An Open-label, Long-term Extended Access Protocol for Rapastinel as Adjunctive or Monotherapy Treatment in Patients With Major Depressive Disorder
Phase: PHASE3
Conditions: Depressive Disorder, Major
Sponsor: Naurex, Inc, an affiliate of Allergan plc

NCT03668600 
 
Study ID: RAP‐MD‐99 
 
 
Title: An Open‐label, Long‐Term Extended Access Protocol for Rapastinel as Adjunctive 
or Monotherapy Treatment in Patients with Major Depressive Disorder 
 
Protocol Date: 03 July 2018 
 
 
 

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TITLE PAGE
An Open-label, Long-term Extended Access Protocol for Rapastinel as Adjunctive
or Monotherapy Treatment in Patients with Major Depressive Disorder
RAP-MD-99
(3106-399-008)
IND # 107,974 and 136,870
Original Protocol Date:
03 Jul 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 TREATMENT PROTOCOL SYNOPSIS: Treatment protocol RAP-MD-99
Protocol Number
RAP-MD-99 (3106-399-008)
Title of Protocol
An Open-label, Long-term Extended Access Protocol for 
Rapastinel as Adjunctive or Monotherapy Treatment in 
Patients with Major Depressive Disorder
Study Centers (Country)
Approximately 225 study centers
Development Phase
3
Objective
To provide continued access to rapastinel for patients with 
major depressive disorder (MDD) who have completed 
specified prior rapastinel studies
Methodology
Multicenter, open-label, long-term extended access treatment 
protocol in adult patients with a primary diagnosis of MDD.
Patients must enter RAP-MD-99 after completion of 
prespecified rapastinel studies (henceforth referred to as 
lead-in studies) including RAP-MD-04, RAP-MD-05
(GLYX13C203), RAP-MD-06, and RAP-MD-33.
The final visit from the lead-in study may serve as the first 
visit in RAP-MD-99 and, after obtaining informed consent, 
open-label rapastinel may be administered to ensure 
continuity of treatment. Patients may also enter RAP-MD-99
at a visit independent of the lead-in study occurring within 
approximately 1 month after completion of the lead-in study
(with the exception of patients who are entering after 
completion of RAP-MD-06 in which case there specified 
time limit).
This treatment protocol consists of an open-label treatment 
period (OLTP) of indeterminate duration. During the OLTP,
patients will return to the study center for visits at which
administration of rapastinel and wellness check for 
collection of adverse event (AE) and concommitant 
medication information are conducted.  Visits should 
typically be spaced weekly or biweekly but may be up to 4 
weeks apart (based on investigator discretion). Appropriate 
safety follow-up upon discontinuation of patients from 
treatment will be at the discretion of the investigator. 
Number of Patients
Up to approximately 1800 patients are planned to be enrolled

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Diagnosis and Main Criteria for 
Inclusion

Completion of lead-in study:
o
RAP-MD-06, regardless of date of completion
o
RAP-MD-04, with date of completion (as a 
nonrandomized completer or randomized 
completer) within approximately 1 month prior 
to Visit 1
o
RAP-MD-05, with date of completion within 
approximately 1 month prior to Visit 1
o
RAP-MD-33, with date of completion within 
approximately 1 month prior to Visit 1

Adequate therapeutic benefit in the lead-in study to 
justify continuation of treatment with rapastinel in the 
judgment of the investigator
Test Product, Dosage, and Mode 
of Administration
Patients will receive intravenous (IV) rapastinel (450 mg)
generally given weekly or biweekly but up to once every 4 
weeks is allowed (based on investigator discretion).  
Duration of Participation
Indeterminate.  Treatment protocol will be terminated upon 
drug availability following marketing approval in each 
participating country, termination of rapastinel development, 
or if sponsor determines that treatment protocol termination 
is appropriate for other reasons.
Reference Therapy, Dosage, and 
Mode of Administration
N/A  
Criteria for Evaluation
Safety Measures

AEs
Statistical Methods
The Open-label Safety Population will consist of all 
screened patients who receive at least 1 dose of 
investigational product (IP) during the OLTP.
AEs will be analyzed descriptively for the Open-Label 
Safety Population.

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Approval Page
Name of Investigational Product:   Rapastinel
Document:  RAP-MD-99 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..................................................................................................................5
4.0
LIST OF ABBREVIATIONS...........................................................................................................8
5.0
ETHICAL CONSIDERATIONS....................................................................................................10
5.1
Institutional Review Board and Independent Ethics Committee ......................................10
5.2
Ethical Conduct of the Treatment protocol.......................................................................10
5.3
Patient Information and Informed Consent.......................................................................11
6.0
INVESTIGATORS AND TREATMENT PROTOCOL ADMINISTRATIVE STRUCTURE .....12
7.0
INTRODUCTION ..........................................................................................................................13
8.0
TREATMENT PROTOCOL OBJECTIVES..................................................................................17
9.0
INVESTIGATIONAL PLAN .........................................................................................................18
9.1
Overall Treatment protocol Design and Plan: Description...............................................18
9.1.1
Open-label Treatment Period..............................................................................18
9.2
Discussion of Treatment protocol Design.........................................................................19
9.3
Selection of Treatment protocol Population .....................................................................19
9.3.1
Inclusion Criteria................................................................................................19
9.3.2
Exclusion Criteria...............................................................................................20
9.3.3
Removal of Patients from Therapy or Assessment.............................................21
9.3.3.1
Criteria for Required Removal of Patients from Therapy or 
Assessment.......................................................................................22
9.3.4
Patient Replacement Procedures ........................................................................22
9.4
Treatments ........................................................................................................................23
9.4.1
Treatments Administered ...................................................................................23
9.4.2
Identity of Investigational Products....................................................................23
9.4.3
Handling of Investigational Products .................................................................24
9.4.4
Method of Assigning Patients to Treatment Groups ..........................................24
9.4.5
Selection of Dosages in the Treatment Protocol.................................................25
9.4.6
Selection and Timing of Dose for Each Patient..................................................25
9.4.6.1
Open-label Treatment Period............................................................25
9.4.7
Blinding..............................................................................................................25
9.4.8
Unblinding..........................................................................................................25
9.4.9
Prior and Concomitant Therapy .........................................................................25
9.4.10
Other Restrictions...............................................................................................26
9.4.10.1
Participation in Clinical Trials..........................................................26
Patients may not participate in any other interventional clinical trial while 
taking part in this treatment protocol................................................26
9.4.10.2
Alcohol .............................................................................................26
9.4.10.3
Contraception ...................................................................................26
9.4.11
Monitoring Treatment Compliance ....................................................................27
9.4.12
Treatment After Discontinuation........................................................................27

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9.5
Efficacy and Safety Assessments......................................................................................27
9.5.1
Diagnostic and Efficacy Assessments ................................................................27
9.5.2
Safety Assessments ............................................................................................27
9.5.2.1
Adverse Events.................................................................................27
9.5.2.2
Immediate Reporting of Serious Adverse Events.............................31
9.5.2.3
Reporting of Pregnancies Occurring During the Treatment 
Protocol ............................................................................................32
9.5.3
Investigational Product Concentration Measurements .......................................33
9.5.4
Health Economic and Outcomes Research Assessments....................................33
9.6
Data Quality Assurance ....................................................................................................35
9.6.1
Data Monitoring .................................................................................................35
9.6.2
Data Recording and Documentation...................................................................35
9.7
Statistical Methods and Determination of Sample Size....................................................36
9.7.1
Analysis Populations ..........................................................................................36
9.7.1.1
Open-label Safety Population...........................................................36
9.7.2
Patient Disposition .............................................................................................36
9.7.3
Demographics and Other Baseline Characteristics.............................................36
9.7.4
Extent of Exposure and Treatment Compliance.................................................37
9.7.4.1
Extent of Exposure ...........................................................................37
9.7.4.2
Prior and Concomitant Medication...................................................37
9.7.4.3
Measurement of Treatment Compliance...........................................37
9.7.5
Efficacy Analyses...............................................................................................37
9.7.6
Safety Analyses ..................................................................................................37
9.7.6.1
Adverse Events.................................................................................38
9.7.7
Interim Analysis .................................................................................................38
9.7.8
Determination of Sample Size............................................................................38
9.7.9
Statistical Software.............................................................................................39
9.8
Data and Safety Monitoring Board...................................................................................39
9.9
Changes in the Conduct of the Treatment protocol or Planned Analyses.........................39
9.10
Protocol Deviations ..........................................................................................................40
10.0
TREATMENT PROTOCOL SPONSORSHIP...............................................................................41
10.1
Treatment protocol Termination.......................................................................................41
10.2
Reporting and Publication ................................................................................................41
11.0
INVESTIGATOR OBLIGATIONS................................................................................................42
11.1
Documentation..................................................................................................................42
11.2
Performance......................................................................................................................43
11.3
Use of Investigational Materials.......................................................................................43
11.4
Case Report Forms ...........................................................................................................43
11.5
Retention and Review of Records.....................................................................................43
11.6
Patient Confidentiality......................................................................................................44
12.0
INVESTIGATOR’S STATEMENT ...............................................................................................45
13.0
APPENDICES ................................................................................................................................46
Appendix I.
Elements of Informed Consent...........................................................................46
Appendix II.
Contact Information............................................................................................48

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LITERATURE CITED ...................................................................................................................49

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LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
CFR
Code of Federal Regulations
 
DALYs
disability adjusted life years
DSMB
Data and Safety Monitoring Board
EC
Ethics Committee
eCRF
electronic case report form
EDC
electronic data capture
FDA
Food and Drug Administration
FR
Federal Register
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IND
Investigational New Drug (application)
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IWRS
Interactive Web Response System
MDD
major depressive disorder
NMDAR 
N-methyl-D-aspartate receptor
OLTP
open-label treatment period
PID
patient identification
SAE
serious adverse event
SD
standard deviation
SNRI
selective serotonin and norepinephrine reuptake inhibitor
SOC
system organ class

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SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event

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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE
United States
Approval by the Institutional Review Board (IRB) before the start of the treatment 
protocol 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 
treatment protocol, the investigator will provide timely and accurate reports to the IRB on 
the progress of the treatment protocol, 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 protocol, informed consent form (ICF), information sheet,
advertisements (as 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 treatment protocol 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 treatment protocol
begins, the study centers will require approval from an EC/IRB and government agency. 
During the course of the treatment protocol, the sponsor or authorized representative will 
provide timely and accurate reports to the EC/IRB on the progress of the treatment 
protocol, at intervals not exceeding 1 year (or as appropriate) and will notify the EC/IRB
of SAEs or other significant safety findings. The 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 TREATMENT PROTOCOL
This treatment protocol will be conducted in accordance with the ethical principles that 
have their origins in the Declaration of Helsinki.
This treatment protocol will comply with the ICH Guidance on General Considerations 
for Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP (ICH-E6; 62 FR 
25692, 09 May 1997), as well as Part 312 of the US CFR.

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5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the treatment protocol and before participating in any 
treatment protocol procedures, each patient must provide written informed consent that 
meets the requirements of 21 CFR 50 (where applicable), local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/EC or study center.
Each patient will read and sign an ICF and/or other authorization form as per local 
regulations; each patient will be made aware that he or she may withdraw from the 
treatment protocol at any time.
The ICF contains all the elements of informed consent listed in Appendix I of this 
treatment 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 TREATMENT PROTOCOL
ADMINISTRATIVE STRUCTURE
This treatment protocol will be performed at approximately 225 study centers in North 
America, Europe, and Asia.
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 treatment protocol and/or prior to participating in any treatment protocol-
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 treatment protocol’s conduct and the study center 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 treatment protocol investigational 
plan. The investigator at each study center will be responsible for the management of the 
treatment protocol conduct, including maintaining the study center 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. 

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Patients vary greatly in their response to antidepressants and it is not possible to reliably 
predict whether an individual patient will respond to a given antidepressant. This leads to 
clinicians often using a trial-and-error approach to identify an effective antidepressant. 
Due to the gradual development of the full therapeutic effect of currently available 
antidepressants, each antidepressant needs to be administered for 4 weeks or longer in 
order to determine the individual therapeutic benefit, making the process of finding an 
effective antidepressant lengthy for patients who are often severely depressed and at a 
high risk for suicide. A drug that could induce a rapid antidepressant effect would 
represent a major advancement for these patients.
Clearly, there is a substantial need for the development of novel treatments with a better 
safety/tolerability profile and a faster onset of full therapeutic benefit. Rapastinel has 
initially shown substantially improved safety/tolerability as well as promising efficacy, in 
both speed of onset and overall magnitude, for therapy in MDD. 
Rapastinel as a Novel Approach to Major Depressive Disorder Treatment
The mechanism of action of rapastinel is entirely different from that of first-line 
antidepressants (SSRIs, SNRIs) or adjuvant drugs currently approved for treatment of 
MDD such as atypical antipsychotics. Rapastinel is an N-methyl-D-aspartate receptor 
(NMDAR) modulator with a novel and complex pharmacological mechanism of action, 
acting as a nonselective agent at NR2 subunits and displaying properties as a functional 
partial agonist in a number of pharmacological assays. 
Rapastinel has demonstrated antidepressant properties in relevant animal models, 
displays cognitive enhancing properties in treated animals, and facilitates hippocampal 
long-term potentiation of synaptic transmission in preclinical models. In contrast to 
ketamine, no signal of abuse liability was detected in informative animal models. 
Rapastinel is available as an intravenous (IV) formulation only. In 2 Phase 2 clinical 
studies in patients with MDD, single IV doses of rapastinel 5 mg/kg and 10 mg/kg have 
been shown to produce marked antidepressant effects within 1 day that lasted for 
approximately 1 week or longer in responding patients. These antidepressant effects are 
very similar to ketamine’s effects when administered at a low dose as an infusion. In a 
systematic review and meta-analysis of ketamine and other NMDAR antagonists in the 
treatment of major depression, a single infusion of ketamine produced a rapid, yet 
transient antidepressant effect, accompanied by brief psychotomimetic and dissociative 
effects (Newport et al, 2015). In contrast to ketamine, rapastinel has not shown a high 
likelihood to induce psychotomimetic or dissociative effects in humans so far.

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The data available to date demonstrated a favorable safety and tolerability profile of 
rapastinel. Multiple requests have been received from study centers participating in 
ongoing studies for establishment of a continued access mechanism for patients who are 
completing participation of clinical trials of rapastinel. Investigators have indicated 
several anecdotal instances where patients have reported dramatic improvements in MDD 
symptoms as well as in their functioning.
The purpose of this treatment protocol is to provide continued access to rapastinel for 
patients with major depressive disorder (MDD) who have completed specified prior 
rapastinel studies.

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8.0
TREATMENT PROTOCOL OBJECTIVES
The objective of this treatment protocol is to provide continued access to rapastinel for 
patients with MDD who have completed specified prior rapastinel studies.

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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL TREATMENT PROTOCOL DESIGN AND PLAN: 
DESCRIPTION
Treatment Protocol RAP-MD-99 is a multicenter, open-label extended access treatment 
protocol in adult patients with MDD who completed  lead-in studies RAP-MD-04, RAP-
MD-05 (GLYX13C203), or RAP-MD-33 within approximately 1 month of Visit 1, or 
RAP-MD-06 at any time prior to Visit 1.  The final visit from the lead-in study may serve 
as the first visit of protocol RAP-MD-99 where practical to maintian continuity of 
treatment.  In other cases the first visit of RAP-MD-99 may be conducted independent of 
the final visit of the lead-in study. 
This treatment protocol will be conducted as an Open-label Treatment Period (OLTP) of 
indeterminate duration.
There is no predetermined limit specified for the number of patients that may be enrolled
in the OLTP.
The treatment protocol will be terminated upon drug availability following marketing 
approval in each participating country, termination of rapastinel development, or if 
sponsor determines that treatment protocol termination is appropriate for other reasons.
9.1.1
Open-label Treatment Period
Patients will enroll from RAP-MD-04, RAP-MD-05, RAP-MD-06, or RAP-MD-33. The 
final visit from the lead-in study may serve as the initial visit of protocol RAP-MD-99. 
Following consent at the initial visit, patients will be screened and those who meet entry 
criteria may enter the OLTP and receive the first dose of open-label treatment 
(rapastinel).  Consent, screening and dosing may all be conducted in a single visit at the 
discretion of the investigator to facilitate continuity of treatment.  Patients may also enter 
RAP-MD-99 at a visit independent of the lead-in study occurring within approximately 1 
month after completion of the lead-in study (with the exception of patients entering from 
RAP-MD-06 for whom there is no specified time limit [see Inclusion Criterion 2]).
During the OLTP, patients will return to the study center for visits at which 
administration of rapastinel and wellness check are conducted, including the capture of 
AEs and concomitant medications. Visits should typically be spaced weekly or biweekly 
but may be up to 4 weeks apart (based on investigator discretion).
Each patient will be treated until the investigator discontinues them from the treatment 
protocol at their discretion, the patient discontinues for other reasons, or until the 
treatment protocol or study center is terminated by the sponsor.

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Appropriate safety follow-up upon discontinuation of patients from treatment will be at 
the discretion of the investigator.
9.2
DISCUSSION OF TREATMENT PROTOCOL DESIGN
This multicenter, open-label, treatment protocol was designed taking into account prior 
studies that established rapastinel efficacy and safety in adult patients with MDD. 
Study centers will have experience with the patient population and will be encouraged to 
apply available guidelines to minimize patient risk or distress.   All study centers will 
have experience with rapastinel in the lead-in studies and all patients will have 
participated in the lead-in studies.
Dose selection information is presented in Section 9.4.5. The planned dosing regimen is 
based on experience from previous rapastinel studies. 
In the event of insufficient therapeutic response or worsening of the patient’s initial 
condition, the IP may be discontinued at the investigator’s discretion and an alternative 
treatment begun. 
9.3
SELECTION OF TREATMENT PROTOCOL POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the treatment protocol, patients must meet the following 
criteria:
Criteria to be assessed at Visit 1
1. Written informed consent, obtained from the patient before the initiation of any 
treatment protocol-specific procedures (Section 5.3) 
2. Completion of lead-in study:
a.
RAP-MD-06 regardless of date of completion
b. RAP-MD-04 with date of completion (as a nonrandomized completer or 
randomized completer) within approximately 1 month prior to Visit 1
c.
RAP-MD-05 with date of completion within approximately 1 month prior 
to Visit 1
d. RAP-MD-33 with date of completion within approximately 1 month prior 
to Visit 1

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3. Adequate therapeutic benefit in the lead-in study to justify continuation of treatment 
with rapastinel in the judgement of the investigator 
4. Ability to follow treatment protocol instructions and likely to be compliant with 
protocol requirements
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
treatment protocol:
Exclusion criteria to be assessed at Visit 1
Psychiatric and Treatment-Related Criteria
1. Suicide risk, as determined by meeting any of the following criteria:
a.
A suicide attempt within the past year
b. Significant risk, as judged by the investigator, based on the 
psychiatric interview or information collected in the Columbia-
Suicide Severity Rating Scale (C-SSRS) at any visit in the lead-in 
study
c.
Montgomery-Åsberg Depression Rating Scale (MADRS) Item 10 
score ≥ 5 at any visit during participation in the lead-in study
where MADRS was conducted.
2. At imminent risk of injuring self or others or causing significant damage to property, 
as judged by the investigator
 
 
 
  
 
 

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Other Criteria
 
 
 
 
 
 
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 treatment protocol, regardless of circumstances, before the completion 
of the treatment protocol visits and procedures. Patients can be prematurely discontinued 
from the treatment protocol after careful consideration for one of the following reasons:

Screen failure (failure to meet inclusion/exclusion criteria)

Pregnancy

Withdrawal of consent 

AE

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
Lack of efficacy

Protocol violation

Lost to follow-up 

Treatment protocol terminated by sponsor

Study center terminated by sponsor

Other 
Appropriate safety follow-up upon discontinuation of patients from treatment will be at 
the discretion of the investigator.
The reason for premature discontinuation from the treatment protocol will be recorded on 
the Treatment Protocol Disposition Page of the eCRF.
9.3.3.1
Criteria for Required Removal of Patients from Therapy or 
Assessment
Patients who require an alteration of MDD treatment regimen at any point during 
participation (including but not limited to addition of new therapeutic agent, increase in 
dose of any background ADT therapy the patient may be taking) due to an inadequate 
therapeutic response based on the judgment of the investigator should be withdrawn from 
participation.
Any patient who meets any of the following criteria at any point during participation
must be withdrawn from participation, due to AEs related to suicide:

A suicide attempt

Significant risk for suicidal behavior, as judged by the investigator
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 treatment protocol.
9.3.4
Patient Replacement Procedures
Patients who prematurely discontinue treatment will not be replaced.

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9.4
TREATMENTS
During the OLTP, all eligible patients will receive open-label IV rapastinel (450 mg)
typically weekly or biweekly but the interval may be up to 4 weeks at the investigator’s 
discretion. 
9.4.1
Treatments Administered
IP will only be administered to eligible patients by a medically qualified person as per the 
local and/or state regulations. The range of persons who can administer an IV can be a 
physician, a physician assistant, nurse, or nurse practitioner, etc, depending on the local 
and/or state law.  
The IP will be administered using the provided prefilled syringes in a “slow bolus” 
injection to an upper extremity vein within approximately 1 to 2 minutes.
During IP administration and until completion of postadministration evaluation, 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 country and/or local regulations/standard of care, to resuscitate a patient in the 
event of a medical emergency.  
At IP administration visits, the patient should not be released from the study center until 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.
9.4.2
Identity of Investigational Products
Rapastinel 450-mg IV Prefilled Syringes: 
 
 
 
 
 
 

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The prefilled syringe will be labeled with the treatment protocol number and kit number.
The study center personnel will write the PID number on the prefilled syringe associated 
with the kit mentioned above. The prefilled syringe label 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 treatment protocol, 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 Treatment Protocol Reference Manual or contact the 
sponsor or its designee for further instructions. 
At the end of the treatment protocol, all IP must be accounted for. In addition, at the end 
of the treatment protocol, all unused IP should be returned to the sponsor or the local 
distributor at the address provided in the Treatment Protocol Reference Manual.
9.4.4
Method of Assigning Patients to Treatment Groups
After a patient signs the consent form at Visit 1, study center personnel will register the 
patient in the IWRS. 
 
 
 
 
This PID number will be used to identify the patient throughout the treatment protocol
(ie, at all periods of the treatment protocol).
The IP will be labeled with medication kit numbers. The IWRS will provide the study 
center with the specific medication kit number(s) for each patient at each administration. 
Study centers will dispense IP according to the IWRS instructions. Study centers will also 
log on to the IWRS at subsequent visits to obtain an IP 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 treatment protocol source documents.

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9.4.5
Selection of Dosages in the Treatment Protocol
The doses of rapastinel in this treatment protocol were selected based on two 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.
9.4.6
Selection and Timing of Dose for Each Patient
9.4.6.1
Open-label Treatment Period
The IP will be administered IV using the assigned single-use prefilled syringes weekly, 
biweekly, or at intervals up to 4 weeks apart based on the discretion of the investigator. A 
patient may be switched between treatment frequencies at any time during the OLTP 
based on clinical presentation and the investigator’s discretion. 
9.4.7
Blinding
Not applicable
9.4.8
Unblinding
Not applicable
9.4.9
Prior and Concomitant Therapy
Patients should continue any non-IP MDD treatment regimen that was in place upon 
completion of the lead-in study (including any background ADT treatment for those who 
were in lead-in studies of the IP as an adjunctive therapy). Patients who require an 
alteration of MDD treatment regimen at any point during participation (including but not 
limited to addition of new therapeutic agent, increase in dose of any background ADT 
therapy the patient may be taking) due to an inadequate therapeutic response based on the 
judgment of the investigator should be withdrawn from participation.
Investigators should consult the lead-in study protocol from which each patient entered as 
a source of guidance regarding any other medications/treatments. Therapy considered 
necessary for the patient's welfare may be given at the discretion of the investigator.

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Medication history (psychotropic medication history and all other medications during the 
past 12 months [to the extent feasible]) will be recorded in the lead-in study in the eCRF. 
Thereafter, any changes in concomitant medications or any new medications added will 
be recorded in the eCRF.  
9.4.10
Other Restrictions
9.4.10.1
Participation in Clinical Trials
Patients may not participate in any other interventional clinical trial while taking part in 
this treatment protocol.
9.4.10.2
Alcohol 
It is recommended that patients abstain from alcohol consumption during participation.
9.4.10.3
Contraception
For purposes of this protocol, females will be considered of childbearing potential unless 
they are naturally postmenopausal or permanently sterilized (ie, hysterectomy). Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any 
other obvious pathological or physiological cause. 
For women of childbearing potential and male partners of women of childbearing 
potential who may participate in the treatment protocol, 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 [IUD], surgical sterilization (bilateral tubal ligation, bilateral 
salpingectomy), implantable permanent birth control device (ie 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 treatment protocol (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).

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The investigator and each patient will determine the appropriate method of contraception 
for the patient during the participation in the treatment protocol 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
Not applicable
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 OLTP should discontinue the treatment 
protocol and start appropriate treatment at the investigator’s discretion. This new 
treatment will not be provided by the sponsor. Patients who initiate a new treatment for 
MDD must be discontinued from the treatment protocol.
9.5
EFFICACY AND SAFETY ASSESSMENTS
9.5.1
Diagnostic and Efficacy Assessments
Not applicable.
9.5.2
Safety Assessments
Provision for standard of care monitoring and procedures including those described 
below are the responsibility of the investigator and will not be provided by the sponsor. 
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 should be completed at each protocol visit.
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A).

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For the purpose of the study center’s data collection responsibilities, any untoward event 
that was reported from the time the patient signed the ICF until 30 days after the 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 treatment protocol
Please note that medical procedures scheduled prior to consenting, but occurring during 
the treatment protocol should not be captured as AEs, but should be listed in the medical 
history if related to a pre-existing condition.
9.5.2.1.1
Causality Assessment
For each AE, the investigator must provide an assessment of causal relationship to the IP. 
The causality assessment must be recorded on the appropriate AE reporting page of the 
patient’s eCRF. Causal relationship must be assessed by answering the following 
question:
Is there a reasonable possibility the IP caused the event?
Yes:
There is evidence to suggest a causal relationship between the IP and AE, ie: 

There is a reasonable temporal relationship between the IP and the event, 
and/or 

The event is unlikely to be attributed to underlying/concurrent disease or other 
factors, and/or

Positive dechallenge and/or rechallenge exist
No:
There is no evidence to suggest a causal relationship between the IP and AE, 
ie:

There is no reasonable temporal relationship between the IP and the event, or

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
The patient did not take the IP, or

The event is likely to be attributed to underlying/concurrent disease or other 
factors, or

The event is commonly occurring in the (treatment protocol) population 
independent of IP exposure
9.5.2.1.2
Severity Assessment
The investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. Severity,
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 9.5.2.1.3). Severity will be 
assessed according to the following scale:
Mild:
A type of AE that is usually transient and may require only minimal
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort, but poses no significant or permanent risk of harm to 
the research participant.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
9.5.2.1.3
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect

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Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in patient hospitalization, or the 
development of IP dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (eg, elective procedures for pre-existing conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.
9.5.2.1.4
Reporting Adverse Events and Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study center personnel will 
record all pertinent information in the patient’s eCRF. 
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF 
whether or not they are considered causally related to the IP.
For every AE, the investigator must:

Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as 
the severity and casual relationship

Document all actions taken with regard to the IP

Detail any other treatment measures taken for the AE

Document the outcome of the AE
In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify study center personnel of any AEs occurring during the 30-day 
posttreatment protocol 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).

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Any AEs that are ongoing at the time of patient exit from the protocol will be followed 
until the condition returns to pre-treatment protocol 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 last known dose of 
IP.
9.5.2.2
Immediate Reporting of Serious Adverse Events
The sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study center personnel must report the event to Global Drug Safety on the SAE Form for 
Clinical Trials. The Study Physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The study center must transmit the SAE Form for Clinical Trials to the SAE email 
address or fax number shown below. Even if an initial report is made by telephone, the 
SAE Form for Clinical Trials completed with all available details must still be emailed or 
faxed within 24 hours of knowledge of the event at the study center.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs are to be followed by 
the study center staff until resolution or until the SAE is deemed stable. The sponsor may 
contact the study center to solicit additional information or follow up on the event.

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9.5.2.3
Reporting of Pregnancies Occurring During the Treatment Protocol
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 must be followed to term and the outcome 
reported by completing a follow-up Clinical Trial Pregnancy Form. If the pregnancy is 
associated with an SAE (eg, if the mother is hospitalized for hemorrhage), a separate 
SAE Form for Clinical Trials must be filed as described in Section 9.5.2.2, with the 
appropriate serious criterion (eg, hospitalization) indicated in addition to the pregnancy 
form.
 
 
 
 
 
 
 
 
 
 
 
 

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9.5.3
Investigational Product Concentration Measurements
Not applicable.
9.5.4
Health Economic and Outcomes Research Assessments
Not applicable.
9.5.5
Schedule of Assessments
The descriptions of the procedures to be performed at each visit are provided in the 
following sections.
9
1
 
 
 
 

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9.5.5.2
Unscheduled Visits
Not applicable.
9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the treatment protocol, a representative of the sponsor will meet
(in person or via telephone) with the investigator and the study center staff to review the 
procedures to be followed during the treatment protocol. 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 treatment protocol 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 treatment protocol-related 
documents. The investigator and the study center staff will be responsible for data entry 
of patient data into the eCRFs via the EDC system, resolving data queries generated via 
the EDC system and providing missing or corrected data. The investigator or designee 
will be responsible for approving all changes performed on the data, and endorsing the 
patient data within the EDC system. This approval method will include applying an 
electronic signature linked to a uniquely assigned username and password that together 
will represent a traditional handwritten signature used in the past.
9.6.2
Data Recording and Documentation
Data collection will involve the use of the EDC system, to which only authorized 
personnel will have access. Patient’s data are to be entered into the EDC system by the 
investigator or designee using their assigned EDC user account. After data entry into the 
EDC system by the investigator or designee, a combination of manual and programmatic 
edit checks will be used to review the data for completeness, logic, and adherence to
protocol. As a result of these edit checks, data monitoring, and reviews, queries may be 
electronically issued to the study center and should be answered electronically via the 
EDC system.
Each query will carry identifying information (assigned username, date, and time) to 
assist the sponsor and the investigator on the origin of the data clarification request and 
the response provided by the investigator. All data changes made to the patient’s data via 
a data query will be approved by the investigator prior to final database lock.

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After all data have been reviewed and all issues have been resolved, the database will be 
locked.
All data collected in the context of this treatment protocol 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. Treatment 
protocol records (eg, copies of eCRFs, regulatory documents) will be retained at the 
study center, along with adequate source documentation, according to FDA and ICH 
requirements. All treatment protocol records must be available for inspection by the 
sponsor, its authorized representatives, the FDA, or other health authorities.
9.7
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
9.7.1
Analysis Populations
One analysis population will be considered for the statistical analysis of the treatment 
protocol, as specified in the following subsections.
9.7.1.1
Open-label Safety Population
The Open-label Safety Population will consist of all patients who signed the RAP-MD-99 
ICF and who received at least 1 dose of open-label rapastinel during the OLTP of the 
protocol.
9.7.2
Patient Disposition
The number and percentage of patients who participated in the OLTP, and who 
prematurely discontinued from the OLTP will be summarized overall and by reasons for 
premature discontinuation for the Open-label Safety Population. 
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters and other baseline characteristics (eg, age, race, ethnicity, sex, 
weight, height, body mass index) will be summarized overall for the Open-label Safety 
Population. 

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9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to open-label rapastinel for the Open-label Safety Population during the OLTP
will be summarized for treatment duration, calculated as the number of days from the 
date of the first dose of open-label rapastinel taken to the date of the last dose taken 
during the OLTP, inclusive. Descriptive statistics (number of patients, mean, SD, 
minimum, median, and maximum) will be presented.
9.7.4.2
Prior and Concomitant Medication
Prior medication is defined as any medication started before the date of first dose of 
open-label IP. Concomitant medication during the OLTP is defined as any medication 
taken on or after the date of the first dose of open-label IP during the OLTP. 
The use of prior medication will be summarized by the number and percentage of patients 
receiving each medication within each therapeutic class for the Open-label Safety 
Population. The use of concomitant medications during the OLTP will be summarized by 
the number and percentage of patients receiving each medication within each therapeutic 
class for the Open-label Safety Population. 
9.7.4.3
Measurement of Treatment Compliance
Not applicable.
9.7.5
Efficacy Analyses
Not applicable.
9.7.6
Safety Analyses
The safety analyses for the OLTP will be performed using the Open-label Safety 
Population. The summarization will be overall for the OLTP without consideration for 
dosing frequency.
Safety parameters will be limited to AEs.
For each safety parameter, the baseline of the lead-in study will be used as the baseline 
for all analyses of that safety parameter, unless stated otherwise.

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9.7.6.1
Adverse Events
AEs will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities.
An AE (classified by preferred term) that occurs during the OLTP or thereafter will be 
considered a treatment-emergent adverse event (TEAE) if it was not present before the 
date of the first dose of IP in the OLTP or was present before the first dose of IP of the 
first lead-in study and increased in severity during the OLTP or thereafter. If more than 1 
AE is reported before the date of the first dose of IP in the OLTP and coded to the same 
preferred term, the AE with the greatest severity will be used as the benchmark for 
comparison with the AEs occurring during the OLTP that were also coded to that 
preferred term.
The number and percentage of patients reporting TEAEs during the OLTP will be 
tabulated by SOC, 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 during the OLTP, the patient will be counted only once for that preferred term 
using the most severe and most related occurrence for the summarization by severity and 
by causal relationship to the IP.
The incidence of common (≥ 2% of patients) TEAEs during the OLTP will be 
summarized by preferred term and will be sorted by decreasing frequency. 
An SAE that occurred between the date of the first dose of the 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 had on-therapy SAEs during the OLTP will be 
summarized by preferred term and sorted by decreasing frequency. 
The number and percentage of patients who had fatal on-therapy SAEs during the OLTP
will be summarized by preferred term and sorted by decreasing frequency. 
The incidence of TEAEs leading to premature discontinuation of IP during the OLTP will 
be summarized by preferred term and will be sorted by decreasing frequency. 
Listings will be presented for all patients with SAEs, patients with AEs leading to 
discontinuation, and patients who died (if any).
9.7.7
Interim Analysis
No interim analysis is planned for this treatment protocol. 
9.7.8
Determination of Sample Size
Not applicable.

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9.7.9
Statistical Software
Statistical analyses will be performed using version 9.3 (or newer) of SAS.
9.8
DATA AND SAFETY MONITORING BOARD
The treatment protocol will be conducted under the supervision of an independent DSMB 
to be chartered to review safety data at predetermined points during the treatment 
protocol. 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 treatment protocol and for making recommendations 
concerning the continuation, modification, and termination of the treatment protocol
(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 treatment protocol. 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 TREATMENT 
PROTOCOL 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 other applicable oversight bodies 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 treatment protocol, 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 treatment protocol
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 treatment protocol 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 
treatment protocol data. The IRB/EC must be notified within the time period dictated by 
the IRB/EC associated with this treatment protocol. 

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10.0
TREATMENT PROTOCOL SPONSORSHIP
This treatment protocol is sponsored by Naurex, Inc., an indirect subsidiary of Allergan, 
plc. 
10.1
TREATMENT PROTOCOL TERMINATION
The sponsor reserves the right to terminate the treatment protocol in its entirety or at a 
specific study center before treatment protocol completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this treatment protocol are the property of the sponsor. An 
integrated clinical and statistical report will be prepared at the completion of the 
treatment protocol.
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 treatment 
protocol 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 treatment protocol, 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 or 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 treatment protocol. If the 
treatment protocol 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 (as applicable)

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 treatment protocol and for 1 year after completion of 
the treatment protocol.

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11.2
PERFORMANCE
The investigator must demonstrate reasonable efforts to obtain qualified patients for the 
treatment protocol.
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 treatment protocol 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 treatment 
protocol 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 treatment protocol 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 treatment protocol, including 
eCRFs, source documents, consent forms, regulatory documents, clinical laboratory 
results, calibration logs, or reports (including, but not limited to, all 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 treatment protocol
completion unless local regulations or institutional policies require a longer retention 
period or otherwise notified in writing by the sponsor. 
No treatment protocol records shall be destroyed without notifying the sponsor and 
providing the sponsor the opportunity to arrange long-term storage for such treatment 
protocol records or authorizing in writing the destruction of records after the required 
retention period.

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The investigator must permit access to any documentation relating to the treatment 
protocol upon request of the sponsor or applicable regulatory authorities. If the 
investigator for the treatment protocol retires, relocates, or for other reasons withdraws 
from the responsibility of keeping the treatment protocol 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.
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 treatment protocol-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 treatment protocol in accordance with this protocol (RAP-MD-99, 
dated 03 Jul 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 treatment protocol. This consent must include the following items:

A statement that the treatment protocol 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 
treatment protocol, the consent form must state the amount that he/she will receive 
and the schedule of payment (to ensure neither coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA, the 
sponsor, the IRB/EC, or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the investigator as the 
contact. The guidance of the IRB/EC may be required)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled

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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the treatment protocol

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 treatment protocol 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 Treatment Protocol
Reference Manual.

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14.0
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