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

NCT03675776 
 
Study ID: RAP‐MD‐30 
 
 
Title: A Randomized, Double‐blind, Placebo‐controlled, Multicenter Study of Rapastinel as 
Monotherapy in Patients with Major Depressive Disorder 
 
Protocol Date: 17 Apr 2018 
 
 

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TITLE PAGE
A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel as 
Monotherapy in Patients with Major Depressive Disorder
RAP-MD-30
(3106-330-008)
IND # 136,870
Original Protocol Date:
17 Apr 2018
Sponsor:
Naurex Inc., an indirect subsidiary 
of Allergan, plc
5 Giralda Farms
Madison, NJ 07940
Allergan, Ltd.
Marlow International 
The Parkway
Marlow Buckinghamshire
SL7 1YL, UK
Confidentiality Statement
This document is the property of Allergan, plc and may not—in full or part—be passed on, 
reproduced, published, distributed, or submitted to any regulatory authority without the express 
written permission of Allergan, plc.

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SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study RAP-MD-30
Study Number
RAP-MD-30 (3106-330-008)
Title of Study
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study of Rapastinel as Monotherapy in Patients with Major 
Depressive Disorder
Study Centers (Country)
Approximately 54 study centers (primarily in Japan and Eastern 
Europe)
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of rapastinel as a 
monotherapy treatment in patients with major depressive disorder 
(MDD)
Methodology
Multicenter, randomized, 6-week double-blind, 
placebo-controlled, parallel-group study of two doses of 
intravenous (IV) rapastinel (450 mg and 225 mg) vs IV placebo
(randomized 1:1:1) as monotherapy treatment in patients with 
MDD
Duration of Participation

Up to 2-week screening period

Followed by a 6-week double-blind treatment period

Followed by a 2-week safety follow-up period (for patients 
who do not roll over into the extension study)
Number of Patients
Approximately 690 planned to be enrolled
Diagnosis and Main Criteria for 
Inclusion

Male and female outpatients who are 18 to 75 years of age

Meet Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria for MDD
 
 
with a current major depressive episode of at 
least 8 weeks and not exceeding 18 months in duration at 
Visit 1
 
 

Treatment naive (defined as those who have not received 
antidepressant or those who have received antidepressant but 
not meeting adequate dose or duration criteria per the 
Antidepressant Treatment Response Questionnaire [ATRQ]) 
in the present episode or inadequate response (< 50% 
reduction in depressive symptoms) to 1 to 3 antidepressant 
therapies [ADTs] given at adequate doses (as defined by the 
ADT package insert) and duration of ≥4 weeks during the 
present episode as documented using the ATRQ

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Test Product, Dosage, and Mode of 
Administration

450 mg rapastinel (prefilled syringe, weekly intravenous [IV] 
administration)

225 mg rapastinel (prefilled syringe, weekly IV 
administration)
Reference Therapy, Dosage, and 
Mode of Administration
Placebo (prefilled syringe, weekly IV administration)
Criteria for Evaluation
Primary Endpoint
Change from baseline in MADRS total score at the end of the
double-blind treatment period (end of Week 6)
Key Secondary Endpoint
Change from baseline in MADRS total score at 1 day after first 
dose of treatment
 
 
 
 
 
 
 
 
 
 

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

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Approval Page
Name of Investigational Product:   Rapastinel
Document:  RAP-MD-30 Protocol

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TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................................................1
2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS....................................................................................2
3.0
TABLE OF CONTENTS................................................................................................................................8
LIST OF FIGURES.......................................................................................................................................10
4.0
LIST OF ABBREVIATIONS .......................................................................................................................11
5.0
ETHICAL CONSIDERATIONS ..................................................................................................................13
5.1
Institutional Review Board and Independent Ethics Committee.....................................................13
5.2
Ethical Conduct of the Study ..........................................................................................................13
5.3
Patient Information and Informed Consent.....................................................................................13
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ....................................................15
7.0
INTRODUCTION.........................................................................................................................................16
8.0
STUDY OBJECTIVES.................................................................................................................................19
9.0
INVESTIGATIONAL PLAN .......................................................................................................................21
9.1
Overall Study Design and Plan: Description...................................................................................21
9.1.1
Screening Period...............................................................................................................21
9.1.2
Double-Blind Treatment Period........................................................................................21
9.1.3
Safety Follow-up Period...................................................................................................22
9.2
Discussion of Study Design, Including the Choice of Control Groups...........................................23
9.3
Selection of Study Population.........................................................................................................24
9.3.1
Inclusion Criteria ..............................................................................................................24
9.3.2
Exclusion Criteria .............................................................................................................25
9.3.3
Removal of Patients from Therapy or Assessment...........................................................29
9.3.3.1
Criteria for Required Removal of Patients from Therapy or Assessment.......29
9.3.4
Patient Replacement Procedures.......................................................................................30
9.4
Treatments.......................................................................................................................................30
9.4.1
Treatments Administered..................................................................................................30
9.4.2
Identity of Investigational Products..................................................................................31
9.4.3
Handling of Investigational Products................................................................................31
9.4.4
Method of Assigning Patients to Treatment Groups.........................................................32
9.4.5
Selection of Dosages in the Study ....................................................................................32
9.4.6
Selection and Timing of Dose for Each Patient................................................................32
9.4.6.1
Screening Period.............................................................................................32
9.4.6.2
Double-blind Treatment Period ......................................................................33
9.4.6.3
Safety Follow-up Period .................................................................................33
9.4.7
Blinding ............................................................................................................................33
9.4.8
Unblinding........................................................................................................................33
9.4.9
Prior and Concomitant Therapy........................................................................................33
9.4.10
Other Restrictions .............................................................................................................35
9.4.10.1
Alcohol ...........................................................................................................35
9.4.10.2
Contraception..................................................................................................35
9.4.11
Monitoring Treatment Compliance...................................................................................36
9.4.12
Treatment After Discontinuation......................................................................................36

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9.5
Efficacy and Safety Variables.........................................................................................................37
9.5.1
Diagnostic and Efficacy Assessments ..............................................................................37
9.5.1.2
Efficacy Assessments......................................................................................38
9.5.1.3
Patient Centricity Assessments.......................................................................40
9.5.2
Safety Assessments...........................................................................................................40
9.5.2.1
Adverse Events ...............................................................................................40
9.5.2.2
Immediate Reporting of Serious Adverse Events ...........................................43
9.5.2.3
Reporting of Pregnancies Occurring During the Study ..................................44
9.6
Data Quality Assurance ..................................................................................................................59
9.6.1
Data Monitoring................................................................................................................59
9.6.2
Data Recording and Documentation.................................................................................60
9.7
Statistical Methods and Determination of Sample Size ..................................................................60
9.7.1
Analysis Populations ........................................................................................................60
9.7.1.1
Safety Population............................................................................................60
9.7.1.2
Modified Intent-to-Treat Population...............................................................61
9.7.1.3
Pharmacokinetic Population ...........................................................................61
9.7.2
Patient Disposition............................................................................................................61
9.7.3
Demographics and Other Baseline Characteristics...........................................................61
9.7.4
Extent of Exposure and Treatment Compliance ...............................................................61
9.7.4.1
Extent of Exposure..........................................................................................61
9.7.4.2
Prior and Concomitant Medication.................................................................62
9.7.4.3
Measurement of Treatment Compliance.........................................................62
9.7.5
Efficacy Analyses .............................................................................................................62
9.7.5.1
Primary Efficacy Analyses .............................................................................63
9.7.5.2
Key Secondary Efficacy Analysis...................................................................63
9.7.6
Safety Analyses ................................................................................................................66
9.7.6.1
Adverse Events ...............................................................................................66

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9.7.9
Interim Analysis................................................................................................................69
9.7.10
Determination of Sample Size ..........................................................................................70
9.7.11
Statistical Software ...........................................................................................................70
9.8
Data and Safety Monitoring Board .................................................................................................70
9.9
Changes in the Conduct of the Study or Planned Analyses ............................................................70
9.10
Protocol Deviations.........................................................................................................................71
10.0
STUDY SPONSORSHIP..............................................................................................................................72
10.1
Study Termination...........................................................................................................................72
10.2
Reporting and Publication...............................................................................................................72
11.0
INVESTIGATOR OBLIGATIONS..............................................................................................................73
11.1
Documentation................................................................................................................................73
11.2
Performance ....................................................................................................................................73
11.3
Use of Investigational Materials .....................................................................................................74
11.4
Case Report Forms..........................................................................................................................74
11.5
Retention and Review of Records...................................................................................................74
11.6
Patient Confidentiality ....................................................................................................................75
12.0
INVESTIGATOR’S STATEMENT .............................................................................................................76
13.0
APPENDICES...............................................................................................................................................77
Appendix I.
Elements of Informed Consent .........................................................................................77
Appendix II.
Contact Information..........................................................................................................79
Appendix IV.
Scales and Questionnaires ................................................................................................84
14.0
LITERATURE CITED..................................................................................................................................85
LIST OF FIGURES

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LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CI
confidence interval
 
DALYs
disability adjusted life years
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSMB
Data and Safety Monitoring Board
DSST
Digit Symbol Substitution Test 
DxV
Diagnostic Validation 
EC
Ethics Committee
ECG
electrocardiogram, electrocardiographic
ECT
electroconvulsive therapy
eCRF
electronic case report form
EDC
electronic data capture
 
ET
early termination
FDA
Food and Drug Administration
FR
Federal Register
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form

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ICH
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
IND
Investigational New Drug (application)
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
IWRS
Interactive Web Response System
MADRS
Montgomery-Åsberg Depression Rating Scale
MDD
major depressive disorder
mITT
modified Intent-to-Treat
MMRM
mixed-effect model for repeated measures
NMDAR 
N-methyl-D-aspartate receptor
PCS
potentially clinically significant
PID
patient identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/[RR]½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/[RR]⅓)
SAE
serious adverse event
SAP
Statistical Analysis Plan
 
SD
standard deviation
SNRI
selective serotonin and norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
T3
triiodothyronine
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid-stimulating hormone
UDS
urine drug screen
ULN
upper limit of normal

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ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE
United States
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the investigator. A copy of the approval letter will be supplied to the sponsor, 
along with a roster of IRB members or the US Department of Health and Human Services 
general assurance number. During the course of the study, the investigator will provide timely 
and accurate reports to the IRB on the progress of the study, at intervals not exceeding 1 year (or 
as appropriate), and will notify the IRB of serious adverse events (SAEs) or other significant 
safety findings. The study protocol, informed consent form (ICF), information sheet,
advertisements (if applicable), and amendments (if any) will be approved by the IRBs at the
study centers in conformance with the US CFR, Title 21, Part 56.
Outside the United States
This study will be carried out in full compliance with the guidelines of the independent ethics 
committee (EC) or IRB (as applicable) and/or government agencies as applicable for each 
respective country as well as the European Union Clinical Trial Directive (Directive 
2001/20/EC), where applicable. Before the study begins, the study centers will require approval 
from an EC/IRB and government agency. During the course of the study, the sponsor or 
authorized representative will provide timely and accurate reports to the EC/IRB on the progress 
of the study, at intervals not exceeding 1 year (or as appropriate) and will notify the EC/IRB of
SAEs or other significant safety findings. The study protocol, ICF, information sheet,
advertisements (if applicable), and amendments (if any) will be approved by the EC/IRB at the 
study centers in conformance with CFR, Title 21, Part 56, the European Union Clinical Trial 
Directive (Directive 2001/20/EC), and local regulations.
5.2
ETHICAL CONDUCT OF THE STUDY
This clinical study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki.
This clinical study will comply with the ICH Guidance on General Considerations for Clinical 
Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP (ICH-E6; 62 FR 25692, 09 May 1997), as 
well as Part 312 of the US CFR.
5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the study and before participating in any study procedures, 
each patient must provide written informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC or 
study center.

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

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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
This study will be performed at approximately 54 study centers in Japan and Eastern Europe.
The investigator is responsible for ensuring that the investigation is conducted according to the 
signed investigator statement, the investigational plan, GCP guidelines, and applicable 
regulations; for protecting the rights, safety, and welfare of patients under the investigator’s care; 
and for the control of investigational products under investigation. An investigator shall obtain 
the informed consent for each patient prior to the patient enrolling in the study and/or prior to 
participating in any study-related activity. 
The investigator at each study center must meet his or her obligations to the patients, ethics 
committee, sponsor, and regulatory authorities by maintaining oversight and control of the 
study’s conduct and the study staff. It is the responsibility of the investigator to ensure that any 
and all delegated duties be assigned to qualified staff by education, experience, and licensure (in 
accordance with local regulations) and that the investigator oversight is documented and 
assessment of staff capabilities and performance is consistent with the study investigational plan. 
The investigator at each study center will be responsible for the management of the study, 
including maintaining the study file and the patient records, corresponding with the IRB/EC
(where applicable), and completing the electronic case report forms (eCRFs).

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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 Norepinephrine Reuptake 
Inhibitors in Major Depressive Disorder
Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine 
reuptake inhibitors (SNRIs) currently represent the first line of treatment of depression in the 
United States. Unfortunately, a large number of patients do not experience therapeutic benefit 
from these first-line agents (Rosenzweig-Lipson et al, 2007). Lack of sufficient response to 
adequate treatment remains a critical problem in the management of patients with MDD. Up to 
two-thirds of patients treated with first-line antidepressant monotherapy do not reach full 
remission, and as many as a third become treatment resistant (Fava and Davidson, 1996; 
Trivedi et al, 2006). Not achieving remission has been shown to be predictive of poorer 
psychosocial functioning, higher rates of relapse, and higher rates of rehospitalization 
(McIntyre and Donovan, 2004). The results of the STAR*D study suggest that with successive 
failures of treatment, patients are less and less likely to respond to subsequent treatment, and 
those who do respond are more likely to relapse (Rush et al, 2006). Present strategies available to 
treat patients who do not respond to first-line antidepressant monotherapy include switching of 
antidepressant (either within or between classes); combination therapy in which multiple 
antidepressants are used simultaneously; augmentation of ongoing antidepressant monotherapy 
with adjunctive use of drugs such as mood stabilizers or atypical antipsychotics 
(Boland and Keller, 2006), and nonpharmacologic treatments including psychotherapy and 
phototherapy, vagus nerve stimulation, transcranial magnetic stimulation, and electroconvulsive 
therapy. Clearly, there remains a critically important unmet medical need for this patient 
population.
Existing antidepressants have a number of limitations, leading to considerable unmet medical 
need in the effective treatment of MDD, with up to 50% of patients with MDD having an 
inadequate response or failing current antidepressant therapy (ADT). Currently available first-
line antidepressants (SSRIs, SNRIs) typically take 3 to 4 weeks or more of continuous daily 
dosing to relieve symptoms of MDD and are associated with side effects related to their 
pharmacological mechanisms of action (sexual dysfunction, weight gain, jitteriness, sleep 
disturbances), which are further associated with poor patient compliance (Masand, 2003;
Ashton et al, 2005). Patients often experience undesirable side effects before they experience an 
improvement in depressive symptoms, which could lead to premature discontinuation of therapy. 
Taken together, these factors define significant areas for improvement of ADT. 
Patients vary greatly in their response to antidepressants and it is not possible to reliably predict 
whether an individual patient will respond to a given antidepressant. This leads to clinicians 
often using a trial-and-error approach to identify an effective antidepressant. Due to the gradual 
development of the full therapeutic effect of currently available antidepressants, each 
antidepressant needs to be administered for 4 weeks or longer in order to determine the 
individual therapeutic benefit, making the process of finding an effective antidepressant lengthy 
for patients who are often severely depressed and at a high risk for suicide. A drug that could 
induce a rapid antidepressant effect would represent a major advancement for these patients.
Clearly, there is a substantial need for the development of novel treatments with a better 
safety/tolerability profile and a faster onset of full therapeutic benefit. Rapastinel has initially 
shown substantially improved safety/tolerability as well as promising efficacy, in both speed of 
onset and overall magnitude, for therapy in MDD. 

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Rapastinel as a Novel Approach to Major Depressive Disorder Treatment
The mechanism of action of rapastinel is entirely different from that of first-line antidepressants 
(SSRIs, SNRIs) or adjuvant drugs currently approved for treatment of MDD such as atypical 
antipsychotics. Rapastinel is an N-methyl-D-aspartate receptor (NMDAR) modulator with a 
novel and complex pharmacological mechanism of action, acting as a nonselective agent at NR2 
subunits and displaying properties as a functional partial agonist in a number of pharmacological 
assays. 
Rapastinel has demonstrated antidepressant properties in relevant animal models, displays 
cognitive enhancing properties in treated animals, and facilitates hippocampal long-term 
potentiation of synaptic transmission in preclinical models. In contrast to ketamine, no signal of 
abuse liability was detected in informative animal models. 
Rapastinel is available as an intravenous (IV) formulation only. In 2 Phase 2 clinical studies in 
patients with MDD, single IV doses of rapastinel 5 mg/kg and 10 mg/kg have been shown to 
produce marked antidepressant effects within 1 day that lasted for approximately 1 week or 
longer in responding patients. These antidepressant effects are very similar to ketamine’s effects 
when administered at a low dose as an infusion. In a systematic review and meta-analysis of 
ketamine and other NMDAR antagonists in the treatment of major depression, a single infusion 
of ketamine produced a rapid, yet transient antidepressant effect, accompanied by brief 
psychotomimetic and dissociative effects (Newport et al, 2015). 
The available Phase 1 and 2 data demonstrated a favorable safety and tolerability profile of 
rapastinel. In contrast to ketamine, rapastinel has not shown a high likelihood to induce 
psychotomimetic or dissociative effects in humans so far. 
The purpose of this study is to prospectively confirm that rapastinel, when administered at a dose 
of 450 or 225 mg as a slow bolus IV injection in patients with MDD, is significantly superior to 
placebo in rapidly reducing depressive symptoms. Furthermore, the safety and tolerability of 
rapastinel will be investigated. The study is intended to support an application for regulatory 
approval of rapastinel as monotherapy treatment for MDD.

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8.0
STUDY OBJECTIVES
The objectives of this study are to evaluate efficacy, safety, and tolerability of rapastinel as a 
monotherapy treatment in patients with MDD.
Efficacy Objectives

Primary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) versus placebo 
and rapastinel (225 mg IV) versus placebo in the treatment of MDD, as measured by the 
change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 
end of treatment (end of week 6)

Key secondary efficacy objective: To evaluate the efficacy of rapastinel (450 mg IV) versus
placebo and rapastinel (225 mg IV) versus placebo in the treatment of MDD, as measured by 
the change from baseline MADRS total score at 1 day post-first dose of treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 3-arm 
fixed-dose study of weekly IV rapastinel 450 mg, rapastinel 225 mg, and placebo in outpatients 
with a diagnosis of MDD as defined by Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria.
The study will include a total of 10 visits and will be approximately 8 weeks in duration 
(Figure 9.1.3–1): 

Up to 2-week screening period

6-week double-blind treatment period 

2-week safety follow-up period (no treatment) for patients who do not roll over into the 
extension study
Approximately 690 patients are planned to be randomized in the double-blind treatment period 
(230 patients per treatment group). Note that the sponsor may restrict enrollment based on 
patient treatment history to ensure an appropriate balance of patients with an inadequate response 
to 1 to 3 ADTs if deemed necessary during study conduct.
9.1.1
Screening Period
After providing written consent, patients will enter a screening period of up to 2 weeks, prior to 
Visit 2. Patients will not receive any investigational product (IP) during the screening period. 
Patients will wash out of any ADT and prohibited medications under the supervision of the study 
investigator staff during the screening period. Patients meeting the eligibility criteria at the end 
of Visit 2 (Baseline) will be assigned a treatment by the interactive web response system (IWRS) 
and enter the double-blind treatment period.
9.1.2
Double-Blind Treatment Period
Patients will be randomized in a ratio of 1:1:1 to 1 of 3 treatment groups: rapastinel 225 mg IV 
weekly, rapastinel 450 mg IV weekly, or placebo IV weekly. 
During the double-blind treatment period:

Patients will have 2 study visits during the first week (treatment day [Visit 2] and 1 day 
following the treatment day [Visit 3]). Visits 2 and 3 should be conducted 1 day apart.  
Visit 4 will occur approximately 7 days following Visit 2 with subsequent visits 
occurring at weekly intervals. 

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

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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
This multicenter, randomized, placebo-controlled, parallel-group study, with a 6-week double-
blind treatment period, was designed based on prior studies that established rapastinel efficacy 
and safety in adult patients with MDD. In this study, investigators will enroll patients 18 through 
75 years of age who meet the DSM-5 criteria for MDD (American Psychiatric Association, 
2013). 
 
he symptoms 
and severity of MDD will be assessed using the MADRS (Section 9.5.1.2.1). 
Study centers will have experience with the study population and will be encouraged to apply
applicable local guidelines to minimize patient risk or distress. 
Dose selection information is presented in Section 9.4.5. The planned dosing regimen is based on 
experience from previous rapastinel studies. 

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A placebo treatment group is included in the study to comply with worldwide regulatory 
preferences (Laughren, 2001; Gispen-de Wied et al, 2012), since placebo-controlled superiority 
trials have been shown to be conducive to higher quality studies and to provide more reliable 
outcomes (Feifel, 2008; Laughren, 2001; Gispen-de Wied et al, 2012). Additionally, from a 
scientific point of view, randomized double-blind comparisons versus placebo are needed to 
permit adequate evaluation of efficacy. Comparison to a placebo treatment is also of value for 
distinguishing disease manifestations from adverse reactions of the IP (EMA guidance, 2013). 
The use of placebo in place of the standard therapy should not cause irreversible health problems 
or extreme suffering (depression is recognized by the FDA as a condition in which there is 
substantial improvement and variability in placebo groups) (FDA Guidance for Industry: E10, 
May 2001). 
In Study RAP-MD-30, safety and efficacy assessments are included at every visit to determine 
adequacy of response, safety, and tolerability. In the event of insufficient therapeutic response or 
worsening of the patient’s initial condition, the IP should be discontinued and an alternative 
treatment will then be allowed (Section 9.4.12). An independent Data and Safety Monitoring 
Board (DSMB) will evaluate safety data during the study (Section 9.8).
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
Criteria to be assessed at Visit 1 (Screening)
1. Written informed consent, obtained from the patient before the initiation of any 
study-specific procedures (Section 5.3) 
2. Male or female outpatients, 18 to 75 (inclusive) years of age at Visit 1
3. Meet DSM-5 criteria for MDD (based on confirmation from the SCID), with a current major 
depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1
(Patients in their first depressive episode may only be enrolled after documented discussion 
with the sponsor representative)
 
 

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

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

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

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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases participation 
in the study, regardless of circumstances, before the completion of the study visits and 
procedures. Patients can be prematurely discontinued from the study after careful consideration 
for one of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria)

Pregnancy

Withdrawal of consent 

AE

Lack of efficacy

Protocol deviation

Noncompliance with IP

Lost to follow-up 

Study terminated by sponsor

Study center terminated by sponsor

Other 
All randomized patients who prematurely discontinue from the study, regardless of cause, should 
be seen for a final assessment at an ET Visit. A final assessment will be defined as completion of 
the evaluations scheduled for all patients at Visit 9. All patients discontinuing the study 
prematurely should enter the 2-week safety follow-up period.
Patients who discontinue from the study and do not return to the study center for final 
assessments must be requested in writing to return to the study center for a final assessment. A 
copy of the letter, together with the source documentation, will be kept in the investigator’s files. 
The reason for premature discontinuation from the study will be recorded on the Study 
Termination Page of the eCRF. Study center staff will be contacted by the sponsor or designee 
after each premature discontinuation to ensure proper characterization of the reason for 
discontinuation is captured.
9.3.3.1
Criteria for Required Removal of Patients from Therapy or Assessment
Any patient who meets any of the following criteria at any point during the study must be 
withdrawn from participation, due to AEs related to suicide:

A suicide attempt

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
Significant risk, as judged by the investigator, based on the psychiatric interview or 
information collected in the C-SSRS

Rater-administered or computer-administered MADRS Item 10 score ≥ 5
In the event that a patient is withdrawn for a suicide-related AE, the patient should be referred 
for additional treatment or hospitalization, as clinically indicated, in addition to withdrawing the 
patient from the study.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.4
TREATMENTS
Patients meeting the eligibility criteria at the end of Visit 2 (Baseline) will be randomized in 
double-blind fashion to 1 of 3 treatment groups: placebo, rapastinel 450 mg, or rapastinel 
225 mg. 
9.4.1
Treatments Administered
The IP will only be administered to eligible patients by a medically qualified person as per the 
country and/or local regulations. The range of persons who can administer an IV can be a 
physician, a physician assistant, nurse, or nurse practitioner, etc, depending on applicable 
country, local, and/or state regulations.  
IP should be administered after all efficacy and safety assessments with the exception of the 
postdose assessments described below.
The IP will be administered using the provided prefilled syringe in a “slow bolus” single 
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 they are medically able to leave the study center
(recommended not less than 15 minutes following administration).
During IP administration and until completion of postadministration assessments, a licensed 
physician must be immediately available and in close proximity to the patient(s) to attend to 
medical emergencies.  The facility must have the capabilities, in accordance with the applicable 
country, local, and/or state regulations and standard of care, to resuscitate a patient in the event 
of a medical emergency.  
At IP administration visits, the patient should not be released from the study center until the 
following are completed:

Postadministration pulse rate and BP measures (approximately 15 minutes after 
administration)

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
Patient is clinically assessed and determined to not be at increased risk of suicidality in 
the opinion of the investigator (or medically qualified subinvestigator)

Patient is assessed for mental status and is determined to be free of perceptual 
disturbances or other conditions that would deem them not ready for release from the 
study center, in the opinion of the investigator (or medically qualified subinvestigator)

A physician licensed in the country, state, or other local regulatory authority (investigator 
or subinvestigator) determines that they are medically able to leave the study center and 
provides written signoff not less than 15 minutes following administration (see IV 
Administration and Evaluation Notes document in Study Reference Manual)
9.4.2
Identity of Investigational Products
Rapastinel 450 mg IV Prefilled Syringes: 
 
Placebo rapastinel IV Prefilled Syringes: 
 
.
 
 
 
 
 
The study center personnel will complete the kit label and attach the tear-off portion to the 
source documents. 
The prefilled syringes will be labeled with the protocol number and kit number. The study center 
personnel will write the PID number on each prefilled syringe associated with the kit mentioned 
above. The prefilled syringe labels will not have a tear-off portion and will remain on the 
prefilled syringe.
9.4.3
Handling of Investigational Products
The IP must be stored in a secure area and administered only to patients entered into the clinical 
study, at no cost to the patient, in accordance with the conditions specified in this protocol.
 
Study centers must report any temperature excursions as described in the 
Study Reference Manual or contact the sponsor or its designee for further instructions. 

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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.
9.4.4
Method of Assigning Patients to Treatment Groups
After a patient signs the ICF at Screening (Visit 1), study personnel will register the patient in the 
IWRS, and the system will assign the patient a sequential PID. 
 
 
 
 
 
The IP will be labeled with medication kit numbers. The IWRS will provide the study center
with the specific medication kit number(s) for each randomized patient during Visit 2. Study 
centers will dispense IP according to the IWRS instructions. For randomized patients, study 
centers will also log onto the IWRS at subsequent dosing visits to obtain a study medication kit 
number for dispensing the IP. Study centers will receive the IWRS confirmation notifications for 
each transaction. All notifications are to be maintained with the study source documents.
9.4.5
Selection of Dosages in the Study
The doses of rapastinel in this study were selected based on 2 Phase 2 clinical studies in patients 
with MDD, in which single IV doses of rapastinel 5 mg/kg and 10 mg/kg were shown to produce 
marked antidepressant effects within 1 day that lasted approximately 1 week or longer in 
responding patients.
A 450-mg IV unit dose is expected to be appropriate for most patients as this represents a dose of 
4.5 mg/kg in a 100-kg patient and a dose of 9 mg/kg in a 50-kg patient.
A 225-mg IV unit dose arm has been included to allow for further evaluation of the dose-
response profile after multiple dosing.  
9.4.6
Selection and Timing of Dose for Each Patient
The IP will be administered IV using the assigned single-use prefilled syringes at Visits 2, 4, 5, 
6, 7, and 8.
9.4.6.1
Screening Period
At Screening (Visit 1) after written consent is obtained, patients enter a screening period of up to 
2 weeks. No IP is administered during the screening period.

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9.4.6.2
Double-blind Treatment Period
Patients who meet all eligibility criteria at Screening (Visit 1) and who continue to meet all the 
eligibility criteria for participation in the study at the Baseline Visit (Visit 2) will be assigned an 
IP kit number via IWRS at Baseline (Visit 2). Patients will receive the first dose of randomized 
IP that day. The IP kit numbers will also be assigned by IWRS at subsequent treatment visits.
Patients will receive rapastinel 450 mg, rapastinel 225 mg, or placebo from a prefilled single-
dose syringe at Visits 2, 4, 5, 6, 7, and 8. 
9.4.6.3
Safety Follow-up Period 
Patients who complete 6 weeks of randomized treatment are eligible to enter the RAP-MD-33 
extension study. If they do not enter RAP-MD-33, they should enter the safety follow-up period. 
Patients who discontinue the study prematurely should enter the safety follow-up period. No IP 
is administered during the safety follow-up period.
9.4.7
Blinding
A list of patient randomization codes will be generated by Statistical Programming and 
implemented by the IWRS vendor (an electronic version will be stored on a secure server). This 
list will identify each patient by randomization number and include the patient’s corresponding 
treatment assignment.
All study treatments will be provided in identical syringes and cartons to maintain masking of 
the study.
9.4.8
Unblinding
Any unblinding at the study-center level should be done only in an emergency that requires 
identification of the IP for the medical management of the patient. The investigator must notify 
the Study Physician immediately (refer to Appendix II) and a full written explanation must be 
provided if the blind is broken. Before IP is unblinded, every attempt should be made to discuss 
the case with the Study Physician. Breaking the code at the study center will immediately 
disqualify the patient from further participation in the study.
Treatment codes may be broken by Global Drug Safety for regulatory reporting purposes. In 
such cases, the study staff will be kept blinded and the patient will not need to be disqualified 
from the study.
In an emergency, the investigator can obtain the treatment assignment of any patient at his or her 
study center through the IWRS. The investigator will access the IWRS to break the blind.
9.4.9
Prior and Concomitant Therapy
A list of example medications that are allowed and not allowed as concomitant medications for 
either episodic or chronic use is provided in Appendix III. 

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Medication history (psychotropic medication history during the previous 5 years [to the extent 
possible] and all other medications during the past 12 months) will be recorded at Screening 
(Visit 1) in the eCRF. Thereafter, any changes in concomitant medications or any new 
medications added will be recorded in the eCRF.
9
1
 
 
 
 
 
 
 
 
 
 

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

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For women of childbearing potential and male partners of women of childbearing potential who 
may participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable: hormonal contraceptives (ie, oral, patch, injection, implant), male 
condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal 
contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation, bilateral 
salpingectomy), implantable permanent birth control device (eg, Essure; note: device must be in 
place at least 3 months and completed confirmation test), vasectomized partner, or complete 
abstinence for the duration of the study (periodic abstinence [such as calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of 
contraception).
Note: In Germany, the Czech Republic and other local regions as applicable, acceptable methods 
of contraception include complete abstinence; single barrier (diaphragm or condom) combined 
with the use of IUD or contraceptive (oral, implantable or injectable); or double barrier 
(diaphragm with condom).
The investigator and each patient will determine the appropriate method of contraception for the 
patient during the participation in the study with consideration for local regulatory or IRB/EC 
requirements.
See Section 9.5.2.3 for pregnancy reporting procedures.
9.4.11
Monitoring Treatment Compliance
IP compliance during any period will be closely monitored by capturing the date and time of 
each injection of IP. If a scheduled injection does not occur, the sponsor must be notified and the 
reason captured in the eCRF.
9.4.12
Treatment After Discontinuation
Patients whose MDD symptoms worsen or are determined by the investigator not to be 
adequately controlled prior to completing the double-blind treatment period will be allowed to 
discontinue the study and start appropriate treatment at the investigator’s discretion. This new 
treatment will not be provided by the sponsor. 

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9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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.
9.5.1.2
Efficacy Assessments
The efficacy assessments will be administered by a psychiatrist, doctoral-level clinical 
psychologist, or other clinician who has extensive professional training and experience in the 
diagnosis of mental illness and who meets the training requirements and qualifications standards 
set by the sponsor and rater training vendor.
9.5.1.2.1
The Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery and Åsberg, 1979) is a clinician-rated scale. The MADRS will be 
used to assess depressive symptomatology. Patients are rated on 10 items to assess feelings of
sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty 
concentrating, and lack of interest. Each item will be scored on a 7-point scale. A score of 0 
indicates the absence of symptoms, and a score of 6 indicates symptoms of maximum severity. 

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The MADRS will be evaluated at the timepoints indicated in Schedule of Evaluations 
(Section 2.0) using the Structured Interview Guide for the MADRS (SIGMA) methodology 
(Williams and Kobak, 2008).  At Visit 3 (visit occurring 1 day following IP administration), the 
MADRS will be administered with a look-back timeframe of “since last evaluation”.  At all other 
administrations, the MADRS will be administered with a look-back timeframe of 1 week.
A qualified rater (ie, who meets the training requirements and qualifications set by the rater 
training vendor) at each investigational center will conduct the MADRS assessment.  The rater-
administered MADRS will be used for analyses. In addition to MADRS administration by a 
qualified rater, each patient will complete an interactive, computer-administered MADRS 
interview on the dedicated study device. Data from the computer-administered interview will be 
compared with data derived from the rater-administered interview on an ongoing basis as part of 
a remote quality assurance program conducted by an independent vendor appointed by the 
sponsor.
At each visit with a MADRS assessment, the rater-administered MADRS interview will be audio 
recorded. The computer-administered interview will involve a series of probe and follow-up 
questions with multiple-choice response options. At the Screening Visit, the computer 
administered MADRS will be conducted prior to the rater-administered MADRS. At all other 
visits, the rater-administered MADRS will be conducted first.
 
 
 
 
 
  
 
 

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9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care professional at 
every visit and the evaluation must be documented. The procedures discussed below will be 
completed at the designated visits.
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product (ICH-E2A).
For the purpose of the study center’s data collection responsibilities, any untoward event that 
was reported from the time the patient signed the ICF until 30 days after the final protocol-
defined study visit or the last known dose of IP (if the final visit does not occur) is to be 
considered an AE.
Examples of AEs are as follows:

Changes in the general condition of the patient

Subjective symptoms offered by or elicited from the patient

Objective signs observed by the investigator or other study center personnel

All diseases that occur after signing informed consent, including any change in severity or 
frequency of pre-existing disease

All clinically relevant abnormalities in laboratory values or clinically relevant physical 
findings that occur during the study schedule

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Please note that medical procedures scheduled prior to consenting, but occurring during the study 
should not be captured as AEs, but should be listed in the medical history if related to a pre-
existing condition.
9.5.2.1.1
Causality Assessment
For each AE, the investigator must provide an assessment of causal relationship to the IP. The 
causality assessment must be recorded on the appropriate AE reporting page of the patient’s 
eCRF. Causal relationship must be assessed by answering the following question:
Is there a reasonable possibility the IP caused the event?
Yes:
There is evidence to suggest a causal relationship between the IP and AE, ie: 

There is a reasonable temporal relationship between the IP and the event, and/or 

The event is unlikely to be attributed to underlying/concurrent disease or other 
factors, and/or

Positive dechallenge and/or rechallenge exist
No:
There is no evidence to suggest a causal relationship between the IP and AE, ie:

There is no reasonable temporal relationship between the IP and the event, or

The patient did not take the IP, or

The event is likely to be attributed to underlying/concurrent disease or other factors, 
or

The event is commonly occurring in the (study) population independent of IP
exposure
9.5.2.1.2
Severity Assessment
The investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the patient’s eCRF. Severity, which is a 
description of the intensity of manifestation of the AE, is distinct from seriousness, which 
implies a patient outcome or AE-required treatment measure associated with a threat to life or 
functionality (Section 9.5.2.1.3). Severity will be assessed according to the following scale:
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.

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Moderate:
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
9.5.2.1.3
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in patient hospitalization, or the development of IP dependency 
or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of the 
other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (eg, elective procedures for pre-existing conditions that did not 
worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE reporting.
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:

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
Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as the 
severity and casual relationship

Document all actions taken with regard to the IP

Detail any other treatment measures taken for the AE

Document the outcome of the AE
In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify study center personnel of any AEs occurring during the 30-day 
poststudy period. Any AEs reported by the patient (or patient representative) during this period 
are to be recorded in original source documents. AEs are also to be recorded in the eCRF if at 
least one of the following conditions is met: 1) the event meets the criteria for an SAE (see 
Sections 9.5.2.1.3 and 9.5.2.1.4), and/or 2) the event is judged by the investigator to be 
potentially causally related to IP (Section 9.5.2.1.1).
Any AEs that are ongoing at the time of the final protocol-defined study visit will be followed 
until the condition returns to prestudy status, has resolved or stabilized, or can be explained as 
being unrelated to the IP. If a follow-up visit is deemed necessary for appropriate safety 
surveillance, it will take place within 30 days of the final protocol-defined study visit.
9.5.2.2
Immediate Reporting of Serious Adverse Events
The sponsor is required to inform worldwide regulatory authorities of SAEs that meet specific 
criteria. Therefore, the sponsor must be notified immediately regarding any SAE that occurs after 
informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the study center
personnel must report the event to Global Drug Safety on the SAE Form for Clinical Trials. The
Study Physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
The study center must transmit the SAE Form for Clinical Trials to the SAE email address or fax 
number shown below. Even if an initial report is made by telephone, the SAE Form for Clinical 
Trials completed with all available details must still be emailed or faxed within 24 hours of 
knowledge of the event at the study center.
Supplemental information should be submitted as soon as available and may include laboratory 
results, radiology reports, progress notes, hospital admission and emergency room notes, holding 
and observation notes, discharge summaries, autopsy reports, and death certificates.

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The investigator is expected to take all therapeutic measures necessary for resolution of the SAE. 
Any medications or procedures necessary for treatment of the SAE must be recorded on the 
appropriate pages of the patient’s eCRF. All SAEs are to be followed by the study staff until 
resolution or until the SAE is deemed stable. The sponsor may contact the study center to solicit 
additional information or follow up on the event.
Email or Fax the SAE Form for Clinical Trials to the sponsor.
9.5.2.3
Reporting of Pregnancies Occurring During the Study
Study center personnel must report every pregnancy from the time the patient signs the ICF until 
30 days after the last dose of IP. Within 24 hours of learning of the pregnancy, the study center
personnel must report the event to Global Drug Safety on the Clinical Trial Pregnancy Form and 
email or fax it to the SAE/Pregnancy email address or fax number provided in Section 9.5.2.2, 
even if no AE has occurred. Pregnancies in female partners of male patients occurring during the 
time frame described above must also be reported. 
Any pregnancy of a patient treated with IP or in female partners of male patients occurring 
during the time frame described above must be followed to term and the outcome reported by 
completing a follow-up Clinical Trial Pregnancy Form. If the pregnancy is associated with an 
SAE (eg, if the mother is hospitalized for hemorrhage), a separate SAE Form for Clinical Trials 
must be filed as described in Section 9.5.2.2, with the appropriate serious criterion (eg, 
hospitalization) indicated in addition to the pregnancy form.
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9.5.6.11
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, regulatory documents) will be retained at the study center, along with adequate source 
documentation, according to FDA and ICH requirements. All study records must be available for 
inspection by the sponsor, its authorized representatives, the FDA, or other health authorities.
 
 
 Source documents will be used at the study 
centers and may include a patient’s medical record, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as laboratory tests, 
ECGs, etc. A centralized clinical laboratory will be used for the analysis of all blood samples. 
Additional information on the collection and handling of samples is detailed in the Lab 
Procedure Manual.
9.7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
9.7.1
Analysis Populations
The following populations will be considered in the statistical analysis of the study, as specified 
in the following subsections.
9.7.1.1
Safety Population
The Safety Population will consist of all randomized patients who received at least 1 dose of 
randomized IP.

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9.7.1.2
Modified Intent-to-Treat Population
The modified Intent-to-Treat (mITT) Population will consist of all patients in the Safety 
Population who had at least 1 postbaseline assessment of the MADRS total score. 
9.7.1.3
Pharmacokinetic Population
The PK Population will consist of all patients in the Safety Population with at least 1 evaluable 
PK sample.
9.7.2
Patient Disposition
The number and percentage of patients in the mITT Population will be summarized by treatment 
group.
Screen failures (ie, patients screened but not randomized) and the associated reasons for failure 
to randomize will be tabulated overall for the screened patients. The number and percentage of 
patients who complete the double-blind treatment period, patients who prematurely discontinue 
during the same period and who enter the safety follow-up period will be presented for each 
treatment group and pooled across treatment groups for all randomized patients. The reasons for 
premature discontinuation from the double-blind treatment period as recorded on the termination 
pages of the eCRFs will be summarized (number and percentage) by treatment group for all 
randomized patients.
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters and other baseline characteristics (eg, age, race, ethnicity, sex, weight, 
height, body mass index [BMI]) will be summarized by treatment group for the mITT 
Population. 
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to randomized IP for the Safety Population during the double-blind treatment period 
will be summarized in terms of treatment duration, calculated as the number of days from the 
date of first dose of randomized IP received to the date of the last dose received, inclusive. 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be presented by 
treatment group for IP exposure.  
The total number of IV doses actually received by a patient during the double-blind treatment 
period will be summarized by treatment group for the Safety Population.

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9.7.4.2
Prior and Concomitant Medication
Prior medication is defined as any medication taken before the date of the first dose of 
randomized IP. Concomitant medication is defined as any medication taken on or after the date 
of the first dose of randomized IP. 
Both prior and concomitant medication use will be summarized by the number and proportion of 
patients in each treatment group receiving each medication within each therapeutic class for the 
Safety Population. 
9.7.4.3
Measurement of Treatment Compliance
Dosing compliance for the double-blind treatment period is defined as the total number of IV 
doses actually received by a patient during that period divided by the number of IV doses that 
were expected to be received during the same period multiplied by 100. Descriptive statistics for 
IP compliance will be presented by treatment group for each week, as well as for the whole 
double-blind treatment period of the study for the Safety Population.
9.7.5
Efficacy Analyses
All efficacy analyses will be based on the mITT Population, unless stated otherwise. The 
baseline for each specific efficacy endpoint is defined as the last measurement prior to the first 
dose of randomized treatment. All statistical hypothesis tests will be performed at the 2-sided 5% 
significance level for main effects. All confidence intervals (CIs) will be 2-sided 95% CIs, unless 
stated otherwise. 
For efficacy analyses in which study center is a factor, a small center will be defined as a center 
with < 2 patients in ≥ 1 treatment group in the mITT Population. Small centers will be pooled to 
form pseudo-centers so that each treatment group includes ≥ 2 mITT patients within the center. 
Pooling will be done using the following algorithm: 
Based on the number of mITT patients, small centers will be ordered from the largest to the 
smallest, and centers of the same size will be ordered from the largest center code to the smallest 
center code. The pooling process starts with the largest small center from the top, which will be 
pooled with the smallest from the bottom until a non-small center is formed. The process will be 
repeated using the small centers left out after the first pass. If any centers are left out at the end 
of the process, they will be pooled with the smallest pseudo-center. If there is > 1 smallest 
pseudo-center, the pseudo-center with the smallest center code will be selected. In case the 
pseudo-center formed by pooling all small centers is still a small center, it will be pooled with 
the smallest non-small center. If there is > 1 smallest non-small center, the one with the smallest 
center code will be selected. 
An additional analysis plan specific to European Medicines Agency will be presented in a stand-
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9.7.5.1
Primary Efficacy Analyses
The primary efficacy parameter will be the change from baseline in MADRS total score at the 
end of treatment (end of Week 6). The primary parameter will be analyzed using a mixed model 
for repeated measures (MMRM) with terms for treatment, study center, visit, baseline, and 
treatment-by-visit and baseline-by-visit interactions. An unstructured covariance matrix will be 
used to model the covariance of within-patient scores. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom (Kenward et al, 1997).  This analysis will 
only use the observed postbaseline scores without imputation of missing values.  The treatment 
differences for rapastinel 450 mg versus placebo and rapastinel 225 mg versus placebo will be 
estimated and reported along with the corresponding 95% CIs and the p-values for superiority 
testing. 
In the case that the MMRM model with unstructured covariance fails to converge with the 
default algorithm, then the Fisher scoring algorithm will be used to provide better initial values 
of the covariance parameters; if the model still does not converge, a simplified model without 
term for study center will be used to find the initial values of the covariance parameters. In the 
rare event that model still does not converge after using those initial values, simplified 
covariance structures will be used to fit the model in the following order: (1) ante-dependence, 
(2) heterogeneous autoregressive, (3) Toeplitz, and (4) compound symmetry.
To assess the robustness of the primary MMRM results to the possible violation of the missing-
at-random assumption, a sensitivity analysis will be conducted.
The sensitivity analysis will use a pattern-mixture model based on non-future- dependent 
missing-value restrictions (Kenward et al, 2003). The pattern for the pattern-mixture model will 
be defined by the patient’s last visit with observed value. The observed MADRS total score at a 
visit is assumed to have a linear relationship with the patient’s prior measurements. The missing 
values will be imputed under the assumption that the distribution of the missing observations 
differs from the observed only by a shift parameter value Δ. The dataset with observed and 
imputed values will be analyzed using the same model as the primary analysis for between-
treatment group comparisons at the end of the treatment. The imputation of missing values and 
the analysis will be performed 20 times and the inference of this sensitivity analysis will be 
based on the combined estimates using the standard multiple imputation technique. The values or 
Δ will be selected as 0 to 8.
9.7.5.2
Key Secondary Efficacy Analysis
The key secondary efficacy parameter will be the change from baseline in MADRS total score at 
1 day after first dose of treatment. The key secondary analysis will be analyzed using the same 
MMRM model for the primary efficacy parameter. The treatment differences for rapastinel 
450 mg versus placebo and rapastinel 225 mg versus placebo will be estimated and reported 
along with the corresponding 95% CIs and the p-values for superiority testing.

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The following serial gatekeeping procedure will be applied to control the overall type I error rate 
at the 0.05 level for the primary and secondary hypotheses.
Step 1: Rapastinel 450 mg is superior to placebo in MADRS at Week 6.
Step 2: Rapastinel 450 mg is superior to placebo in MADRS at Day 1.
Step 3: Rapastinel 225 mg is superior to placebo in MADRS at Week 6.
Step 4: Rapastinel 225 mg is superior to placebo in MADRS at Day 1.
The above hypotheses will be tested in the specified order. If at any step a test fails, the test 
procedure will stop and no further hypotheses will be tested.
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9.7.6
Safety Analyses
The safety analysis will be performed using the Safety Population. The safety parameters will 
include AEs; clinical laboratory, vital sign, and ECG parameters; 
 
. For each safety parameter, the last nonmissing safety assessment before the first 
dose of IP will be used as the baseline 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. 
9.7.6.1
Adverse Events
All AEs will be coded by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities.
An AE (classified by preferred term) that occurs during the double-blind treatment period will be 
considered a treatment-emergent adverse event (TEAE) if it was not present before the first dose 
of IP or was present before the date of the first dose of IP and increased in severity after the first 
dose of IP. If more than 1 AE is reported before the first dose of IP and coded to the same 
preferred term, the AE with the greatest severity will be used for comparison with the AEs 
occurring during the double-blind treatment period that were also coded to that preferred term. 
An AE that occurs more than 30 days after the date of the last dose of IP will not be considered 
as a TEAE.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term and further categorized by severity and causal 
relationship to the IP. If more than 1 AE is coded to the same preferred term for the same patient, 
the patient will be counted only once for that preferred term using the greatest severity and 
strictest causality for the summarization by severity and causal relationship.
The incidence of common (≥ 2% of patients in any treatment group) TEAEs and AEs leading to 
premature discontinuation of IP will be summarized by preferred term and treatment group and 
sorted by decreasing frequency for the test treatment. 
An SAE that occurred between the date of the first dose of IP and 30 days after the date of the 
last dose of IP, inclusive, will be considered an on-therapy SAE. The number and percentage of 
patients who have on-therapy SAEs will be summarized by preferred term and treatment group. 
In addition, the incidence of on-therapy SAEs that led to death will be summarized separately by 
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9.7.9
Interim Analysis
A blinded sample size reestimation will be conducted after approximately 60% of patients have 
completed the double-blind treatment period. This reestimation will be conducted in a blinded 
manner and will be based upon the observed variability of the overall treatment effect during the 
double-blind treatment period. The detailed procedure for blinded sample size reestimation will 
be described in the SAP. 

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9.7.10
Determination of Sample Size
This study will randomize approximately 690 patients to the rapastinel 450 mg, rapastinel 
225 mg, and placebo groups in a 1:1:1 ratio. The primary efficacy endpoint is the change from 
baseline in the MADRS total score at the end of Week 6. Assuming the SD is 10 points, within-
patient correlation is 0.6, and dropout rate over 6 weeks is 20%, adjusting for multiple 
comparisons of 2 rapastinel groups with placebo across the primary and secondary endpoints by 
using the serial gatekeeping procedure (Section 9.7.5.2) a sample size of 230 patients per 
treatment group will provide 90% power to detect a difference of 3.5 points for a rapastinel dose 
versus placebo at a 2-sided significance level of 5%.
9.7.11
Statistical Software
Statistical analyses will be performed using version 9.3 (or newer) of SAS.
9.8
DATA AND SAFETY MONITORING BOARD
The study will be conducted under the supervision of an independent DSMB to be chartered to 
review safety data at predetermined points during the study. The DSMB may also decide to meet 
and review safety data at other time points should it be deemed necessary. The DSMB is 
responsible for the ongoing review of safety data in the clinical study and for making 
recommendations concerning the continuation, modification, and termination of the study (FDA 
Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data 
Monitoring Committees, March 2006; European Medicines Agency Guideline on Data 
Monitoring Committees, EMEA/CHMP/EWP/5872/03, July 2005).
All analyses that are required to support the DSMB will be performed by independent
statistician(s) not otherwise involved in the study. Details of the DSMB membership, meeting 
schedule, and data review and analysis will be documented in the DSMB Charter.
9.9
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the investigator in writing by the sponsor. 
No protocol amendment may be implemented (with the exceptions noted below) before it has 
been approved by the IRB/EC and the signature page, signed by the investigator, and has been 
received by the sponsor. If the protocol is amended to eliminate or reduce the risk to patients, the 
amendment may be implemented before IRB/EC review and approval in jurisdictions where 
regulatory authorities allow such implementation. However, the IRB/EC must be informed in 
writing of such an amendment, and approval must be obtained within reasonable time limits. 
If unclarities arise with regard to interpretation or conduct of the approved protocol during the 
conduct of the study, the sponsor will provide guidance in the form of a protocol clarification 
letter.  Such guidance will be used to clarify only within the bounds of the approved protocol.

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

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

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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The following must be in place and filed with the sponsor before the start of the study at each 
study center:

A completed and signed Form FDA 1572 (for investigators in the US) or Investigator’s 
Information & Agreement in lieu of FDA 1572 (for investigators outside the US). If, during 
the course of the study, any changes are made that are not reflected on Form FDA 1572 or 
Investigator’s Information & Agreement in lieu of FDA 1572, a new Form FDA 1572 or 
Investigator’s Information & Agreement in lieu of FDA 1572 must be completed and 
returned to the sponsor

A fully executed contract

The curricula vitae for the investigator and all subinvestigators listed on Form FDA 1572
Investigator’s Information & Agreement in lieu of FDA 1572, including a copy of each 
physician’s license

A copy of the original IRB/EC approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent modifications must be 
submitted and approved by the IRB/EC, as stated in Section 5.1.

A copy of the IRB/EC-approved ICF

A copy of the HIPAA authorization form, or other applicable local privacy forms

A list of the IRB/EC members or the US Department of Health and Human Services general 
assurance number

A copy of the laboratory certifications and reference ranges

The investigator’s Statement page in this protocol signed and dated by the investigator

Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after 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 (or equivalent). The IP must be stored in a secured
place and must be locked. At study initiation, a representative from the sponsor will inventory 
the IP at the study center. The investigator must maintain adequate records documenting the 
receipt and disposition of all study supplies. The sponsor will supply forms on which to record 
the date the IP was received and a dispensing record in which to record each patient’s use. All 
unused IP must be returned to the sponsor. 
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by the sponsor
through the EDC system. The investigator is responsible for verifying that all data entries in the 
eCRFs are accurate and correct by electronically signing the completed eCRF casebook 
submitted to the sponsor. The investigator must maintain and retain accurate documentation that 
supports the information entered into the EDC system for source document verification and 
possible regulatory inspection.
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents, consent forms, regulatory documents, clinical laboratory results, calibration logs, or 
reports (including, but not limited to, all local and central laboratory results and ECG reports), 
and medication inventory records in all formats (including, but not limited to, written, electronic, 
magnetic, and optical records, and scans, x-rays, and ECGs) must be retained by the investigator
for a period of at least 15 years after study completion unless local regulations or institutional 
policies require a longer retention period or otherwise notified in writing by the sponsor. 
No study records shall be destroyed without notifying the sponsor and providing the sponsor the 
opportunity to arrange long-term storage for such study records or authorizing in writing the 
destruction of records after the required retention period.
The investigator must permit access to any documentation relating to the study upon request of 
the sponsor or applicable regulatory authorities. If the investigator for the study retires, relocates, 
or for other reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a suitable alternate custodian employee of the institution or to a suitably 
qualified and responsible third party. The sponsor must be notified in writing of the name and 
address of the new custodian in advance of the transfer.

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11.6
PATIENT CONFIDENTIALITY

Participants will be assigned a unique identifier (PID). Any participant records or datasets 
that are transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.

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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (RAP-MD-30, dated 17 Apr 2018)
and with all applicable government regulations and good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name

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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312, local regulations, ICH guidelines, 
HIPAA requirements, where applicable, and the IRB/IEC or study center. Signed informed 
consent will be obtained from each patient participating in a clinical research study. This consent 
must include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any
procedures that are experimental; and the expected duration of the patient’s participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be expected from 
the research. If the patient is to be paid for participating in the study, the consent form must 
state the amount that he/she will receive and the schedule of payment (to ensure neither 
coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records identifying the 
patient will be maintained and noting the possibility that the FDA, the sponsor, the IRB/EC,
or an authorized contract research organization may inspect the records

For research involving more than minimal risk, an explanation of whether any medical 
treatment is available if injury occurs and, if so, what it consists of or where further 
information may be obtained

An explanation of whom to contact, including the relevant telephone number, for answers to 
pertinent questions about the research and the research patient’s rights and whom to contact 
in the event of a research-related injury to the patient. (Note: In some cases, it may be 
necessary to identify a person other than the investigator as the contact. The guidance of the 
IRB/EC may be required)

A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the patient is otherwise entitled, and that the patient may 
discontinue participation at any time without penalty or loss of benefits to which the patient
is otherwise entitled

A statement that the particular treatment or procedures may involve risks to the patient (or to 
the embryo or fetus if the patient is, or may become, pregnant) that are at present 
unforeseeable

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

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

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APPENDIX IV.
SCALES AND QUESTIONNAIRES
Please refer to the Study Reference Manual for reference copies of scales and questionnaires.

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