the (study) population independent of IP 
exposure
9.5.2.1.2
Severity Assessment
The Investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. Severity,
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 9.5.2.1.3). Severity will be 
assessed according to the following scale:
Mild:
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort, but poses no significant or permanent risk of harm to 
the research participant.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
9.5.2.1.3
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect
 
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Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in patient hospitalization, or the 
development of IP dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (eg, elective procedures for pre-existing conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.
9.5.2.1.4
Reporting Adverse Events and Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study center personnel will 
record all pertinent information in the patient’s eCRF. 
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF 
whether or not they are considered causally related to the IP.
For every AE, the Investigator must:

Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as 
the severity and casual relationship

Document all actions taken with regard to the IP

Detail any other treatment measures taken for the AE

Document the outcome of the AE
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 Section 9.5.2.1.3 and Section 9.5.2.1.4), and/or 2) the event is judged by the 
Investigator to be potentially causally related to IP.
 
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Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the IP. If a follow-up visit is deemed necessary for 
appropriate safety surveillance, it will take place within 30 days of the final protocol-
defined study visit.
9.5.2.2
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the Sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study center personnel must report the event to Global Drug Safety on the SAE Form for 
Clinical Trials. The Study Physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The study center must transmit the SAE Form for Clinical Trials to the SAE fax number 
provided at the end of this section. Even if an initial report is made by telephone, the SAE 
Form for Clinical Trials completed with all available details must still be faxed within 
24 hours of knowledge of the event at the study center.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The Investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs are to be followed by 
the study staff until resolution or until the SAE is deemed stable. The Sponsor may 
contact the study center to solicit additional information or follow up on the event.
Fax the SAE Form for Clinical Trials to the Sponsor.
 
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9.5.2.3
Reporting of Pregnancies Occurring During the Study
Study center personnel must report every pregnancy from the time the patient signs the 
ICF until 30 days after the last dose of IP. Within 24 hours of learning of the pregnancy, 
the study center personnel must report the event to Global Drug Safety on the Clinical 
Trial Pregnancy Form and fax it to the SAE/pregnancy fax number provided in 
Section 9.5.2.2, even if no AE has occurred. Pregnancies in female partners of male 
patients occurring during the timeframe described above must also be reported. 
Any pregnancy of a patient treated with IP 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.
9.5.2.4
Potential Hy’s Law Cases
The criteria for potential Hy’s Law cases are as follows:

ALT or AST ≥ 3 × ULN and 

Total bilirubin ≥ 2 × ULN and 

Alkaline phosphatase < 2 × ULN
Study center personnel must report every patient who meets these potential criteria. 
Typically, all 3 analytes will be obtained from the same sample, but they may come from 
multiple samples taken within a 24-hour period. This requirement applies from the time 
the ICF is signed for the study until 30 days after the final protocol-defined study visit or 
the last known dose of IP (if the final visit does not occur). 
A laboratory alert for potential Hy’s Law cases will be in place, and the laboratory must 
notify investigators and the Sponsor immediately when the above criteria have been met. 
A potential Hy’s Law case must be faxed to the Sponsor on an AE of Interest Form as 
soon as possible (within 24 hours of learning of the potential Hy’s Law) to the 
SAE/pregnancy fax number stated in Section 9.5.2.2, even if no AE has occurred. The 
eCRF for potential Hy’s Law cases must be completed within 7 calendar days. Every 
effort to determine the cause of the liver enzyme abnormalities must be made, and close 
monitoring should be initiated in conjunction with the Study Physician and in accordance 
with the FDA Guidance for Industry: Drug Induced Liver Injury - Pre-Marketing Clinical 
Evaluation, July 2009.
 
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9.5.2.5
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected as detailed in the 
Schedule of Evaluations (Section 2.0). During screening, the Investigator will assess the
clinical significance of any values that are outside the reference ranges provided by the 
central laboratory; patients with abnormalities judged to be clinically significant will be 
excluded from the study.
Patients will be asked to fast overnight or for at least 8 hours before arriving at the study 
center for appointments involving the collection of clinical laboratory blood tests.
The following clinical laboratory levels will be measured:
Hematology:
Absolute and differential white blood cell count, erythrocyte 
count, hemoglobin, hematocrit, platelet count, and red blood cell 
indices (mean corpuscular volume, mean corpuscular hemoglobin, 
and mean corpuscular hemoglobin concentration)
Chemistry:
Sodium, potassium, calcium, chloride, bicarbonate, magnesium,
gamma glutamyl transferase, phosphate, glucose, blood urea 
nitrogen, creatinine, creatine phosphokinase, total protein, 
alkaline phosphatase, albumin, bilirubin (total; direct; indirect), 
ALT, AST, total cholesterol, low-density lipoprotein, high-density 
lipoprotein, and triglycerides
HbA1c and fasting insulin: As specified in the Schedule of Evaluations (Section 2.0)
Urinalysis:
Specific gravity, pH, protein, glucose, ketones, and blood
Thyroid function:
Thyroid function test at Screening (Visit 1) and periodically as 
specified in the Schedule of Evaluations (Section 2.0)
UDS:
Benzoylecgonine (cocaine), barbiturates, amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, 
phencyclidine, performed at Screening (Visit 1), and periodically 
as specified in the Schedule of Evaluations (Section 2.0) (and at 
Investigator’s discretion)
Serum β-hCG:
Serum β-hCG will be performed at Screening (Visit 1) and 
periodically as specified in the Schedule of Evaluations 
(Section 2.0) (and at Investigator’s discretion)
 
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Hepatitis screening:
Hepatitis–C virus antibody, hepatitis–B surface antigen, and 
hepatitis-B core antibody total will be tested. Reflex hepatitis-B 
core antibody IgM will be performed for all hepatitis–B core 
antibody total positive or reactive results. Positive test results will 
be sent for confirmation testing. Hepatitis screening is to be 
conducted at Screening (Visit 1) on de novo patients only 
(new patients who did not participate in RAP-MD-04).
Clinical laboratory tests may be performed under special circumstances (and at 
Investigator’s discretion).
A negative UDS (except for benzodiazepines if prescribed by the Investigator as per the 
protocol) is required before Baseline (Visit 2) for the patient to continue in the study. A 
UDS may be performed at any time during the study at the discretion of the Investigator. 
A patient with a positive UDS for benzodiazepines or opiates at any visit may be allowed 
to continue in the study provided the patient has been prescribed the medication and it is 
being used for legitimate medical purpose in the Investigator’s judgment.
Serum pregnancy test will be performed as specified in the Schedule of Evaluations
(Section 2.0). Positive results on the pregnancy test at Screening (Visit 1) will exclude 
patients from participating in the study. Positive pregnancy test results during the study 
will result in patient termination from the study.
Other laboratory assessments may be repeated at any visit if there was an abnormal 
finding at the most recent previous evaluation or if additional information is clinically 
necessary to appropriately evaluate the patient’s current condition, follow up, and/or 
manage an adverse experience. 
A central laboratory will be used to evaluate all urine and blood samples, which will be 
collected, processed, and stored according to the instructions provided by the laboratory. 
9.5.2.6
Vital Signs
Vital signs (pulse rate, systolic and diastolic BP, oral or tympanic temperature, and body 
weight) will be assessed at every visit during the OLTP. Height will be assessed at Visit 1
for de novo patients only (Section 2.0).
BP and radial pulse rate will be measured in the supine position followed by the standing 
position. The standing measurements should be assessed after a sufficient amount of time 
has been elapsed to allow the BP to equilibrate in the standing state.
Radial pulse rate should be measured after BP measurements. BP may be measured 
manually or by machine, but radial pulse rate should only be measured manually and for 
a sufficient time to acquire an accurate measurement.
 
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Patients should be instructed not to wear clothing with tight sleeves when they come for 
clinic visits. Additionally, patients should be kept as calm and undisturbed as possible 
while BP and pulse rate measurements are taken (eg, there should be no talking while the 
BP is being measured). The same arm and BP cuff (appropriate to the arm circumference) 
should be used for all BP measurements.
Whenever possible, the patient’s weight will be measured at the same time of day; 
patients should wear their usual indoor clothing, but take off their jacket and shoes. For 
each patient, body weight should be determined using the same equipment during the 
study after ensuring its proper calibration.
9.5.2.7
Electrocardiograms
A 12-lead ECG will be performed at the visits outlined in the Schedule of Evaluations
(Section 2.0). The ECGs will be performed and electronically transmitted to a central 
ECG laboratory for analysis according to the instructions provided by the central ECG 
laboratory. Measurements (in msec) will be recorded for the following parameters: 
PR interval, QRS duration, and uncorrected QT interval. QTcB (Bazett corrected 
QT interval) and QTcF (Fridericia corrected QT interval) will be calculated. 
The overall interpretation and determination of the clinical relevance of ECG findings 
using the central ECG interpretation laboratory report will be the responsibility of the 
Investigator and will be recorded in the patient’s eCRF. For eligibility criteria, the values 
reported on the central ECG interpretation report will be used (not the values printed on 
the tracing itself).
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9.5.2.8.3
Brief Psychiatric Rating Scale - Positive Symptoms Subscale 
The BPRS is an 18-item evaluation that assesses psychiatric symptoms and unusual 
behavior (Overall and Gorham, 1962).  The BPRS+ is a subset of the BPRS that assesses 
4 components of the BPRS+ related to the degree of psychosis: Conceptual 
Disorganization, Suspiciousness, Hallucinatory Behavior, and Unusual Thought Content. 
Only the 4 items of the BPRS+ subscale will be collected and analyzed. The BPRS+ will 
be administered by the Investigator or designee with extensive professional training and 
experience in assessing mental illness.
 
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9.5.2.8.4
Clinician Administered Dissociative States Scale 
The Clinician Administered Dissociative States Scale (CADSS) is a 28-item 
clinician-administered measure of perceptual, behavioral, and attentional alterations 
occurring during active dissociative experiences composed of 23 subjective self-reported 
and 5 objective observer-reported ratings, each scored from 0 (not at all) to 4 (extremely). 
Only the 23 subjective items will be collected and analyzed. The CADSS provides a 
validated assessment of dissociative states sensitive to change over time and amenable to 
repeated measures (Bremner et al, 1998). The CADSS will be administered by the 
Investigator or designee with extensive professional training and experience in assessing 
mental illness.
 
 
 
 
 
 
 
 
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9
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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.
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9.5.6.9
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.
 
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9.6.2
Data Recording and Documentation
Data collection will involve the use of the EDC system, to which only authorized 
personnel will have access. Patient’s data are to be entered into the EDC system by the 
Investigator or designee using their assigned EDC user account. After data entry into the 
EDC system by the Investigator or designee, a combination of manual and programmatic 
edit checks will be used to review the data for completeness, logic, and adherence to 
study protocol. As a result of these edit checks, data monitoring, and reviews, queries 
may be electronically issued to the study center and should be answered electronically via 
the EDC system.
Each query will carry identifying information (assigned username, date, and time) to 
assist the Sponsor and the Investigator on the origin of the data clarification request and 
the response provided by the Investigator. All data changes made to the patient’s data via 
a data query will be approved by the Investigator prior to final database lock.
After all data have been reviewed and all issues have been resolved, the database will be 
locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, and regulatory documents) will be retained at the study center, along 
with adequate source documentation, according to FDA and ICH requirements. All study 
records must be available for inspection by the Sponsor, its authorized representatives, 
the FDA, or other health authorities.
Data for the 
 C-SSRS, BPRS+, CADSS, and 
 will be captured 
using an electronic source tablet-based system.  
 
 
 
Source documents will be used at the 
study centers and may include a patient’s medical record, hospital charts, clinic charts, 
the Investigator’s patient study files, as well as the results of diagnostic tests such as 
laboratory tests, ECGs, etc. A centralized clinical laboratory will be used for the analysis 
of all blood samples. Additional information on the collection and handling of samples is 
detailed in the Lab Procedure Manual.
 
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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
Screened Population
The Screened Population will consist of all patients who signed the RAP-MD-06 ICF if 
they participated in Study RAP-MD-04, and all patients who underwent the Screening 
Visit, received a PID number, and signed the ICF if they didn’t participate in Study 
RAP-MD-04.
9.7.1.2
Safety Population
The Safety Population will consist of all patients in the Screened Population who took at 
least 1 dose of rapastinel during the OLTP of the study.
9.7.1.3
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who had at least 1 postbaseline assessment of the MADRS total score during the OLTP
of the study.
9.7.2
Patient Disposition
The number and percentage of patients in the 3 analysis populations will be summarized 
overall by study center. 
For de novo enrolled patients, screen failures (ie, patients who were screened but not 
included in the Safety Population) and the associated reasons for failure to enroll will be 
tabulated overall for the Screened Population.
The number and percentage of patients who complete the OLTP, who prematurely 
discontinue from the OLTP, and who complete the safety follow-up period will be 
summarized overall and by reasons for premature discontinuation for the Safety 
Population.
 
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9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (eg, age, race, ethnicity, sex, weight, height, body mass index) 
and other baseline characteristics will be summarized overall for the Safety Population 
and the ITT Population. 
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to rapastinel for the Safety Population during the OLTP will be summarized for 
treatment duration, calculated as the number of days from the date of the first dose of 
open-label rapastinel taken to the date of the last dose taken during the OLTP, inclusive. 
Descriptive statistics (number of patients, mean, SD, minimum, median, and maximum) 
will be presented.
Prior medication will be defined as any medication started before the date of first dose of 
IP in the first lead-in study for rollover patients or any medication started before the date 
of the first dose of open-label IP in this study for de novo patients. Concomitant 
medication during the OLTP will be defined as any medication taken on or after the date 
of the first dose of open-label IP during the OLTP. 
The use of prior medication will be summarized by the number and percentage of patients 
receiving each medication within each therapeutic class for the Safety Population. The 
use of concomitant medications during the OLTP will be summarized by the number and 
percentage of patients receiving each medication within each therapeutic class for the 
Safety Population. Multiple use of the same medication by a patient will only be counted 
once.
The number and percentage of patients taking each qualifying ADT in the OLTP will be 
summarized for the Safety Population. Mean daily dose and duration of treatment with 
each qualifying ADT will be summarized using descriptive statistics (number of patients, 
mean, SD, median, minimum, and maximum) for the Safety Population.
9.7.4.2
Measurement of Treatment Compliance
Dosing compliance for a specified period is defined as the total number of IV doses 
actually taken by a patient during that period divided by the number of IV doses that were 
expected to be taken during the same period multiplied by 100. Descriptive statistics for 
IP compliance will be presented for each week, as well as for the whole OLTP for the 
Safety Population.
 
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Dosing compliance for the background ADT during a specified period is defined as the 
doses actually taken by a patient during that period divided by the dose expected to be 
taken during the same period multiplied by 100. Descriptive statistics for ADT 
compliance during the OLTP will be presented for each ADT for the Safety Population.
 
 
 
 
 
 
9.7.6
Safety Analyses
The safety analysis will be performed using the Safety Population, defined as all patients 
who receive at least 1 dose of IP during the OLTP. 
The safety parameters will include AEs; clinical laboratory, vital signs, and ECG 
parameters; and the BPRS+, CADSS,
.
For each safety parameter, the last assessment made before the first dose of open-label IP
will be used as the baseline for de novo patients, and the baseline of the first lead-in study 
will be used as the baseline for rollover patients for all analyses of that safety parameter.
Continuous variables will be summarized by number of patients and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number 
and percentage of patients.
 
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9.7.6.1
Adverse Events
AEs will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities.
For rollover patients, an AE (classified by preferred term) that occurs during the OLTP
will be considered a treatment-emergent adverse event (TEAE) if it was not present 
before the first dose of IP in the first lead-in study or was present before the first dose of 
IP in the first lead-in study and increased in severity during the OLTP. If more than 1 AE 
is reported before the first dose of IP in the first lead-in study and coded to the same 
preferred term, the AE with the greatest severity will be used as the benchmark for 
comparison with the AEs occurring during the OLTP that were also coded to that 
preferred term.
For de novo patients, an AE (classified by preferred term) that occurs during the OLTP 
will be considered a TEAE if it was not present before the first dose of open-label IP or 
was present before the date of the first dose of open-label IP and increased in severity 
after the first dose of open-label IP. If more than 1 AE is reported before the first dose of 
open-label IP and is coded to the same preferred term, the AE with the greatest severity 
will be used for comparison with the AEs occurring during the OLTP 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 a TEAE.
A TEAE occurring during the OLTP will be considered a newly emergent AE (NEAE) if 
the AE was not present before the first dose of open-label IP or was present before the 
first dose of open-label IP but increased in severity during the OLTP. The number and 
percentage of patients reporting NEAEs during the OLTP will be summarized by SOC
and preferred term.
The number and percentage of patients reporting TEAEs will be tabulated by SOC and 
preferred term and further categorized by severity and causal relationship to the IP. If 
more than 1 AE is coded to the same preferred term for the same patient, the patient will 
be counted only once for that preferred term using the greatest severity and strictest 
causality for the summarization by severity and causal relationship.
The distribution of TEAEs by severity and relationship to the IP will be summarized. 
An AE that occurs more than 30 days after the date of the last dose of IP will not be 
summarized.
The incidence of common (≥ 2% of patients) TEAEs and AEs leading to premature 
discontinuation of IP will be summarized by preferred term and will be sorted by 
decreasing frequency. 
 
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An SAE that occurred between the date of the first dose of the open-label IP and 30 days 
after the date of the last dose of IP, inclusive, will be considered an on-therapy SAE. 
The number and percentage of patients who have on-therapy SAEs will be summarized 
by preferred term. In addition, the incidence of on-therapy SAEs that led to death will be 
summarized separately by preferred term.
The incidence of AEs leading to premature discontinuation of IP during the OLTP will be 
summarized by preferred term and will be sorted by decreasing frequency. 
Listings will be presented for all patients with SAEs, patients with AEs leading to 
discontinuation, and patients who die (if any). All patients with SAEs, including SAEs 
reported during the screening period and the safety follow-up period, and patients 
discontinuing because of AEs occurring before the start of IP will be included in these 
listings.
9.7.6.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline 
values at each assessment timepoint will be presented for each clinical laboratory 
parameter.
In addition, descriptive statistics for values and changes from the baseline values in 
conventional units at each assessment timepoint will be presented for selected clinical 
laboratory parameters listed in the Statistical Analysis Plan (SAP).
The number and percentage of patients who have potentially clinically significant (PCS) 
postbaseline clinical laboratory values will be tabulated. The criteria for PCS laboratory 
values will be detailed in the SAP. The percentages will be calculated relative to the 
number of patients with available non-PCS baseline values and at least 1 postbaseline 
assessment for the OLTP. The numerator will be the total number of patients with 
available non-PCS baseline values and at least 1 PCS postbaseline value. A supportive 
tabular display of patients with PCS postbaseline values will be provided, including the 
PID number, baseline, and all postbaseline (including non-PCS) values. In addition, a 
tabular display showing all AEs that occurred in patients who had PCS postbaseline 
clinical laboratory values will be provided.
Shift tables from baseline to end of study for clinical laboratory parameters will be 
presented for the following categories: low, normal, and high, which are provided by the
laboratory vendor.
Patients who meet the potential Hy’s Law criteria from the first dose of IP to within 
30 days after the last dose of IP will be summarized. Supportive tabular displays will also 
be provided.
 
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9.7.6.3
Vital Signs
Descriptive statistics for vital signs (eg, pulse rate, systolic and diastolic BP, body 
weight, oral or tympanic temperature, and body weight) and changes from baseline 
values at each visit and at the end of study will be presented.
Vital sign values will be PCS if they meet both the observed-value criteria and the change 
from baseline value criteria. The criteria for PCS vital sign values will be detailed in the 
SAP. The percentages will be calculated relative to the number of patients with available 
non-PCS baseline values and at least 1 postbaseline assessment for the OLTP or the 
safety follow-up period. The numerator will be the total number of patients with available 
baseline values and at least 1 PCS postbaseline value. A supportive listing of patients 
with postbaseline PCS values will be provided, including the PID number, baseline 
values, and postbaseline values. A listing of all AEs occurring in patients who have PCS 
vital sign values will also be provided.
9.7.6.4
Electrocardiogram
Descriptive statistics for ECG parameters (ie, heart rate, PR interval, QRS interval, RR 
interval, QT interval, QTcB interval, and QTcF interval) and changes from baseline 
values at each assessment timepoint will be presented.
The number and percentage of patients with PCS postbaseline ECG values will be 
tabulated for the OLTP. The criteria for PCS ECG values will be detailed in the SAP. The 
percentages will be calculated relative to the number of patients with available non-PCS 
baseline values and at least 1 postbaseline assessment for the OLTP. The numerator is the 
total number of patients with available non-PCS baseline values and at least 1 PCS 
postbaseline value. A supportive tabular display of patients with PCS postbaseline values 
will be provided, including the PID number, baseline values, all postbaseline (including 
non-PCS) values, and change from baseline. In addition, a tabular display showing all 
AEs that occurred in patients who had postbaseline PCS ECG values will be provided.
A shift table from baseline to the end of study in the Investigator’s overall interpretation 
of the ECG will be presented for the following categories:  normal; abnormal, not 
clinically significant; and abnormal, clinically significant. A tabular display showing 
patients with postbaseline clinically significant ECG abnormalities according to the 
Investigator’s overall interpretation will be provided.
The number and percentage of patients with change from baseline QTc > 30 msec but not 
exceeding 60 msec and of patients with an increase > 60 msec will be tabulated. A 
supportive listing that includes the PID number, all QTc values (including change from 
baseline values), and all AEs will be provided for all patients who have postbaseline QTc 
changes > 30 msec.
 
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9.7.6.5
Other Safety Parameters
Other safety parameters comprise the BPRS+, CADSS,
Descriptive statistics of actual values and change from baseline for BPRS+ total score 
will be presented at each assessment timepoint during the OLTP.
Descriptive statistics of actual values and change from baseline for CADSS total score 
will be presented at each assessment timepoint during the OLTP. CADSS total score is 
defined as the sum of scores for 23 subjective items.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.7.8
Interim Analysis
No interim analysis is planned for this study.
9.7.9
Determination of Sample Size
Approximately 500 patients are expected to enter the OLTP. The study will be terminated 
when 100 patients have completed the 52-week OLTP.
9.7.10
Computer Methods
Statistical analyses will be performed using 
 
.
9.8
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. 
9.9
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.
Protocol deviations must be reported to the Sponsor either verbally or electronically 
within 5 working days from the day of discovery.
 
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An important protocol deviation is a form of protocol deviation that has a major impact 
on the patient’s rights, safety, or well-being, or on the integrity and authenticity of the 
study data. Important protocol deviations must be reported to the Sponsor within 
24 hours, if possible. The IRB must be notified within the time period dictated by the IRB
associated with this study. 
 
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10.0
STUDY SPONSORSHIP
This study is sponsored by Naurex, 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 DHHS 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-06, dated 
07 Jun 2016) and with all applicable government regulations and good clinical 
practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name
 
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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained for each patient participating in a clinical research study. This consent must 
include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence).

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA, the 
Sponsor, the IRB, or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the Investigator as the 
contact. The guidance of the IRB may be required.)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled
 
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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the Investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of permission, providing consent for the patient to participate (eg, “I 
agree to participate . . .”)

A place for the patient’s signature and date of signing of the ICF

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient.
 
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APPENDIX II.
CONTACT INFORMATION 
Contact information for the Sponsor personnel is maintained in the Study Reference 
Manual.
 
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14.0
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