Conditions: Depression
Keywords: treatment resistant inadequate response
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
This is a multi-site, double-blind, placebo-controlled study of the acute efficacy of brexpiprazole or placebo in combination with intranasal ketamine added to ongoing, stable, and adequate antidepressant therapy (ADT) in the treatment of adults with Major Depressive Disorder with Treatment Resistant Depression.

Detailed description:
This is a five-site, double-blind, placebo-controlled study of the acute efficacy of oral brexpiprazole or placebo combined with intranasal ketamine added to ongoing, stable, and adequate antidepressant therapy (ADT) in the treatment of adults with MDD with TRD. Adequate ADT is defined as a therapeutically sufficient dose for a sufficient treatment period, which would be expected to be effective as listed in the MGH ATRQ.

Arms:
arm 1: brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks arm 2: placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks

Interventions: intervention 1: Brexpiprazole intervention 2: Ketamine intervention 3: Placebo
Intervention descriptions: intervention 1: Administration of up to 3mg brexpiprazole intervention 2: administration 6 times over two weeks of inhaled ketamine intervention 3: Administration of placebo which matches brexpiprazole in size and number of tablets per dose

Protocol document:
Prot_SAP_000.pdf: 
 
A Double-Blind, Placebo-Controlled Study of Brexpiprazole plus Ketamine in 
Treatment-Resistant Depression (TRD) 
 
  
 
 
 
 
May 10, 2019  
PRINCIPAL INVESTIGATOR: 
 
 
Maurizio Fava, M.D. 
Executive Director, MGH Clinical Trials Network and 
Institute (CTNI) 
Executive Vice-Chair, Department of Psychiatry, 
Massachusetts General Hospital 
55 Fruit Street – Bulfinch 351 
Boston MA 02114 
Phone: 617-724-0838 
Fax: 617-726-2688 
Email: MFava@Partners.org 
 
 
STUDY SPONSOR: 
Otsuka Pharmaceuticals 
 
 
 
 
 
 
 
This protocol is the confidential property of MGH CTNI and is intended solely for the guidance of this 
clinical investigation. This protocol may not be disclosed to parties not associated with the clinical 
investigation or used for any other purpose without the prior written consent of MGH CTNI. 
 
 


2 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
A. 
TABLE OF CONTENTS 
B. 
List of Tables ....................................................................................................................................... 5 
C. 
Study Synopsis .................................................................................................................................... 6 
D. 
Background and Introduction ...................................................................................................... 8 
D.1.a. 
Toxicology - Ketamine ....................................................................................................................................... 10 
D.1.b. 
Toxicology - Brexpiprazole ............................................................................................................................. 12 
D.2. 
Clinical Experience – Ketamine and Brexpiprazole ....................................................... 12 
D.2.a. 
Ketamine ................................................................................................................................................................. 12 
D.2.b. 
Brexpiprazole........................................................................................................................................................ 14 
E. 
Study Rationale ............................................................................................................................... 15 
F. 
Objectives .......................................................................................................................................... 16 
F.1. Primary Aim of the Ketamine-Brexpiprazole Trial ........................................................... 16 
F.2. Secondary Aims of the Ketamine-Brexpiprazole Trial ...................................................... 16 
G. 
Study Design ..................................................................................................................................... 17 
G.1. 
Overview ..................................................................................................................... 17 
G.2. 
Methods ...................................................................................................................... 17 
G.3. 
Study Design ................................................................................................................ 17 
H. 
Study Population ............................................................................................................................ 17 
H.1. 
Number of Subjects ..................................................................................................... 17 
H.2. 
Subject Eligibility ......................................................................................................... 18 
H.2.a. 
Inclusion Criteria ................................................................................................................................................. 18 
H.2.b. 
Exclusion Criteria ................................................................................................................................................ 19 
H.3. 
Rationale for the Inclusion/Exclusion Criteria .............................................................. 22 
I. 
Study Assessments – Plan and Methods ..................................................................................... 23 
I.1. 
Study Conduct ................................................................................................................. 23 
I.1.a. 
Screening Phase ................................................................................................................................................... 24 
I.1.b. 
Remote Interview ................................................................................................................................................ 26 
I.1.c. 
Randomization ..................................................................................................................................................... 26 
I.1.d. 
Baseline Visit (Visit 1) (Day 0) ....................................................................................................................... 26 
I.1.e. 
Visit 2 (Day 1) ....................................................................................................................................................... 28 
I.1.f. 
Visit 3 (Day 2) ....................................................................................................................................................... 28 
I.1.g. 
Visit 4 (Day 5) ....................................................................................................................................................... 28 
I.1.h. 
Visit 5 (Day 8) ....................................................................................................................................................... 28 
I.1.i. 
Visit 6 (Day 11) .................................................................................................................................................... 29 
I.1.j. 
Visit 7 (Day 14) .................................................................................................................................................... 29 
I.1.k. 
Visit 8 (Day 17) .................................................................................................................................................... 29 
I.1.l. 
Visit 9 (Day 21) .................................................................................................................................................... 29 


3 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
I.1.m. 
Visit 10 (Day 23) .................................................................................................................................................. 30 
I.1.n. 
Visit 11 (Day 28) .................................................................................................................................................. 30 
I.1.o. 
Early Termination Visit .................................................................................................................................... 30 
I.1.p. 
End of Study Treatment Administration ................................................................................................... 30 
I.1.q. 
Post-Study Follow-Up ........................................................................................................................................ 30 
I.1.r. 
Patient Recruitment ........................................................................................................................................... 30 
I.2. 
Procedures ...................................................................................................................... 31 
I.2.a. 
Laboratory/Diagnostic Procedures ............................................................................................................. 31 
I.2.b. 
Blinding Procedures ........................................................................................................................................... 31 
I.2.c. 
Outcome and Safety Measures ....................................................................................................................... 32 
I.2.d. 
Study Instruments .............................................................................................................................................. 33 
I.2.e. 
Reliability Training ............................................................................................................................................. 34 
I.2.f. 
Patient Adherence to Protocol ....................................................................................................................... 34 
I.3. 
Discontinued Subjects ..................................................................................................... 34 
I.4. 
Evaluation of Adverse Events (AEs) ................................................................................. 34 
I.4.a. 
Definition of AEs .................................................................................................................................................. 35 
I.4.b. 
Reporting of AEs .................................................................................................................................................. 35 
I.4.c. 
Adverse Event Coding ....................................................................................................................................... 39 
I.4.d. 
Pregnancy ............................................................................................................................................................... 39 
I.4.e. 
Causality Collection ............................................................................................................................................ 39 
I.4.f. 
Adverse Events Based on Signs and Symptoms ..................................................................................... 39 
I.4.g. 
Adverse Events Based on Examinations and Tests ............................................................................... 40 
I.4.h. 
Disease Progression or Worsening Depression ..................................................................................... 40 
I.4.i. 
Serious Adverse Events (SAEs) ..................................................................................................................... 40 
I.5. 
Protocol Waivers and Violations ..................................................................................... 41 
I.5.a. 
Protocol Waivers ................................................................................................................................................. 41 
I.5.b. 
Protocol Violations ............................................................................................................................................. 41 
J. 
Treatment ......................................................................................................................................... 43 
J.1. 
Dosing Schedule .............................................................................................................. 43 
J.2. 
Study Product Supplies and Administration .................................................................... 43 
J.3. 
Packaging and Labeling ................................................................................................... 44 
J.3.a. 
Concomitant Open-Label ADT ....................................................................................................................... 44 
J.3.b. 
Blinded Brexpiprazole/Placebo Therapy .................................................................................................. 44 
J.4. 
Dose Modification for Toxicity ........................................................................................ 44 
J.5. 
Concomitant Therapy ..................................................................................................... 44 
J.6. 
Discontinuation from Study Treatment ........................................................................... 44 
J.6.a. 
Procedures for Discontinuation from Study Treatment ..................................................................... 44 
J.7. 
Unblinding Procedure ..................................................................................................... 45 
J.7.a. 
Methods for Ensuring Blinding...................................................................................................................... 45 
J.7.b. 
Methods for Unblinding the Study ............................................................................................................... 45 
K. 
Ethical Considerations .................................................................................................................. 46 


4 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
K.1. 
Risk/Benefit Assessment ............................................................................................. 46 
K.1.a. 
Potential Risks ...................................................................................................................................................... 46 
K.1.b. 
Safety ........................................................................................................................................................................ 46 
K.1.c. 
Confidentiality and Loss of Privacy ............................................................................................................. 47 
K.1.d. 
Planned procedures for protecting against or minimizing potential risks ................................. 47 
K.2. 
Justification of the Use of Placebo Arm ........................................................................ 47 
K.2.a. 
Clinical Monitoring of Subjects and Management of Clinical Deterioration and Emergence 
or Worsening of Suicidal ideation .................................................................................................................................. 48 
K.3. 
Informed Consent ........................................................................................................ 48 
K.4. 
IRB Review ................................................................................................................... 48 
K.5. 
Potential Benefits to Study Participants and Others .................................................... 48 
L. 
Data Handling and Record Keeping ......................................................................................... 49 
L.1. 
Completion of eCRF ........................................................................................................ 49 
L.2. 
Procedure for Corrections ............................................................................................... 49 
L.3. 
Record Retention ............................................................................................................ 49 
L.4. 
Data Confidentiality ........................................................................................................ 50 
M. 
Monitoring and Oversight ........................................................................................................... 50 
M.1. 
Evaluation of Study Sites ............................................................................................. 50 
M.2. 
Initiation of Study Sites ................................................................................................ 50 
M.3. 
Periodic Monitoring Visits ............................................................................................ 50 
M.4. 
Study Closeout Visit ..................................................................................................... 51 
M.5. 
Direct Access to Source Data/Documents .................................................................... 51 
M.6. 
Interim Analysis ........................................................................................................... 51 
M.7. 
Medical Monitoring ..................................................................................................... 51 
N. 
Data Analysis.................................................................................................................................... 53 
O. 
Protocol Signature Page ............................................................................................................... 54 
Appendix 1 Concomitant Medications ............................................................................................... 55 
Appendix 2 References ............................................................................................................................ 63 
 
 
 


5 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
B. 
LIST OF TABLES 
TABLE 1-EXCLUSIONARY SAFETY VALUES OF POTENTIAL CLINICAL CONCERN ....................................................................................... 22 
TABLE 2– OVERVIEW OF STUDY SCHEDULE ................................................................................................................................... 23 
TABLE 3– STUDY SCHEDULE ....................................................................................................................................................... 25 
TABLE 4– LABORATORY TESTS .................................................................................................................................................... 31 
TABLE 5 - LIST OF EXAMPLES OF PROTOCOL VIOLATIONS .................................................................................................................. 42 
TABLE 6   BREXPIPRAZOLE DOSING .......................................................................................................................................... 43 
 
 


6 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
C. 
STUDY SYNOPSIS 
Title of Study: 
A Double-Blind, Placebo-Controlled Study of Brexpiprazole plus 
Ketamine in Treatment-Resistant Depression (TRD) 
Objective: 
To evaluate the efficacy, safety, and tolerability of brexpiprazole in 
combination with intranasal ketamine (40 mg biweekly for 2 weeks and 
weekly for 2 weeks), compared to placebo, as a rapidly acting treatment 
for TRD 
Methodology: 
This is a multi-site, double-blind, placebo-controlled study of the acute 
efficacy of brexpiprazole or placebo in combination with intranasal 
ketamine added to ongoing, stable, and adequate antidepressant 
therapy (ADT) in the treatment of adults with MDD with TRD. 
Number of Patients: 
52 Patients  
Diagnosis and  
Main Criteria for Inclusion: 
Male and female outpatients (aged 18 to 65 years) who meet DSM-5 
(Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) 
criteria for MDD, have a current depressive episode of at least 8 weeks, 
and meet all of the following criteria: 
• <50% response to current antidepressant treatment (at least 8 
weeks at an adequate dose, stable dose for at least 4 weeks) 
• >1 and <8 failed trials in the current episode as per MGH ATRQ 
• MADRS ≥ 20 at screening and at baseline 
• Good general health 
• BMI= 18-35 kg/m2 
• Willing to use birth control if the patient is of child bearing 
potential 
Test Product, Dosage, and 
Mode of Administration: 
Subjects will be randomly assigned to one of two arms in a 1:1 fashion: 
brexpiprazole 0.5-3 mg/day or placebo for four weeks in combination 
with bi-weekly administration of intranasal ketamine (40 mg) for two 
weeks, and then weekly administration of intranasal ketamine (40 mg) 
for two weeks.  
Visit Schedule: 
Screening Visit, Baseline visit (Visit 1), Visits 1 and 2 days after the 
Baseline Visit (Visits 2 and 3), and then every 3 days after that for 26 
days, with end of study visit one week after the last double-blind visit. 
Primary Outcome Measure: 
Symptom improvement will be evaluated by assessing changes in the 
SDQ. 
Secondary Outcome 
Measures: 
MADRS, HAMD-6, CGI-S, CGI-I. 


7 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Safety and Tolerability 
Measures: 
Adverse event (AE) recording, clinical laboratory measures, vital sign 
parameters, electrocardiograms (ECGs), physical examinations, CHRT. 
 
Statistical Justification: 
 
The sample size was chosen to ensure 80% power to detect an effect size 
of 0.8 on the SDQ between brexpiprazole and placebo at a two-sided 
0.05 significance level. This assumes 52 subjects (26 subjects per arm). 


8 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
D. 
BACKGROUND AND INTRODUCTION 
Public Health Significance of Major Depressive Disorder (MDD) 
Major Depressive Disorder (MDD) is a serious, debilitating, life-shortening illness that affects many 
persons of all ages and backgrounds. The point prevalence of MDD is high (2.3-3.2% in men; 4.5-9.3% 
in women) and the lifetime risk for MDD is 7.0-12.0% for men and 20.0-25.0% for women (Kessler et 
al, 2003). MDD is a disabling disorder that costs the U.S. over $80 billion per year in direct and indirect 
costs (Greenberg et al, 2003). Specifically, the annual cost of depression (approximately $83.1 billion 
in 2000) includes $26.1 billion (31%) in direct medical costs (e.g., diagnosis, treatments, and overall 
cost to the community), $5.4 billion (7%) in suicide-related mortality costs, and $51.5 billion (62%) in 
workplace costs (Greenberg et al, 2003). Depression substantially impairs work productivity, 
increasing work absence and reducing work performance (Stewart et al, 2003). Depressed workers 
report significantly more total health-related Lost Productive Time (LPT) than non-depressed workers 
(a mean 5.6 hours/week versus an expected 1.5 hours/week) (Stewart et al, 2003). Depression is also 
associated with increased health care utilization for general medical conditions, and at least a 50% 
increase in total health services costs (Simon et al, 2003, 1995; Unützer et al, 1997). Depression also 
has detrimental effects on all aspects of social functioning (e.g., self-care, social role, and family life, 
including household, marital, kinship, and parental roles) – costs not traditionally calculated 
(Fergusson et al, 1995; Wiersma, 1996; Paykel, 1999). Finally, recovery from depression is associated 
with lower primary care costs and less missed work time due to illness (Simon et al, 2002). 
Modest Efficacy of Currently Available Therapies for MDD 
All FDA-approved antidepressants used as monotherapies have shown only modest benefits. In fact, 
in acute (6-8 week) studies, typically with relatively uncomplicated, non-chronic forms of MDD, 
response rates (e.g., 50.0% or greater reduction in depressive symptoms) range between 45.0-55.0% 
and remission rates (e.g., minimal or no depressive symptoms) range between 30.0-35.0% (Steffens 
et al, 1997; Anderson, 2000; Anderson, 2001; Entsuah et al, 2001). Similarly, the efficacy of 
psychotherapy for the treatment of depression has been found to be modest as well, with effect 
sizes comparable to those of standard antidepressants (Cuijpers et al, 2010). Although the 
combination of antidepressants and psychotherapy appears to be somewhat more efficacious than 
either one approach alone, the efficacy of this combination treatment also remains limited (Cuijpers 
et al, 2009). Even after multiple, sequential interventions, only about 50-60% of patients achieve 
complete remission (Rush et al, 2006; Nelson, 2006; Insel and Wang, 2009). 
Treatment-Resistant Depression (TRD) 
Treatment-resistant depression (TRD) typically refers to the occurrence of an inadequate response 
following adequate antidepressant therapy among patients suffering from MDD (Fava, 2003). What 
constitutes inadequate response has been an object of considerable debate in the field, and most 


9 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
experts would currently argue that inadequate response is the failure to achieve remission (Fava, 
2003). Although the more traditional view of treatment resistance has focused on nonresponse (e.g., 
patients who have reported minimal or no improvement with drug therapy), failure to achieve 
remission despite adequate treatment represents a significant challenge for both clinicians and 
patients/consumers. In addition, response without remission has a potentially poorer outlook, as 
residual symptoms are associated with poorer outcome and increased relapse risk (Judd et al, 1998; 
Van Londen, et al 1998). Finally, response without remission following antidepressant treatment is 
associated with a significantly greater number of somatic symptoms than remission and with 
impaired social functioning (Denninger, et al 2006; Paykel, 2002). For these reasons, it has been 
argued that “complete remission should be the goal in the treatment of patients with MDD, because 
it leads to a symptom-free state and a return to premorbid levels of functioning” (Bakish, 2001). With 
this treatment approach in mind, inadequate response implies that the treatment failed to achieve 
remission. Several operational definitions of remission have been proposed, but from the clinician 
and patient perspective, remission typically implies achieving a relatively asymptomatic state (Frank 
et al, 1991). Since treatment resistance in depression typically concerns the occurrence of an 
inadequate response following adequate antidepressant therapy, it is apparent that the number of 
failed adequate antidepressant trials may range from one to countless. However, the most common 
definition of TRD is that of inadequate response (e.g., failure to achieve remission) to at least one 
antidepressant trial of adequate dose and duration (Fava and Davidson, 1996). The findings of the 
largest clinical trial in MDD, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) 
trial, have shown that approximately two thirds of MDD patients do not achieve remission following 
an initial adequate trial of antidepressant therapy, suggesting that TRD is highly common in practice 
(Trivedi et al, 2006). 
There are two approaches to the study of treatments for TRD. One uses the prospective ascertaining 
of treatment resistance, with the goal of minimizing the possible confounding effect of the patients’ 
recall bias. Patients who are currently symptomatic may underestimate the degree of improvement 
experienced in the course of the index episode, particularly with prior treatments. As a result of recall 
biases, relapses during antidepressant treatment may be misdiagnosed as nonresponse. When 
treatment resistance is assessed prospectively, patients are followed by the study clinicians 
throughout sequential trials of antidepressant medications, using standard measures of depressive 
symptoms to monitor clinical progress. When a retrospective assessment is used, researchers use 
one of three instruments to assess treatment resistance in depression. Two are clinician-rated [the 
Antidepressant Treatment History Form (ATHF) (Sackeim, 2001) and the Harvard Antidepressant 
Treatment History (HATH) (Nierenberg et al, 1991)], and one is self-rated [the Massachusetts General 
Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) (Fava and Davidson, 
1996)). Of these three instruments, only two, the ATHF and the MGH ATRQ, have been empirically 
validated (Sackeim, 2001; Chandler et al, 2010). 


10 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
There is substantial mortality and morbidity associated with TRD, and both depression and general 
medical health care expenditures tend to increase with the degree of TRD (Russell et al, 2004). TRD 
is associated with poorer clinical outcome, particularly among those who require multiple 
antidepressant medications (Fekadu et al, 2009). The scope of this problem is therefore highly 
significant both in terms of the numbers of affected individuals and the resultant societal and 
economic burdens. Despite the enormous public health significance of this problem, systematic 
research on TRD has yielded only limited success (Nierenberg et al, 2007). 
Lag Time Limitations of Current Therapies for TRD 
There are only three pharmacological treatments approved by the FDA for adjunctive treatment in 
patients with TRD: aripiprazole, quetiapine, and olanzapine (Papakostas et al, 2007; Bauer et al, 2010; 
Nelson and Papakostas, 2009; Tohen et al, 2010). In addition, only three non-pharmacological 
therapies have been approved for TRD: transcranial magnetic stimulation (TMS) (O’Reardon et al, 
2007), vagus nerve stimulation (VNS), and electroconvulsive therapy (ECT) (Bajbouj et al, 2010; 
Trevino et al, 2010). However, as currently delivered, none of these pharmacologic and non-
pharmacologic treatments has been shown to result in rapid symptom resolution (defined as a 
sizeable and statistically significant treatment effect versus placebo that is apparent as early as 24 to 
72 hours post-initiation of therapy), despite the tremendous need for rapid antidepressant therapies 
that would allow for meaningful clinical improvements within the context of very short hospital 
admissions for TRD patients. 
Promising Preliminary Results with Ketamine Therapy 
Over the last decade, a series of studies has demonstrated the ability of novel approaches – such as 
ketamine, an N-Methyl-D-aspartate (NMDA) antagonist,– to provide significant amelioration of 
symptoms within a few hours, with symptoms typically returning within a period of days after 
discontinuation of the acute intervention (Machado-Vieira et al, 2009). The exact mechanism of 
action of ketamine (see below) is not clear (Machado-Vieira et al, 2009). However, the promising 
results seen in these trials with ketamine therapy highly suggest that a more ambitious program of 
research might accelerate development of rapid-onset antidepressant treatment. 
D.1.a. TOXICOLOGY - KETAMINE 
D.1.a.1. 
SINGLE DOSE TOXICITY STUDIES 
The LD50 for ketamine ranges between 140.0 mg/kg (rat, intraperitoneal injection) and 616.0 mg/kg 
(mouse, oral administration) (CVMP, 1997). These high LD50-values highly exceed the dose level of 
ketamine in the proposed study. 
D.1.a.2. 
REPEAT-DOSE TOXICITY STUDIES 


11 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
In rats daily intravenous doses of 2.5, 5.0 or 10.0 mg/kg for six weeks provoked a slight decrease in 
food intake and moderate body weight gain suppression (CVMP, 1997). In a 6-week dog study, 
ketamine was injected intramuscularly at 4.0, 20.0 or 40.0 mg/kg/day. At all dose levels there was 
some degree of weight loss and anorexia. Some blood parameters were dose-dependently elevated. 
Histological changes in the liver were minor (CVMP, 1997). The magnitude of the dose levels 
associated with these effects, and the duration of treatment in these rat and dog studies, highly 
exceed the dose level of ketamine in this study. 
D.1.a.3. 
NEUROTOXICITY 
Ketamine has been shown to induce neuronal vacuolation and apoptotic cell death in the posterior 
cingulate and retrosplenial cortex of adult rats (40.0-60.0 mg/kg, single subcutaneous or 
intraperitoneal dose) and adult mice (50.0 mg/kg/day intraperitoneally for 7 days) (Olney 1989; 
Jevtovic-Torodovic 2000, 2001, 2005; Zuo 2007). In the hippocampus of adult mice treated with 
ketamine at 5.0 mg/kg intraperitoneally for 5 days, increased cell death was reported (Majewski-
Tiedeken 2008). The relevance to adult humans is unknown. The magnitude of the dose levels 
associated with these rodent findings highly exceed the dose level of ketamine in the proposed study. 
D.1.a.4. 
DEVELOPMENTAL OR REPRODUCTIVE TOXICITY STUDIES 
An embryo-fetal developmental toxicity study in rats given intraperitoneal doses of 25.0, 50.0 or 
100.0 mg/kg during days 1-15 or 5-15 of gestation showed pathological degenerative changes in the 
fetuses at histological examination (focal nuclear hypochromatosis and interfibrillary edema of the 
heart; parenchymal liver cell degeneration; proximal convoluted tubule degeneration). This 
degenerative effect was observed at all dose levels, and was dependent upon the dose and the 
duration of treatment (CVMP, 1997; Kochhar 1986). In an embryo-fetal developmental toxicity study 
mice were injected with ketamine (50.0 mg/kg/day) intravenously during the period of 
organogenesis. No treatment-related effects were noted (Abdel-Rahman and Ismail 2000). 
Reproduction studies in dogs, injected with 25.0 mg/kg ketamine intramuscularly six times during 
one trimester of pregnancy (twice a week over a three-week period), did not show apparent adverse 
effects. Rats were injected during the premating period (10.0 mg/kg intravenously), the period of 
organogenesis (20.0 mg/kg intramuscularly) and the perinatal period (20.0 mg intramuscularly), and 
rabbits were injected during the period of organogenesis (20.0 mg/kg intramuscularly). Ketamine did 
not affect reproduction (CVMP, 1997). From these studies, no definitive conclusions can be drawn 
on the reproductive toxicity potential of ketamine. The magnitude of the dose levels associated with 
the rat fetal toxicity findings highly exceed the dose level of ketamine in the proposed study. 
D.1.a.5. 
GENETIC TOXICITY STUDIES 
In an Ames test, ketamine did not show a mutagenic effect. Ketamine has been reported to show 
genotoxic potential in an in vitro sister chromatic exchange assay in Chinese Hamster ovary cells 
(Adhvaryu et al., 1986; CVMP, 1997) and an in vitro micronucleus test in Chinese Hamster lung 


12 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
fibroblasts (Toyama 2006). From these studies, no definitive conclusions can be drawn on the 
genotoxic potential of ketamine. 
D.1.b. TOXICOLOGY – BREXPIPRAZOLE 
 
D.1.b.1. 
CARCINOGENESIS  
Lifetime carcinogenicity studies were conducted in ICR mice and SD rats. Brexpiprazole was 
administered orally for two years to male and female mice at doses of 0.75, 2 and 5 mg/kg/day (0.9 
to 6.1 times the oral MRHD of 4 mg/day based on mg/m2 body surface area) and to male and female 
rats at doses of 1, 3, and 10 mg/kg and 3, 10, and 30 mg/kg/day, respectively (2.4 to 24 and 7.3 to 73 
times the oral MRHD, males and females). In female mice, the incidence of mammary gland 
adenocarcinoma was increased at all doses and the incidence of adenosquamous carcinoma was 
increased at 2.4 and 6.1 times the MRHD. No increase in the incidence of tumors was observed in 
male mice. In the rat study, brexpiprazole was not carcinogenic in either sex at doses up to 73 times 
the MRHD. Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents 
have been observed following chronic administration of antipsychotic drugs and are considered to 
be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown 
in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine 
tumors in rodents is unknown.  
D.1.b.2. 
MUTAGENESIS  
Brexpiprazole was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames 
test). Brexpiprazole was negative for clastogenic activity in the in vivo micronucleus assay in rats, and 
was not genotoxic in the in vivo/in vitro unscheduled DNA synthesis assay in rats. In vitro with 
mammalian cells brexpiprazole was clastogenic but only at doses that induced cytotoxicity. Based on 
a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans.  
D.1.b.3. 
IMPAIRMENT OF FERTILITY  
Female rats were treated with oral doses of 0.3, 3 or 30 mg/kg/day (0.7, 7.3, and 73 times the oral 
MRHD on a mg/m2 basis) prior to mating with untreated males and continuing through conception 
and implantation. Estrus cycle irregularities and decreased fertility were observed at 3 and 
30  mg/kg/day. Prolonged duration of pairing and increased preimplantation losses were observed 
at 30 mg/kg/day. Male rats were treated with oral doses of 3, 10, or 100 mg/kg/day (7.3, 24 and 240 
times the oral MRHD on a mg/m2 basis) for 63 days prior to mating with untreated females and 
throughout the 14 days of mating. No differences were observed in the duration of mating or fertility 
indices in males at any dose of brexpiprazole 
D.2. CLINICAL EXPERIENCE – KETAMINE AND BREXPIPRAZOLE 
D.2.a. KETAMINE 


13 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Ketamine is a noncompetitive antagonist of NMDA glutamate receptors and it has been safely used 
for anesthesia and analgesia for many years. Early case reports indicated a possible antidepressant 
effect of ketamine administered as an anesthetic to patients with depression undergoing surgical 
procedures (Kudoh, 2002, Correll, 2006). In a small double-blind trial of a single IV ketamine infusion, 
patients with TRD (defined as at least two failed trials of an antidepressant) showed a dramatic 
decrease in depressive symptoms, which was sustained for approximately 3 days (Berman, 2000). 
More recent reports have confirmed the antidepressant effects of intravenous ketamine. In a double-
blind, crossover study in 18 patients with TRD, the IV administration of a single dose of ketamine (0.5 
mg/kg) led to a significant rapid improvement in depressive symptoms sustained up to seven days 
after the infusion (Zarate, 2006). In two open-label trials on patients with TRD, ketamine infusion 
rapidly reduced depressive symptoms (Phelps, 2009; Price, 2009). Most importantly, ketamine 
produced a rapid and robust reduction not only in global depression scores, but in severity of suicidal 
ideation, supporting the use and safety of ketamine in acutely suicidal depressed patients. The 
patients enrolled in those studies had a depression rated as moderate to severe, were on no other 
psychotropic medications and were followed for a short period of time. Another recent open label 
study supported the safety of repeated intravenous ketamine administrations (6 infusions over 2 
weeks) for patients with TRD who had significantly improved after a single infusion (Rot, 2010). 
More recently, clinical researchers have examined the utility of a more user-friendly administration 
route, intranasal, for ketamine. In a randomized, double-blind, crossover study (Lapidus et al, 2014) 
designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with 
depression who had failed at least one prior antidepressant trial, 20 patients with major depression 
were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride 
(40 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 
24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating 
Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, 
changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, 
hemodynamic, and general adverse effects associated with ketamine were also measured. Patients 
showed significant improvement in depressive symptoms at 24 hours after ketamine compared to 
placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score 
difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 
patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p 
= .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects 
and was not associated with clinically significant changes in hemodynamic parameters. This study 
provided the first controlled evidence for the rapid antidepressant effects and safety of intranasal 
ketamine.  
A recent meta-analysis (Xu et al, 2016) identified nine trials, including 201 patients (52% female, 
mean age 46 years), with six trials assessing low-dose ketamine (0.5mg/kg i.v.) and 3 testing very 


14 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
low-dose ketamine (one trial assessed 50mg intra-nasal spray, another assessed 0.1-0.4mg/kg i.v., 
and another assessed 0.1-0.5mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression 
severity score was less marked in the very low-dose trials (P homogeneity <.05). The absolute 
benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). There is substantial 
heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most 
others having benefits that are less durable.  
D.2.a.1. 
KETAMINE SAFETY 
For a summary of clinical information regarding the efficacy (for anesthesia) and safety of ketamine, 
refer to the latest version of the U.S. package insert. 
Ketamine administration at sub-anesthetic doses appears to present an acceptable level of risk for 
carefully screened populations of medically healthy human subjects in the context of clinical research 
programs that intensively monitor subjects throughout their study participation (Perry, 2007). 
D.2.a.2. 
KETAMINE PHARMACOKINETIC STUDIES AND DRUG-DRUG INTERACTIONS 
Bioavailability following an intramuscular dose is 93.0%, intranasal dose 25.0-50.0%, and oral dose 
20±7.0%. Ketamine is rapidly distributed into brain and other highly perfused tissues, and is 12.0% 
bound in plasma. The plasma half-life is 2.3 ± 0.5 hours. Oral administration produces lower peak 
concentrations of ketamine, but increased amounts of the metabolites norketamine and 
dehydronorketamine. Ketamine and its metabolites undergo hydroxylation and conjugation. 
Norketamine produces effects similar to those of ketamine. There are no significant differences 
between the pharmacokinetic properties of the S-(+) and R-(-)-isomers. 
Drug Interactions: Midazolam attenuates altered perception and thought processes. Lorazepam may 
decrease ketamine-associated emotional distress but does not decrease cognitive or behavioral 
effects of ketamine. Acute administration of diazepam increases the half-life of ketamine. 
Lamotrigine significantly decreases ketamine-induced perceptual abnormalities, but increases the 
mood elevating effects. Haloperidol may decrease impairment by ketamine in executive control 
functions, but does not affect psychosis, perceptual changes, negative schizophrenic-like symptoms, 
or euphoria. Alfentanil is additive to ketamine in decreasing pain and increasing cognitive 
impairment. Physostigmine and 4-aminopyridine can antagonize some pharmacodynamic effects of 
ketamine. 
D.2.b. BREXPIPRAZOLE 
Brexpiprazole (Rexulti(®)) is a serotonin-dopamine activity modulator, with a unique receptor 
binding profile and low intrinsic D2 activity suggestive of a lower potential than aripiprazole to cause 
activation-like adverse effects, such as akathisia (McKeage K, 2016). The drug was recently approved 
by the US FDA for adjunctive therapy with antidepressant treatment (ADT) in patients with major 
depressive disorder (MDD) and inadequate response to ADT. In two phase III trials, adjunctive oral 


15 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
brexpiprazole 2 or 3 mg once daily was more effective than monotherapy with ADT in improving 
depressive symptoms in adults with MDD who demonstrated an incomplete response to previous 
treatment with ADT (McKeage K, 2016). Adjunctive brexpiprazole was generally well tolerated in 
clinical trials, which included treatment periods of up to 52 weeks (McKeage K, 2016). There is 
preliminary evidence that adjunctive treatment with brexpiprazole may represent a strategy for 
patients with MDD and inadequate response to antidepressant treatment who have symptoms of 
irritability (Fava M et al, 2016) and anxiety (McIntyre RS et al, 2016).  
E. 
STUDY RATIONALE 
Primary Aim: The primary objective is to investigate whether brexpiprazole (initial dose .5 mg/day 
titrating to 3 mg/day over 21 days) is superior to placebo when combined with intranasal ketamine 
in the acute treatment of patients with TRD at two weeks (Day 14), when added to ongoing and 
stable antidepressant therapy with respect to the study primary outcome measure [change in the 
SDQ total score]. 
Secondary Aim 1: The secondary objective #1 is to investigate whether brexpiprazole (initial dose .5 
mg/day titrating to 3 mg/day over 21 days) is superior to placebo when combined with intranasal 
ketamine in the acute treatment of patients with TRD within 48 hours (Day 2), when added to 
ongoing and stable antidepressant therapy with respect to the study primary outcome measure 
[change in the SDQ total score]. 
Secondary Aim 2: The secondary objective #2 is to investigate whether brexpiprazole (initial dose .5 
mg/day titrating to 3 mg/day over 21 days) is superior to placebo when combined with intranasal 
ketamine in the acute treatment of patients with TRD at four weeks (Day 28), when added to ongoing 
and stable antidepressant therapy with respect to the study primary outcome measure [change in 
the SDQ total score]. 
Secondary Aim 3: The secondary objective #3 is to investigate whether brexpiprazole (initial dose .5 
mg/day titrating to 3 mg/day over 21 days) is superior to placebo when combined with intranasal 
ketamine in the acute treatment of patients with TRD at four weeks (Day 28), when added to ongoing 
and stable antidepressant therapy with respect to the rates of sustained response [50% or greater 
reduction in the MADRS total score].  
Secondary Aim 4: The secondary objective #4 is to investigate whether brexpiprazole (initial dose .5 
mg/day titrating to 3 mg/day over 21 days) is superior to placebo when combined with intranasal 
ketamine in the acute treatment of patients with TRD at Day 2, Day 14, and Day 28, when added to 
ongoing and stable antidepressant therapy with respect to the study secondary outcome measures 
[MADRS, HAMD-6, CGI-S, CGI-I]. 


16 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Secondary Aim 5: The secondary objective #5 is to characterize the safety and tolerability of  
brexpiprazole or placebo treatment during the acute, 4-week treatment period. 
F. 
OBJECTIVES 
F.1. PRIMARY AIM OF THE KETAMINE-BREXPIPRAZOLE TRIAL 
The primary objective is to investigate whether the degree of improvement in SDQ total score on 
brexpiprazole (initial dose .5 mg/day titrating to 3 mg/day over 21 days is superior to placebo when 
combined with intranasal ketamine in the acute treatment of patients with TRD at two weeks (Day 
14), when added to ongoing and stable antidepressant therapy with respect to the study primary 
outcome measure. Superiority will be demonstrated by a statistically significant greater decrease 
(p<0.05, 2-sided) on the SDQ total score for patients receiving brexpiprazole versus placebo therapy.    
F.2. SECONDARY AIMS OF THE KETAMINE-BREXPIPRAZOLE TRIAL 
The secondary objectives are to: 
- 
Investigate whether brexpiprazole (initial dose .5 mg/day titrating to 3 mg/day over 21 days) 
is superior to placebo when combined with intranasal ketamine in the acute treatment of 
patients with TRD within 48 hours (Day 2), when added to ongoing and stable antidepressant 
therapy with respect to the study primary outcome measure [change in the SDQ total score]. 
Superiority will be demonstrated by a statistically significant greater decrease (p<0.05, 2-
sided) on the SDQ total score for patients receiving brexpiprazole versus placebo therapy.  
- 
Investigate whether the degree of improvement in SDQ total score on brexpiprazole (initial 
dose .5 mg/day titrating to 3 mg/day over 21 days) is superior to placebo when combined 
with intranasal ketamine in the acute treatment of patients with TRD at four weeks (Day 28), 
when added to ongoing and stable antidepressant therapy with respect to the study primary 
outcome measure. Superiority will be demonstrated by a statistically significant greater 
decrease (p<0.05, 2-sided) on the SDQ total score for patients receiving brexpiprazole versus 
placebo therapy.   
- 
Investigate whether brexpiprazole (initial dose .5 mg/day titrating to 3 mg/day over 21 days) 
is superior to placebo when combined with intranasal ketamine in the acute treatment of 
patients with TRD at 4 weeks (Day 28), when added to ongoing and stable antidepressant 
therapy with respect to the rates of sustained response [50% or greater reduction in the 
MADRS total score]. Superiority will be demonstrated by a statistically significant greater 
(p<0.05, 2-sided) of sustained response for patients receiving brexpiprazole versus placebo 
therapy. 


17 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
- 
Investigate whether the degrees of improvement in secondary outcome measures [MADRS, 
HAMD-6, CGI-S, CGI-I] total scores on brexpiprazole (initial dose .5 mg/day titrating to 3 
mg/day over 21 days) are superior to placebo when combined with intranasal ketamine in 
the acute treatment of patients with TRD at Day 2, Day 14, and Day 28, when added to 
ongoing and stable antidepressant therapy with respect to the study primary outcome 
measure. Superiority will be demonstrated by a statistically significant greater decrease 
(p<0.05, 2-sided) on the total scores of these secondary measures for patients receiving 
brexpiprazole versus placebo therapy.   
- 
Characterize the safety and tolerability of brexpiprazole compared to placebo using the 
following information: vital signs, treatment-emergent adverse events, the CHRT, 12-lead 
electrocardiogram (ECG), and other laboratory analyses. 
G. 
STUDY DESIGN 
G.1. OVERVIEW 
This is a  multi-site, double-blind, placebo-controlled study of the acute efficacy of oral brexpiprazole 
or placebo combined with intranasal ketamine added to ongoing, stable, and adequate 
antidepressant therapy (ADT) in the treatment of adults with MDD with TRD. Adequate ADT is 
defined as a therapeutically sufficient dose for a sufficient treatment period, which would be 
expected to be effective as listed in the MGH ATRQ.  
G.2. METHODS 
Following a washout period for patients on prohibited psychotropic agents, 52 eligible subjects will 
be randomly assigned to one of two arms in a 1:1 fashion: brexpiprazole (initial dose .5 mg/day 
titrating to 3 mg/day over 21 days) or placebo for four weeks in combination with bi-weekly 
administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of 
intranasal ketamine (40 mg) for two weeks. All subjects will be followed for 28 days to examine the 
efficacy and tolerability of the study drugs’ effects. 
G.3. STUDY DESIGN 
The study will consist of a screening period and a randomization period. Patients who meet eligibility 
during the screening period will be randomized to double-blind treatment with brexpiprazole plus 
intranasal ketamine treatment or placebo as described above.  
H. 
STUDY POPULATION 
H.1. NUMBER OF SUBJECTS 


18 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
52 subjects will enter the double-blind treatment phase of the study. This trial will be conducted 
according to the U.S. FDA guidelines and the Declaration of Helsinki. IRB- approved written informed 
consent will be obtained from all patients before any protocol-specified procedures are carried out. 
The subjects will be drawn from an outpatient sample of patients with MDD, diagnosed with the use 
of the Structured Clinical Interview for DSM-5 Axis I Disorders–Patient Edition (SCID-5), currently on 
an adequate dose of antidepressant therapy, as defined by the MGH ATRQ, for at least 8 weeks, with 
the dose being stable for at least 4 weeks, and with TRD (see definition below). For entry into the 
study, all inclusion criteria must be met, and none of the exclusion criteria can be met. 
H.2. SUBJECT ELIGIBILITY 
H.2.a. INCLUSION CRITERIA 
A subject will be eligible for inclusion only if all of the following criteria are met: 
1. 
Male or female, 18 to 65 years of age, inclusive, at screening. 
2. 
Able to read, understand, and provide written, dated informed consent prior to screening. 
Participants will be deemed likely to comply with study protocol and communicate with study 
personnel about adverse events and other clinically important information. 
3. 
Diagnosed with MDD, single or recurrent, and currently experiencing a major depressive 
episode (MDE) of at least eight weeks in duration, prior to screening, according to the criteria 
defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 
The diagnosis of MDD will be made by a site psychiatrist and supported by the SCID-5. The 
diagnosis will be confirmed by remote, independent raters from the MGH CTNI (Clinical Trials 
Network and Institute) with a SAFER interview. 
4. 
Has a history of TRD during the current MDE, as assessed by the investigator and remote 
centralized rater using the MGH ATRQ. TRD is defined as failure to achieve a satisfactory 
response (e.g., less than 50% improvement of depression symptoms), as perceived by the 
participant, to at least 2 “treatment courses” during the current episode of a therapeutic dose 
of an antidepressant therapy of at least 8 weeks duration (including the current ADT). The 
adequacy of dose and duration of the antidepressant therapy will be determined as per the 
MGH ATRQ criteria. The TRD status will be confirmed by remote, independent raters from 
the MGH CTNI who will administer the MGH ATRQ, via teleconference, between the 
screening visit and the baseline visit. Participants must currently be on a stable (for at least 4 
weeks) and adequate (according to the MGH ATRQ) dose of ongoing antidepressant therapy 
(any antidepressant therapy, with the exception of MAOIs or antipsychotics), of which total 
duration must be at least 8 weeks. 
5. 
Meet the threshold on the total MADRS score of >20 at both the screen visit and the baseline 
visit (Day -7/-28 and Day 0), and as confirmed by the remote centralized MGH CTNI rater 
between the screen visit and the baseline visit. 


19 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
6. 
In good general health, as ascertained by medical history, physical examination (PE) (including 
measurement of supine and standing vital signs), clinical laboratory evaluations, and ECG. 
7. 
If female, a status of non-childbearing potential or use of an acceptable form of birth control 
per the following specific criteria: 
a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, 
i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or 
is post-menopausal with her last menses at least one year prior to screening); or 
b. Childbearing potential, and meets the following criteria: 
i. 
Childbearing potential, including women using any form of hormonal 
birth control, on hormone replacement therapy started prior to 12 
months of amenorrhea, using an intrauterine device (IUD), having a 
monogamous relationship with a partner who has had a vasectomy, or is 
sexually abstinent. 
ii. 
Negative urinary pregnancy test at screening, confirmed by a negative 
urinary pregnancy test at randomization prior to receiving study 
treatment. 
iii. 
Willing and able to continuously use one of the following methods of 
birth control during the course of the study, defined as those which 
result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly: implants, injectable or patch hormonal 
contraception, oral contraceptives, IUD, double-barrier contraception, 
sexual abstinence. The form of birth control will be documented at 
screening and baseline. 
8. 
Body mass index between 18-35 kg/m2. 
9. 
Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, 
insight-oriented, et al.) and frequency (e.g., weekly or monthly) of the therapy has been 
stable for at least three months prior to screening and if the type and frequency of the 
therapy is expected to remain stable during the course of the subject’s participation in the 
study. 
10. 
Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines or 
trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to 
screening and if it is expected to remain stable during the course of the subject’s participation 
in the study.  Patients can also continue treatment with benzodiazepines used for anxiety if 
therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain 
stable during the course of the subject’s participation in the study. 
 
H.2.b. EXCLUSION CRITERIA 


20 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
A potential participant will NOT be eligible for participation in this study if any of the following criteria 
are met: 
1. 
Female of childbearing potential who is not willing to use one of the specified forms of birth 
control during the study. 
2. 
Female that is pregnant or breastfeeding. 
3. 
Female with a positive pregnancy test at screening or baseline. 
4. 
History during the current MDE of failure to achieve satisfactory response (e.g., less than 50% 
improvement of depression symptoms) to >7 treatment courses of a therapeutic dose of an 
antidepressant therapy of at least 8 weeks duration, according to the MGH ATRQ, as 
confirmed by the remote, independent MGH CTNI rater. 
5. 
Total MADRS score of <20 at the screen visit or the baseline visit, or as assessed by the 
remote, independent MGH CTNI rater and reported to the site. 
6. 
Current diagnosis of a substance use disorder (abuse or dependence, as defined by  DSM V-
TR™), with the exception of nicotine dependence, at screening or within 6 months prior to 
screening. 
7. 
Current Axis I disorder, diagnosed at screening with the use of the Structured Clinical 
Interview for DSM-5 AXIS I Disorders (SCID-5), that is the principal focus of treatment and MDD 
the secondary focus of treatment for the past 6 months or more.  
8. 
History of bipolar disorder, schizophrenia or schizoaffective disorders, or any history of 
psychotic symptoms in the current or previous depressive episodes. 
9. 
History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, 
within 5 years of screening. 
10. 
Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has 
been predominant to their MDD at any time within 6 months prior to screening. 
11. 
In the judgment of the investigator, the subject is considered at significant risk for suicidal 
behavior during the course of his/her participation in the study. 
12. 
Has failed to respond to ECT during the current depressive episode. 
13. 
Has received VNS at any time prior to screening. 
14. 
Has dementia, delirium, amnestic, or any other cognitive disorder. 
15. 
Has a clinically significant abnormality on the screening physical examination that might 
affect safety, study participation, or confound interpretation of study results according to the 
study clinician. 
16. 
Participation in any clinical trial with an investigational drug or device within the past month 
or concurrent to study participation. 
17. 
Current episode of: 
a. Hypertension, Stage 1 as defined by a systolic blood pressure ≥160 mmHg or 
diastolic blood pressure ≥100 mHg at the Screening and Baseline Visits within 1.5 


21 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
hours prior to randomization on two of three measurements (standing and 
supine) at least 15 minutes apart. 
b. Recent myocardial infarction (within one year) or a history of myocardial 
infarction. 
c. Syncopal event within the past year. 
d. Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2 
e. Angina pectoris. 
f. Heart rate <45 or >110 beats per minute at screening or randomization (Baseline 
Visit). 
g. QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline 
Visit). 
18. 
Chronic lung disease excluding asthma. 
19. 
Lifetime history of surgical procedures involving the brain or meninges, encephalitis, 
meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer’s or 
Parkinson’s 
Disease), 
epilepsy, 
mental 
retardation, 
or 
any 
other 
disease/procedure/accident/intervention which, according to the screening clinician, is 
deemed associated with significant injury to or malfunction of the CNS, or history of 
significant head trauma within the past 2 years. 
20. 
Presents with any of the following lab abnormalities: 
a. Thyroid stimulating hormone (TSH) outside of the normal limits and clinically significant 
as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level 
is high. Subject will be excluded if T4 level is clinically significant. 
b. Patients with diabetes mellitus fulfilling any of the following criteria: 
i. 
Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at 
screening. 
ii. 
Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus-
related illness in the past 12 weeks. 
iii. 
Not under physician care for diabetes mellitus. 
iv. 
Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 
4 weeks prior to screening. For thiazolidinediones (glitazones) this period should 
not be less than 8 weeks. 
c. Any other clinically significant abnormal laboratory result (determined as such by the 
investigator and MGH CTNI medical monitor) at the time of the screening. 
21. 
History of hypothyroidism and has been on a stable dosage of thyroid replacement 
medication for less than 2 months prior to screening. (Subjects on a stable dosage of thyroid 
replacement medication for at least   3 months or more prior to screening are eligible for 
enrollment.) 


22 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
22. 
History of hyperthyroidism which was treated (medically or surgically) less than 6 months 
prior to screening. 
23. 
History of positive screening urine test for drugs of abuse at screening: cannabinoids (if the 
patient has a legitimate medical prescription for cannabis, patient must agree to abstain 
during the entirety of the study and to have a negative test at baseline), cocaine, 
amphetamines, barbiturates, opiates (unless use is in accordance with guidance provided in 
table of allowed and excluded medications). 
24. 
Patients with exclusionary laboratory values (see Table 1), or requiring treatment with 
exclusionary concomitant medications (see Appendix 1). 
25. 
Patients on exclusionary concomitant psychotropic medications, the half-life of which would 
not allow sufficient time for patients to have been free of the medication post-taper for five 
half-lives within the maximum screening period (28 days). 
26. 
Patients with a history of narrow angle glaucoma. 
27. 
Liver or renal Function tests  which meet the exclusion criteria in Table 1, or a history 
of hepatic or renal dysfunction. 
 
TABLE 1-EXCLUSIONARY SAFETY VALUES OF POTENTIAL CLINICAL CONCERN 
Hematology 
Leukocytes 
<2 or >17.5 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Chemistry 
Total bilirubin 
>2 times the upper limit of the reference range 
AST* 
>2.5 times upper limit of the reference range 
ALT* 
>2.5 times upper limit of the reference range 
GGT* 
>2.5 times upper limit of the reference range 
Alk Phosphatase* 
>2.5 times upper limit of the reference range 
Creatinine 
>1.3 times upper limit of the reference range 
BUN/Urea 
>1.3 times upper limit of the reference range 
Glucose 
< 70 mg/dl or >2 times the limits of the reference range 
Uric acid 
>1.5 times upper limit of the reference range 
*LFTs higher than 2.5 times ULN will be exclusionary. 
H.3. RATIONALE FOR THE INCLUSION/EXCLUSION CRITERIA 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study are meaningful in support of the research 
hypotheses. It is imperative that subjects fully meet all eligibility criteria. 
 
 


23 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
I. 
STUDY ASSESSMENTS – PLAN AND METHODS 
 
I.1. 
STUDY CONDUCT 
An overview of the schedule of visits and procedures is shown in Table 2. 
 
TABLE 2– OVERVIEW OF STUDY SCHEDULE 
Screen 
Visit 
Screening 
Period 
V1 / 
Baseline 
Visit 
V2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
V 9 
V 10 
V 11 
Day -
28 to  
Day -7 
Taper (opt.) 
5 half-lives 
of excluded 
psychotropic 
drug(s) 
Day 0 
Day 1 
Day 2 
Day 5 
Day 8 
Day 11 
 
Day 14 
 
Day 17 
 
Day 21 
 
Day 23 
 
Day 28 
 
 
 
Baseline 
Assess. 
Assess. 
Assess.  
Assess.  
Assess.  
Assess.  
Assess.  
Assess.  
Assess.  
Assess.  
Assess.  
 
 
Intranasal 
Ketamine 
Admin. 
Assess. 
Assess.  
Intranasal 
Ketamine 
Admin. 
Intranasal 
Ketamine 
Admin. 
Intranasal 
Ketamine 
Admin. 
Intranasal 
Ketamine 
Admin. 
Assess.  
Intranasal 
Ketamine 
Admin. 
Assess.  
Assess.  
 
 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
Study 
Drug* 
*Brexpiprazole or Placebo 
Subjects will be screened for eligibility as detailed above. Study participants will be consented prior 
to the administration of any procedure or wash-out. Following a washout period, under the close 
supervision and monitoring of the study clinicians, for patients on psychotropic drugs (with the 
exception of ongoing antidepressant therapy and of ongoing hypnotic therapy), baseline assessment, 
MGH CTNI remote interview, and re-confirmation that all criteria for entry into the study are met, 
eligible subjects will be randomly assigned to one of two arms: brexpiprazole plus intranasal 
ketamine (n=25) or placebo plus intranasal ketamine (n=25). The brexpiprazole dose will be titrated 
in the following manner: 0.5 mg/day during the first week, at the Visit 5/Day 8 visit, the dose will be 
increased to 1 mg/day , at Visit 7/Day 14 the dose will be increased to 2 mg/day, and at Visit 9,/Day 
21, the dose will be increased to 3 mg/day. If the dose escalation is not tolerated, patient can go back 
to previous dose (fixed-flexible dose escalation). As per Table 2, all subjects will be followed for 28 
days to examine the efficacy and tolerability of brexpiprazole plus intranasal ketamine’s effects. The 
study assessments will be performed at Days 0, 1, 2, 5, 8, 11, 14, 17, 21, 23, and 28 to assess the 
safety and efficacy of brexpiprazole plus intranasal ketamine compared to placebo plus intranasal 
ketamine treatment therapy in depressed patients who have demonstrated an inadequate response 


24 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
to at least 2 adequate antidepressant therapies (ADTs) during the current MDE. Intranasal ketamine 
(40 mg) will be administered after all the assessments are completed on Days 0, 5, 8, 11, 14, and 21. 
 
I.1.a. SCREENING PHASE 
The screening period will range from a minimum of 7 days to a maximum 28 days. The purpose is to 
ensure that only appropriate patients are entered into the study. The investigator will determine 
that the patients meet eligibility criteria and will collect the demographic and medical data 
permitting full characterization of the patients. The screening period is also designed to ensure that 
any prohibited pharmacotherapy is washed out. Benzodiazepine therapy is allowed per the 
requirements in Appendix I. The screening period begins when informed consent is signed. Screening 
evaluations are to be conducted as outlined in the Study Schedule ( 
TABLE 3– STUDY SCHEDULE 
). 
The screening period will range from a minimum of 7 days to a maximum of 28 days. The screening 
period begins when informed consent is signed. Only the study physicians will perform the informed 
consent procedures. Once patients agree to participate in the study by signing the informed consent 
document, a full medical and psychiatric history will be taken and a physical and laboratory 
examination will be performed, as outlined in the Table 3. 
Only patients currently on stable antidepressant therapy will be eligible for the study. During 
screening, investigators must document history during the current episode of inadequate response 
to at least 2 trials of antidepressant treatment of adequate dose and duration, as specified by the 
MGH ATRQ (Fava and Davidson, 1996; Fava, 2003; Chandler et al, 2010). Such determination will be 
confirmed by the remote, independent MGH CTNI raters. 
We have observed in 3 multi-center trials recently completed by the MGH CTNI that the placebo 
responses among subjects who have not responded to antidepressant therapy and are still on the 
antidepressant at the time of the screening assessment are comparable or even lower than the 
placebo response rates reported in trials with the prospective determination of resistance, such as 
the aripiprazole augmentation trials (Fava et al, 2010; Fava et al, 2012; Nelson et al, 2009). 
The screening period is also designed to allow the gradual taper and discontinuation of the ongoing 
excluded psychotropic drugs so that any prohibited psychotropic medication is washed out under 
supervision of a study physician. The study physician and/or site staff will maintain ongoing 
telephone contact with the patient during the washout period in order to ensure patient safety 
during this time. Patients will discontinue their excluded psychotropic drugs documented during the 


25 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
screening phase to allow proper wash-out at the baseline/randomization visit (e.g., at least 5 half-
lives of the drug). The screening period (between the screen visit and baseline visit) can be extended 
to allow for a clinically appropriate tapering of such medications, again under the close supervision 
of the study physician, who will see them weekly during the taper phase and to ensure that the 
discontinuation of the excluded psychotropic medications occurs at least 5 half-lives prior to the 
baseline visit. The investigator will determine that patients meet eligibility criteria and will collect the 
demographic and medical data permitting full characterization of the patient. 
TABLE 3– STUDY SCHEDULE 
 
 
Screen Visit 
Remote, 
Indep. 
SAFER 
Rater 
Only 
V1 Baseline 
Visit 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
V 9 
V 10 
V 11 
 
Day -28 to 
Day -7 
 
Day 0 
Day 1 
Day 2 
Day 5 
+/- 2 
days 
Day 8 
+/- 2 
days 
Day 11 
+/- 2 
days 
 Day 14 
+/- 2 
days 
Day 17 
+/- 3 
days 
Day 21 
+/- 3 
days 
Day 23 
+/- 4 
days 
Day 28 
+/- 4 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SDQ 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D17 
 
 
X 
 
 
 
 
 
 
 
 
 
 
HAM-D6 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MGH ATRQ 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CHRT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Menopause and 
Hormonal Status 
(RLHQ)†† 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs and 
AEs** 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
Urine tox screen 
test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 


26 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Pregnancy test 
(urine) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry, CBC ** 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
TSH, HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Intranasal  
ketamine 
administration 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
 
Study Drug 
Dispensation 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
*Performed by MGH CTNI remote, independent rater. **Refer to Table 4 for specific tests to be performed. 
††Menopause and hormonal status questionnaire (RLHLQ, Modules 1 and 2 in all women, and Module 3 (Day 30) in pre-
menopausal women only). 
I.1.b. REMOTE INTERVIEW 
To ensure that the appropriate patients are entered into the trial, remote diagnostic assessments 
(SAFER Interview), and baseline depression severity and treatment history assessments (MGH ATRQ, 
MADRS, and CGI-S) will be performed remotely by the independent MGH CTNI rater, and the patient 
will be contacted by telephone while they are off-site between the screen visit and the baseline visit, 
during which call the above assessments will be performed. Sites will be notified of the results within 
24 hours of the interview. 
I.1.c. RANDOMIZATION 
For entry into the study and randomization, all eligibility criteria MUST be met (e.g., all inclusion 
criteria and no exclusion criteria). Patients who meet inclusion/exclusion criteria at the baseline visit 
(Day 0) will be randomized in a 1:1 fashion to either brexpiprazole plus intranasal ketamine treatment 
or placebo plus intranasal ketamine. All subjects will be followed for up to 28 days post 
randomization in order to examine the efficacy, safety, and tolerability of the study drug as well as 
the durability of the study drug’s effects. 
Specifically, patients will return for outcome assessments 24 hours after initiating treatment (Day 1), 
48 hours after initiating treatment (Day 2), and then every 3 days after that for 26 days, with end of 
study visit one week after the last double-blind visit. (See Table 3 for the Study Schedule of the 
events.)  
Patients with a MADRS score below 20 at either the screening or baseline visits will be excluded from 
further participation in the study. Upon determining at the baseline visit (Day 0) that a patient still 
meets all entry criteria for the study, the patient will be assigned (by study subject number assigned 
at consent) to the next randomization slot from the randomization list that will have been generated 
by the MGH Biostatistician.  
I.1.d. BASELINE VISIT (VISIT 1) (DAY 0) 


27 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
The patient should be instructed to refrain from eating and avoid alcohol as well as opioid and 
narcotic analgesics the day of the baseline visit (after midnight), as well as benzodiazepines within 
2 hours of the intranasal administration. For visits in the afternoon, patients may have a light meal 
in the morning no less than 3 hours before the study visit. 
 
Upon arrival, the patient will be administered the SDQ, , the 17-item Hamilton Rating for Depression 
(HAM-D-17), the MADRS, the CGI-I, the CGI-S, and the CHRT by the site rater.  
Upon completion of all study-related inclusion procedures as listed in Table 3 and upon the 
investigator’s confirmation that the patient still meets all of the study inclusion criteria and none of 
the exclusion criteria, the patient may be randomized.  
All subjects will be dispensed brexpiprazole or placebo, as well as 40 mg of ketamine administered 
intranasally.  The study drug ( brexpiprazole or placebo) should be taken by the patient before 
ketamine administration.  Detailed instructions for ketamine dose preparation will be provided to  
the pharmacist in an additional guidance document. Storage conditions should be followed according 
to the package insert. Dosing procedures will be provided to the clinical unit in a separate document. 
Physiological Monitoring: Medical staff monitoring the ketamine administration will be prepared to 
treat increases in blood pressure greater than 180/110 mm Hg or heart rate greater than 110 bpm, 
or follow their institutional guidelines if more conservative. If these elevations resolve spontaneously 
within a short time period, they will generally not be treated.  Heart rate and blood pressure should 
be recorded at 15 minutes post dose, 30 minutes post dose, 45 minutes post dose, 1 hour post dose, 
90 minutes post dose and 2 hours post dose.  The ketamine intranasal administration will be 
discontinued in the event that three consecutive measurements remain above protocol-defined 
limits, or according to institutional guidelines if more conservative, despite antihypertensive 
administration. A study psychiatrist will release the subject at the conclusion of the testing period at 
the end of the visit. A trained research assistant along with a research nurse will be present during 
the entire administration and monitoring period. All side effects will be recorded during the ketamine 
treatment and for the 2 hours following. Clinically relevant vital sign changes will be recorded as 
adverse events. 
A  study physician (MD or DO)  will be present in the unit throughout the administration of ketamine 
so that potential adverse events can be evaluated and treated promptly, and will assess the patient 
for AEs, both physical and psychiatric, at Hours 1 and 2 following completion of the ketamine 
administration.  They will remain available in the study site until discharge. The study physician will 
have a current certificate for ACLS training.  An emergency medical cart will be available with oxygen 
delivery capability. The study physician will remain in the unit for at least one hour following the 
termination of the ketamine treatment or until the patient meets Aldrete criteria (good respiration, 
O2 saturation, consciousness, circulation, and activity) for Phase 2 post-anesthesia care, whichever 


28 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
period is longer.  For sites which are not hospital-based, procedures for emergency transfer to the 
Emergency Department will be described in the Manual of Operations (MOP). 
 
Discharge Procedure: Discharge procedures should not begin earlier than 3 hours following 
completion of the intranasal administration of ketamine. Before being discharged patients should be 
awake and alert, feeling well, with no nausea, vertigo, or dizziness. There should be no significant 
change in vital signs from prior to ketamine administration. 
They will be given a small meal before discharge. 
Patients will be instructed not to drive. The study coordinator will release them to the care of an 
adult escort, who will accompany the patient home. 
I.1.e. VISIT 2 (DAY 1) 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, , the CGI-I, the CGI-S, and the 
CHRT. Following completion of the scales, the remaining procedures listed in Table 3 should be 
completed. 
I.1.f. VISIT 3 (DAY 2) 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of the scales, the remaining procedures listed in Table 3 
should be completed. 
I.1.g. VISIT 4 (DAY 5) 
The patient should be instructed to refrain from eating and avoid alcohol as well as opioid and 
narcotic analgesics the day of the baseline visit (after midnight) , as well as benzodiazepines within 
2 hours of the intranasal administration. For visits in the afternoon, patients may have a light meal 
in the morning no less than 3 hours before the study visit.  
 
 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales the procedures listed in Table 3 should be 
completed. 
The procedures for administration of ketamine and dispensation of blinded study drug will be the 
same as in section I.1.d and the Manual of Operations for the study. 
I.1.h. VISIT 5 (DAY 8) 
The patient should be instructed to refrain from eating and avoid alcohol as well as opioid and 
narcotic analgesics the day of the baseline visit (after midnight), as well as benzodiazepines within 
2 hours of the intranasal administration. For visits in the afternoon, patients may have a light meal 
in the morning no less than 3 hours before the study visit. 


29 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
The procedures for administration of ketamine and dispensation of blinded study drug will be the 
same as in sectionI.1.d. , and the Manual of Operations for the study. 
I.1.i. 
VISIT 6 (DAY 11) 
The patient should be instructed to refrain from eating and avoid alcohol as well as opioid and 
narcotic analgesics the day of the baseline visit (after midnight), as well as benzodiazepines within 
2 hours of the intranasal administration. For visits in the afternoon, patients may have a light meal 
in the morning no less than 3 hours before the study visit. 
 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
The procedures for administration of ketamine and dispensation of blinded study drug will be the 
same as in section H.1.d. , and the Manual of Operations for the study. 
I.1.j. 
VISIT 7 (DAY 14) 
The patient should be instructed to refrain from eating and avoid alcohol as well as opioid and 
narcotic analgesics the day of the baseline visit (after midnight), as well as benzodiazepines within 
2 hours of the intranasal administration. For visits in the afternoon, patients may have a light meal 
in the morning no less than 3 hours before the study visit. 
 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
The procedures for administration of ketamine and dispensation of blinded study drug will be the 
same as in section H.1.d. , and the Manual of Operations for the study. 
I.1.k. VISIT 8 (DAY 17) 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
I.1.l. 
VISIT 9 (DAY 21) 


30 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
The patient should be instructed to refrain from eating and avoid alcohol as well as opioid and 
narcotic analgesics the day of the baseline visit (after midnight), as well as benzodiazepines within 
2 hours of the intranasal administration. For visits in the afternoon, patients may have a light meal 
in the morning no less than 3 hours before the study visit. 
 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
The procedures for administration of ketamine and dispensation of blinded study drug will be the 
same as in section H.1.d. , and the Manual of Operations for the study. 
I.1.m. VISIT 10 (DAY 23) 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
I.1.n. VISIT 11 (DAY 28) 
Upon arrival, the patient will be administered the SDQ, the HAM-D6, the MADRS, the CGI-I, the CGI-
S, and the CHRT. Following completion of these scales, the procedures listed in Table 3 should be 
completed. 
I.1.o. EARLY TERMINATION VISIT 
If a patient is terminated from the study before completion, but after at least one dose of ketamine 
and/or study drug, the procedures listed in Table 3 for Visit 11 (Day 28) should be completed.  
I.1.p. END OF STUDY TREATMENT ADMINISTRATION 
At the end of double-blind treatment (Day 28), both patients and clinicians will be asked to guess 
treatment assignment. 
I.1.q. POST-STUDY FOLLOW-UP 
Patients who are non-responders at the completion of Visit 11 (Day 28) will be offered a referral for 
treatment. 
I.1.r. PATIENT RECRUITMENT 
Patients will be recruited through advertisement, as well as clinician referral and self-referral. Self-
referred patients will call the study sites and will be screened over the phone by the study 
coordinators. Those deemed potentially eligible will be scheduled for a screening visit with one of 
the study physicians at the sites. Based on clinical and human subject protection considerations, a 
potential subject will, under no circumstance, be advised to taper his/her current medication 
regimen prior to the screening visit. 


31 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Participants will also be recruited through physician referral. Each site will recruit subjects via referral 
from primary care and specialty clinics from the communities surrounding each study site. Each site 
will utilize the experience of the MGH CTNI to conduct outreach activities to community 
organizations, colleges and other resources. Sites will regularly collaborate on strategies to recruit 
women and minorities, and sites will employ strategies specific to their local community, in ways 
that are culturally sensitive and specific to the local minority population. Retention will be enhanced 
with fair reimbursement (as deemed appropriate by the local IRB) for participants’ time. 
Assessments and procedures within the study visits will occur as shown in Table 3. A summary 
description of each data collection instrument is provided later in this section. 
I.2. 
PROCEDURES 
I.2.a. LABORATORY/DIAGNOSTIC PROCEDURES 
Once the patient has signed the informed consent document, the urine pregnancy and toxicity test 
will be performed at screen and baseline visits. 12 lead ECGs will be measured at the screen visit and 
at visits 4,5,6,7 and 9 as required by the physiological monitoring procedures in the Manual of 
Operations .  A Chemistry and CBC will also be obtained at the screening visit, and at Visits 7 and 11. 
If TSH is high, subject may be tested for T4 at the request of the PI.  Weight, oral temperature, and 
seated and supine pulse and blood pressure (Vital Signs) will be recorded at each visit.  Height is 
recorded at the Screening Visit only.  (BMI is calculated automatically in the EDC). At the screen visit, 
Visit 7 and at Visit 11, patients will have a physical examination. The laboratory tests required are 
listed in Table 4, below. Laboratory tests will be performed at the site, and each site will provide their 
laboratory normal to the coordinating center. 
TABLE 4– LABORATORY TESTS  
Laboratory Test 
Frequency 
CBC 
Screen, Visit 7, Visit 11 
Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, 
Glucose, Uric Acid) 
Screen, Visit 7, Visit 11 
TSH, HbA1c 
Screen 
Pregnancy Test 
Screen, Visit 1 
Urine Tox Screen 
Screen, Visit 1 
 
I.2.b. BLINDING PROCEDURES 


32 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Individual treatment codes, indicating the treatment randomization for each randomized patient, 
will be available to the investigator(s) or site pharmacists from a member of the MGH CTNI unblinded 
staff. The treatment code must not be broken except in medical emergencies when the appropriate 
management of the patient necessitates knowledge of the treatment randomization. The 
investigator documents and reports the action to MGH CTNI study staff, in accordance with the 
procedures in the Manual of Operations, without revealing the treatment given to the patient to 
MGH CTNI blinded staff. Treatment codes will not be broken for the planned analyses of data until 
all decisions on the evaluability of the data from each individual patient have been made and 
documented. 
I.2.c. OUTCOME AND SAFETY MEASURES 
I.2.c.1. OUTCOME MEASURES 
Symptom improvement will be evaluated by assessing changes in the primary outcome measure, 
the self-rated Symptoms of Depression Questionnaire (SDQ) (Pedrelli et al, 2014). Brexpiprazole 
has shown in recent studies to have significant benefits in domains such as irritability, anger, 
anxiety, and nervousness. These domains are not captured or are only partially captured by 
standard scales such as HAMD or MADRS.  In a recent study of NSI-189, the SDQ slightly 
outperformed the MADRS in detecting a change over placebo because of the broader symptom net 
cast by the SDQ. 
  
Secondary outcome measures include the HAM-D6, which has shown greater sensitivity to change 
and greater effect sizes compared to the longer, multidimensional versions of the HAM-D (e.g., HAM-
D-17 and HAM-D-28) (Faries et al, 2000; Bech et al, 2010), the MADRS and the CGI-S and CGI-I (Guy, 
1976). 
I.2.c.2. SAFETY MEASURES 
Vital signs will be obtained at every visit.  At screening and at  visits 1, 4, 5, 6, 7 and 9, digital ECGs 
will be obtained after the patient has been resting in a semi-recumbent position for at least 10 
minutes. All digital ECGs will be documented by recording date, time, heart rate, QRS duration, PR 
interval, RR interval, QT interval, and QTcF interval. QTcF intervals will be calculated using the 
Fridericia formula (Puddu et al 1988). If indicated, additional ECG assessments can be made at the 
discretion of the investigator. The investigator will judge the overall interpretation as normal or 
abnormal. If abnormal, it will be decided as to whether or not the abnormality is clinically significant 
or not clinically significant and the reason for the abnormality will be recorded on the eCRF. 
Abnormal values shall not be recorded as AEs unless deemed clinically significant. 
The patient's blood pressure will be measured a total of three times at both the screen and baseline 
visits (prior to randomization), with each measurement taken at least 15 minutes after the previous 
measure. If two out of three measurements are within the range for inclusion at each visit (see 


33 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Exclusion 17a and 17b), the patient will be considered to have met the enrollment criteria for normal 
blood pressure.  The baseline blood pressure should be measured within 1.5 hours prior to 
randomization. 
At the screen visit and the baseline visit (Visit 1) and at Visit 7 and Visit 11, patients will have their 
blood drawn for Chemistry and CBC testing. At the screen visit, patients will also have TSH and HbA1c 
measured.  At the screen visit and at Visit 7 and Visit 11, patients will have a physical examination. 
The presence of any side effect or adverse event will be carefully documented at screen and at every 
subsequent visit covering events since the last visit. Reasons for premature discontinuation, including 
intolerable side effects, will be recorded. 
I.2.d. STUDY INSTRUMENTS 
The following instruments will be administered according to the schedule in Table 3: 
I.2.d.1. DIAGNOSTIC INSTRUMENTS 
Structured Clinical Interview for DSM-5 (SCID 5): The SCID, administered by the clinician, includes 
modules aimed at diagnosing possible Axis I disorders. Questions here are asked exactly as written, 
and each is based on the individual criteria from DSM-5. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) 
(Fava and Davidson, 1996; Fava, 2003): This is a clinician assisted questionnaire that examines the 
antidepressant treatment history, using specific anchor points to define the adequacy of both dose 
and duration of each antidepressant trial, as well as the degree of symptomatic improvement 
obtained with each trial. This questionnaire, which has been validated, allows for the determination 
of treatment resistance in depression (Chandler et al, 2010). 
Reproductive Lifecycle and Hormone Questionnaire (RLHQ) (Freeman et al, 2013). This is a standard 
brief questionnaire implemented systematically at baseline in clinical trials for MDD to assess 
reproductive lifecycle status and the use of exogenous hormones. This study will use Modules 1 and 
2 in all women, and add Module 3 (menstrual cycle tracking) in applicable women. 
I.2.d.2. EFFICACY MEASURES 
Symptoms of Depression Questionnaire (SDQ) (Pedrelli et al, 2014): This validated self-rating 
instrument has 44 items on a scale of 1-6, measuring multiple depressive symptom domains. The 
time frame for this scale is the past 3 days. 
6 and17-item Hamilton Rating Scale for Depression (HAM-D6)(HAM-D17) (Hamilton, 1960, 1967): 
This instrument is completed with a structured interview guide developed by Per Bech by the 
clinician based on his/her assessment of the patient's symptoms (Bech et al, 1986). This structured 
interview has been validated in the DUAG studies for use with time frames shorter than one week 


34 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
(Gram, 2008). The HAM-D6 has been shown greater sensitivity to change and greater effect sizes 
compared to the longer, multidimensional versions of the HAM-D (HAMD-17 and HAMD-28) (Faries 
et al, 2000; Bech et al, 2010). The time frame for this scale is the past 24 hours. Only once, at the 
baseline visit (Visit 1), will the 17-item version of the HAM-D be administered, in order to examine 
for the presence of anxious MDD (which is based on the anxiety somatization subscale of the HAM-
D17), with the time frame of the past 3 days. 
Clinical Global Impressions–Severity (CGI-S) and Clinical Global Impressions–Improvement (CGI-I) 
scales (Guy, 1976): These clinician-rated scales rate the severity of the disorder and the global 
improvement since beginning of the study. The time frames for these two scales are the past 3 days. 
Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979): This 10-
item clinician-rated instrument measures depression severity. It will be administered with a 
structured interview guide. The time frame for this scale is the past 3 days. 
I.2.d.3. SAFETY MEASURES 
The Concise Health Risk Tracking (CHRT) (Trivedi et al, 2011): The Concise Health Risk Tracking 
(CHRT) is a validated clinician-rated scale evaluating three independent factors (current suicidal 
thoughts and plans, perceived lack of social support, and hopelessness). It has excellent psychometric 
properties and can be used to monitor suicidal risk in clinical practice and research settings. The time 
scale for the CHRT is the last three days. 
I.2.e. RELIABILITY TRAINING 
All site study staff chosen to be involved in the assessment of study subjects are very familiar with 
standardized clinician-rated measures such as the SCID-5, the HAM-D6, the MADRS and the CHRT. 
They have all received extensive training in the use of these instruments through videotaped and live 
interviews of mock patients. 
I.2.f. PATIENT ADHERENCE TO PROTOCOL 
Every effort will be made to encourage patients to comply with the procedures and the assessments 
involved in study. Patients will be compensated for their time at each visit, at a rate determined 
appropriate by the IRB (estimated compensation: $20.00/hour). We believe that this level of subject 
compensation, while non-coercive, facilitates adherence to assessments and procedures that require 
frequent, inconvenient visits. Subjects and clinicians will be asked to guess which arm of the study 
the subjects were in at the end of the study to assess if blinding was successful. 
I.3. 
DISCONTINUED SUBJECTS 
Sites will follow the procedures in Section I.1.o. for discontinued patients. 
I.4. 
EVALUATION OF ADVERSE EVENTS (AES) 


35 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
I.4.a. DEFINITION OF AES 
Adverse Event 
 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonization [ICH]). 
This definition includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
I.4.b. REPORTING OF AES 
Observed and spontaneously reported adverse events will be recorded at each visit. Spontaneously-
reported adverse events will be classified as mild, moderate or severe. Patients shall be allowed to 
contact the investigator or a member of his staff at any time between visits concerning adverse 
events or worsening of symptoms. 
 All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated Informed Consent Form (ICF) is obtained until completion of the 
subject's last study-related procedure (which may include contact for follow-up of safety). Serious 
adverse events, including those spontaneously reported to the site-investigator from the time a 
signed and dated ICF is obtained until within 30 days after the last dose of study drug must be 
reported using the Serious Adverse Event Form. The Investigator-Sponsor will evaluate any safety 
information that is spontaneously reported by a site- investigator beyond the time frame specified 
in the protocol. 
 
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. 
 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, must 
be recorded using medical terminology in the source document and the Electronic Case Report Form 
(eCRF). Whenever possible, diagnoses should be given when signs and symptoms can be ascribed to 
a common medical etiology with reasonable certainty as per site clinician (e.g., cough, runny nose, 
sneezing, sore throat, and head congestion should be reported as "upper respiratory infection" when 
such a determination is made with reasonable certainty as per site clinician). Investigators must 
record in the eCRF their opinion concerning the relationship of the adverse event to study therapy. 


36 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
All measures required for adverse event management must be recorded in the source document and 
reported according to Investigator-Sponsor instructions. 
 
The Investigator-Sponsor assumes responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The Investigator-Sponsor will also report to site investigators all serious 
adverse events that are unlisted (unexpected) and associated with the use of the study drug. The site 
investigator will report these events to the appropriate IRB. 
I.4.b.1. TIME PERIOD FOR COLLECTION OF ADVERSE EVENTS 
Adverse events and SAEs will be collected from the time of signature of informed consent throughout 
the treatment period and including the observation period. Unsolicited SAEs will be collected for 30 
days post last study treatment. 
I.4.b.2. FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS 
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. MGH CTNI 
or its designee retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
 


37 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
I.4.b.3. VARIABLES 
The following variables will be collected for each AE: 
- AE (verbatim) 
- The date and time when the AE started and stopped 
- Maximum intensity or intensity or changes in intensity 
- Whether the AE is serious or not 
- Investigator causality rating against study drug (yes or no) 
- Action taken with regard to IP 
- AE caused patient’s withdrawal from the study (yes or no) 
- Outcome 
In addition, the following variables will be collected for SAEs: 
- Date AE met criteria for SAE 
- Date investigator became aware of SAE 
- AE is serious due to [insert reason] 
- Date of hospitalization 
- Date of discharge 
- Probable cause of death 
- Date of death 
- Autopsy performed 
- Causality assessment in relation to study procedure(s) 
- Causality assessment in relation to study drug 
- Causality assessment in relation to other medication 
- Description of AE 


38 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Intensities will be reported for each AE in the following categories: a) Mild (awareness of sign or 
symptom, but easily tolerated); b) Moderate (discomfort sufficient to cause interference with normal 
activities); c) Severe (incapacitating, with inability to perform normal activities). 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section H.4.d. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE. On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke, but would be an SAE. 
Worsening symptoms of the primary study condition (i.e., MDD) should not be recorded as an AE. 
However, worsening of MDD will be reported as an adverse event if, in the opinion of the 
investigator, clinically significant worsening of depression occurs following intranasal ketamine 
administration. In addition, hospitalization resulting from worsening psychiatric symptoms should be 
recorded as an SAE in the eCRF.  
Should an overdose of study drug occur, it must be reported in accordance with the procedures 
described below. An overdose associated with symptoms must be reported as an AE, while an 
overdose without associated symptoms, must be reported only on the separate MGH CTNI Clinical 
Study Overdose Report Form. Any overdose will also be considered a protocol violation and reported 
as such. 
I.4.b.4. SUICIDAL IDEATION AND BEHAVIOR 
The documentation and proper management of suicidal ideation by sites will be documented with 
the use of the CHRT completed by site clinicians during all visits. 
Any patient who, based on the investigator’s judgment, poses an imminent risk of suicide should be 
discontinued from the study (see Section J.6). All efforts should be taken to minimize the risk of 
suicide and the investigator should carefully monitor the patient. If during the course of the study, a 
patient shows evidence of suicidal behavior, the patient should be evaluated immediately or referred 
to their attending psychiatrist or a local emergency room for further evaluation to see if they are safe 
to continue in the study. The site should have the ability to direct any patient that requires 
emergency hospitalization to an emergency room or inpatient psychiatric unit that is within a 50-
mile radius of the site. In addition, the patient should be able to contact someone at the site 24 hours 
per day should they have serious worsening of their condition. 
Suicide and attempted suicide, irrespective of the method, but occurring in connection with the use 
of IP, should be reported as AEs (all suicides are SAEs; attempted suicides can be either serious or 
non-serious adverse events). The event should be identified as suicide or attempted suicide, and the 
method of the suicide or attempt should be provided. If an attempted suicide meets the criteria for 


39 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
an SAE, the event must be reported according to the guidelines in Section I.4.i.2.  If a suicide attempt 
does not meet the criteria for an SAE, it should be considered a reportable event.  
All events of suicidal ideation and behavior will be carefully monitored. These include events of 
suicide attempts, emergence or significant worsening of suicidal ideation, completed suicides, and 
suicidal behavior. If a suicidal behavior meets the criteria for a SAE, according to the guidelines in 
I.4.i.2, investigators are required to report the event according to the guidelines for SAEs described 
in Sections I.4.i.2 
I.4.c. ADVERSE EVENT CODING 
The latest version of the AE dictionary, Medical Dictionary for Regulatory Activities (MedDRA), will 
be used by the CRO staff for the classification and analysis of AEs entered in the study database. For 
regulatory reporting, SAEs will be processed in the electronic data capture (EDC) system and coded 
using MedDRA.  
I.4.d. PREGNANCY 
If a subject (or subject’s partner) becomes pregnant during the study, it must be reported in within 
24 business hours of the time the investigator becomes aware of the event and in accordance with 
the procedures described on the Pregnancy Report Form. Pregnancy in itself is not regarded as an 
AE unless there is a suspicion that a study drug may have interfered with the effectiveness of a 
contraceptive medication. Any pregnancy that occurs from Day 1 to 30 days following the last dose 
given will be followed for gestational outcome and the outcome would be reported to the Sponsor. 
I.4.e. CAUSALITY COLLECTION 
The investigator will assess the causal relationship (i.e., the relationship to study treatment) between 
the IP and AEs, and answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?” 
Causal relationship in cases where the disease under study has deteriorated due to lack of effect will 
be classified as no reasonable possibility.  
For SAEs, causal relationship will also be assessed. Note that for SAEs that could be associated with 
any study procedure, the causal relationship is implied as “yes.” 
A guide to the interpretation of the causality question is found in the MOP. 
I.4.f. ADVERSE EVENTS BASED ON SIGNS AND SYMPTOMS 
All AEs spontaneously reported by the patient in response to the open question from the study 
personnel: “Have you had any health problems since the previous visit?” or revealed by observation 
will be collected and recorded in the eCRF. In the collection of AEs, the recording of diagnoses is 
preferred (when possible) over the recording of a list of signs and symptoms. However, if a diagnosis 


40 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
is known and there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
I.4.g. ADVERSE EVENTS BASED ON EXAMINATIONS AND TESTS 
The results from protocol-mandated laboratory tests and vital signs will be summarized in the clinical 
study report (CSR). Deterioration as compared with baseline in protocol-mandated laboratory values 
and vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the study drug.  
If deterioration in a laboratory value/vital sign is associated with clinically significant signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result/vital 
sign will be considered as additional information. Wherever possible, the reporting investigator uses 
the clinical, rather than the laboratory term (e.g., anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically significant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Any new or aggravated clinically significant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
I.4.h. DISEASE PROGRESSION OR WORSENING DEPRESSION 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the study drug is being studied. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of worsening 
depression should be considered as disease progression and not an AE. Events, which are 
unequivocally due to disease progression, should not be reported as an AE during the study. 
However, if worsening of depression occurs during ketamine treatment, in the opinion of the 
investigator, is to be reported as an adverse event. 
I.4.i. 
SERIOUS ADVERSE EVENTS (SAES) 
The EDC platform will provide a mechanism for sites to report SAEs, and for the Site Investigators 
and MGH CTNI Medical Monitor to sign off on the SAE reports. Reportable (related and/or 
unexpected) SAEs will be sent to the Sponsor or their designee within regulatory timelines. 
I.4.i.1. DEFINITION OF SAES 
The following criteria define a SAE:  
- 
Death 
- 
Life-threatening event 
- 
Hospitalization or prolongation of hospitalization 
- 
Persistent or significant disability/incapacity 
- 
Congenital anomaly/birth defect 


41 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
- 
Medically important event, as defined in this protocol* 
 
*Medical and scientific judgment will be exercised in deciding whether expedited reporting is also 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These will usually 
be considered serious. 
I.4.i.2. REPORTING OF SAES 
When a SAE is discovered at the site, it will be reported immediately (within 24 business hours), as 
described below. Reportable serious adverse events will be reported according to the central  IRB 
reporting policy and FDA regulations. Reportable events may include (but will not be limited to): (a) 
changes in the health status of the patient, (b) unexplained or severe psychiatric complications, and 
(c) clinically significant development or worsening of suicidal ideation or behavior. The Site 
Investigator will determine whether the event is study-related. All reportable serious adverse events 
will be reported by CTNI within 48 business hours to the CTNI medical monitor and the study site PIs. 
I.5. 
PROTOCOL WAIVERS AND VIOLATIONS 
I.5.a. PROTOCOL WAIVERS 
Protocol waivers will not be allowed for this study. 
I.5.b. PROTOCOL VIOLATIONS 
I.5.b.1. PROCEDURE FOR NON-COMPLIANT PATIENTS 
Patients will be scheduled for the period of study participation when they are available to come in 
for study visits. Patients who miss one visit will be allowed to make up that visit within a window that 
depends on the visit. Every effort will be made by the site to adhere to the study visit schedule, in 
order for assessments to be able to be performed at the stipulated time points. Patients who miss 
more than one visit will be discontinued from the study. However, patients who either complete the 
study or discontinue prematurely will be eligible for three months of free care at the clinic where 
they were enrolled. Patients who withdraw consent will no longer have data collected for the study. 
Every effort will be made to maintain contact with patients who are discontinued, but who do not 
withdraw consent, according to the study schedule (Table 3) for 30 days post-treatment in order to 
collect safety data. 
 
 


42 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
I.5.b.2. PROTOCOL VIOLATION DEFINITIONS 
 
TABLE 5 - LIST OF EXAMPLES OF PROTOCOL VIOLATIONS 
 
Major Protocol Violation 
Minor Protocol Violation 
The list of examples is intended as a guide and is not all-inclusive. 
Definition 
A violation that may: 
Impact subject safety, 
Affect the integrity of study data, and/ or 
Affect the subject’s willingness to participate 
in the study. 
A violation that does not: 
Impact subject safety, 
Compromise the integrity of study data, and/ 
or 
Affect the subject’s willingness to participate 
in the study. 
Examples  
(not all-inclusive) 
Failure to obtain informed consent 
Informed consent obtained by an 
unauthorized individual 
Enrollment of a subject who did not meet 
eligibility criteria for whom a protocol 
exception was not obtained 
Performing a study procedure that is not 
approved by the IRB and/or is not in the 
protocol 
Failure to perform a required lab test that, in 
the opinion of the Site Investigator, may 
affect subject safety or data integrity 
Failure to perform or follow a study 
procedure that, in the opinion of the Site 
Investigator, may affect subject safety or data 
integrity 
Failure to follow safety (AE) management plan 
Failure to report a SAE to the IRB and/or 
Coordination Center 
Implementation of unapproved recruitment 
procedures 
Only a photocopy of the signed/ dated 
consent form is available (the original is 
missing) 
Pages are missing from the signed/ dated 
informed consent form 
Use of invalid consent form (i.e., without IRB 
approval or outdated/expired form) 
Failure to perform or follow an approved 
study procedure that, in the opinion of the 
Site Investigator, does not affect subject 
safety or data integrity 
Study procedure conducted out of sequence 
Failure to perform a required lab test 
Missing lab results 
Study Visit out of approved window 
Over-enrollment 


43 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Enrollment of subjects after IRB approval of 
the study has expired 
Failure to submit a continuing review 
application to the IRB before study expiration  
Reporting 
Requirements 
Record the date discovered, date occurred, 
description of event in the Protocol Deviation 
Log. 
Notify the Coordinating Center within 24 
business hours. 
Record the date discovered, date occurred, 
description of event in the Protocol Deviation 
Log. 
Notify the Coordinating Center  
 
I.5.b.3. PROTOCOL VIOLATION REPORTING 
Protocol violations will be reported as described in the MOP. 
J. 
TREATMENT 
J.1. 
DOSING SCHEDULE 
Ketamine 40 mg will be administered intranasally six times during the study. Ketamine will be 
administered at the respective visits, by study staff, onsite. Brexpiprazole or matching placebo will 
be administered orally daily for 28 days according to the fixed-flexible dose escalation schedule. 
J.2. 
STUDY PRODUCT SUPPLIES AND ADMINISTRATION 
 
Intranasal ketamine will be prepared  as described in the Manual of Procedures.  The intranasal 
ketamine will be supplied in a metered MAD Nasal™ Intranasal Mucosal Atomization Device. Each 
Intranasal Mucosal Atomization Device will contain 1mL of 40mg/mL Ketamine and be used for one 
administration.  A total of two sprays, with one spray (a volume of 0.5 mL) given in each nostril, will 
be administered. A total of six  atomization devices will be prepared for each patient. 
Brexpiprazole and matching placebo, in .5 mg and 1 mg tablets, will be supplied to each site by Otsuka 
Pharmaceuticals. The site pharmacist will package the brexpiprazole and placebo tablets in bottles, 
and supply 4 bottles for each patient, according to the randomization scheme.  Each bottle will 
contain 10, 20 or 30 pills, according to the dosage requirements listed below, of either brexpiprazole 
or placebo, and be labeled with the randomization number for that patient.   
TABLE 6   BREXPIPRAZOLE DOSING 


44 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Visit/Day 
Visit 1/Day 0 
Visit 5/Day 8 
Visit 7/Day 14 
Visit 9/Day 21 
Dose/day 
.5 mg 
1mg 
2 mg 
3 mg 
Number of Pills  per Dose 
1 
1 
2 
3 
Number of Pills per Bottle 
10 
10 
20 
30 
 
J.3. 
PACKAGING AND LABELING 
J.3.a. CONCOMITANT OPEN-LABEL ADT 
Open-label ADT will be provided to allow for continuing the same dose of ADT throughout the study. 
The amount of open-label study medication (ADT) dispensed to a patient at any given visit is 
contingent upon the prescribed daily dose of ADT. ADT will be provided through prescriptions, and 
patients will be reimbursed for any out of pocket expenses they incur for filling the prescription. 
J.3.b. BLINDED BREXPIPRAZOLE/PLACEBO THERAPY 
Blinded study drug will be provided to each subject at Visits 1, 5, 7 and 9,  and a pill count will be 
performed by study site personnel at each study visit.  Patients will be instructed to bring their pill 
bottles to every visit. 
J.4. 
DOSE MODIFICATION FOR TOXICITY 
Dose modifications will be allowed, if patient cannot tolerate the dose increases.  If a dose 
modification is necessary, patients should return to the previous tolerable dose. 
J.5. 
CONCOMITANT THERAPY 
All concomitant medications taken during the study will be recorded in the Concomitant Medication 
Log for each patient, along with dosage information and start and stop dates. Allowed concomitant 
medications include any prescription or over-the-counter medication not specifically excluded by the 
protocol (see Appendix 1), as well as stable, ongoing antidepressant therapy and stable allowed 
hypnotic therapy. Patients requiring excluded drugs will be discontinued from the study. 
J.6. 
DISCONTINUATION FROM STUDY TREATMENT 
Every effort will be made to keep the patient in the study for the full study period consisting of one 
day of acute treatment plus 6 follow-up assessments. Acceptable reasons for early discontinuation 
include the following: 1) request of patient, 2) decision of physician, 3) serious adverse event, and 4) 
protocol violation. 
J.6.a. PROCEDURES FOR DISCONTINUATION FROM STUDY TREATMENT 


45 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
J.6.a.1. 
MEDICAL REASONS FOR DISCONTINUATION 
In the event that the patient’s blood pressure rises to an unacceptable level during treatment, in the 
opinion of the attending physician, the physician will discontinue treatment and initiate appropriate 
measures according to usual medical practice. 
A patient who decides to discontinue participation in the study will always be asked about the 
reason(s) and the presence of any AEs. If possible, they will be seen and assessed by an investigator. 
AEs will be followed up until resolution (see Section I.4.b). 
If a patient discontinues from the study before randomization, then no further follow-up will be 
expected. However, if the patient discontinues after randomization, but before receiving any study 
treatment, the patient will be asked to return for a final study visit, during which the procedures 
outlined in the Early Termination Visit procedures will be completed, including AEs and concomitant 
medication assessments. 
If a patient discontinues from the study before completion and has received a dose of study drug, 
the patient will be asked to return for a final study visit, at which the procedures outlined in the Early 
Termination Visit will be completed. Every effort should be made to follow up with patients who 
discontinue from the study prior to Visit 11 (Day 28). If patients refuse to return to the clinic for the 
study-related assessments, a modified follow-up through, for example, regular telephone contact or 
a contact at study closure should be arranged, if agreed to by the patient and in compliance with 
local data privacy laws/practices. If the patient refuses follow-up, the reason for the refusal and last 
contact date should be documented in the eCRF and source documents. 
Patients who discontinue from the study will not be replaced. 
J.7. 
UNBLINDING PROCEDURE 
 
J.7.a. METHODS FOR ENSURING BLINDING 
The investigator, patient, and study staff will be blinded. Packaging and labeling of the study drugs 
will be performed in a way to ensure blinding throughout the study. 
No members of the study team at study sites will have access to the randomization scheme during 
the conduct of the study. 
The randomization schedule for blinding of randomized treatment will be maintained by MGH CTNI 
or representative and will not be disclosed until after database lock. 
J.7.b. METHODS FOR UNBLINDING THE STUDY 


46 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Individual treatment codes, indicating the treatment randomization for each randomized patient, 
will be available to the investigator(s) or pharmacists from MGH CTNI or its designee. 
The treatment code must not be broken except in medical emergencies when the appropriate 
management of the patient necessitates knowledge of the treatment randomization. The 
investigator documents and reports the action to MGH CTNI or representative, without revealing the 
treatment given to the patient to MGH CTNI or representative’s staff. 
MGH CTNI retains the right to break the code for serious adverse events (SAEs) that are unexpected 
and are suspected to be causally related to a study drug and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been made 
and documented. 
K. 
ETHICAL CONSIDERATIONS 
K.1. RISK/BENEFIT ASSESSMENT 
K.1.a. POTENTIAL RISKS 
Participants must be capable of understanding the nature of this study, its potential risks, 
discomforts and benefits. Study physicians will obtain consent after they have fully explained the 
study purpose and its procedures, and potential participants have demonstrated an understanding 
of the protocol, willingness to participate, and competency to consent. 
K.1.b. SAFETY 
Ketamine was well tolerated after single-dose administration up to 60.0 mg, multiple-dose 
administration up to 35.0 mg, and single-dose administration up to 25.0 mg. There were no deaths 
or SAEs reported in any published study. One (1) subject was discontinued due to a treatment-related 
AE of mild ventricular tachycardia in one study, and no subjects were discontinued due to AEs in two 
other studies. The most common AEs considered by the investigator to be related to ketamine 
(occurring >1 incidence) were: headache (6 events), diarrhea (4 events), nausea (3 events), and 
anxiety (2 events), dyspepsia (5 events), pruritus generalized (3 events), headache (2 events), 
diarrhea (2 events), and abdominal pain (2 events). In these three studies, there were no clinically 
significant values, changes, or trends in clinical laboratory data. No clinically significant changes were 
observed in the hypothalamic-pituitary-adrenal axis hormones of cortisol, prolactin, and luteinizing 
hormone. There were no clinically significant changes in vital signs and electrocardiograms (ECGs), 
including no evidence of changes in corrected QT (QTc) prolongation. 


47 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
The most frequent adverse events with brexpiprazole are akathisia, headache, and weight increase. 
Mean changes from baseline in Abnormal Involuntary Movement Scale and Barnes Akathisia Rating 
Scale total scores are significantly greater with brexpiprazole 3 mg versus placebo.  
K.1.c. CONFIDENTIALITY AND LOSS OF PRIVACY 
The risk of loss of privacy is judged to be minimal. Confidentiality will be maintained by numerically 
coding all data, by disguising identifying information, and by keeping all data in locked file drawers 
or on password-protected databases on password-protected and encrypted computers in locked 
offices. Subject information will be accessible only to research staff. Information about study 
participants will not leave our institution in any form that would identify individual subjects. Sites 
will enter subject data directly into the study database, which will be managed by the MGH CTNI 
team. Subjects will be assigned study ID numbers. 
K.1.d. PLANNED PROCEDURES FOR PROTECTING AGAINST OR MINIMIZING POTENTIAL RISKS 
Participants must be capable of understanding the nature of this study, its potential risks, 
discomforts and benefits. Study physicians will obtain consent after they have fully explained the 
study purpose and its procedures, and the potential participant has demonstrated an understanding 
of the protocol, willingness to participate, and competency to consent. Confidentiality will be 
maintained by numerically coding all data, by disguising identifying information, and by keeping all 
data in locked file drawers or on password-protected databases on password-protected and 
encrypted computers in locked offices. Subject information will be accessible only to research staff. 
Information about study participants will not leave our institution in any form that would identify 
individual subjects. Data will be transmitted with subjects identified by code. 
Regarding confidentiality and privacy, the risk of loss of privacy is judged to be minimal. 
Confidentiality will be maintained by numerically coding all data, by disguising identifying 
information, and by keeping all data in locked file drawers or on password-protected databases on 
password-protected and encrypted computers in locked offices. Subject information will be 
accessible only to research staff. Information about study participants will not leave our institution 
in any form that would identify individual subjects. Data will be transmitted with subjects identified 
by code. 
K.2. JUSTIFICATION OF THE USE OF PLACEBO ARM 
MDD is a serious illness. The decision to conduct placebo-controlled trials was carefully considered. 
Randomized trials utilizing a placebo control group are the gold standard for the establishment of 
treatment efficacy. The use of a placebo treatment is a method of providing a control group in the 
study design, minimizes investigator bias in assessments, promotes retention of the control group, 
and controls for the natural course of the disease (Vickers and deCraen, 2000). Therefore, lack of 
adequate control comparisons would limit the contribution of the data from this trial.  


48 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
K.2.a. CLINICAL MONITORING OF SUBJECTS AND MANAGEMENT OF CLINICAL DETERIORATION AND EMERGENCE 
OR WORSENING OF SUICIDAL IDEATION 
All patients will receive monitoring for clinical deterioration, support, attention, and reassurance in 
the context of a therapeutic alliance. By definition, the target population is one in which subjects 
have not responded to available antidepressant therapies. Both active treatment and 
placebo/control groups in each trial will receive comprehensive evaluation and careful monitoring. 
Close monitoring by a trained psychiatrist is beneficial for individuals with mood disorders. If patients 
are in need of more intensive psychiatric treatment at any time during the course of the trial, study 
personnel will assist in needed evaluation and referral to appropriate treatment settings. Subjects 
will be carefully monitored regarding depressive and other psychiatric symptoms. Non-responders 
to study treatment will be offered referrals for treatment at the end of the trial. 
K.3. INFORMED CONSENT 
The Investigator must ensure that patients are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical trials in which they volunteer to participate. 
Preparation of the consent form is the responsibility of the Investigator and must include all elements 
required by CFR 21 Part 50.25 and the local IRB.  
All subjects will receive the consent form for the study. These documents will be read by the patients 
and also reviewed by the patient with a clinician on the research staff prior to participating in the 
study. Any questions, concerns, or ambiguities will be clarified by the site’s PI or another study 
clinician prior to the patient signing consent. Patients will sign informed consent and only then will 
begin participation in the study. 
K.4. IRB REVIEW 
Before study initiation, the Investigator must have written and dated approval/favorable opinion 
from the IRB for the protocol, consent form, patient recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to patients. 
The Investigator should provide the IRB with reports, updates, and other information (e.g., Safety 
Updates, Amendments, and Administrative Letters) according to regulatory requirements and 
Institution procedures. 
A detailed list of required regulatory documents also to be submitted to MGH CTNI will be sent upon 
final approval of the protocol. 
K.5. POTENTIAL BENEFITS TO STUDY PARTICIPANTS AND OTHERS 


49 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Potential benefits of the research to participants and others: This study will potentially help 
individuals with TRD. If we discover that this intervention is effective, these results will lead to a full 
clinical development program of this treatment for TRD. 
Risks to subjects relative to the anticipated benefits to research participants and others: The 
treatment has been selected with consideration of safety in mind. Additionally, exposure to the 
intervention will be brief and carefully monitored. The risks of participation in the study are therefore 
judged to be small, and adequate protections are in place to monitor the medical wellbeing of 
participants. In contrast, the morbidity and mortality associated with TRD risks are well known to be 
very high, given the long-term disability associated with MDD. 
Because of the tremendous public health impact of depression, if these treatments are shown to be 
effective for TRD, they could reduce the burden of depression-related morbidity and mortality. 
Risks to subjects in relation to the importance of the knowledge that reasonably may be expected to 
result: The aforementioned data suggest that risks to subjects are minimal. The benefit to society 
from the development of efficacious interventions with rapid onset for TRD would be a substantial 
public health benefit. 
L. 
DATA HANDLING AND RECORD KEEPING 
L.1. COMPLETION OF ECRF 
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
with the investigational product or entered as a control in the investigation. 
L.2. PROCEDURE FOR CORRECTIONS 
An EDC system will be built for the study. The EDC system will include eCRFs designed to capture 
study information, which are completed by trained site staff. Specific details of the procedures for 
Data Management are found in the Data Management Plan and details regarding the EDC system 
training process can be found in the Study MOP. 
L.3. RECORD RETENTION 
The Investigator must retain investigational product disposition records, case report forms, and 
source documents for the maximum period required by applicable regulations and guidelines, or 
Institution procedures, and at least for 10 years. 
If the Investigator withdraws from the study (e.g., relocation, retirement) the records shall be 
transferred to a mutually agreed upon designee (e.g., another Investigator, IRB).  


50 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
L.4. DATA CONFIDENTIALITY 
Potential risks to data confidentiality will be mitigated by requirements for the de-identification of 
all study data and by security protocols for all data capture systems. All users of the EDC system will 
be tracked and provided access in a secure fashion following established SOPs for this process.  
As with all research data, information gathered by the study will be used only for aggregate analysis; 
it will not be released with any information that identifies research participants. The data managers, 
statistician, Investigator, and Sponsor do not have access to the identities of patients. That 
information is retained only at the clinical centers. Uses and risks related to data collection will be 
outlined in the informed consent and reviewed with the subjects. 
M. 
MONITORING AND OVERSIGHT 
M.1. EVALUATION OF STUDY SITES 
Potential study sites have been evaluated by MGH CTNI to determine suitability for the proposed 
study. Information reviewed included, but was not limited to, facility details and site capabilities, 
past performance in similar studies, investigator, and staff experience, ongoing studies at the site, 
projected enrollment in this study, and FDA or other agency audit findings. Study sites may be asked 
to complete a study-specific Site Selection Questionnaire and other documents for consideration for 
participation and MGH CTNI or clinical study monitors may make a Site Qualification Visit prior to 
completing the evaluation process. 
M.2. INITIATION OF STUDY SITES 
Prior to subject enrollment, a study initiation visit will be completed at each investigational site to 
ensure the following: IRB approval has been obtained and documented prior to subject screening, 
the Investigators and study personnel are appropriately trained and clearly understand the study, 
the Investigators and study personnel accept the obligations incurred in undertaking this clinical 
investigation. 
M.3. PERIODIC MONITORING VISITS  
Qualified MGH clinical monitors or qualified contract monitors representing MGH CTNI will conduct 
investigational site monitoring visits to ensure that all Investigators conduct the study in compliance 
with the protocol and applicable regulations. The site will receive notification prior to each 
monitoring visit during the course of the study. It is expected that the Investigator and/or sub-
Investigator and other appropriately trained study staff are available on the day of the visit in case 
any questions might arise. 


51 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Periodic monitoring visits will be made in accordance with the approved monitoring plan at all active 
study sites throughout the clinical study to assure that the Investigator obligations are fulfilled and 
all applicable regulations and guidelines are being followed. These visits will assure that the facilities 
are still acceptable, the protocol and investigational plan are being followed, the IRB has been 
notified of approved protocol changes as required, complete records are being maintained, 
appropriate and timely reports have been made to the Sponsor and the IRB, and the Investigator is 
executing all agreed activities. 
MGH CTNI retains the right to remove either the investigator or the investigational site from the 
study for issues of non-compliance with the protocol or regulatory requirements. 
On one or more occasions, the study site may be inspected or audited by the MGH CTNI 
representative or a third party. The Investigator will be informed in advance of this visit. 
M.4. STUDY CLOSEOUT VISIT 
Upon completion of the clinical study (when all subjects at the site have completed follow up visits, 
all data has been entered in the EDC system and cleaned, all queries resolved, and final electronic 
signatures have been obtained), a study closeout visit will be performed. Any unused study materials 
and equipment will be collected and returned to MGH CTNI. The Monitor will ensure that the 
Investigator’s regulatory files are up to date and complete and that any outstanding issues from 
previous visits have been resolved. Other issues which will be reviewed at this visit include: discussing 
retention of study files, possibility of site audits, publication policy, and ensuring that the Investigator 
will notify the IRB regarding study closeout. 
M.5. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Subcontracts with study sites will specify that MGH CTNI or its representatives will have direct access 
to source data and documents for study monitoring. Additionally, NIMH, and the site IRBs may review 
source data following appropriate guidelines for this process. 
M.6. INTERIM ANALYSIS 
No interim analysis is planned for this study. 
M.7. MEDICAL MONITORING 
The medical monitor for this trial will be an M.D. designated by MGH CTNI. Throughout the course 
of the study the MGH CTNI Medical Monitor will review all adverse events, review issues related to 
subject eligibility, and assess the benefits and risks of protocols on an ongoing basis. 
In addition, the Medical Monitor will be available for site questions. The Medical Monitor will be 
available to sites for questions regarding inclusion/exclusion criteria, protocol conduct, and safety. 


52 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Trained and qualified MGH CTNI staff physicians will be available to provide coverage during times 
when the Medical Monitor is unavailable. Sites will be provided with the Medical Monitor’s cell 
phone number for emergency situations. Otherwise, sites are instructed to contact the Medical 
Monitor through email. All communications with sites will be documented by the Medical Monitor 
and kept in a file managed by the MGH CTNI Research Assistant, and reviewed periodically by the 
MGH CTNI Program Manager. 
Each month the Medical Monitor will receive a listing of protocol violations for review and 
identification of possible trends. 
Serious adverse events and clinically significant suicidal ideation or behavior will be reported by the 
site within 24 business hours of their knowledge of the event. For reportable (unexpected and/or 
related) serious adverse events and clinically significant suicidal ideation or behavior, the Medical 
Monitor will contact the Sponsor-Investigator within 48 business hours of the notice by the site. In 
addition, the Medical Monitor may request individual patient records, including laboratory data, 
clinical records, and other study related data, to evaluate these events against the known safety 
profile of the study treatment and the disease. Any records sent to the Medical Monitor by the site 
will be redacted for any identifying information before transmission. The Medical Monitor may 
recommend actions including partial or complete unblinding, and/or modifying or terminating the 
study. In addition to safety monitoring, the Medical Monitor may review enrollment data, 
demographic information, retention status, and other reports prepared by the study statistician that 
describe study performance and progress. The Medical Monitor will provide a report to the sSponsor-
Investigator that describes study safety, progress and performance and provide recommendations 
regarding safe continuation or early termination of the trial. After review and evaluation of the 
specified periodic reports prepared by the statistician, the Medical Monitor will prepare a summary 
cover letter, according to pre-specified criteria, for submission to the Sponsor-Investigator. The letter 
will provide comments on the report, discuss any concerns or suggestions for change, and 
recommend continuation or cessation of the trial. 
Urgent Clinical Situations: During the course of the study, a patient will be reassessed for continued 
participation based on clinical judgment of the investigators. All subjects will be offered access to 
24/7 coverage for medical emergencies through the clinical staff at each site. Treatment options and 
their risks and benefits, including continued study participation and other treatment options, will be 
sensitively explained. All investigators have extensive clinical experience in the treatment of MDD 
and TRD, and can make the decision (while blinded) as to removal of subjects from the trial, 
particularly in the event of clinical deterioration or emergence/worsening of suicidal ideation. When 
a patient is removed from the trial based on clinical judgment, investigators will implement an 
appropriate treatment plan and arrange for follow-up for the patient. 


53 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
N. 
DATA ANALYSIS 
To analyze the primary outcome data, we will use a linear mixed model for the observations taken 
at baseline, and subsequent visits, with terms for visit, and visit*treatment for visits other than 
baseline, the primary contrast of interest being the difference between the two weeks (Day 14) value 
for active treatment and placebo. To address missing data, we will use all available data and use a 
restricted maximum likelihood estimation procedure, as implemented by SAS Proc MIXED. The 
model will include a site, a site*time effect and a site*time*treatment interaction. The latter will be 
removed if not significant. Number of comorbid medical and psychiatric disorders and duration of 
illness, as measured prior to randomization, will be included as covariates. For the continuous 
secondary efficacy variables, the same approach as for the primary efficacy variable will be used for 
the analysis. 
Power analysis: the sample size was chosen to ensure 80% power to detect an effect size of 0.8 on 
the SDQ between brexpiprazole plus intranasal ketamine treatment and placebo at a two-sided 0.05 
significance level. This assumes the randomization of 52 subjects (26 subjects per arm). 
 
 


54 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
 
O. 
PROTOCOL SIGNATURE PAGE 
 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this 
protocol and all pertinent information to the study personnel under my supervision. I will discuss this 
material with them and ensure they are fully informed regarding the conduct of the study according 
to 21 CFR parts 50, 54, 56 and 812, 45 CFR 46, to GCP as described in ICH guideline E6 and to hospital 
Institutional Review Boards. 
 
 
_____________________________ 
 
Clinical Site 
 
 
 
 
_____________________________ 
 
 
_____________________ 
Principal Investigator Signature 
 
 
 
Date 
 
 
 
_____________________________ 
Principal Investigator  
Printed Name 
 


55 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
APPENDIX 1 CONCOMITANT MEDICATIONS 
Medications Allowed (Y) and Not Allowed (N) as Concomitant Medications 
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Analgesics 
Y 
Y 
Nonnarcotic analgesics are allowed. 
Medically appropriate episodic use of 
narcotic analgesics is allowed for acute 
medical indications but is limited to no 
more than 3 days for each episode, and may 
not be taken the day of the  ketamine 
administration starting at midnight. Chronic 
NSAID use is exclusionary; tramadol is also 
not allowed. 
Anesthetics, general 
Y 
(except for 
ketamine, which is 
excluded) 
— 
If procedures requiring general anesthesia 
are to occur/have occurred, please contact 
MGH CTNI to report the medical 
condition(s). 
Anesthetics, local 
Y 
N 
— 
Anorexics 
N 
N 
— 
Antacids 
Y 
Y 
— 
Antiacne 
Y 
Y 
Topical agents only, including topical 
antibiotics. Isotretinoin (Accutane) is not 
allowed. 
Antianginal agents 
N 
N 
— 
Antiarrhythmics 
N 
N 
Amiodarone is excluded 
Antiasthma agents 
Y 
Y 
— 
Antibiotics 
Y 
Y 
Chronic use of topical antibiotics for acne is 
allowed, with the exception of the MAOI 
linezolid (Zyvox) and isoniazid, which are 
not allowed. Erythromycin, clarithromycin, 
rifampin are excluded. 
Anticoagulants 
N 
N 
Warfarin (Coumadin) is not allowed. 
Antiplatelet agents are allowed (see 
“Antiplatelets”). 


56 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Anticholinergics 
Y 
Y 
Except for scopolamine. 
Anticonvulsants 
N 
Y 
Gabapentin, and pregabalin are allowed. 
Other anticonvulsants are not allowed, 
including lamotrigine and carbamazepine. 
Stable in dosing at least four weeks prior to 
randomization is required. 
Antidepressants 
N 
Y 
Stable (for at least 4 weeks prior to 
screening), ongoing antidepressant therapy 
is required during the course of the study. 
No dose changes are allowed during the 
study. Monoamine oxidase inhibitors (which 
may have unknown drug-drug interactions) 
are excluded. Concomitant use of trazodone 
(up to 200mg daily) is allowed. Nefazodone 
is excluded. 
Antidiarrheal preparations 
Y 
N 
Only loperamide HCl (Imodium), bismuth 
subsalicylate (Pepto-Bismol), and kaolin 
preparations are allowed. 
Antifungals, systemic 
N 
Y 
— 
Antifungals, topical 
Y 
Y 
Ketoconazole and itraconzole are excluded 
Antihistamines 
Y 
Y 
The use of combinations containing 
pseudoephedrine or phenylephrine is not 
allowed. Combination products containing 
the word nighttime or are specifically 
marketed for before sleep routinely include 
an antihistamine and are not allowed. 
Combination products ending in “-D” 
routinely contain a stimulant such as 
phenylephrine, and the appropriate limits 
above apply to them. (See “Cough and Cold 
Preparations” for combination products.) 


57 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Antihypertensives 
N 
Y 
Diltiazem, verapamil are excluded 
Anti-impotence medications 
Y 
Y 
— 
Anti-inflammatory drugs 
Y 
Ya 
Indomethacin (Indocin) and systemic 
corticosteroids are not allowed. Chronic 
NSAID use is exclusionary. 
Antifungal 
Y 
Y 
Itraconazole is excluded 
Antimigraine 
N 
N 
Triptans are not allowed 
Antinauseants/Antiemetics 
Y 
N 
Phosphoric acid preparations (Emetrol, 
Emecheck), bismuth subsalicylate (Pepto-
Bismol), cola syrup, 5-HT3 receptor 
antagonists (e.g., ondansetron), and 
prokinetic agents (metoclopramide) are 
allowed. Scopolamine is not allowed (see 
section on antihistamines). 
Antineoplastics/ 
Immunosuppressant agents 
N 
Yc 
Interferons, methotrexate, and other 
immunosuppressant agents are not 
allowed. Call MGH CTNI for approval for 
certain cases in cancer remission 
maintaining therapy. 


58 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Antiobesity/Appetite 
suppressants 
N 
N 
OTC Alli (Xenical), sibutramine (Meridia), 
and phentermine (Adipex-P and others) are 
not allowed. 
Antiplatelet agents 
N 
Yb 
Aspirin (maximum 325 mg/day) and 
clopidogrel (Plavix) are allowed. Note that 
use of an SSRI or of a triple uptake inhibitor 
may increase bleeding times and possibly 
prothrombin times. 
Antipsoriatic treatments 
Y 
Y 
Only topical agents are allowed. Acitretin 
(Soriatane) is not allowed. 
Antipsychotics 
N 
N 
Antismoking medications 
N 
Yc 
Varenicline (Chantix) is not allowed. Chronic 
nicotine replacement may be allowed in 
certain cases after review with MGH CTNI. 
Antiviral agents 
Y 
Y 
Only oral or topical agents are allowed. Only 
acyclovir, famciclovir, valacyclovir, 
penciclovir, docosanal, trifluridine, and 
vidarabine are allowed. 
Amantadine,rimantadine, indinavir, 
nelfinavir, ritonavir, saquinavir are not 
allowed. Tamiflu (oseltamivir phosphate), 
and Relenza (zanamivir) inhalants are 
permitted for influenza prophylaxis but use 
is limited to a 7- to 14-day course in 
accordance with prescribing information. 
Interferons are not allowed.  
Anxiolytics 
N 
Y 
Chronic, stable treatment with 
benzodiazepines is allowed. Stable in dosing 
at least four weeks prior to randomization is 
required. Benzodiazepines should not be 
taken within 2 hours of ketamine 
administration. 
Barbiturates 
N 
N 
Barbiturates are not allowed. 


59 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Benign prostatic hyperplasia 
treatments 
N 
Yb 
Male patients who have symptoms of 
obstructed voiding should not be included 
in the study. Surgically or medically treated 
patients must be asymptomatic and 
receiving a stable dosage of allowed 
medications (α-1 blockers, finasteride, or 
dutasteride) for 1 month before screening. 
Buspirone 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Cough/cold preparations 
Y 
N 
Use of cough and cold preparations 
containing pseudoephedrine or 
dextromethorphan is not allowed, as are 
those containing 
phenylephrineCombination products ending 
in “-D” routinely contain a stimulant such as 
phenylephrine, and the appropriate limits 
apply to them. (See “Antihistamines”.) 
Diuretics 
Y 
Yb 
Episodic use of diuretics is restricted to 
treatment of premenstrual symptoms. For 
chronic use, medication and dosage should 
be stable for 1 month before screening. 
Dopaminergics 
N 
Y 
Dopamine agonists for restless leg 
syndrome are allowed. 
Gastrointestinal: 
• 
H2-blockers/ 
• 
proton pump 
inhibitors/ 
• 
prokinetic agents 
Y 
Y 
Cimetidine (Tagamet) is not allowed. 
Metoclopramide is not allowed. 
Hormonal (noncontraceptive) 
therapies 
N 
Y 
See below. 
Hormone suppressants 
N 
Yb 
Only finasteride (Proscar) and dutasteride 
(Avodart) are allowed. 


60 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Hormones: reproductive 
N 
Y 
Systemic hormonal contraceptives (oral 
contraceptives of estrogen and progestin 
combinations, depot injections such as 
Depo-Provera, the contraceptive implant 
Implanon, or transdermally delivered 
contraceptives such as Ortho Evra) are 
allowed 
Hormones: thyroid 
N 
Y 
Thyroid hormone replacement is allowed 
(dosage of thyroid medication should be 
stable for 3 months before screening). 
Therapeutic use for psychiatric disorders 
(e.g., T3 augmentation) is not allowed  
Hypoglycemic agents 
N 
Y 
Oral hypoglycemic agents are allowed. 
Insulin is not allowed 
Hypolipidemics 
N 
Yb 
Ezetimibe (Zetia) is allowed 
Hypolipidemics: 
bile acid sequestrants 
N 
N 
— 
Hypolipidemics: fibrates 
N 
Yb 
Gemfibrozil and fenofibrate are allowed 
Hypolipidemics: niacin 
N 
N 
Niacin and niacinamide are not allowed 
Hypolipidemics: statins 
N 
Yb 
Lovastatin, simvastatin, pravastatin, 
atorvastatin, fluvastatin, and rosuvastatin 
are allowed 
Laxatives 
Y 
Ya 
Only fiber-based products and docusate 
sodium (Colace) are allowed 
Lithium 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Medications that are primarily 
metabolized by CYP2C8 (e.g., 
cerivastatin, paclitaxel, 
repaglinide, sorafenib, and 
torsemide) 
N 
N 
— 
Muscle relaxants 
N 
N 
— 
NMDA receptor antagonist 
N 
N 
Memantine is excluded. 


61 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Opioid agonists/analgesics 
(e.g., codeine, hydrocodone, 
methadone, morphine, 
maperidine, propoxyphene) 
and antagonists (e.g., 
naltrexone, naloxone, 
nalmefene) 
N* 
N* 
See section on analgesics for exceptions 
Proton pump inhibitors or H2 
receptor blockers 
Y 
Y 
Cimetidine 
Sedatives/hypnotics 
N 
Y 
Ongoing, stable hypnotic therapy (e.g., 
zolpidem, zaleplon, benzodiazepine 
hypnotics, and low-dose trazodone 50-
200mg) will be allowed during the course of 
the study. Eszopiclone is not allowed. 
Patients should not take benzodiazepines, 
within 2 hours of  ketamine administration. 
Steroids/systemic 
Y 
N 
Systemic steroid treatment will be allowed 
only for medical emergencies, such as 
severe allergic reactions 
Steroids/topical and inhalant 
Y 
Y 
— 
Steroids/intra-articular 
Y 
NA 
— 
Stimulants 
N 
N 
Oral or transdermal methylphenidate, 
amphetamine products or prodrugs, 
pseudoephedrine, modafinil (Provigil), and 
other medications of same category are 
notallowed 
Vaccines 
Y 
NA 
— 


62 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
a 
If being taken prior to enrolling in the study. 
b 
If being taken for at least 3 months prior to enrolling in the study and the dose has been stable for at least 
1 month. 
c 
If approved by MGH CTNI Medical Monitor5-HT3 = 5-hydroxytryptomine receptor type 3; 5-HTP = 5-
hydroxytryptophan; ACE = angiotensin-converting enzyme; CR = controlled release; DHEA = 
dehydroepiandrosterone; N = no; NA = not applicable; OTC = over the counter; PRN = as needed 
(prorenataT3prorenataT3=triiodothyronine; Y = yes. 
 
 


63 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
APPENDIX 2 REFERENCES 
 
Anderson IM.Meta-analytical studies on new antidepressants. Br Med Bull 2001. 57:161-78. 
Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-
analysis of efficacy and tolerability. J Affect Disord 2000. 58(1):19-36. 
Abdel-Rahman MS, Ismail EE. Teratogenic effect of ketamine and cocaine in CF-1 mice. Teratology. 
2000 Apr;61(4):291-6. 
 
Adhvaryu SG, Trivedi AH, Jani KH, Vyas RC, Dave BJ. Genotoxic effects of ketamine on CHO cells. 
Arch Toxicol. 1986 Jul;59(2):124-5. 
 
 
Bajbouj M, Merkl A, Schlaepfer TE, Frick C, Zobel A, Maier W, O'Keane V, Corcoran C, Adolfsson R, 
Trimble M, Rau H, Hoff HJ, Padberg F, Müller-Siecheneder F, Audenaert K, van den Abbeele D, 
Matthews K, Christmas D, Eljamel S, and Heuser I. Two-year outcome of vagus nerve stimulation in 
treatment-resistant depression. J Clin Psychopharmacol 2010. 30(3):273-81. 
Bakish D. New standard of depression treatment: Remission and full recovery. J Clin Psychiatry 2001. 
62(Suppl 26):5–9. 
Bauer M, El-Khalili N, Datto C, Szamosi J, and Eriksson H.A pooled analysis of two randomised, 
placebo-controlled studies of extended release quetiapinefumarate adjunctive to antidepressant 
therapy in patients with major depressive disorder. J Affect Disord 2010. 127(1-3):19-30. 
Bech P, Allerup P, Gram LF, Reisby N, Rosenberg R, Jacobsen O, and Nagy A.The Hamilton depression 
scale. Evaluation of objectivity using logistic models. Acta Psychiatr Scand 1981. 63(3):290-9. 
Bech P, Wilson P, Wessel T, Lunde M, Fava M. A validation analysis of two self-reported HAM-D6 
versions. Acta Psychiatr Scand 2009: 119: 298–303. 
Bech P. Fifty Years with the Hamilton Scales for Anxiety and Depression: A Tribute to Max Hamilton. 
Psychother Psychosom 2009; 78:202–211. 
Bech P, Boyer P, Germain JM, Padmanabhan K, Haudiquet V, Pitrosky B, Tourian KA. HAM-D17 and 
HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in 
major depressive disorder.Pharmacopsychiatry 2010. 43(7):271-6. 
Bech, P, Kastrup M, and Rafaelsen OJ. Mini-compendium of rating scales for states of anxiety 
depression mania schizophrenia with corresponding DSM-III syndromes. Acta Psychiatr Scand 1986. 
73(suppl. 326):1-37. 
Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. J Trauma 
Stress.1998 Jan;11(1):125-36. 


64 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant 
effects of ketamine in depressed patients. Biol Psychiatry 2000; 47(4):351-4. 
Chandler GM, Iosifescu DV, Pollack MH, Targum SD, and Fava M. Validation of the Massachusetts 
General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS NeurosciTher 2010. 
16(5):322-5. 
Committee for Medicinal Products for Veterinary Use (CVMP). Summary Report 2007. 
Correll GE, Futter GE: Two case studies of patients with major depressive disorder given low-dose 
(subanesthetic) ketamine infusions. Pain Med 2006; 7(1):92-5. 
Cuijpers P, van Straten A, Bohlmeijer E, Hollon SD, Andersson G. The effects of psychotherapy for 
adult depression are overestimated: a meta-analysis of study quality and effect size. Psychol Med 
2010. 40(2):211-23. 
Cuijpers P, van Straten A, Warmerdam L, and Andersson G. Psychotherapy versus the combination 
of psychotherapy and pharmacotherapy in the treatment of depression: a meta-analysis. Depress 
Anxiety 2009. 26(3):279-88. 
Deckersbach T, Hoelzel, BK, Eisner LR, Stange JP, Peckham AD, Dougherty DD, Rauch SL, Lazar S, 
Nierenberg AA. Mindfulness-based cognitive therapy for non-remitted patients with bipolar 
disorder. CNS Neurosci Ther 2011. 17:410-419. 
Denninger JW, Papakostas GI, Mahal Y, Merens W, Alpert JE, Nierenberg AA, Yeung A, and Fava M. 
Somatic symptoms in outpatients with major depressive disorder treated with fluoxetine. 
Psychosomatics 2006. 47(4):348-52. 
Dunnett, CW "A multiple comparison procedure for comparing several treatments with a control", 
Journal of the American Statistical Association 1955. 50:1096–1121. 
Entsuah AR, Huang H, and Thase ME. Response and remission rates in different subpopulations with 
major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or 
placebo. J Clin Psychiatry 2001. 62(11):869-877. 
Faries D, Herrera J, Rayamajhi J, DeBrota D, Demitrack M, and Potter WZ. The responsiveness of the 
Hamilton Depression Rating Scale. J Psychiatr Res 2000. 34(1):3-10. 
Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003. 53:649–
659. 
Fava M and Davidson KG.Definition and epidemiology of treatment-resistant depression. Psychiatr 
Clin North Am 1996. 19:179–200. 
Fava M, Mischoulon D, Iosifescu D, Witte J, Pencina M, Flynn M, Harper L, Levy M, Rickels K, Pollack 
M. A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy 
among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT-A 
Study). Psychother Psychosom. 2012; 81(2):87-97. 


65 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Fava M, Shelton R, Zajecka J, Rickels K, Clain A, Baer L, Schoenfeld D, Nelson E, Barbee J, Lydiard B, 
Mischoulon D, Alpert J, Zisook S, Papakostas G. L-Methylfolate Augmentation of Selective Serotonin 
Reuptake Inhibitors (SSRIs) for SSRI-Resistant Major Depressive Disorder: Results of Two 
Randomized, Double-Blind Trials. Poster presented at the 49th Annual ACNP Meeting, Miami, FL: 
2010. 
Fava M, Ménard F, Davidsen CK, Baker RA. Adjunctive Brexpiprazole in Patients With Major 
Depressive Disorder and Irritability: An Exploratory Study. J Clin Psychiatry. 2016 Jul 5. doi: 
10.4088/JCP.15m10470. [Epub ahead of print]. 
Fawcett J, Epstein P, Fiester SJ, Elkin I, and Autry JH. Clinical Management-Imipramine/Placebo 
Administration Manual: NIMH Treatment of Depression Collaborative Research Program. 
Psychopharm Bull 1987. 23:309-324. 
Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, and Cleare AJ. What 
happens to patients with treatment-resistant depression? A systematic review of medium to long 
term outcome studies. J Affect Disord 2009. 116(1-2):4-11. 
Fergusson DM, Horwood LJ, and Lynskey MT. Maternal depressive symptoms and depressive 
symptoms in adolescents.J Child Psychol Psychiatry 1995.36(7):1161-1178.First BM, Spitzer RL, 
Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders - Patient Edition 
(SCID I/P). Biometrics Research Department, New York State Psychiatric Institute, 1995. 
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, and Weissman MM. 
Conceptualization and rationale for consensus definitions of terms in major depressive disorder. 
Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991.48:851–855. 
Freeman MP, Walker R, Laughren T, Miller KK, Fava M. Female Reproductive Hormones and Lifecycle 
Status: Methodology to Improve Clinical Trials. Journal of Clinical Psychiatry 2013 Oct., 74(10) 1018-
21.. 
Furey ML and Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a 
randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 2006. 63(10):1121-9. 
Gram LF; Danish University Antidepressant Group (DUAG). Acute and continuation therapy in 
unipolar depression: observations from the run-in phase of a maintenance trial. Acta Psychiatr Scand 
2008. 118(2):123-9. 
Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA, and Corey-Lisle PK. The 
economic burden of depression in the United States: how did it change between 1990 and 2000? J 
Clin Psychiatry 2003. 64(12):1465-1475. 
Guy W. Clinical Global Impression (CGI) ECDEU Assessment manual for Psychopharmacology. 
Rockville, MD: U.S. Dept Health Education and Welfare 1976. 
Hamilton M.A rating scale for depression. J Neurol Neurosurg Psychiatry 1960. 23:56-62. 


66 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Hamilton M. Development of a rating scale for primary depressive illness. Br J Social Clin Psychology 
1967. 6:278-296. 
Ingrande J. and Lemmens H.J.M. Dose adjustment of anaesthetics in the morbidly obese. Br J 
Anaesth. (2010). 105 (suppl 1): i16-i23. 
Insel TR and Wang PS. The STAR*D trial: revealing the need for better treatments. Psychiatr Serv 
2009. 60(11):1466-7. 
Institute of Medicine (US) Forum on Neuroscience and Nervous System Disorders. CNS Clinical Trials: 
Suicidality and Data Collection, Workshop Summary. Washington (DC): National Academies Press 
(US); 2010. 
Jevtovic-Todorovic, Vesna, and Lisa B. Carter. "The anesthetics nitrous oxide and ketamine are 
more neurotoxic to old than to young rat brain." Neurobiology of aging 26.6 (2005): 947-956. 
Jevtovic-Todorovic, Vesna, et al. "A comparative evaluation of the neurotoxic properties of 
ketamine and nitrous oxide." Brain research 895. 1 (2001): 264-267. 
Jevtovic‐Todorovic, Vesna, Nicholas Benshoff, and John W. Olney. "Ketamine potentiates 
cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats." Br J 
Pharmacology 130.7 (2000): 1692-1698. 
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL, Leon AC, Mueller 
TI, Rice JA, and Keller MB. Major depressive disorder: A prospective study of residual subthreshold 
depressive symptoms as predictor of rapid relapse. J Affect Disord 1998. 50:97–108. 
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS; 
National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results 
from the National Comorbidity Survey Replication (NCS-R). JAMA 2003. 289(23):3095-3105. 
Kochhar MM, Aykac I, Davidson PP, Fraley ED. Teratologic effects of d,1-2-(o-chlorophenyl)-2-
(methylamino) cyclohexanone hydrochloride (ketamine hydrochloride) in rats. Res Commun Chem 
Pathol Pharmacol 1986 Dec;54(3):413-6. 
 
Kudoh A, Takahira Y, Katagai H, Takazawa T: Small-dose ketamine improves the postoperative state 
of depressed patients. Anesth Analg 2002; 95(1):114-8. 
Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, Feder A, Iosifescu DV, Charney 
DS, Murrough JW. A randomized controlled trial of intranasal ketamine in major depressive disorder. 
Biol Psychiatry. 2014 Dec 15;76(12):970-6. 
Levine J and Schooler NR. SAFTEE: a technique for the systematic assessment of side effects in clinical 
trials. Psychopharmacol Bull 1986. 22(2):343-81. 
Machado-Vieira R, Salvadore G, Diazgranados N, and Zarate CA Jr. Ketamine and the next generation 
of antidepressants with a rapid onset of action. Pharmacol Ther 2009. 123(2):143-50. PMC ID: 
PMC2726824. 


67 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Majewski-Tiedeken CR1, Rabin CR, Siegel SJ. Ketamine exposure in adult mice leads to increased 
cell death in C3H, DBA2 and FVB inbred mouse strains. Drug Alcohol Depend. 2008 Jan 1;92(1-
3):217-27. Epub 2007 Oct 24. 
Montgomery SA and Asberg M. A new depression rating scale designed to be sensitive to change. Br 
J Psychiatry 1979. 134:382–389. 
McIntyre RS, Weiller E, Zhang P, Weiss C. Brexpiprazole as adjunctive treatment of major depressive 
disorder with anxious distress: Results from a post-hoc analysis of two randomised controlled trials. 
J Affect Disord. 2016 Sep 1;201:116-23. doi: 10.1016/j.jad.2016.05.013. Epub 2016 May 12. 
McKeage K. Adjunctive Brexpiprazole: A Review in Major Depressive Disorder. CNS Drugs. 2016 
Feb;30(2):91-9. doi: 10.1007/s40263-016-0320-0. 
Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry 2006. 
163(11):1864-6. 
Nelson JC and Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a 
meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009. 166(9):980-91. 
Nierenberg AA, Katz J, and Fava M.A critical overview of the pharmacologic management of 
treatment-resistant depression. Psychiatr Clin North Am 2007. 30(1):13-29. 
Nierenberg AA, Keck P, Samson J, Rothschild AJ, and Schatzberg AF. Methodological considerations 
for the study of treatment-resistant depression. In: Amsterdam JD, editor. Refractory Depression. 
New York: Raven Press 1991. 1–12. 
Olney, John W., Joann Labruyere, and Madelon T. Price. Pathological changes induced in 
cerebrocortical neurons by phencyclidine and related drugs. Science 244.4910 (1989):1360-1362. 
 
O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, 
Fitzgerald PB, Loo C, Demitrack MA, George MS, and Sackeim HA. Efficacy and safety of transcranial 
magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled 
trial. Biol Psychiatry 2007. 62(11):1208-16. 
O'Sullivan RL, Fava M, Agustin C, Baer L, and Rosenbaum JF.Sensitivity of the six-item Hamilton 
Depression Rating Scale.ActaPsychiatrScand 1997. 95(5):379-84.Papakostas GI, Shelton RC, Smith J, 
and Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-
resistant major depressive disorder: a meta-analysis. J Clin Psychiatry 2007. 68(6):826-31. 
Papakostas GI, Charles D, Fava M.  Are typical starting doses of the selective serotonin reuptake 
inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebo-controlled, dose-
finding studies in major depressive disorder.  World J Biol Psychiatry.  2007 Jul 13:1-8. 
 
Paykel ES.Achieving gains beyond response. Acta Psychiatr Scand 2002. 415(suppl):12–17. 
Paykel ES.Social functioning and the depressed patient. Int J Psychiatry Clin Pract 1999. 3:S9-S11. 


68 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Pedrelli P, Blais MA, Alpert JE, Shelton RC, Walker RS, Fava M. Reliability and validity of the Symptoms 
of Depression  Questionnaire (SDQ). CNS Spectr. 2014 Dec;19(6):535-46. 
Perry EB, Cramer J, Cho H-S, Petrakis I, Karper L, Genovese A, O’Donnell E, Krystal J and D’Souza C. 
Psychiatric Safety of Ketamine in psychopharmacology research. Psychopharmacology (2007) 
192:253-260. 
Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA, Jr.: Family history of alcohol 
dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol 
Psychiatry 2009; 65(2):181-4. 
Posner K, Oquendo MA, Gould M, Stanley B, and Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk 
analysis of antidepressants. Am J Psychiatry 2007. 164:1035-1043. 
Price RB, Nock MK, Charney DS, Mathew SJ: Effects of intravenous ketamine on explicit and implicit 
measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66(5):522-6. 
Puddu PE., Jouve R., Marlotti S., et al. Evaluation of 10 QT prediction formulas in 881 middle-aged 
men from the Seven Countries study: emphasis on the cubic root Fridericia's equation. J 
Electrocardiol 1988;2:219–229. 
aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ: Safety and 
efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 
2010; 67(2):139-45 
Rush, AJ. Kraemer HC, Sackeim HA, Fava M, Trivedi MH, Frank E, Ninan PT, Thase ME, Gelenberg AJ, 
Regier DA, Rosenbaum JF, Ray O, and Schatzberg AF. Report by the ACNP Task Force on Response 
and Remission in Major Depressive Disorder. Neuropsychopharmacology 2006. 31:1841-1853. 
Russell JM, Hawkins K, Ozminkowski RJ, Orsini L, Crown WH, Kennedy S, Finkelstein S, Berndt E, and 
Rush AJ. The cost consequences of treatment-resistant depression. J Clin Psychiatry 2004. 65(3):341-
7. 
Sackeim HA.The definition and meaning of treatment resistant depression. J Clin Psychiatry 2001. 
62(suppl 16):10–17. 
Simon GE. Social and economic burden of mood disorders. Biol Psychiatry 2003. 54(3):208-215. 
Simon GE, VonKorff M, and Barlow W. Health care costs of primary care patients with recognized 
depression. Arch Gen Psychiatry 1995. 52:850-856. 
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment 
of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry 1995 Jul;167(1):99-103. 
Steffens DC, Krishnan KR, and Helms MJ. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: 
a meta-analysis. Depress Anxiety 1997. 6(1):10-8. 


69 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Stewart WF, Ricci JA, Chee E, Hahn SR, and Morganstein D. Cost of lost productive work time among 
US workers with depression. JAMA 2003. 289(23):3135-3144. 
Tohen M, Case M, Trivedi MH, Thase ME, Burke SJ, and Durell TM. Olanzapine/fluoxetine 
combination in patients with treatment-resistant depression: rapid onset of therapeutic response 
and its predictive value for subsequent overall response in a pooled analysis of 5 studies. J Clin 
Psychiatry 2010. 71(4):451-62. 
Toyama Y, Shimizu H, Suzuki Y, Miyakoshi Y, Yoshioka H..Genotoxic effects of N-nitrosoketamine 
and ketamine as assessed by in vitro micronucleus test in Chinese hamster lung fibroblast cell line. 
Environ Health Prev Med 2006 May;11(3):120-7. doi: 10.1265/ehpm.11.120. 
Trevino K, McClintock SM, and Husain MM. A review of continuation electroconvulsive therapy: 
application, safety, and efficacy. J ECT 2010. 26(3):186-95. 
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, 
Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, and Fava M; STAR*D Study 
Team. Evaluation of outcomes with citalopram for depression using measurement-based care in 
STAR*D: implications for clinical practice. Am J Psychiatry 2006. 163(1):28-40. 
Trivedi MH, Wisniewski SR, Morris DW, Fava M, Gollan JK, Warden D, Nierenberg AA, Gaynes BN, 
Husain MM, Luther JF, Zisook S, Rush AJ. Concise Health Risk Tracking scale: a brief self-report and 
clinician rating of suicidal risk. J Clin Psychiatry 2011 Jun;72(6):757-64. 
Trivedi MH, Wisniewski SR, Morris DW, Fava M, Kurian B, Gollan JK. Nierenberg AA, Warden D, 
Gaynes BN, Luther JF, Rush AJ. Concise Associated Symptoms Tracking (CAST) Scale: A Brief Self and 
Clinician Rating of Symptoms Associated with Suicidality. J Clin Psychiatry 2011 Jun;72(6):765-74. 
Unützer J, Patrick DL, Simon G, Grembowski D, Walker E, Rutter C, and Katon W. Depressive 
symptoms and the cost of health services in HMO patients aged 65 years and older. A 4-year 
prospective study. JAMA 1997. 277:1618-1623. 
Van Londen L, Molenaar RP, Goekoop JG, Zwinderman AH, and Rooijmans HG. Three- to 5-year 
prospective follow-up of outcome in major depression. Psychol Med 1998.28:731–735. 
Vickers A and deCraen A. Why use placebos in clinical trials? A narrative review of the methodological 
literature. J ClinEpidemiol 2000. 53:157-61. 
Wiersma D. Measuring social disabilities in mental health. Social Psychiatry and Psychiatric 
Epidemiology 1996. 31(3-4):101-108. 
Xu Y, Hackett M, Carter G, Loo C, Gálvez V, Glozier N, Glue P, Lapidus K, McGirr A, Somogyi AA, 
Mitchell PB, Rodgers A. Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major 
Depression: a Systematic Review and Meta-Analysis. Int J Neuropsychopharmacol. 2016 Apr 
20;19(4). pii: pyv124. doi: 10.1093/ijnp/pyv124. Print 2016 Apr. 


70 
MGH CTNI – CONFIDENTIAL 
 
Version 4.0:  May 10, 2019  
Zarate CA, Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK: A 
randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. 
Arch Gen Psychiatry 2006; 63(8):856-64 
Zuo DY, Wu YL, Yao WX, Cao Y, Wu CF, Tana.ka M: Effect of MK-801 and ketamine on hydroxyl radical 
generation in the posterior cingulate and retrosplenial cortex of free-moving mice, as determined by 
in vivo microdialysis. Pharmacology Biochemistry and Behavior 2007 Jan;86(1):1-7. Epub 2006 Jun 27