Conditions: Bipolar Disorder Depression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 488
Healthy volunteers: no

Brief summary:
This study investigates the efficacy of a fixed-dose regimen of cariprazine 1.5 milligram (mg)/day or 3 mg/day compared to placebo for treatment of the depressive episode in participants with bipolar I disorder. The safety and tolerability of the fixed-dose regimens will be evaluated.

Detailed description:

Arms:
arm 1: Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks. arm 2: Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks. arm 3: Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 milligram (mg) capsule, one per day, orally beginning on Day 15 for 4 weeks.

Interventions: intervention 1: Cariprazine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
NCT02670551 
Study ID: RGH‐MD‐54 
 
Title:  A Phase 3, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group, Multicenter, Fixed‐
Dose Clinical Trial Evaluating The Efficacy, Safety And Tolerability Of Cariprazine In Patients With  
Bipolar I Depression 
 
 
Protocol Amendment 2 Date: 17‐Feb‐2016 
 
 
 


1.0
TITLE PAGE
Forest Laboratories, LLC, an Allergan Affiliate
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, MULTICENTER, FIXED-DOSE CLINICAL TRIAL 
EVALUATING THE EFFICACY, SAFETY AND TOLERABILITY OF 
CARIPRAZINE IN PATIENTS WITH BIPOLAR I DEPRESSION
RGH-MD-54
IND #77,726
Original Protocol Date:
12 Nov 2015
Amendment #1 Date:
02 Feb 2016
Amendment #2 Date:
17 Feb 2016
Confidentiality Statement
This document is the property of Forest Laboratories, LLC, an Allergan Affiliate, and 
may not—in full or part—be passed on, reproduced, published, distributed, or submitted 
to any regulatory authority without the express written permission of Forest 
Laboratories, LLC.
 
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2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study RGH-MD-54
Title of Study
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Multicenter, Fixed-Dose Clinical Trial Evaluating the Efficacy, Safety and 
Tolerability of Cariprazine in Patients with Bipolar I Depression
Study Centers (Country)
Approximately 85 study centers (United States, non-United States)
Development Phase
3
Objective
To evaluate the efficacy, safety, and tolerability of cariprazine 1.5 mg/day 
and 3.0 mg/day relative to placebo in patients with bipolar I depression
Methodology
Multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
fixed-dose study
Number of Patients
480 planned (approximately 160 per treatment group)
Diagnosis and 
Main Criteria for Inclusion
Male and female outpatients who are 18 to 65 years of age, meet Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria 
for bipolar I disorder without psychotic features confirmed by the 
administration of the Mini International Neuropsychiatric Interview (MINI), 
with a current major depressive episode of at least 4 weeks and not exceeding 
12 months in duration, a minimum score of 20 on the 17-item Hamilton 
Depression Rating Scale (HAMD-17), a minimum score of 2 on item 1 of the 
HAMD-17, and a minimum score of 4 on the Clinical Global Impressions-
Severity Scale (CGI-S) at Visit 1. 
Test Product, Dosage, and Mode of 
Administration
Cariprazine 1.5 mg/day and 3.0 mg/day capsules, oral administration
Duration of Treatment
A no-drug screening period of approximately 7-14 days, followed by 6 weeks 
of double-blind treatment and a 1-week, no investigational product safety 
follow-up period.
Reference Therapy, Dosage, and 
Mode of Administration
Matching placebo capsules, oral administration
Criteria for Evaluation
Primary Outcome Measure
Montgomery-Åsberg Depression Rating Scale (MADRS)
Secondary Outcome Measure
CGI-S
 
 
 
 
 
 
 
 
 
 
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Statistical Methods
The primary efficacy parameter will be the change from baseline to Week 6 
in MADRS total score. The primary analysis will be performed using a 
mixed-effects model for repeated measures (MMRM) with treatment group, 
study center, visit, and treatment group–by-visit interaction as fixed effects 
and the baseline value and baseline by-visit interaction as covariates. An 
unstructured covariance matrix will be used to model the covariance of 
within-patient scores. 
The secondary efficacy parameter will be the change from baseline to Week 6 
in CGI-S score. The secondary efficacy parameter will be analyzed using an 
MMRM as used for the primary analysis.
Matched parallel gatekeeping procedure will be used to control the overall 
type I error rate for multiple comparisons of the 2 cariprazine dose groups 
(1.5 mg/day or 3.0 mg/day) with placebo at Week 6 for the primary and 
secondary efficacy parameters. Statistical significance will be determined by 
comparing the adjusted p-values to α = 0.050.
 
 
 
 
 
 
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3.0 OVERALL TABLE OF CONTENTS 
 
 
Page
1.0 TITLE PAGE ..............................................................................................
 
2.0 SYNOPSIS AND SCHEDULE OF EVALUATIONS ...............................
 
3.0 OVERALL TABLE OF CONTENTS ........................................................
 
3.1 LIST OF IN-TEXT FIGURES.................................................................
 
3.2 LIST OF IN-TEXT TABLES ..................................................................
 
4.0 LIST OF ABBREVIATIONS .....................................................................
 
5.0 ETHICAL CONSIDERATIONS ................................................................
 
5.1 INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE ................................................................................
 
5.2 ETHICAL CONDUCT OF THE STUDY ...............................................
 
5.3 PATIENT INFORMATION AND INFORMED CONSENT .................
 
6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................
 
7.0 INTRODUCTION ......................................................................................
 
8.0 STUDY OBJECTIVES ...............................................................................
 
9.0 INVESTIGATIONAL PLAN .....................................................................
 
9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ...............
 
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS .............................................................................
 
9.3 SELECTION OF STUDY POPULATION .............................................
 
9.3.1 Inclusion Criteria ...............................................................................
 
9.3.2 Exclusion Criteria ..............................................................................
 
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9.3.3 Removal of Patients from Therapy or Assessment ...........................
 
9.3.4 Patient Replacement Procedures .......................................................
 
9.4 TREATMENTS .......................................................................................
 
9.4.1 Treatments Administered ..................................................................
 
9.4.2 Identity of Investigational Product(s) ................................................
 
9.4.3 Method of Assigning Patients to Treatment Groups .........................
 
9.4.4 Selection of Dosages in the Study .....................................................
 
9.4.5 Selection and Timing of Dose for Each Patient ................................
 
9.4.6 Blinding .............................................................................................
 
9.4.7 Unblinding .........................................................................................
 
9.4.8 Prior and Concomitant Therapy ........................................................
 
9.4.9 Monitoring Treatment Compliance ...................................................
 
9.5 EFFICACY AND SAFETY VARIABLES .............................................
 
9.5.1 Diagnostic and Efficacy Assessments ...............................................
 
9.5.1.1 Diagnostic Assessment ...............................................................
 
9.5.1.2 Primary Efficacy Assessment .....................................................
 
9.5.1.3 Secondary Efficacy Assessment .................................................
 
 
 
9.5.2.1 Adverse Events ...........................................................................
 
9.5.2.2 Causality Assessment..................................................................
 
9.5.2.3 Severity Assessment ...................................................................
 
9.5.2.4 Serious Adverse Events ..............................................................
 
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9.5.2.5 Reporting Adverse Events and Serious Adverse Events ............
 
9.5.2.6 Immediate Reporting of Serious Adverse Events and Events 
of Special Interest ...................................................................................
 
9.5.2.7 Reporting of Pregnancies Occurring During the Study ..............
 
9.5.2.8 Potential Hy’s Law Cases ...........................................................
 
 ...........................................
 
 
 
 
 
 
 
 
9.5.3 Investigational Product Concentration Measurements ......................
 
9.5.4 Health Economic and Outcomes Research Assessments ..................
 
9.5.5 Schedule of Assessments ..................................................................
 
 
 
 
 
 
9.6 DATA QUALITY ASSURANCE...........................................................
 
9.6.1 Data Monitoring ................................................................................
 
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9.6.2 Data Recording and Documentation .................................................
 
9.7 STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..............................................................................................
 
9.7.1 Patient Populations ............................................................................
 
9.7.1.1 Screened Population ....................................................................
 
9.7.1.2 Randomized Population ..............................................................
 
9.7.1.3 Safety Population ........................................................................
 
9.7.1.4 Intent-to-Treat Population ...........................................................
 
9.7.2 Patient Disposition ............................................................................
 
9.7.3 Demographics and Other Baseline Characteristics ...........................
 
9.7.4 Extent of Exposure and Treatment Compliance ...............................
 
9.7.4.1 Extent of Exposure ......................................................................
 
9.7.4.2 Measurement of Treatment Compliance .....................................
 
9.7.5 Efficacy Analyses ..............................................................................
 
9.7.5.1 Primary Efficacy Parameters ......................................................
 
9.7.5.2 Secondary Efficacy Parameters ..................................................
 
 ..................................................
 
 
 
 
 
 
 
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9.7.6.6 Investigational Product Plasma Concentration Parameters ........
 
9.7.7 Health Economics and Outcomes Research Analyses ......................
 
9.7.8 Interim Analysis ................................................................................
 
9.7.9 Determination of Sample Size ...........................................................
 
9.7.10 Computer Methods ..........................................................................
 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ..................................................................................................
 
9.9 PROTOCOL DEVIATIONS AND VIOLATIONS ................................
 
10.0 STUDY SPONSORSHIP..........................................................................
 
10.1 STUDY TERMINATION .....................................................................
 
10.2 REPORTING AND PUBLICATION ...................................................
 
11.0 INVESTIGATOR OBLIGATIONS .........................................................
 
11.1 DOCUMENTATION ............................................................................
 
11.2 PERFORMANCE ..................................................................................
 
11.3 USE OF INVESTIGATIONAL MATERIALS ....................................
 
11.4 CASE REPORT FORMS ......................................................................
 
11.5 RETENTION AND REVIEW OF RECORDS .....................................
 
11.6 PATIENT CONFIDENTIALITY..........................................................
 
12.0 INVESTIGATOR’S STATEMENT .........................................................
 
13.0 APPENDICES ..........................................................................................
 
APPENDIX I. ELEMENTS OF INFORMED CONSENT ...........................
 
APPENDIX II. CONTACT INFORMATION ..............................................
 
APPENDIX III. CONCOMITANT MEDICATIONS ..................................
 
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APPENDIX IV. MONTGOMERY-ÅSBERG DEPRESSION RATING 
SCALE...........................................................................................................
 
 
 
APPENDIX VII. CLINICAL GLOBAL IMPRESSIONS–SEVERITY .......
 
 
 
 
 
 
 
 
 
14.0 LITERATURE CITED .............................................................................
 
 
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3.1 LIST OF IN-TEXT FIGURES 
 
 
Page
 
 
 
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3.2 LIST OF IN-TEXT TABLES 
 
 
Page
Table 9.4.5–1. Blister Card Configuration and Dosing Regimen .....................
 
 
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4.0
LIST OF ABBREVIATIONS
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CGI-S
Clinical Global Impressions–Severity
C-SSRS
Columbia–Suicide Severity Rating Scale
DHHS
Department of Health and Human Services
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EDC
electronic data capture
EPS
extrapyramidal symptom
ET
early termination
FDA
Food and Drug Administration
FR
Federal Register
GCP
good clinical practice
HAM-A
Hamilton Rating Scale for Anxiety
HAMD-17
17-item Hamilton Depression Rating Scale
HIPAA
Health Insurance Portability and Accountability Act of 1996
 
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ICF
informed consent form
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITT
intent to treat
IxRS
Interactive Voice/Interactive Web Response System
MADRS
Montgomery-Åsberg Depression Rating Scale
MMRM
mixed-effects model for repeated measures
NA
not applicable
NDA
New Drug Application
PCS
potentially clinically significant
PI
principal investigator
PID
patient identification
PRN
as needed (pro re nata)
QIDS-SR16
Quick Inventory of Depressive Symptomatology – Self-Report
QTc
QT interval correct for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
QTcF
QT interval corrected for heart rate using the Fridericia formula 
RSM
Regional Site Manager
SAE
serious adverse event
SAS
Simpson-Angus Scale
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
YMRS
Young Mania Rating Scale
 
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5.0
ETHICAL CONSIDERATIONS
This clinical study is designed to comply with the International Conference on 
Harmonisation (ICH) Guidance on General Considerations for Clinical Trials (ICH-E8; 
62 FR 66113, 17 Dec 1997) and Good Clinical Practice (GCP) (ICH E6; 62 FR 25692, 
09 May 1997).
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT
ETHICS COMMITTEE
United States
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the investigator. A copy of the approval letter will be supplied to the 
Sponsor, along with a roster of IRB members or the US Department of Health and 
Human Services (DHHS) general assurance number. During the course of the study, the 
investigator will provide timely and accurate reports to the IRB on the progress of the 
study, at intervals not exceeding 1 year (or as appropriate), and will notify the IRB of 
serious adverse events (SAEs) or other significant safety findings. The study protocol, 
informed consent form (ICF), information sheet advertisements, and amendments (if any) 
will be approved by the IRBs at the study centers in conformance with the US Code of 
Federal Regulations (CFR), Title 21, Part 56.
Outside the United States
This study will be carried out in full compliance with the guidelines of the independent 
ethics committee (IEC) and government agencies of each respective country as well as 
the European Union Clinical Trial Directive (Directive 2001/20/EC), where applicable. 
Before the study begins, the site will require approval from an IEC and government 
agency. During the course of the study, the Sponsor or authorized representative will 
provide timely and accurate reports to the IEC on the progress of the study, at intervals 
not exceeding 1 year (or as appropriate) and will notify the IEC of SAEs or other 
significant safety findings. The study protocol, ICF, information sheet advertisements, 
and amendments (if any) will be approved by the IEC at the study site in conformance 
with CFR, Title 21, Part 56, the European Union Clinical Trial Directive 
(Directive 2001/20/EC), and local regulations.
5.2
ETHICAL CONDUCT OF THE STUDY
The study will be conducted in full compliance with US Food and Drug Administration 
(FDA) guidelines for GCP and in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki and 21 CFR § 312.120.
 
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5.3
PATIENT INFORMATION AND INFORMED CONSENT
Patients, after being given an explanation of the study, will give voluntary and written 
informed consent and HIPAA (Health Insurance Portability and Accountability Act of 
1996) authorization (in compliance with 21 CFR, Parts 50 and 312), data protection 
consent (Europe only), or other written documentation in accordance with the relevant 
country and local privacy requirements (where applicable) before participating in any 
study-related procedures.
Each patient will read and sign an instrument of informed consent and the HIPAA 
authorization form (in countries where applicable), data protection consent (Europe only), 
or other written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) after having had an opportunity to discuss them with the 
principal investigator (PI) before signing; each patient will be made aware that he or she 
may withdraw from the study at any time.
The informed consent statement contains all the elements of informed consent listed in 
Appendix I of the protocol; the HIPAA authorization contains all the core elements and 
mandatory statements as defined in the CFR. Signed copies of the ICF and the HIPAA 
authorization form or other locally applicable form will be given to the patient, and both 
documents will be placed in the PI’s study files. A unique patient identification (PID) 
number will be assigned according to Section 9.4.3 at the time the patient signs the ICF.
 
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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 85 study centers.
The investigator is responsible for ensuring that an investigation is conducted according 
to the signed investigator statement, the investigational plan, GCP guidelines, and 
applicable regulations; for protecting the rights, safety, and welfare of patients under the 
investigator’s care; and for the control of investigational products under investigation. An 
investigator shall obtain the informed consent of each human patient prior to the patient
enrolling in the study and/or prior to participating in any study-related activity. 
The investigator at each site must meet their obligations to the patients, ethics committee, 
Sponsor, and regulatory authorities by maintaining oversight and control of the study’s 
conduct and the study staff. It is the responsibility of the investigator to ensure that any 
and all delegated duties be assigned to qualified staff by education, experience, and 
licensure (in accordance with local regulations) and that the investigator oversight is
documented and assessment of their capabilities and performance consistent with the
study investigational plan. The investigator at each site will be responsible for the 
management of the study, including maintaining the study file and the patient records, 
corresponding with the IRB, and completing the electronic case report forms (eCRFs).
The following information can be found on FDA Form 1572 and/or study contacts page 
and/or Trial Master File: Name and contact information of sponsor study personnel and 
Emergency Telephone Numbers; name, address, and statement of qualifications of each 
investigator; name of each subinvestigator working under the supervision of the 
investigator; name and address of the research facilities to be used; name and address of 
each reviewing IRB; US 21 CFR 312.23 section 6(iii)b.
 
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7.0
INTRODUCTION
Bipolar disorder is a complex, chronic illness causing dramatic mood swings and unusual 
shifts in energy and behavior, ultimately resulting in functional impairments. It manifests 
itself as alterations in mood and energy from euphoria and excitability (mania or 
hypomania) to depression and psychomotor retardation (Goodwin and Jamison, 1990) 
and is associated with significant morbidity and mortality. Bipolar disorder in the 
United States affects 5.7 million adults or about 2.6% of the population 18 years and 
older in any given year (Kessler et al, 2005) and has a considerable economic effect on 
our society (Wyatt and Henter, 1995). In the year 2000, this disorder ranked as the 
seventh leading cause of worldwide nonfatal disease burden (World Health Organization, 
2001). Suicide rates within this population are among the highest of all psychiatric 
illnesses (Muller-Oerlinghausen et al, 2002).
The depressive phase of bipolar disorder causes significantly more morbidity and 
mortality than the manic or hypomanic phase. Patients with bipolar disorder experience 
depressive symptoms much more frequently than manic or hypomanic symptoms 
(Hlastala et al, 1997; Judd et al, 2002, 2003; Keller et al, 1986; Post, 2005; Post et al, 
2003). In addition, compared with bipolar mania, bipolar depression is associated with an 
increased risk of suicide and psychosocial impairment (Altshuler et al, 2002; Calabrese 
et al, 2003, 2004; Dilsaver et al, 1997; Leverich et al, 2003; MacQueen et al, 2001).
Although there is a substantial burden associated with bipolar depression, the treatment 
of this phase of bipolar disorder has not been as widely studied as the treatment of bipolar 
mania, and pharmacotherapeutic options are limited. At present, only Seroquel 
(quetiapine), Seroquel XR (quetiapine XR), Symbyax (olanzapine and fluoxetine), and 
Latuda (lurasidone HCl) are approved by the FDA for the treatment of patients with 
bipolar depression. Other common pharmacotherapies include lithium, anticonvulsants 
(eg, valproate, lamotrigine), antidepressants, atypical antipsychotics, or combinations of 
these.
Treatment needs are not completely met by the currently available therapies; and only a 
low percentage of patients persistently benefit from them. A significant percentage of 
patients do not fully respond to the currently available treatments and continue to 
experience subthreshold symptoms and even relapse. Side effects commonly associated 
with the currently available treatments for bipolar depression include tremors, 
psychomotor slowing, cognitive impairment, exacerbation of agitation, nephrotoxicity, 
altered thyroid function, and sexual dysfunction. Atypical antipsychotics in particular 
have been associated with an increased risk of metabolic side effects, including body 
weight gain, dyslipidemia, glucose intolerance, and type 2 diabetes. The use of 
antidepressants has been shown to increase the risk of switching to the manic phase. 
More effective therapies with improved side effect profiles are still needed to enhance 
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Dysfunction in dopamine (DA) neurotransmission has been implicated in the 
pathophysiology of bipolar disorder. Several lines of evidence suggest that the manic 
phase is associated with increased DA neurotransmission and the depressive phase with 
decreased DA neurotransmission. It has been hypothesized that the cyclical nature of 
bipolar disorder is due to alterations between these hyper- and hypodopaminergic states
(Berk et al, 2007). The contributions of individual D2-like receptor subtypes (D2, D3, D4) 
to bipolar disorder are not fully established. However, there is increasing evidence that 
D3 receptors may play an important role in depression. Evidence for this has been derived 
mainly from studies in mice with a targeted disruption of D3 receptors (D3(-/-) mice). 
These animals are more resistant to stressful procedures, display anxiolytic-like behavior,
and are more sensitive to antidepressants in behavioral models compared with the 
wild-type littermates (Leggio et al, 2008; Steiner et al, 1997). A compound with a 
“DA system stabilizing” effect and with preferable D3 receptor functional antagonist 
properties may prove to be most beneficial for the treatment of all the phases of bipolar 
disorder including bipolar depression. RGH-188 (cariprazine) exhibits these 
characteristics.
Cariprazine is an orally active and potent dopamine D3-preferring D3/D2 receptor partial 
agonist discovered by Gedeon Richter Plc., Budapest, Hungary, and currently in 
development by Forest Laboratories, LLC (an Allergan Affiliate), and Gedeon Richter 
Plc, for the treatment of schizophrenia, acute bipolar mania, bipolar depression, and as 
adjunctive treatment for major depressive disorder. In September 2015, cariprazine 
(VRAYLAR™) was approved in the United States for the treatment of schizophrenia, at 
doses of 1.5 to 6 mg/day, and for the acute treatment of manic or mixed episodes 
associated with bipolar I disorder, at doses of 3 to 6 mg/day. 
The chemical name of the hydrochloride salt of cariprazine is trans-N-{4-[2-[4-
(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexyl}-N’,N’-dimethylurea
hydrochloride. Its molecular formula is C21H32Cl2N4O HCl; its molecular weight is 
463.87. Two main metabolites, desmethyl and didesmethyl cariprazine, have been 
identified. The receptor binding profile of both these metabolites is similar to that of the 
parent compound.
A unique feature of cariprazine is that it binds with significantly higher affinity to D3 than 
to D2 receptors. Its affinity for D3 receptors is approximately 1 order of magnitude greater 
than that for D2 receptors. Similar to aripiprazole, but unlike other atypical 
antipsychotics, cariprazine acts as a “DA system stabilizer.” Cariprazine displays partial 
agonist as well as antagonist activity on biosynthesis- (and release-) modulating 
presynaptic D2 receptors and has preferential dopaminergic actions in the limbic regions. 
However, cariprazine is more potent than aripiprazole, and the degree of its apparent 
partial agonist activity is greater.
 
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Cariprazine also has considerable affinity for, and is a partial agonist and antagonist at, 
the serotonin 5-HT1A and 5-HT2B receptors, respectively. Antidepressant-like and/or 
anxiolytic-like effects of cariprazine may also be mediated through these receptors. 
Cariprazine has low potency at other receptor sites, such as the 5-HT2C, histamine H1, and 
adrenergic receptor sites.
Cariprazine was evaluated in patients with bipolar depression in 2 multicenter, 
randomized, double-blind, placebo-controlled studies (Study RGH-MD-52 [2011] and 
Study RGH-MD-56 [2014]). 
Study RGH-MD-52 was 11 weeks in duration: a no-drug washout period of up to 1 week, 
8 weeks of double-blind treatment, and 2 weeks of safety follow-up with treatment as 
determined by the PI. This was a fixed-flexible dose study. A total of 227 Bipolar I and II
patients were randomized to 1 of 3 treatment groups and received at least 1 dose of the 
investigational product: placebo (n = 77), cariprazine low dose (0.25-0.75 mg/day, 
n = 75) and cariprazine high dose (1.5-3.0 mg/day, n = 75). The dose was fixed for first 
4 weeks of double-blind treatment; all patients received the lower of the dose range 
(1 capsule; placebo, cariprazine 0.25 mg/day, or cariprazine 1.5 mg/day). At the end of 
Week 4, the dose could be increased to 2 capsules if response was not adequate 
(< 40% reduction in Montgomery-Åsberg Depression Rating Scale [MADRS] score from 
baseline) and there were no significant tolerability issues as judged by the Investigator. 
Approximately 76% of the patients completed the study: 78% in the placebo group, 
84% in the cariprazine low-dose group, and 65% in the cariprazine high-dose group. 
More patients discontinued for adverse events (AEs) in the cariprazine high-dose group 
(9.3%) than in the placebo group (2.6%) and cariprazine low-dose group (4.0%). The 
average patient age was 39 years, and approximately 64% were female. The 3 treatment 
groups were balanced with respect to demographics and baseline characteristics. For the 
primary efficacy parameter, the change from baseline to the end of Week 8 in the 
MADRS total score using mixed-effects model for repeated measures (MMRM), the 
overall p-value was not statistically significant. Numerical improvement was seen in the 
cariprazine high-dose group relative to the placebo group up to end of week 6. Similar 
results were seen for other efficacy parameters. SAEs were reported in 6 patients 
(2 patients in the placebo group, 2 patients in the cariprazine low-dose group, and 
2 patients in the cariprazine high-dose group). Treatment-emergent adverse events 
(TEAEs) reported in at least 10% of patients in any treatment group included insomnia, 
akathisia, headache, dry mouth, nausea, upper respiratory tract infection and diarrhea. Of 
these, insomnia, akathisia, dry mouth, nausea and diarrhea were reported more frequently 
in the cariprazine-treated patients.
 
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Study RGH-MD-56 was 11 weeks in duration and comprised up to 14 days of screening 
followed by 8 weeks of double-blind treatment and 1 week of safety follow-up. A total of 
584 bipolar I patients were randomized to 1 of 4 treatment groups and 578 patients 
received at least 1 dose of the investigational product: placebo (n = 145), cariprazine 
0.75 mg/day (n = 141), cariprazine 1.5 mg/day (n = 146), cariprazine 3 mg/day (n = 146). 
Overall, 72.5% of the patients completed the study: 72.4% in the placebo group, 73.0% in 
the cariprazine 0.75 mg/day group, 80.1% in the cariprazine 1.5 mg/day group, and 
64.4% in the cariprazine 3 mg/day group. The average patient age was 42 years, and 
approximately 62% were female. For both the primary and secondary efficacy 
parameters, change from baseline in MADRS total score and Clinical Global 
Impressions-Severity (CGI-S) score at Week 6, statistically significant improvement was 
demonstrated for the cariprazine 1.5 mg dose relative to placebo. Nominally significant 
improvement was shown for cariprazine 3 mg, which did not remain statistically 
significant after adjusting for multiplicity. No statistically significant treatment effect was 
shown for the 0.75 mg dose at Week 6. A post-hoc analysis of patients who completed 
the full 8 weeks of treatment (completer population) in Study RGH-MD-56 demonstrated 
similar reductions from baseline relative to placebo in MADRS total score for the 
cariprazine 1.5 and 3 mg/day groups at Week 6 and Week 8. Cariprazine was generally 
well-tolerated. No deaths were reported during the study. Serious adverse events were 
reported for 5 patients (3.4%) in the placebo group, 1 patient (0.7%) in the cariprazine 
0.75 mg group, and 2 patients (1.4%) each in the cariprazine 1.5 mg and 3 mg treatment 
groups. Adverse events that led to discontinuation were reported in similar proportions of 
patients across the placebo (10.3%) and cariprazine (8.2%-11.6%) treatment groups. The 
most common AEs that led to discontinuation were akathisia, agitation, anxiety, and 
depression. Overall, TEAEs were reported for 55% of patients in the placebo treatment 
group and 57%-62% of patients in the cariprazine treatment groups. Akathisia and 
irritability were the only TEAEs reported for ≥ 5% of patients in any cariprazine 
treatment group and at an incidence at least twice that of the placebo group. 
Based upon these data, the current study is designed to prospectively confirm the efficacy 
of a fixed-dose regimen of cariprazine 1.5 mg/day or 3 mg/day compared to placebo for 
treatment of the depressive episode in patients with bipolar I disorder. The safety and 
tolerability of the fixed-dose regimens will be evaluated. 
A description of the chemistry, pharmacology, toxicology, pharmacokinetics, and clinical 
results of cariprazine is provided in the Investigator’s Brochure (RGH-188 [cariprazine], 
2015).
 
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8.0
STUDY OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
cariprazine 1.5 mg/day and 3.0 mg/day relative to placebo in patients with bipolar I 
depression.
 
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This clinical study will be a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, fixed-dose study in adult patients with a Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association, 
2013) diagnosis of Bipolar I disorder who are currently experiencing a major depressive 
episode.
The study will be conducted in outpatients (i.e., non-hospitalized) and will consist of 
approximately 7 to 14 days of screening and washout followed by 6 weeks of 
double-blind treatment and a 1-week safety follow-up period. At the end of the screening
period, patients meeting the eligibility criteria for this study will be randomized (1:1:1) to 
1 of 3 treatment groups (placebo, cariprazine 1.5 mg/day, cariprazine 3 mg/day). The 
study is designed to enroll outpatients, but as per local clinical practice, patients may be 
hospitalized for up to 7 days during the screening period or during the first week of 
treatment with double-blind investigational product. Further need for hospitalization will 
require consultation with the Study Physician. A total of 480 patients are planned to be 
randomized in this study.
Patients who complete 6 weeks of double-blind treatment or who prematurely 
discontinue before completing 6 weeks of double-blind treatment will be followed for 
1 more week (safety follow-up period). During the safety follow-up period, patients may 
be started on a standard treatment as determined by the PI. No investigational product 
will be administered during the safety follow-up period.
 
 
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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
The double-blind design was adopted to minimize systematic bias resulting from the 
Investigator or the patient knowing the treatment being administered. Randomization is 
expected to minimize patient selection bias and increase baseline comparability among 
the treatment groups. The doses of cariprazine under study were chosen on the basis of 
experience from the RGH-MD-52 and RGH-MD-56 studies (see Section 7.0), as well as 
experience in the cariprazine development program in healthy volunteers and patients 
with other indications and other atypical antipsychotics for the treatment of bipolar 
depression. The use of a placebo control is critical to the study to allow discrimination of 
patient outcomes caused by the individual dose levels of cariprazine from outcomes 
caused by other factors (e.g., the observer or patient expectations, the natural progression 
of the disease, the conditions of being in a study).
No double-blind down-taper has been included as cessation of cariprazine at doses 
comparable to those under study has not given rise to appreciable discontinuation 
symptoms.
 
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9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
Inclusion criteria to be assessed at Visit 1 (Screening)
1. Written informed consent, signed, obtained from the patient before the initiation of 
any study-specific procedures
2. Male or female patients 18 to 65 years of age, inclusive
3. Currently meet the DSM-5 criteria for bipolar I disorder without psychotic features 
confirmed by the administration of the Mini International Neuropsychiatric Interview 
(MINI), with a current major depressive episode of at least 4 weeks and not 
exceeding 12 months in duration 
4. Currently treated as an outpatient at the time of enrollment 
5. A verified previous manic or mixed episode. Verification must include one of the 
following sources:
a.
Treatment of mania with an anti-manic agent (eg, lithium or 
divalproate) or antipsychotic medication with an approved 
indication for mania
b. Hospital records/Medical records
c.
Patient report corroborated by caretaker or previous or current 
treating clinician 
6. 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≥ 20
7. HAMD-17 item 1 score ≥ 2
8. CGI-S score ≥ 4
9. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test (women of 
childbearing potential only)
10. Normal physical examination, clinical laboratory test results, and electrocardiogram 
(ECG) results or abnormal findings that are judged not clinically significant by the PI 
 
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Inclusion criteria to be assessed at Visit 2 (Baseline)
11. Continue to meet Visit 1 inclusion criteria
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
Exclusion criteria to be assessed at Visit 1 (Screening)
Psychiatric Criteria
1. Young Mania Rating Scale (YMRS) total score > 12
2. Four or more episodes of a mood disturbance (depression, mania, hypomania, or 
mixed state) within the 12 months before Visit 1
3. Any current axis 1 psychiatric diagnosis other than bipolar disorder with the 
exception of specific phobias 
4. History of meeting DSM-5 criteria for:
○
Dementia, amnesic, or other cognitive disorder
○
Schizophrenia, schizoaffective, or other psychotic disorder
○
Mental retardation
5. DSM-5–based diagnosis of borderline or antisocial personality disorder or other 
axis II disorder of sufficient severity to interfere with participation in this study
6. History of meeting DSM-5 criteria for substance-related disorders (excluding 
caffeine-related and tobacco-related disorders) within the 6 months before Visit 1
7. Positive result on blood alcohol test or urine drug screen for any prohibited 
medication. Exception: 
○
patients with a positive cannabinoid on entry may be retested before 
randomization. If the patient remains positive, the patient is no longer eligible 
○
patients positive for opiates on entry, discussion with Study Physician is required.
 
 
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Treatment-Related Criteria:
14. Electroconvulsive therapy in the 3 months before Visit 1
15. Previous lack of response to electroconvulsive therapy
16. Treatment with a depot antipsychotic drug within 6 months prior to Visit 1
17. Treatment with clozapine in a dose of > 50 mg/day in the past 2 years
 
 
 
 
 
19. Previous treatment with vagus nerve stimulation or transcranial magnetic stimulation 
within 6 months before Visit 1
 
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20. Prior participation with any clinical trials, involving experimental or investigational 
drugs, within 6 months before Visit 1 or during the study
21. Initiation or termination of psychotherapy for depression within the 3 months 
preceding Visit 1, or plans to initiate, terminate, or change such therapy during the 
course of the study. 
22. Initiation or termination of phototherapy within the 2 weeks before screening, or 
plans to initiate same during the course of the study
Other Medical Criteria:
23.
 
 
 
24. Female patients who meet the following criteria:
o
Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the 
study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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30. Gastric bypass or any condition that would be expected to affect drug absorption 
(lap band procedures are acceptable if there is no problem with absorption)
 
 
 
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32. Known history of cataracts or retinal detachment
33. Known human immunodeficiency virus infection
 
 
 
 
Other Criteria:
38. Employee, or immediate relative of an employee, of the Sponsor, any of its affiliates 
or partners, or the study center
 
 
 
 
 
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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of the 
protocol. Patients can be prematurely discontinued from the study for one of the 
following reasons:

Screen Failure (Failure to meet inclusion/exclusion criteria)

Withdrawal of consent

Adverse event

Lack of Efficacy

Protocol violation

Non-compliance with Study Drug

Lost to follow-up

Study terminated by Sponsor

Site terminated by Sponsor

Other
A patient completing Visits 1 through 6 will be considered a completer. All randomized
patients who prematurely discontinue from the study, regardless of the cause, should be
seen for a final assessment at an early termination (ET) visit. A final assessment will be 
defined as completion of the evaluations scheduled for Visit 6/ET). All investigational 
products dispensed at earlier visits that had not been previously collected should be 
collected at the final visit. Patients refusing to come in for a final visit must be requested 
in writing, with a registered letter, to come in for an ET visit and to return any unused 
investigational product. A copy of the letter, together with the source documentation, will 
be kept by the Investigator. The reasons for premature discontinuation from the study will 
be reflected on the study termination record of the eCRF.
Patients with Visit 6/ET more than 4 days after the last dose of double-blind 
investigational product will be administered safety assessments only.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
 
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9.4
TREATMENTS
9.4.1
Treatments Administered
Investigational product in the form of capsules packaged in blister packs will be provided 
by the Sponsor. No investigational product will be administered during the screening 
period or the safety follow-up period. For the 6-week double-blind treatment period, 
patients will be supplied with identically appearing capsules of either cariprazine or 
placebo.
9.4.2
Identity of Investigational Product(s)
Investigational product will be supplied in blister packs containing 10 capsules and will 
be labeled with the protocol number, the visit number/space to write visit number, storage 
information, warning language (viz, “Caution: New Drug—Limited by Federal Law to 
Investigational Use”), and instructions to take the capsules once daily as directed, and the 
medication identification number. Investigational product labels will be country specific. 
Immediately before dispensing the investigational product, the Investigator will write the 
patient’s initials, site number, and date on the label.
All investigational products will be provided by the Sponsor, or designees, to the study 
centers. Investigational product must be stored in an appropriate secure area (e.g., a 
locked cabinet in a locked room) at controlled room temperature 
 
with excursions permitted between 
) and must be 
protected from light, heat, and moisture.
The Investigator is responsible for recording the receipt and use of all investigational 
products supplied and for ensuring the supervision of the storage and allocation of these 
supplies. All unused investigational products must be returned; and, whenever 
investigational products are returned, unit counts must be performed. All investigational 
products must be accounted for. At the end of the study, or upon drug expiration, any 
unused investigational product must be returned to the Sponsor or Sponsor's designee.
9.4.3
Method of Assigning Patients to Treatment Groups
 
 
 
 
 
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Each study center will be provided with investigational products. An interactive 
voice/interactive Web response system (IxRS) will be used during the study to monitor 
enrollment and medication allocation. If the patient meets the randomization criteria, the 
study center will contact the IxRS at end of Visit 2 to randomize the patient. IxRS will 
randomize the patient to the appropriate treatment arm (placebo, cariprazine 1.5 mg/day, 
or cariprazine 3.0 mg/day) and determine the investigational product number to be 
assigned to the patient based on the randomization.
9.4.4
Selection of Dosages in the Study
The doses of cariprazine selected for this study were based on the results from 
2 completed studies in patients with bipolar depression (RGH-MD-52 and RGH-MD-56), 
as well as experience in the cariprazine development program in healthy volunteers and 
patients with other indications and other atypical antipsychotics for the treatment of
bipolar depression. Study RGH-MD-52 indicated numerically better results for the 
high-dose cariprazine group (1.5-3.0 mg/day) relative to placebo up to end of Week 6. In 
the cariprazine low-dose group (0.25-0.75 mg/day), better efficacy was observed 
following a dose increase, and tolerability was not compromised. Thus, cariprazine 0.75, 
1.5, and 3.0 mg/day were selected for further evaluation in Study RGH-MD-56.
In Study RGH-MD-56, for both the primary and secondary efficacy parameters, change 
from baseline in MADRS total score and CGI-S score at Week 6, statistically significant 
improvement was demonstrated for the cariprazine 1.5 mg dose relative to placebo. 
Nominally significant improvement was shown for cariprazine 3 mg, which did not 
remain statistically significant after adjusting for multiplicity. No statistically significant 
treatment effect was shown for the 0.75 mg dose at Week 6. A post-hoc analysis of 
patients who completed the full 8 weeks of treatment (completer population) in 
Study RGH-MD-56 demonstrated similar reductions from baseline relative to placebo in 
MADRS total score for the cariprazine 1.5 and 3 mg/day groups at Week 6 and Week 8.
The primary efficacy results and the post-hoc completers analysis in Study RGH-MD-56 
led to the selection of the cariprazine 1.5 and 3 mg/day doses for further evaluation in this 
study. A dose higher than 3 mg/day was not chosen because of concerns related to the 
potential for higher extrapyramidal symptom rates with increasing cariprazine dose.
A fixed-dose regimen allows for unambiguous evaluation of safety and efficacy of 
individual doses.
 
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9.4.5
Selection and Timing of Dose for Each Patient
All investigational products will be dispensed in blister packs. Each blister pack will 
contain 10 capsules arranged in 10 columns and 1 row, adequate for the 7 days of the 
week plus 3 extra days. The configuration of the blister packs is provided in 
Table 9.4.5–1.
At Visit 2, patients who continue to meet all eligibility criteria will be assigned a 
randomization number and dispensed a corresponding blister pack of double-blind 
investigational product for the first week of double-blind treatment. Patients will be 
instructed to take 1 capsule daily, in order from left to right of the blister pack, beginning 
on the evening of Visit 2 or the morning after Visit 2
At Visit 3 (end of week 1 of double-blind treatment) patients will be dispensed 1 blister 
pack. At Visits 4 and 5 (end of week 2 and end of week 4 of double-blind treatment), 
patients will be dispensed 2 blister packs.
All patients randomized to cariprazine dose groups will receive cariprazine 1.5 mg/day 
for 2 weeks, from Day 1 through Day 14. For patients randomized to the cariprazine 
3.0 mg/day group, the dose will be increased to 3.0 mg/day on Day 15. 
Drug holidays (up to a maximum of 3 consecutive days) are allowed if there are 
tolerability problems at the discretion of the Investigator. Patients unable to tolerate the 
fixed dose of the investigational product or patients off drug for 4 or more consecutive 
days will be prematurely discontinued from the study.
All investigational products will be taken orally as a single daily dose at approximately 
the same time of day (morning or evening). The dosing time can be switched if there are 
tolerability problems. Any switch must allow at least 24 hours between 2 consecutive 
doses and must be documented in the eCRF.
At each visit, patients will be instructed to return all unused investigational product.
 
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Table 9.4.5–1.
Blister Card Configuration and Dosing Regimen
Visit 2
Days 1-7 
+ 3 extra days
Visit 3
Days 8-14 
+ 3 extra days
Visit 4 
Days 15-28
+ 6 extra days
Visit 5
Days 29-42
+ 6 extra days
Treatment group: placebo
Row 1
0 mg
0 mg
0 mg
0 mg
Treatment group: cariprazine 1.5 mg/day
Row 1
1.5 mg
1.5 mg
1.5 mg
1.5 mg
Treatment group: cariprazine 3.0 mg/day
Row 1
1.5 mg
1.5 mg
3.0 mg
3.0 mg
Note: At Visit 2 and Visit 3 patients will be dispensed 1 blister pack. At Visit 4 and Visit 5, patients will be dispensed 
2 blister packs. Each blister pack will contain 10 capsules, adequate for 7 days plus 3 extra days.
9.4.6
Blinding
The study will be conducted as a double-blind investigation. A list of patient 
randomization codes will be generated by the Sponsor’s Statistical Programming, and 
implemented by the IxRS vendor (an electronic version will be stored on a secure server). 
This list will identify each patient by randomization number and include the patient’s 
corresponding treatment assignment. 
9.4.7
Unblinding
Any unblinding at the study center level should be done only in an emergency that 
requires for the investigational product to be identified for the medical management of 
the patient. The Investigator has to notify the study physician immediately 
(see Appendix II) and a full written explanation must be provided if the blind is broken. 
Before the investigational product is unblinded, every attempt should be made to discuss 
the case with the Study Physician. Breaking the code at the study center will immediately 
disqualify the patient from further participation in the study.
Treatment codes may be broken by the Sponsor’s Global Drug Safety department, for 
regulatory reporting purposes. In such cases, the study staff will be kept blinded and the 
patient will not need to be disqualified from the study.
In an emergency, the Investigator can obtain the treatment assignment of any patient at 
his or her study site through the IxRS. In an emergency, the Investigator will access the 
IxRS to break the blind.
The unblinding of bioanalytical representatives is to be carried out in a secure manner 
following the Sponsor’s standard operating procedures. Extreme care and diligence will 
be taken to ensure no other individuals outside the bioanalytical team will be unblinded.
 
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9.4.8
Prior and Concomitant Therapy
A complete list of drugs that are allowed and not allowed as concomitant medications for 
either episodic or long-term use is provided in Appendix III. Throughout the duration of 
this study, additional psychotropic medications, including psychostimulants, are not 
allowed, with some notable exceptions listed below. Psychotropic medications include 
the following: antipsychotics, antidepressants (including monoamine oxidase-B 
inhibitors), stimulants, anticonvulsants/mood stabilizers, sedatives/hypnotics/anxiolytics, 
dopamine releasing drugs or dopamine agonists, and psychotropic drugs not otherwise 
specified (including herbal products).
Patients will be asked to abstain from drinking alcohol during the study. Patients who 
have been taking stable doses of benzodiazepines (up to 2 mg/day) for at least 1 month 
before randomization can continue use. Medically appropriate episodic use (up to 3 days)
of narcotic analgesics for acute medical indications (i.e., tooth extraction) is allowed 
during the study.
Medication history, including the use of psychotropic medication and of any other 
medication, will be recorded at Visit 1 (Screening). Thereafter, any changes in 
concomitant medications or new medications added will be recorded in the eCRF.
For insomnia the following will be allowed. It should not be prescribed 
prophylactically.

Zolpidem (maximum of 10 mg/day)

Zolpidem extended release (maximum of 12.5 mg/day)

Zaleplon (maximum of 20 mg/day)

Eszopiclone (maximum of 3 mg/day)

Zopiclone (maximum of 7.5 mg/day)

Chloral hydrate (maximum of 1000 mg/day) may be used acutely with approval from 
Study Physician)
These medications must be administered before bedtime as recommended in their 
prescribing information. The medication must be documented on the concomitant 
medications page of the eCRF. No such medication is permitted within 8 hours of 
psychiatric or neurological assessments.
 
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For EPSs or akathisia:
For EPSs or akathisia that emerge or worsen during the study, the following rescue 
medications will be allowed; however, each of the 3 EPS scales (Abnormal Involuntary 
Movement Scale [AIMS], Barnes Akathisia Rating Scale [BARS], and Simpson Angus 
Scale [SAS]) should first be performed (unless a medical urgency [eg, dystonia, severe 
akathisia, etc] requires otherwise) to support the decision to administer the medications:

Benztropine (up to 4 mg/day orally or up to 2 mg/day if given parenterally) or 
equivalent (eg, trihexyphenidyl up to 6 mg/day in divided doses)

Diphenhydramine (up to 50 mg/day) for EPS

Propranolol for the treatment of akathisia. Daily dose of propranolol depends on heart 
rate and BP (up to 160 mg/day)
The medication listed above should not be used prophylactically. The need for continued 
use of these medications should be regularly assessed by the PI and documented 
appropriately. The EPSs must be documented on the AE page of the eCRF, and the 
medication on the concomitant medications page of the eCRF.
Injectable agents are not allowed, except for the treatment of an acute dystonic reaction if 
deemed necessary.
Rescue medications for agitation, restlessness, and hostility:
Episodic use of lorazepam up to 2 mg/day (or equivalent) and for up to 3 consecutive 
days at a time is allowed for agitation, restlessness, and hostility.
The agitation, restlessness, or hostility must be documented on the AE and/or the medical 
history page of the eCRF. The medication use must be documented on the rescue 
medication page of the eCRF. Efficacy assessments should not be performed within 
8 hours of administration of lorazepam or equivalent benzodiazepine or within 24 hours 
of administration of diazepam.
9.4.9
Monitoring Treatment Compliance
Investigational product compliance will be monitored by counting the number of capsules 
dispensed and the number returned by the patient. Before new investigational product is 
dispensed at any visit, every effort will be made to collect all unused investigational 
product. If a patient demonstrates poor compliance at any time during the study (< 80% 
or > 120% measured by pill counts), then they should be discontinued from the study.
 
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9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Diagnostic and Efficacy Assessments
9.5.1.1
Diagnostic Assessment
Mini International Neuropsychiatric Interview (Version 7.0.0, 01 Jan 2014)
The MINI (Version 7.0.0, 01 Jan 2014) is a clinician-rated diagnostic assessment that will 
be considered a source document in this study. The interview will be administered by the 
PI or Sub-Investigator who is a psychiatrist or a doctoral-level clinical psychologist or 
who has extensive professional training and experience in the diagnosis of mental illness.
9.5.1.2
Primary Efficacy Assessment
Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery and Åsberg, 1979) is a 10-item, clinician-rated scale that 
evaluates the patient’s depressive symptomatology during the past week. Patients are 
rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, 
suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. 
Each item will be scored on a 7-point scale with a score of 0 reflecting no symptoms and 
a score of 6 reflecting symptoms of maximum severity. This scale will be administered 
by a trained rater with adequate experience in the assessment of the patient’s depressive 
symptomatology using the MADRS.
9.5.1.3
Secondary Efficacy Assessment
Clinical Global Impressions–Severity
The CGI-S (Guy, 1976) is a clinician-rated scale that measures the overall severity of a 
patient’s illness in comparison with the severity of other patients the physician has 
observed. The patient is rated on a scale from 1 to 7 with 1 indicating a “normal state” 
and 7 indicating “among the most extremely ill patients.” The CGI-S will be administered 
by the PI or a Sub-Investigator with extensive professional training and experience in 
assessing mental illness.
 
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9
4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A).
 
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For the purpose of the site’s data collection responsibilities, any untoward event that was 
reported from the time the patient signed the ICF until 30 days after the final 
protocol-defined study visit or, if the final visit does not occur, the last known dose of 
investigational product, is to be considered an AE.
Examples of AEs are as follows:

Changes in the general condition of the patient

Subjective symptoms offered by or elicited from the patient

Objective signs observed by the Investigator or other study site personnel

All diseases that occur after signing inform consent, including any change in severity 
or frequency of preexisting disease

All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study schedule
Please note medical procedures scheduled prior to consenting, but occurring during the 
study should not be captured as AEs, but should be listed in the medical history if related 
to a pre-existing condition.
9.5.2.2
Causality Assessment
For each AE, the Investigator must provide an assessment of causal relationship to the 
investigational product. The causality assessment must be recorded on the appropriate 
AE reporting page of the patient’s eCRF. Causal relationship must be assessed by 
answering the following question:
Is there a reasonable possibility the investigational product caused the event?
Yes:
There is evidence to suggest a causal relationship between the investigational 
product and AE; i.e.:

There is a reasonable temporal relationship between the 
investigational product and the event, and/or

The event is unlikely to be attributed to underlying/concurrent 
disease, other investigational products, or other factors, and/or

Positive dechallenge and/or rechallenge exist
 
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No:
There is no evidence to suggest a causal relationship between the 
investigational product and AE, i.e.:

There is no reasonable temporal relationship between the 
investigational product and the event, or

The patient did not take the investigational product, or

The event is likely to be attributed to underlying/concurrent 
disease, other investigational products, or other factors, or

The event is commonly occurring in the (study) population 
independent of investigational product exposure
9.5.2.3
Severity Assessment
The Investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. Severity,
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 9.5.2.4). Severity will be assessed 
according to the following scale:
Mild:
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the research participant.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
9.5.2.4
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization
 
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
Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in patient
hospitalization, or the development of investigational product dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (e.g., elective procedures for preexisting conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) or routine (i.e. required) 
country-specific hospitalization during washout are excluded from SAE reporting.
9.5.2.5
Reporting Adverse Events and Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study site personnel will 
record all pertinent information in the patient’s eCRF. 
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF
whether or not they are considered causally related to the investigational product.
For every AE, the Investigator must:

Provide an assessment of the seriousness of the event (i.e., is it an SAE?), as well as 
the severity and casual relationship

Document all actions taken with regard to the investigational product

Detail any other treatment measures taken for the AE

Document the outcome of the AE
 
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In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify site personnel of any AEs occurring during the 30 day 
post-study period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least one of the following conditions is met: 1) the event meets the criteria for 
an SAE (see Sections 9.5.2.4 and 9.5.2.6), and/or 2) the event is judged by the 
Investigator to be potentially causally related to investigational product.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the investigational product. If a follow-up visit is 
deemed necessary for appropriate safety surveillance, it will take place within 30 days of 
the final protocol-defined study visit.
9.5.2.6
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest
The Sponsor is required to inform worldwide regulatory authorities of SAEs and Ocular 
Events of Special Interest that meet specific criteria. Therefore, the Sponsor must be 
notified immediately regarding any SAE and Ocular Events of Special Interest that occur 
after informed consent is obtained.
The following serious and non-serious adverse events (ie, Ocular Events of Special 
Interest) require a 15-day alert report: 

cataract, lens, or lenticular abnormality or change, opacity, opacification or 
opalescence

blindness, night blindness, visual acuity or vision decrease, abnormality or change,
visual acuity test abnormality or change

retinal, macular, or optic nerve degeneration, abnormality or change; retinal pigment 
epithelium detachment, abnormality or change

color vision decrease, abnormality or change
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study site personnel must report the event to the Sponsor’s Global Drug Safety 
department on the SAE Form for Clinical Trials.
Within 24 hours of learning of any non-serious Ocular Event of Special Interest, the 
study site personnel must report the event on the Ocular Event Reporting Form. Serious 
Ocular Events should be reported on the SAE Form for Clinical Trials.
 
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In addition to completing the appropriate form, the Sponsor’s Study Safety Physician
may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE.
The site must transmit the SAE Form for Clinical Trials or the Ocular Event of Special 
Interest form to the SAE fax number shown below. Even if an initial report is made by
telephone, the SAE Form for Clinical Trials or the Ocular Event of Special Interest form,
completed with all available details, must still be faxed within 24 hours of knowledge of 
the event at the study site.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The Investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs and Ocular Events of 
Special Interest are to be followed by the study staff until resolution or until the SAE or 
Ocular Event of Special Interest is deemed stable. The Sponsor may contact the study 
site to solicit additional information or follow up on the event.
Fax the SAE Form for Clinical Trials to the Sponsor:
SAE Form fax number:
The Medical Emergency Phone number is provided in Regulatory Binder contact list. 
9.5.2.7
Reporting of Pregnancies Occurring During the Study
Study site personnel must report every pregnancy from the time the patient signs the ICF 
until 30 days after the last dose of investigational product. Within 24 hours of learning of 
the pregnancy, the study site personnel must report the event to the Sponsor’s Global 
Drug Safety department on the Clinical Trial Pregnancy Form and fax it to the 
SAE/Pregnancy fax number stated in Section 9.5.2.6, even if no AE has occurred.
Pregnancies in female partners of male patients occurring during the time frame 
described above must also be reported. 
 
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The pregnancy must be followed to term and the outcome reported by completing a 
follow-up a Clinical Trial Pregnancy Form. If the pregnancy is associated with an SAE 
(e.g., if the mother is hospitalized for hemorrhage), a separate SAE Form for Clinical 
Trials must be filed as described in Section 9.5.2.6 with the appropriate serious criterion 
(e.g., hospitalization) indicated in addition to the Pregnancy Form.
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9.5.3
Investigational Product Concentration Measurements
Blood samples will be collected by a qualified phlebotomist via venipuncture using 
lavender-top Vacutainer tubes containing potassium K2EDTA as the anticoagulant. A 
2-mL tube will be used to collect the samples for determination of the plasma 
concentrations of cariprazine and its metabolites.
Four blood samples (2 mL each) will be collected at Visit 4 (Week 2), Visit 5 (Week 4), 
Visit 6/ET (Week 6), and Visit 7 (Week 7). Samples may be collected at any time during 
the visit. The date and time of plasma sampling will be recorded in the eCRF along with 
the date and approximate time of the previous 3 doses of investigational product. Every 
effort should be made to collect PK samples for each patient. However, if for reasons of 
safety or patient refusal, blood sampling is not possible, the PK sample can be skipped. 
All Vacutainer and plasma collection tubes must be prechilled in an ice bath before use.
The clock times of all blood draws will be recorded for each patient. All Vacutainer and 
polypropylene tubes will be labeled at the study center with a code number that 
corresponds to the PID number, visit number, date, and blood draw time. The central 
laboratory will supply the labels with code numbers, blood Vacutainer tubes, and the 
polypropylene tubes. Other laboratory supplies are the responsibility of the Investigator.
Samples must be centrifuged for plasma harvesting within 30 minutes of blood draw.
For details on blood sample collection, plasma separation, storage, and shipment, see the 
instructions from the central laboratory (Central Laboratory Manual).
9.5.4
Health Economic and Outcomes Research Assessments
Not applicable.
9.5.5
Schedule of Assessments
The schedule of study procedures and assessments is tabulated by visit in the Schedule of 
Evaluations in Section 2.0. The descriptions of the procedures to be performed at each 
visit are provided below.
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
 
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9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the study, a Sponsor representative will meet with the 
Investigator and the study site staff to review the procedures to be followed during the 
study. Electronic data capture (EDC) functionality training is provided via 
computer-based training to train Investigators and authorized designees on recording the 
data in the eCRFs using the EDC system. After the first patient is enrolled, the Sponsor
representative, a Regional Site Manager (RSM) or designee, will periodically monitor the 
progress of the study by conducting on-site visits. This RSM or designee will review 
query statuses remotely, possibly warranting more frequent communication and/or site 
visits with the Investigator and the study site staff. The Investigator will make available 
to the RSM or designee source documents (written notes and electronic medical records, 
if used), signed consent forms, and all other study-related documents. The Investigator
and the study site staff will be responsible for data entry of patient data into the eCRFs 
via the EDC system, resolving data queries generated via the EDC system and providing 
missing or corrected data. The Investigator or designee will be responsible for approving 
all changes performed on the data, and endorsing the patient data within the EDC system. 
This approval method will include applying an electronic signature linked to a uniquely 
assigned username and password that together will represent a traditional handwritten 
signature used in the past.
9.6.2
Data Recording and Documentation
Data collection will involve the use of the Sponsor’s EDC system, to which only 
authorized personnel will have access. Patient’s data are to be entered into the EDC 
system by the Investigator or designee using their assigned EDC user account. After data 
entry into the EDC system by the Investigator or designee, a combination of manual and 
programmatic edit checks will be used to review the data for completeness, logic, and 
adherence to study protocol. As a result of these edits checks, data monitoring and
reviews; queries may be electronically issued to the site and should be answered 
electronically via the EDC system.
Each query will carry identifying information (assigned username, date and time) to 
assist the Sponsor and the Investigator on the origin of the data clarification request and 
the response provided by the Investigator. All data changes made to the patient’s data via 
a data query will be approved by the Investigator prior to final database lock.
After all data have been reviewed and all issues have been resolved, the database will be 
locked.
 
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All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (e.g., copies of 
eCRFs, laboratory reports, patient diaries, regulatory documents, etc.) will be retained at 
the site, along with adequate source documentation, according to FDA and ICH 
requirements. All study records must be available for inspection by the Sponsor, its 
authorized representatives, and the FDA or other health authorities.
9.7
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
9.7.1
Patient Populations
Four populations will be considered in the statistical analysis of the study.
9.7.1.1
Screened Population
The Screened Population will consist of all patients who signed informed consent and 
received a PID number.
9.7.1.2
Randomized Population
The Randomized Population will consist of all patients in the Screened Population who
were randomized to a treatment group in the study.
9.7.1.3
Safety Population
The Safety Population will consist of all patients in the Randomized Population who took 
at least 1 dose of double-blind investigational product.
9.7.1.4
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who had at least 1 postbaseline assessment of MADRS total score.
9.7.2
Patient Disposition
The number and percentage of patients in 3 of the study populations (Randomized, 
Safety, and ITT) will be summarized by treatment group and study center; the Screened 
Population will be summarized overall only by study center.
 
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Screen-failure patients (ie, patients screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for the Screened Population. 
The number and percentage of patients who completed the double-blind treatment period, 
and of patients who prematurely discontinued during the same period and who entered 
the safety follow-up period will be presented for each treatment group and pooled across 
treatment groups for the Randomized Population. Patients are considered to have entered 
the safety follow-up period if they had Visit 7 (Week 7). The reasons for premature 
discontinuation from the double-blind treatment period as recorded on the termination 
pages of the eCRFs will be summarized (number and percentage) by treatment group for 
the Randomized Population.
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (e.g., age, race, ethnicity, sex, weight, height, BMI) and other 
baseline characteristics will be summarized by treatment group for the Safety and 
ITT populations.
Prior medication is defined as any medication taken before the date of the first dose of 
double-blind investigational product. Concomitant medication is defined as any 
medication taken on or after the date of the first dose of double-blind investigational 
product.
Both prior and concomitant medication use will be summarized by the number and 
proportion of patients in each treatment group receiving each medication within each 
therapeutic class for the Safety Population. Multiple medication use by a patient will only 
be counted once.
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to double-blind investigational product for the Safety Population during the 
double-blind treatment period will be summarized for treatment duration, calculated as 
the number of days from the date of the first dose of double-blind investigational product 
taken to the date of the last dose taken, inclusive. Descriptive statistics (n, mean, standard
deviation, minimum, median, and maximum) will be presented by treatment group.
 
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9.7.4.2
Measurement of Treatment Compliance
Dosing compliance for a specified period is defined as the total number of capsules 
actually taken by a patient during that period divided by the number of capsules that were 
expected to be taken during the same period multiplied by 100. The total number of 
capsules actually taken during a specific period is calculated as the number of days in that 
period multiplied by the number of capsules taken each day during that period. The 
number of capsules expected to be taken for a specific treatment period will be calculated 
by multiplying the number of days in that period by the number of capsules to be taken 
per day. Descriptive statistics for investigational product compliance will be presented by 
treatment group for each period between 2 consecutive visits, as well as for the whole 
double-blind treatment period of the study for the Safety Population.
9.7.5
Efficacy Analyses
All efficacy analyses will be based on the ITT Population, unless stated otherwise. The 
baseline for each specific efficacy endpoint is defined as the value recorded at 
Visit 2/Week 0. If this value is not available, the last available value before the first dose 
of double-blind investigational product will be used as the baseline value. Efficacy results 
will be considered to be statistically significant after consideration of the 
multiplicity-control strategy for controlling the Type I error at 0.05 level; details are 
described in Section 9.7.5.2. Nominal p-values may be computed for other efficacy 
analyses as a measure of strength of association between the endpoint and the treatment 
effect rather than formal tests of hypotheses. All statistical hypothesis tests will be 
performed at the 2-sided 5% significance level for main effects. All confidence intervals 
will be 2-sided 95% confidence intervals, unless stated otherwise.
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with fewer than 2 patients in at least 1 treatment group in the ITT Population. 
Small centers will be pooled to form pseudo-centers so that each treatment group 
includes at least 2 ITT patients within the center. Pooling will be done within each 
country using the following algorithm: 
Based on the number of ITT patients, small centers will be ordered from the largest to the 
smallest, and centers of the same size will be ordered from the largest center number to 
the smallest center number. The pooling process starts with the largest small center from 
the top, which will be pooled with the smallest from the bottom until a non-small center 
is formed. The process will be repeated using the small centers left out after the first pass. 
If any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is more than 1 smallest pseudo-center, the pseudo-center with the 
smallest center number will be selected. In case that the pseudo center formed by pooling 
all small centers is still a small center, it will be pooled with the smallest non-small 
center. If there is more than 1 smallest non-small center, the one with the smallest center 
number will be selected.
 
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These pseudo-centers will be used for all efficacy analyses when the model is adjusted 
for study center.
 
 
 
 
 
9.7.5.1
Primary Efficacy Parameters
The primary efficacy parameter will be the change from baseline to Week 6 in MADRS 
total score. The primary analysis will be performed using a MMRM with treatment 
group, study center, visit, and treatment group–by-visit interaction as fixed effects and 
the baseline value and baseline by-visit interaction as covariates. An unstructured 
covariance matrix will be used to model the covariance of within-patient scores. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
The analysis will be performed based on all postbaseline scores using only the observed 
cases without imputation of missing values.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
9.7.5.2
Secondary Efficacy Parameters
The secondary efficacy parameter will be change from baseline to Week 6 in CGI-S 
score. The secondary efficacy parameter will be analyzed using an MMRM with 
treatment group, study center, visit, and treatment group–by-visit interaction as fixed 
effects and the baseline CGI-S score and baseline CGI-S score–by-visit interaction as the 
covariates. An unstructured covariance matrix will be used to model the covariance of 
within-patient scores. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.
To control the overall type I error rate for multiple comparisons of 2 active doses versus 
placebo at Week 6 for the primary and secondary efficacy parameters, the parallel 
gatekeeping procedure will be implemented (Chen et al, 2005). The 4 null hypotheses 
will be grouped into 2 families denoted by F1 and F2, with F1 consisting of 2 null 
hypotheses for comparisons of the 2 active doses versus placebo in change from baseline 
to Week 6 in MADRS total score, and F2 consisting of 2 null hypotheses for comparisons 
of the 2 active doses versus placebo in change from baseline to Week 6 in CGI-S score. 
Family F1 will serve as the parallel gatekeeper for F2. The matched gatekeeping 
procedure utilizes the special logical relationship between the primary and the secondary 
parameters to enhance the power of statistical testing. The secondary efficacy parameter 
will be tested at a specific dose only if the corresponding primary efficacy parameter is 
statistically significant. The Simes test will be used to derive the local p-values for the 
interaction hypotheses. The adjusted p-values for the 4 elementary hypotheses will be 
calculated based on the closed testing principle. Statistical significance will be 
determined by comparing the adjusted p-values to α = 0.050.
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9.7.6.6
Investigational Product Plasma Concentration Parameters
Plasma samples will be analyzed for the concentrations of cariprazine and its desmethyl 
and didesmethyl metabolites using a validated bioanalytical method. A population PK 
approach will be used to estimate individual-level drug-exposure parameters 
(i.e., steady-state area-under-the-curve (AUC), steady-state maximum concentration 
[Cmax], steady-state minimum concentration [Cmin]) for each of the 3 analytes. This will 
be performed via the use of appropriate nonlinear mixed-effects modeling software. The 
effects of demographics/covariates (eg, gender, body weight, height, concomitant 
medications) on the pharmacokinetics of the 3 analytes will be evaluated. The 
relationship, if any, between effectiveness and drug-exposure parameters will be 
explored.
9.7.7
Health Economics and Outcomes Research Analyses
Not applicable.
9.7.8
Interim Analysis
No interim analysis is planned for this study.
 
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9.7.9
Determination of Sample Size
The primary efficacy endpoint is the change from baseline at Week 6 in MADRS total 
score. The secondary endpoint is the change from baseline at Week 6 in CGI-S score. For 
the comparison of the primary endpoint, the sample size of 160 subjects per arm will 
provide approximately 82% statistical power to show statistically significantly higher 
effect in each dose of cariprazine versus placebo. The study has statistical power of 90% 
to show at least one of the two cariprazine doses is statistically significantly more 
efficacious than placebo in the primary endpoint. These calculations assumed an effect 
size of 0.36 (treatment group difference relative to SD). For a given successful 
(statistically significant) dose versus placebo with respect to the primary endpoint, its 
probability in detecting an effect size of 0.36 as statistically significant versus placebo 
with respect to the secondary endpoint is 88%. All statistical powers presented in this 
section were calculated adjusting for multiple comparisons using matched parallel 
gatekeeping procedure with the family-wise Type I error rate being controlled at a 0.05 
level (2-sided). The dropout rate is assumed to be 22% at Week 6. Within-person 
correlation for both primary and secondary endpoints is assumed to be 0.6, as well as 
correlation between the two endpoints (primary and secondary) to be 0.6. Assumptions of 
effect sizes, correlation coefficients, and drop-out rate are based on RGH-MD-56 study.
9.7.10
Computer Methods
Statistical analyses will be performed using version 9.1.3 (or newer) of SAS on a 
UNIX operating system.
9.8
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the Investigator in writing by the 
Sponsor. No protocol amendment may be implemented (with the exceptions noted below) 
before it has been approved by the IRB/IEC and the signature page, signed by the 
Investigator, has been received by the Sponsor. If the protocol is amended to eliminate or 
reduce the risk to patients, the amendment may be implemented before IRB/IEC review 
and approval. However, the IRB/IEC must be informed in writing of such an amendment, 
and approval must be obtained within reasonable time limits. Deviating from the protocol 
is permitted only if absolutely necessary for the safety or clinical management of the 
patients and must immediately be reported to the Sponsor. 
 
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9.9
PROTOCOL DEVIATIONS AND VIOLATIONS
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the Investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB/IEC approval or favorable opinion of an 
appropriate amendment and that does not have a major impact on the patient’s rights, 
safety, or well-being, or on the integrity and authenticity of the study data. Deviations 
may include, but are not limited to, departure from inclusion/exclusion criteria, dosing, 
duration of treatment, failure to perform the required assessments at specified time points, 
scheduling of visits not in accordance with specifications, or patient safety. Deviating 
from the protocol is permitted only if absolutely necessary for the safety or clinical 
management of the patients and must immediately be reported to the Sponsor.
Protocol deviations must be reported to the Sponsor either verbally or electronically 
within 5 working days from the day of discovery.
A protocol violation is a form of protocol deviation that has a major impact on the 
patient’s rights, safety, or well-being, or on the integrity and authenticity of the study 
data.
Protocol violations must be reported to the Sponsor within 24 hours, if possible. The 
IRB/IEC must be notified within the time period dictated by the IRB/IEC associated with 
this study. 
 
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10.0
STUDY SPONSORSHIP
10.1
STUDY TERMINATION
The Sponsor reserves the right to terminate the study in its entirety or at a specific study 
center before study completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this study are the property of the Sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
Publication of the results by the Investigator will be subject to mutual agreement between 
the Investigator and the Sponsor, and will follow Sponsor procedures on publications.
 
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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The Investigator must provide the following to the Sponsor before the start of the study:

A completed and signed Form FDA 1572 (for US sites). If, during the course of the 
study, any changes are made that are not reflected on Form FDA 1572, a new Form 
FDA 1572 must be completed and returned to the Sponsor for submission to the FDA

A fully executed contract

The curricula vitae for the Investigator and all Sub-Investigators listed on Form FDA 
1572 (or equivalent), including a copy of each physician’s license. 

A copy of the original IRB/EC approval for conducting the study. If the study is 
ongoing, renewals must be submitted at yearly intervals. All subsequent 
modifications must be submitted and approved by the IRB/EC, as stated in 
Section 5.1

A copy of the IRB/EC-approved ICF

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB/EC members or the DHHS general assurance number

A copy of the laboratory certifications and reference ranges

The Investigator’s Statement page in this protocol signed and dated by the 
Investigator

Financial disclosure agreement completed and signed by the Investigator and all 
Sub-Investigators listed on Form FDA 1572 (or equivalent). The Investigator and all 
Sub-Investigators will provide an updated financial disclosure agreement to the 
Sponsor 1 year after the completion of the study
11.2
PERFORMANCE
The Investigator must demonstrate reasonable efforts to obtain qualified patients for the 
study.
 
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11.3
USE OF INVESTIGATIONAL MATERIALS
The Investigator will acknowledge that the investigational product supplies are 
investigational and as such must be used strictly in accordance with the protocol and only 
under the supervision of the Investigator or Sub-Investigators listed on Form FDA 1572
(or equivalent). The investigational products must be stored in a secured place and must 
be locked. At study initiation, a Sponsor representative, will inventory the investigational 
products at the site. The Investigator must maintain adequate records documenting the 
receipt and disposition of all study supplies. The Sponsor will provide a mechanism to 
document receipt and accountability of investigational product. All unused 
investigational products must be returned to the Sponsor. It is the Investigator’s 
responsibility to ensure that patients return their investigational product.
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by the 
Sponsor through the EDC system. The Investigator is responsible for verifying that all 
data entries in the eCRFs are accurate and correct by electronically signing the completed 
eCRF casebook submitted to the Sponsor. The Investigator must maintain and retain 
accurate documentation that supports the information entered into the EDC system for 
source document verification and possible regulatory inspection.
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including case report 
forms, source documents, consent forms, regulatory documents, clinical laboratory 
results, calibration logs, or reports (including, but not limited to, all local and central 
laboratory results and ECG reports), and medication inventory records in all formats 
(including, but not limited to, written, electronic, magnetic, and optical records, and 
scans, x-rays, and ECGs) must be retained by the Investigator for a period of at least 
15 years after study completion unless local regulations or institutional policies require a 
longer retention period or otherwise notified in writing by the Sponsor. 
No study records shall be destroyed without notifying the Sponsor and providing the 
Sponsor the opportunity to arrange long-term storage for such study records or 
authorizing in writing the destruction of records after the required retention period.
The Investigator must permit access to any documentation relating to the study upon 
request of the Sponsor or applicable regulatory authorities. If the Investigator for the 
study retires, relocates, or for other reasons withdraws from the responsibility of keeping 
the study records, custody must be transferred to a suitable alternate custodian employee 
of the institution or to a suitably qualified and responsible third party. The Sponsor must 
be notified in writing of the name and address of the new custodian in advance of the 
transfer.
 
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11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by initials and PID number. Patients’ names are 
not to be transmitted to the Sponsor. The Investigator will keep a master patient list on 
which the PID number and the full name, address, and telephone number of each patient
are listed.
 
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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (RGH-MD-54
Amendment #2, dated 17 Feb 2016) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name
 
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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study or from the patient’s 
legally authorized representative. This consent must include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA; the 
Sponsor; the IRB; or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the Investigator as the 
contact. The guidance of the IRB/EC may be required)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled
 
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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the Investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of consent (e.g., “I agree to participate . . .”)

A place for the patient’s signature and date of signing

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient.
 
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APPENDIX II.
CONTACT INFORMATION 
Contact information for sponsor personnel is maintained in the Regulatory Binder.
 
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APPENDIX III.
CONCOMITANT MEDICATIONS
Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Analgesics
Y
Y
Nonnarcotic analgesics are allowed.
Medically appropriate episodic use of 
narcotic analgesics for acute medical 
indications limited to 3 days for an episode 
is allowed
Anesthetics
General
N
N
If procedures requiring general anesthesia 
are to occur/have occurred, please contact 
the Sponsor Medical Director to report the 
medical condition(s)
Local
Y
N
—
Anorexics
N
N
—
Antacids
Y
Y
—
Antiacne agents
Y
Y
Topical agents only, including topical 
antibiotics. Isotretinoin (Accutane) is not
allowed
Antianginal agents
Y
Y
—
Antiarrhythmics and other 
cardiac agents
N
Y
Only class II agents (eg, propranolol), 
class IV agents (eg, diltiazem, verapamil), 
and digoxin are allowed. Dosage must be 
stable for 1 month before screening.
Adenosine, parasympatholytics (atropine) 
and sympathomimetics (epinephrine, 
dopamine) are not allowed.
Antiasthma agents
Y
Y
Systemic steroids are not allowed; inhaled 
steroids at approved dosages are allowed
Antibiotics
Y
N
Linezolid (Zyvox) and Isoniazid are not
allowed. Clarithromycin, telithromycin, 
chloramphenicol, rifampicin and rifabutin 
are not allowed.
Anticonvulsants
N
N
Anticoagulants
N
N
Warfarin (Coumadin) is not allowed
Anticonvulsants
N
N
—
Antidepressants
N
N
—
Antidiarrheal agents
Y
N
Only loperamide (Imodium), bismuth 
subsalicylate (Pepto-Bismol), and kaolin 
preparations are allowed
 
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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Antiemetics/Antinauseants
Y
N
Antidopaminergic agents (such as 
metoclopramide and phenothiazines), 
domperidone, scopolamine, 5-HT3 receptor 
antagonists (eg, ondansetron) and sedating 
(H1) antihistamines are not allowed. 
Phosphoric acid preparations (Emetrol, 
Emecheck), bismuth subsalicylate 
(Pepto-Bismol), and cola syrup are allowed.
Antifungal agents
Systemic
N
N
—
Topical
Y
Y
—
Antihistamines
Y
Y
Sedating (H1) antihistamines are not 
allowed. Only Allegra (fexofenadine), 
Zyrtec (cetirizine), Xyzal (levocetirizine), 
Claritin (loratadine), and Clarinex 
(desloratadine) are allowed for episodic or 
chronic use. Combination products 
containing the word nighttime or some 
synonym routinely include a sedating 
antihistamine and are not allowed (see 
Cough/cold Preparations for combination 
products). Terfenadine is not allowed.
Antihypertensives
N
Y
Diupres (chlorothiazide and reserpine), 
clonidine (Catapres), guanabenz 
(Wytensin), guanfacine (Tenex), 
guanethidine (Ismelin), methyldopa 
(Aldomet), direct vasodilators (hydralazine, 
minoxidil), sodium nitroprusside, 
nitroglycerin, and diazoxide are not 
allowed. For all others (β-blockers, calcium 
channel blockers, ACE inhibitors, etc) the 
medication and dosage should be stable for 
1 month before screening
Anti-impotence medications
Y
Y
—
Anti-inflammatory drugs
Y
Y
Indomethacin and systemic corticosteroids 
are not allowed
Antimigraine
Y
N
Triptans allowed. Ergotamine or ergot 
derivatives are not allowed. Narcotics, 
antidepressants, and anticonvulsants are not 
allowed
Antineoplastics
N
N
—
 
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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Antiobesity drugs/appetite 
suppressants
N
N
—
Antiplatelet agents
N
Y
Aspirin (maximum dosage of 325mg/day) 
and clopidogrel (Plavix) are allowed
Antipsoriatic treatments
Y
Y
Acitretin (Soriatane) is not allowed
Antiparkinsonian drugs
N
N
Dopamine-releasing drugs, dopamine 
agonists, amantadine, levodopa, and 
monoamine oxidase–B inhibitors are not 
allowed. For extrapyramidal symptoms, 
diphenhydramine (50 mg/day) and 
benztropine (up to 4 mg/day or up to 
2 mg/day, if given parenterally) are allowed 
(see Section 9.4.8). Propranolol may also be 
used for treatment of akathisia
Antipsychotics
N
N
—
Antismoking medications
N
N
Varenicline (Chantix) is not allowed.
Nicotine replacement therapies are allowed
Antiviral agents
Y
Y
The following agents are allowed: 
acyclovir, famciclovir, valacyclovir, 
penciclovir, docosanol, trifluridine, and 
vidarabine. Amantadine and rimantadine are 
not allowed. Interferons are not allowed
Anxiolytics
Y
N
Lorazepam or its equivalent benzodiazepine 
may be prescribed as rescue medication for 
agitation, restlessness, or hostility. Episodic 
use of lorazepam up to 2 mg/day (or 
equivalent) and for up to 3 consecutive 
days at a time is allowed for agitation, 
restlessness, and hostility.
Lorazepam or other benzodiazepines may 
not be used in the 8 hours before any 
behavioral assessments. Diazepam may not 
be used in the 24 hours before any 
behavioral assessments.
 
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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Cough/cold preparations
Y
N
Cough preparations containing 
dextromethorphan or narcotics are not 
allowed. Decongestant preparations 
containing pseudoephedrine or 
phenylpropanolamine are not allowed. 
Phenylephrine nasal sprays are allowed for 
brief medically appropriate use for up to 
5 days (also see Antihistamines)
Diuretics
N
Y
Medication and dosage must be stable for 
1 month before screening
Drugs used to treat 
constipation
Y
N*
*Bulk laxatives, emollient laxatives are 
allowed
Episodic use of stimulant laxatives 
containing senna, bisacodyl, and 
anthraquinone derivatives is allowed. 
Osmotic laxatives such as oral magnesium 
hydroxide (milk of magnesia), oral sodium 
citrate and sodium biphosphate are allowed. 
Hyperosmotic laxatives such as sorbitol, 
lactulose, and polyethylene glycol are not 
allowed
Gastrointestinal:
H2-blockers/
proton pump inhibitors/
prokinetic agents
Y
Y
Cimetidine (Tagamet) is not allowed.
Metoclopramide and cisapride are not 
allowed
Hormones
N
Y
Thyroid hormone replacement is allowed. 
Therapeutic use in psychiatric disorders 
(eg, T3 augmentation therapy) is not 
allowed. Dosage of thyroid medication must 
be stable for 1 month before screening.
Systemic contraceptives (oral contraceptives 
of estrogen and progestin combinations, 
contraceptive implants such as 
Depo-Provera and Norplant, or 
transdermally delivered contraceptives such 
as Ortho Evra) are allowed but must be 
stable for 1 month before screening
Hormone suppressants
N
Y
Only Proscar (finasteride) and Avodart 
(dutasteride) are allowed. Dosage must be 
stable for 3 months before screening
 
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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Hypoglycemic agents
N
Y
Oral hypoglycemic agents are allowed, 
except the strong CYP3A inducers 
pioglitazone and troglitazone are not 
allowed. Chronic use of insulin is allowed. 
Consult Study Physician for episodic use of 
insulin. Dosage must be stable for 1 month 
before screening
Hypolipidemics
N
Y
Statins (lovastatin, pravastatin, simvastatin, 
atorvastatin, fluvastatin, rosuvastatin), 
fibrates (gemfibrozil, fenofibrate), and 
ezetimibe are allowed. Dosage must be 
stable for 1 month before screening. The 
Study Physician must be consulted for 
combined use of hypolipidemic agents. Bile 
sequestrants are not allowed. Niacin and 
niacinamide may be allowed if patient has 
taken these agents chronically ≥12 months
Mood stabilizers
N
N
—
Muscle relaxants
N
N
—
Psychotropic drugs not 
otherwise specified 
(including herbal products)
N
N
No drugs with psychomotor effects or with 
anxiolytic, stimulant, antipsychotic, or 
sedative properties are allowed. 
Herbal/dietary products and supplements 
with potential psychoactive actions 
including St. John’s wort, kava kava, 
SAMe, valerian root, DHEA, tyrosine, and 
5-HTP are not allowed
Sedatives/hypnotics
Y
Y
Zolpidem extended release (maximum of 
12.5 mg/day), zolpidem (maximum of 
10 mg/day), zaleplon (maximum of 
20 mg/day), chloral hydrate (maximum 
of 1000 mg/day), and eszopiclone
(maximum of 3 mg/day) are allowed for 
sleep. Sedatives/hypnotics may not be used 
in the 8 hours before any behavioral 
assessments
Steroids
Systemic
N
N
—
Topical
Y
Y
—
Inhalant
Y
Y
—
Intra-articular
Y
NA
—
 
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Medications Allowed (Y) and Medications Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Stimulants
N
N
Oral or transdermal methylphenidate, 
amphetamine products or prodrugs, 
pseudoephedrine, modafinil (Provigil), and 
armodafinil (Nuvigil) are not allowed
Vaccines
Y
NA
—
N = not allowed; NA = not applicable; PRN = as needed; Y = yes, allowed
 
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APPENDIX IV.
MONTGOMERY-ÅSBERG DEPRESSION RATING SCALE
Montgomery Åsberg Depression Rating Scale (MADRS)
The rating should be based on a clinical interview moving from broadly phrased 
questions about symptoms to more detailed ones which allow a precise rating of severity. 
The rater must decide whether the rating lies on predefined scale steps (0, 2, 4, 6) or 
between them (1, 3, 5).
It is important to remember that it is only on rare occasions that a depressed patient is 
encountered who cannot be rated on the items in the scale. If definite answers cannot be 
elicited from the patient all relevant clues as well as information from other sources 
should be used as a basis for the rating in line with customary clinical practice.
The scale may be used for any time interval between ratings, be it weekly or otherwise, 
but this must be recorded.
Item List
1.
Apparent sadness
2.
Reported sadness
3.
Inner tension
4.
Reduced sleep
5.
Reduced appetite
6.
Concentration difficulties
7.
Lassitude
8.
Inability to feel
9.
Pessimistic thoughts
10.
Suicidal thoughts
 
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1. Apparent Sadness
Representing despondency, gloom and despair, (more than just ordinary transient low 
spirits) reflected in speech, facial expression, and posture. Rate by depth and inability to 
brighten up.
0
No sadness.
1
2
Looks dispirited but does brighten up without difficulty.
3
4
Appears sad and unhappy most of the time.
5
6
Looks miserable all the time. Extremely despondent.
2. Reported sadness
Representing reports of depressed mood, regardless of whether it is reflected in 
appearance or not. Includes low spirits, despondency or the feeling of being beyond help 
and without hope. Rate according to intensity, duration and the extent to which the mood 
is reported to be influenced by events.
0
Occasional sadness in keeping with the circumstances.
1
2
Sad or low but brightens up without difficulty.
3
4
Pervasive feelings of sadness or gloominess. The mood is still influenced by 
external circumstances.
5
6
Continuous or unvarying sadness, misery or despondency.
 
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3. Inner tension
Representing feeling of ill-defined discomfort, edginess, inner turmoil, mental tension 
mounting to either panic, dread or anguish. Rate according to intensity, frequency, 
duration and the extent of reassurance called for.
0
Placid. Only fleeting inner tension.
1
2
Occasional feelings of edginess and ill-defined discomfort.
3
4
Continuous feelings of inner tension or intermittent panic which the patient can 
only master with some difficulty.
5
6
Unrelenting dread or anguish. Overwhelming panic.
4. Reduced sleep
Representing the experience of reduced duration or depth of sleep compared with the 
subject’s own normal pattern when well.
0
Sleeps as usual.
1
2
Slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep.
3
4
Sleep reduced or broken by at least two hours.
5
6
Less than two or three hours sleep.
 
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5. Reduced appetite
Representing the feeling of a loss of appetite compared with when well. Rate by loss of 
desire for food or the need to force oneself to eat.
0
Normal or increased appetite.
1
2
Slightly reduced appetite.
3
4
No appetite. Food is tasteless.
5
6
Needs persuasion to eat at all.
6. Concentration difficulties
Representing difficulties in collecting one’s thoughts mounting to incapacitating lack of 
concentration. Rate according to intensity, frequency, and degree of incapacity produced.
0
No difficulties in concentrating.
1
2
Occasional difficulties in collecting one’s thoughts.
3
4
Difficulties in concentration and sustaining thought which reduces ability to read 
or hold a conversation.
5
6
Unable to read or converse without great difficulty.
 
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7. Lassitude
Representing a difficulty getting started or slowness initiating and performing 
everyday activities.
0
Hardly any difficulty in getting started. No sluggishness.
1
2
Difficulties in starting activities.
3
4
Difficulties in starting simple routine activities which are carried out with effort.
5
6
Complete lassitude. Unable to do anything without help.
8. Inability to feel
Representing the subjective experience of reduced interest in the surroundings, or 
activities that normally give pleasure. The ability to react with adequate emotion to 
circumstances or people is reduced.
0
Normal interest in the surroundings and in other people.
1
2
Reduced ability to enjoy usual interests.
3
4
Loss of interest in the surroundings. Loss of feelings for friends and 
acquaintances.
5
6
The experience of being emotionally paralyzed, inability to feel anger, grief or 
pleasure and a complete or even painful failure to feel for close relatives and 
friends.
 
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9. Pessimistic thoughts
Representing thoughts of guilt, inferiority, self-reproach, sinfulness, remorse
and ruin.
0
No pessimistic thoughts.
1
2
Fluctuating ideas of failure, self-reproach or self-depreciation.
3
4
Persistent self-accusations, or definite but still rational ideas of guilt or sin. 
Increasingly pessimistic about the future.
5
6
Delusions of ruin, remorse or unredeemable sin. Self-accusations which are 
absurd and unshakable.
10. Suicidal thoughts
Representing the feeling that life is not worth living, that a natural death would be 
welcome, suicidal thoughts and preparations for suicide.
Suicidal attempts should not in themselves influence the rating.
0
Enjoys life or takes it as it comes.
1
2
Weary of life. Only fleeting suicidal thoughts.
3
4
Probably better off dead. Suicidal thoughts are common and suicide is considered 
as a possible solution, but without specific plans or intention.
5
6
Explicit plans for suicide when there is an opportunity. Active preparations for 
suicide.
© 1979 The Royal College of Psychiatrists. Montgomery, S.A. & Åsberg, M. (1979). A new 
depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382-389. 
Written permission must be obtained from the Royal College of Psychiatrists for copying and 
distribution to others or for republication (in print, online or by any other medium).
 
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APPENDIX VII.
CLINICAL GLOBAL IMPRESSIONS–SEVERITY
SEVERITY OF ILLNESS
Considering your total clinical experience with this population, how mentally ill is the 
patient at this time?
Check one:
1 = Normal, not at all ill
2 = Borderline ill
3 = Mildly ill
4 = Moderately ill
5 = Markedly ill
6 = Severely ill
7 = Among the most extremely ill patients
 
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14.0
LITERATURE CITED
Altshuler LL, Gitlin MJ, Mintz J, et al. Subsyndromal depression is associated with 
functional impairment in patients with bipolar disorder. J Clin Psychiatry 
2002;63:807-11.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 
Fifth Edition. Washington, DC: American Psychiatric Association; 2013.
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672-6.
Berk M, Dodd S, Kauer-Sant’anna M, et al. Dopamine dysregulation syndrome: 
implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand 
Suppl 2007;434:41-9.
Calabrese JR, Hirschfeld RM, Reed M, et al. Impact of bipolar disorder on a US 
community sample. J Clin Psychiatry 2003;64:425-32.
Calabrese JR, Hirschfeld RM, Frye MA, et al. Impact of depressive symptoms compared 
with manic symptoms in bipolar disorder: results of a US community-based sample. 
J Clin Psychiatry 2004;65:1499-504.
Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-
controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J 
Psychiatry 2005; 162(7):1351-60.
Chen X, Luo X, Capizzi T. The application of enhanced parallel gatekeeping strategies. 
Statist Med 2005;24:1385-97.
Dilsaver SC, Chen YW, Swann AC, et al. Suicidality, panic disorder and psychosis in 
bipolar depression, depressive-mania and pure-mania. Psychiatry Res 1997 Nov 14;73 
(1-2):47-56. 
Goodwin FK, Jamison KR. Treatment. In: Manic-depressive illness. New York: Oxford 
University Press; 1990. p. 642-7.
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. DHEW 
publication, no. (ADM) 76-338. Rockville, MD: US. Dept of Health, Education, and 
Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, National Institute of Mental Health, Psychopharmacology Research 
Branch, Division of Extramural Research Programs; 1976;218-22.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50-5.
 
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Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiat 
1960;32(1):56-62.
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin 
Psychol 1967;6:278-96.
Hlastala SA, Frank E, Mallinger AG, et al. Bipolar depression: an underestimated 
treatment challenge. Depress Anxiety 1997;5:73-83.
Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly 
symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530-7.
Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural 
history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen 
Psychiatry 2003;60:261-9.
Keller MB, Lavori PW, Coryell W, et al. Differential outcome of pure manic, 
mixed/cycling, and pure depressive episodes in patients with bipolar illness. JAMA
1986;255:3138-42.
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika 2003;90(1):53-71.
Kessler RD, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 
12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen 
Psychiatry 2005;62:617-27.
Leggio GM, Micale V, Drago F. Increased sensitivity to antidepressants of D3 dopamine 
receptor-deficient mice in the forced swim test (FST). Eur Neuropsychopharmacol
2008;18:271-7.
Leverich GS, Altshuler LL, Frye MA, et al. Factors associated with suicide attempts in 
648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. J Clin 
Psychiatry 2003;64:506-15.
MacQueen GM, Young LT, Joffe RT. A review of psychosocial outcome in patients with
bipolar disorder. Acta Psychiatr Scand 2001;103:163-70.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry 1979;134:382-9.
Muller-Oerlinghausen B, Berghöfer A, Bauer M. Bipolar disorder. Lancet 
2002;359:241-7.
 
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Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed 
for 1 year with daily prospective ratings on the NIMH life chart method. J Clin 
Psychiatry 2003;64:680-90.
Post RM. The impact of bipolar depression. J Clin Psychiatry 2005;66(Suppl 5)5-10.
RGH-188 (cariprazine). Investigator’s brochure. Edition 11. Jersey City, NJ: Forest 
Laboratories, LLC; 2015 Nov.
Rush JA, Trivedi MH, Ibrahim HM, et al. The 16-item Quick Inventory of Depressive 
Symptomatology (QIDS), Clinician Rating (QIDS-C), and Self-Report (QIDS-SR): A 
psychometric evaluation in patients with chronic major depression. Biol Psychiatry 
2003;573-83.
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr 
Scand Suppl 1970;212:11-9.
Steiner H, Fuchs S, Accili D. D3 dopamine receptor-deficient mouse: evidence for
reduced anxiety. Physiol Behav 1997;63:137-41.
Study RGH-MD-52: A double-blind placebo-controlled evaluation of RGH-188 
(cariprazine) in bipolar depression. Jersey City, NJ: Forest Research Institute, Inc.; 
2011 May 09.
Study RGH-MD-56: A double-blind placebo-controlled evaluation of the safety and 
efficacy of cariprazine in patients with bipolar depression. Jersey City, NJ: Forest 
Research Institute, Inc.; 2014 Oct 09
Suppes T, Datto C, Minkwitz M, et al. Effectiveness of the extended release formulation 
of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect 
Disord 2010; 121(1-2):106-15. 
Thase M, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in 
bipolar I and II depression: a double-blind, placebo-controlled study (The BOLDER II 
Study). J Clin Psychopharmacol. 2006; 27(1):51. 
Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine 
combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 
60(11):1079-88.
World Health Organization. World health report 2001―mental health: new 
understanding, new hope. Available from: http://www.who.int/whr/2001/en/. Accessed
2011 Jan 19.
 
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Wyatt RJ, Henter L. An economic evaluation of manic-depressive illness―1991. Soc 
Psychiatry and Psychiatr Epidemiol 1995;30:213-9.
Young RD, Briggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and 
sensitivity. Brit J Psychiat 1978;33:429-35.
 
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Forest Laboratories, LLC, an Allergan Affiliate
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
SUMMARY OF CHANGES TO PROTOCOL 
RGH-MD-54, A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER, 
FIXED-DOSE CLINICAL TRIAL EVALUATING THE EFFICACY, SAFETY 
AND TOLERABILITY OF CARIPRAZINE IN PATIENTS WITH BIPOLAR I 
DEPRESSION
Amendment #2, 17 Feb 2016
IND #77, 726
Original Protocol Date:
12 Nov 2015
Protocol Amendment #1:
02 Feb 2016
Confidentiality Statement
This document is the property of Forest Laboratories, LLC, an Allergan Affiliate, and 
may not—in full or part—be passed on, reproduced, published, distributed, or submitted 
to any regulatory authority without the express written permission of Forest 
Laboratories, LLC.
 
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Protocol RGH-MD-54 Amendment 2


1.0
INTRODUCTION
Amendment #2 specifies the following change to RGH-MD-54 Protocol Amendment #1, 
dated 02 Feb 2016: 
  
The page and protocol section numbers in the headings of this amendment are those of 
the previous version of the protocol. 
 
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2.0
GLOBAL CHANGES
The following changes have been made globally to the protocol:

None
 
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3.0
SECTIONS DELETED
The following sections have been removed from the protocol:

None
 
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4.0
SECTIONS ADDED

None
 
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5.0
REVISIONS
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
NCT02670551 
Study ID: RGH‐MD‐54 
 
Title:  A Phase 3, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group, Multicenter, Fixed‐
Dose Clinical Trial Evaluating The Efficacy, Safety And Tolerability Of Cariprazine In Patients With  
Bipolar I Depression 
 
 
Statistical Analysis Plan Amendment 1 Date: 2017‐Nov‐29 
 
 
 


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1.
Title Page
STATISTICAL ANALYSIS PLAN
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, 
Fixed-Dose Clinical Trial Evaluating the Efficacy, Safety and Tolerability of Cariprazine in 
Patients with Bipolar I Depression
Original SAP Date: 2017-03-30
Amendment #1 Date: 2017-11-29
Protocol Number:
RGH-MD-54
Development Phase:
3
Product Name:
Cariprazine
Study Statistician:
Sponsor:
Forest Laboratories, LLC, an Allergan Affiliate
This document is the property of Forest Laboratories, LLC, an Allergan Affiliate, and may not, in 
full or part, be passed on, reproduced, published, distributed to any person, or submitted to any 
regulatory authority without the express written permission of Forest Laboratories, LLC, an 
Allergan Affiliate.


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2.
Table of Contents
1.
Title Page ................................................................................................................................. 1
2.
Table of Contents..................................................................................................................... 2
2.1
List of Tables.................................................................................................................. 3
2.2
List of Figures ................................................................................................................ 5
3.
List of Abbreviations and Definition of Terms ........................................................................ 6
4.
Introduction.............................................................................................................................. 7
4.1
Study Design Summary ................................................................................................. 7
4.2
Study Objectives and Endpoints .................................................................................... 8
4.3
Schedule of Evaluations............................................................................................... 13
5.
Statistical Methodology and Study Endpoints....................................................................... 15
5.1
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 15
5.1.1
Statistical and Analytical Plans........................................................................ 15
5.1.1.1
Common Conventions....................................................................... 15
5.1.1.2
Demographics.................................................................................... 19
5.1.1.3
Efficacy and Pharmacokinetic Analyses ........................................... 22
5.1.2
Determination of Sample Size ......................................................................... 32
5.2
Changes in the Conduct of the Study or Planned Analyses ......................................... 33
5.2.1
Changes in the Conduct of the Study............................................................... 33
5.2.2
Changes to Analyses Prior to Database Lock .................................................. 33


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7.
References.............................................................................................................................. 48
2.1
List of Tables
Table 3-1
Abbreviations and Definitions of Terms ................................................................. 6
Table 4-2
Montgomery-Åsberg Depression Rating Scale (MADRS)................................... 10
Table 4-3
Clinical Global Impressions–Severity (CGI-S) .................................................... 10


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Table 5-1
Analysis Populations............................................................................................. 15
Table 5-2
Statistical Methodology ........................................................................................ 16
Table 5-4
Analysis Population Summaries ........................................................................... 19
Table 5-5
Participant Disposition Summaries....................................................................... 19
Table 5-6
Protocol Deviation Summary................................................................................ 20
Table 5-7
Demographic and Baseline Characteristics Summaries ....................................... 20
Table 5-8
Demographic and Baseline Characteristics Summaries ....................................... 20
Table 5-9
Medical History Summary.................................................................................... 21
Table 5-10
Medication Summaries ......................................................................................... 21
Table 5-11
Efficacy Assessments............................................................................................ 22
Table 5-12
Efficacy Endpoint Baseline Definitions................................................................ 23
Table 5-13
Efficacy Analyses.................................................................................................. 23
Table 5-14
Safety Endpoint Baseline Definitions................................................................... 25
Table 5-15
Study Treatment Summaries................................................................................. 25
Table 5-16
AE Terms .............................................................................................................. 26
Table 5-17
AE Summaries ...................................................................................................... 27
Table 5-18
Clinical Laboratory Summaries ............................................................................ 28
Table 5-20
Vital Signs Summaries.......................................................................................... 29
Table 5-21
ECG Summaries.................................................................................................... 30
Table 5-22
YMRS Summaries ................................................................................................ 31
Table 5-23
BARS and SAS Summaries.................................................................................. 31
Table 5-24
C-SSRS Summaries .............................................................................................. 32
Table 6-1
Analysis Day Definitions...................................................................................... 34


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Table 6-2
Efficacy and Safety Analysis Visit Definitions..................................................... 34
Table 6-3
Imputation Scenarios ............................................................................................ 35
Table 6-4
Initial Imputed Date Algorithm............................................................................. 35
Table 6-5
Missing AE Severity and Relationship Imputation Algorithms............................ 40
Table 6-6
AE of Special Interest Terms:  Ocular Events ...................................................... 41
Table 6-7
Clinical Laboratory PCS Criteria.......................................................................... 42
Table 6-8
Clinical Laboratory Descriptive Parameters Using SI Units ................................ 43
Table 6-9
Clinical Laboratory Descriptive Parameters Using Conventional Units .............. 43
Table 6-10
Clinical Laboratory Significant Values ................................................................. 44
2.2
List of Figures
Figure 4-1
Study Design........................................................................................................... 8


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3.
List of Abbreviations and Definition of Terms
Table 3-1
Abbreviations and Definitions of Terms
Abbreviation/Term
Definition
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ANCOVA
analysis of covariance
ATC
Anatomical Therapeutic Chemical
BARS
Barnes Akathisia Rating Scale
CFB
change from baseline
CGI-S
Clinical Global Impressions–Severity
C-SSRS
Columbia–Suicide Severity Rating Scale
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
ET
early termination
HAMD-17
17-item Hamilton Depression Rating Scale
HAM-A
Hamilton Anxiety Rating Scale
ITT
intent-to-treat
LS
least squares
MADRS
Montgomery-Åsberg Depression Rating Scale
MedDRA
Medication Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed-effects model for repeated measures
PCS
potentially clinically significant
PK
pharmacokinetic
PID
participant identification
PT
preferred term
QIDS-SR16
Quick Inventory of Depressive Symptomatology – Self-Report
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Simpson-Angus Scale
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
TEAE
treatment-emergent adverse event
WHO
World Health Organization
YMRS
Young Mania Rating Scale


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4.
Introduction
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the final protocol 
of Study RGH-MD-54 and the most recent amendment (version #2). Specifications of tables, 
figures, and data listings are contained in a separate document. 
This document is organized into 3 main sections:
1. Study overview
2. Statistical Methodology and Study Endpoints
3. Data Handling and Analysis Conventions
4.1
Study Design Summary
Methodology:  
Multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study
Number of Patients:  
480 planned (approximately 160 per treatment group)
Diagnosis and Main Criteria for Inclusion:  
Male and female outpatients who are 18 to 65 years of age, meet Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar I disorder without 
psychotic features confirmed by the administration of the Mini International Neuropsychiatric 
Interview (MINI), with a current major depressive episode of at least 4 weeks and not exceeding 
12 months in duration, a minimum score of 20 on the 17-item Hamilton Depression Rating Scale 
(HAMD-17), a minimum score of  2 on item 1 of the HAMD-17, and a minimum score of 4 on 
the Clinical Global Impressions-Severity Scale (CGI-S) at Visits 1 and 2. 
Test Product, Dosage, and Mode of Administration:  
Cariprazine 1.5 mg/day and 3.0 mg/day capsules, oral administration
Duration of Treatment:  
A no-drug screening period of approximately 7-14 days, followed by 6 weeks of double-blind 
treatment and a 1-week, no investigational product safety follow-up period.


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Reference Therapy, Dosage, and Mode of Administration:  
Matching placebo capsules, oral administration
 
 
4.2
Study Objectives and Endpoints
Each study objective is presented with corresponding endpoint(s) below:
Table 4-1
Study Objectives and Endpoints
Objectives
Endpoints

To evaluate the efficacy of cariprazine 1.5 mg/day 
and 3.0 mg/day relative to placebo in patients with 
bipolar I depression
Primary Efficacy Endpoint

Change from baseline to Week 6 in Montgomery-
Åsberg Depression Rating Scale (MADRS) total 
score
Secondary Efficacy Endpoint

Change from baseline to Week 6 in Clinical Global 
Impressions-Severity Scale (CGI-S)


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4-2
Montgomery-Åsberg Depression Rating Scale (MADRS)
Item Lista
Score Range
1
Apparent sadness
2
Reported sadness
3
Inner tension
4
Reduced sleep
5
Reduced appetite
6
Concentration difficulties
7
Lassitude
8
Inability to feel
9
Pessimistic thoughts
10 Suicidal thoughts
(Each item is rated on a scale from 0 to 6.)
a Scale for each item described in Appendix IV of the 
protocol.  
Table 4-3
Clinical Global Impressions–Severity (CGI-S)
Grade
Description
1
2
3
4
5
6
7
Normal, not at all ill
Borderline ill
Mildly ill
Moderately ill
Markedly ill
Severely ill
Among the most extremely ill patients


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5.
Statistical Methodology and Study Endpoints
5.1
Statistical Methods Planned in the Protocol and Determination of 
Sample Size
This statistical analysis plan (SAP) will be approved prior to database lock. The SAP expands the 
statistical section of the protocol and contains a detailed description of methods to analyze data 
collected in the study. The text portion of the SAP will be included in the CSR report as 
Appendix 16.1.9.
5.1.1
Statistical and Analytical Plans
Statistical analyses will be conducted using SAS Version 9.3 or newer.
5.1.1.1
Common Conventions
5.1.1.1.1
Analysis Populations
The analysis populations will consist of participants as defined below:
Table 5-1
Analysis Populations
Population
Definition
Study Treatment
Screened
All patients who signed informed consent and received a PID 
number
—
Randomized
All patients in the Screened Population who were randomized to 
a treatment group in the study.
Randomized assignment
Safety
All patients in the Randomized Population who took at least 1 
dose of double-blind investigational product
Randomized assignment
Intent-to-Treat (ITT)
All patients in the Safety Population who had at least 1 
postbaseline assessment of the MADRS total score.
Randomized assignment
5.1.1.1.2
Study Treatments
The following treatment groups are defined for this study:

Cariprazine 1.5 mg/day

Cariprazine 3.0 mg/day

Placebo 
5.1.1.1.3
Statistical Methodology
The methodologies defined below apply as specified to individual endpoints defined in this SAP. 
When indicated, 95% two-sided confidence intervals and two-sided p-values will be presented. 
Individual endpoint analyses may specify exceptions (additions or deletions) to these general 
definitions.


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Table 5-2
Statistical Methodology
Methodology
Description
Categorical counts

Number of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
Categorical 
descriptives

Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
o
N1 = number of patients with non-missing baseline
o
For AE summary of sex-specific AEs, the percentage is based on the 
number of participants of the sex
PCS descriptives

Number and percentage of participants meeting potentially clinically significant 
(PCS) criteria
o
Participants with ≥ 1 qualifying event counted once per PCS category 

Percentage denominator = number of participants with non-missing baseline and 
>=1 non-missing postbaseline assessment
o
Unevaluable assessments considered missing

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
Shift analysis

Number and percentage of participants in individual baseline and postbaseline 
categories

Percentage denominator = number of participants in individual baseline categories

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
Continuous 
descriptives

N, mean, standard deviation (SD), median, minimum, maximum
CFB descriptives

Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values
 
 
 
 
CFB MMRM

Continuous descriptives and SE for baseline, postbaseline, and CFB values at each 
analysis visit

Estimates derived from mixed model for CFB value controlling for fixed factors 
(treatment group, pooled study center, and visit), covariates (baseline value), and 
interactions (treatment group by visit, baseline value by visit), with an unstructured 
covariance matrix (compound symmetry if convergence fails).  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.
o
LS means and standard errors
o
LS mean differences, standard errors, and for comparisons of Cariprazine 
1.5 mg/day and Cariprazine 3.0 mg/day vs Placebo 
o
P-values from contrast t-test comparing Cariprazine 1.5 mg/day and 
Cariprazine 3.0 mg/day vs Placebo (Note the nominal p-values for primary 
and secondary endpoints will be adjusted through the matched parallel 
gatekeeping procedure, as described in Section 5.1.1.3.2.)


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Methodology
Description
 
 
 
 
 
 
 
 
 
 
CFB = change from baseline; ANCOVA = analysis of covariance; MMRM = mixed model for repeated measures; 
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document.
 
 
  
 
  
 
 
 
 
 
 
 
 


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5.1.1.1.5
Site Pooling
For efficacy analyses in which study center is a factor, a small center will be defined as a center 
with fewer than 2 patients in at least 1 treatment group in the ITT Population.  Small centers will 
be pooled to form pseudo-centers so that each treatment group includes at least 2 ITT patients 
within the center.  Pooling will be done within each country using the following algorithm:
1. Based on the number of ITT patients, small centers will be ordered from the largest to the 
smallest, and centers of the same size will be ordered from the largest center number to 
the smallest center number. 


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2. The pooling process starts with the largest small center from the top, which will be 
pooled with the smallest from the bottom until a non-small center is formed. 
3. The process will be repeated using the small centers left out after the first pass.
4. If any centers are left out at the end of the process, they will be pooled with the smallest 
pseudo-center. If there is more than 1 smallest pseudo-center, the pseudo-center with the 
smallest center number will be selected. In case that the pseudo center formed by pooling 
all small centers is still a small center, it will be pooled with the smallest non-small 
center. If there is more than 1 smallest non-small center, the one with the smallest center 
number will be selected.
The pseudo-centers will be used for all efficacy analyses when the model is adjusted for study 
center.
5.1.1.2
Demographics
5.1.1.2.1
Analysis Populations
The distribution of participants within the analysis populations will be summarized as follows:
Table 5-4
Analysis Population Summaries
Population 
Description
Timing
Methodology
Screened Population
Distribution overall and within Study 
Center in total
—
Categorical counts
Randomized, Safety,
and ITT Populations
Distribution overall and within Study 
Center in total and by treatment group
—
Categorical counts
5.1.1.2.2
Participant Disposition
Participant disposition encompasses the distribution of participants who enter, complete, and 
discontinue each specified analysis period, along with eCRF-reported discontinuation reasons 
from each respective analysis period. Participant disposition will be summarized as follows:
Table 5-5
Participant Disposition Summaries
Parameter
Description
Timing
Methodology
Screening disposition
Distribution in the Screened Population 
overall and within Study Center in total
Screening Period
Categorical 
descriptives
Double-blind 
disposition
Distribution in the Randomized, Safety
and ITT Population overall and within 
Study Center in total and by treatment 
group
Double-blind 
Treatment Period
Categorical 
descriptives
Double-blind 
disposition
Distribution by reason in the Safety 
Population in total and by treatment group
Double-blind 
Treatment Period
Categorical 
descriptives


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5.1.1.2.3
Protocol Deviations
Protocol deviations will be defined in Protocol Deviation Requirement Specification, including 
importance classification. Protocol deviations will be summarized as follows for the 
Randomized Population:
Table 5-6
Protocol Deviation Summary
Parameter
Description
Timing
Methodology
Important protocol 
deviations1
Distribution in the Randomized Population 
in total and by treatment group
—
Categorical 
descriptives
1Protocol deviations will be listed.
5.1.1.2.4
Demographics
Demographics will be summarized in total and by treatment group for the ITT and Safety 
Populations, as follows:
Table 5-7
Demographic and Baseline Characteristics Summaries
Parameter
Description
Timing
Methodology
Age
Age (years) relative to informed consent 
date
Informed consent
Continuous 
descriptives
Age group

< 20 years

≥20 to < 30 years

≥30 to < 40 years

≥ 40 to < 50 years

≥50 to < 60 years

≥60 years
Informed consent
Categorical 
descriptives
Sex, race, and ethnicity

eCRF categories

Race group
o
White
o
Non-white
Screening Period
Categorical 
descriptives
5.1.1.2.5
Baseline Characteristics
Baseline characteristics will be summarized in total and by treatment group for the ITT and 
Safety Populations, as follows:
Table 5-8
Demographic and Baseline Characteristics Summaries
Parameter
Description
Timing
Methodology
Baseline characteristics

Height (m)

Weight (kg)

Body mass index (BMI)

Weight (kg) / height (m)2
Latest assessment in 
Screening Period
Continuous 
descriptives
Baseline efficacy
Endpoints and timing fully described in 
Section 5.1.1.3

MADRS

CGI-S

Summary for ITT Population only 
—
Continuous 
descriptives


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5.1.1.2.6
Medical History
Medical history, encompassing abnormalities and surgeries reported as occurring before the 
Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.1 or newer. Unique participants who report medical history events will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT) in total and by 
treatment group for the Safety Population as follows:
Table 5-9
Medical History Summary
Parameter
Description
Timing
Methodology
Medical and Surgical 
history
Abnormalities and surgeries occurring 
before the Screening Visit
Screening Period
Categorical 
descriptives
Bipolar History
Bipolar disorder history occurring before 
the Screening Visit
Screening Period
Categorical 
descriptives
Other Psychiatric 
Disorder Medical 
History
Other psychiatric history occurring before 
the Screening Visit
Screening Period
Categorical 
descriptives
Non-Drug Psychiatric 
Treatment History
Non-drug psychiatric treatments taken 
before the Screening Visit
Screening Period
Categorical 
descriptives
History of Ocular 
Events of Special 
Interest
Abnormalities of ocular events occurring 
before the Screening Visit
Screening Period
Categorical 
descriptives
Ophthalmic Medical 
and Surgical History
Ophthalmic medical and surgical history 
occurring before the Screening Visit
Screening Period
Categorical 
descriptives
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group.
5.1.1.2.7
Prior and Concomitant Medications
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version WHODRUG DDE + HD 3Q2016 or newer. Unique participants who reported 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) 4 class and PT in 
total and by treatment group for the Safety Population as described in the table below.    
Additionally, the Concomitant Rescue Medications will be summarized, for each medication, 
with the mean daily dose, in total and by treatment group for the Safety Population.   
Table 5-10
Medication Summaries
Parameter
Description
Timing
Methodology
Prior medications1
Medication taken before the date of the 
first dose of double-blind investigational 
product.
Screening Period
Categorical 
descriptives
Concomitant medications1
Medication taken on or after the date of the 
first dose of double-blind investigational
product.
Double-blind 
Treatment Period
Categorical 
descriptives
Concomitant Medication 
of Interest- Summary of 
Rescue Medication Mean 
Daily Dose1
Rescue Medication taken on or after the 
date of the first dose of double-blind 
investigational
product.
Double-blind 
Treatment Period
Continuous 
descriptives
ATC4 classes will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group.
1Participant data will be listed.


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5.1.1.3
Efficacy and Pharmacokinetic Analyses
Efficacy analyses will be based on the ITT Population.  Pharmacokinetic endpoints and analyses 
will not be described in this SAP.
The following efficacy assessments and terms are defined:
Table 5-11
Efficacy Assessments
Assessment/Term
Description
Montgomery-Åsberg 
Depression Rating 
Scale (MADRS)
10-Item, clinician-rated scale to evaluate the patient’s depressive symptomatology.  Each 
item is scored on a 7-point scale, from 0 to 6 with a score of 0 reflecting no symptoms and a 
score of 6 reflecting symptoms of maximum severity. 
The MADRS total score is the sum of the 10 items from the MADRS at each visit if no 
item has missing score. If the number of missing items at a visit is 2 or less, the MADRS 
total score will be calculated as (sum of nonmissing items) × (total number of items) / 
(number of nonmissing items). If more than 2 items of the MADRS are missing, then the 
total score will be set to missing.
Clinical Global 
Impressions–
Severity (CGI-S)
Clinician-rated scale that measures the overall severity of a patient’s illness in comparison 
with the severity of other patients the physician has observed. The patient is rated on a scale 
from 1 to 7 with 1 indicating a “normal state”
and 7 indicating “among the most extremely ill patients.”.
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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Assessment/Term
Description
 
 
 
Baseline assessments for applicable efficacy endpoints defined as follows:
Table 5-12
Efficacy Endpoint Baseline Definitions
Endpoint
Description
Timing
Clinical Global Impressions–
Severity (CGI-S) and the total 
scores of the following: 
Montgomery-Åsberg Depression 
Rating Scale (MADRS), 
 
 
 
 
 
The baseline for each specific efficacy endpoint is 
defined as the value recorded at Visit 2/Week 0. If 
this value is not available, the last available value 
before the first dose of double-blind investigational 
product will be used as the baseline value.
Treatment Day 1.  
If not available, 
then the last 
available value 
before the first 
dose from Day -14 
to Day 1
5.1.1.3.1
Efficacy Endpoint
The following efficacy variables will be analyzed as described below.
Table 5-13
Efficacy Analyses
Assessment
Parameter
Timing
Methodology
MADRS
Change from baseline in MADRS total 
score to Week 6
Treatment Period:  
Week 6
CFB MMRM
 
 
 
 
  
 
  
 
  
 
  
 
  
 
CGI-S
Change from baseline in CGI-S score by 
visit
Treatment Period:  
Weeks 1, 2, 4, and 6
CFB MMRM
 
  
 
  


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1 Analysis visits defined in Section 6.2.1.
5.1.1.3.2
Multiple Comparisons Procedure for Primary and Secondary 
Endpoints
Procedure:
To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo 
at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure 
will be implemented (Chen et al, 2005). 
Hypotheses:
The 4 null hypotheses will be grouped into 2 families denoted by F1 and F2, with F1 consisting 
of 2 null hypotheses for comparisons of the 2 active doses versus placebo in change from 
baseline to Week 6 in MADRS total score (i.e., F1 = {H11, H12}), and F2 consisting of 2 null 
hypotheses for comparisons of the 2 active doses versus placebo in change from baseline to 
Week 6 in CGI-S score (i.e., F2 = {H21, H22}).  Family F1 will serve as the parallel gatekeeper for 
F2. 
Testing:
The matched gatekeeping procedure utilizes the special logical relationship between the primary 
and the secondary parameters to enhance the power of statistical testing. The secondary efficacy 
parameter will be tested at a specific dose only if the corresponding primary efficacy parameter 
is statistically significant. The Simes test will be used to derive the local p-values for the 
interaction hypotheses. The adjusted p-values for the 4 elementary hypotheses will be calculated 
based on the closed testing principle. Statistical significance will be determined by comparing 
the adjusted p-values to α = 0.050.


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Weights for Intersection Tests in the Matched Parallel Gatekeeping 
Procedure
Intersection hypothesis 
Weights 
H11
H12
H21
H22
H11∩H12∩H21∩H22
0.5
0.5
0
0
H11∩H12∩H21
0.5
0.5
0
0
H11∩H12∩H22
0.5
0.5
0
0
H11∩H12
0.5
0.5
0
0
H11 ∩H21∩H22
0.5
0
0
0.5
H11 ∩H21
1
0
0
0
H11 ∩H22
0.5
0
0
0.5
H11
1
0
0
0
H12∩H21∩H22
0
0.5
0.5
0
H12∩H21
0
0.5
0.5
0
H12 ∩H22
0
1
0
0
H12
0
1
0
0
H21∩H22
0
0
0.5
0.5
H21
0
0
1
0
H22
0
0
0
1
5.1.1.4
Safety Analyses
Safety analyses will be based on the Safety Population.
Baseline assessments for applicable safety endpoints defined as follows:
 
 
 
 
5.1.1.4.1
Study Treatment Exposure and Compliance
Study treatment exposure and compliance will be summarized by treatment group for the Safety 
Population as follows:
Table 5-15
Study Treatment Summaries
Parameter
Description
Timing
Methodology
Study treatment 
exposure (days)
Treatment end date - treatment start date + 
1
Treatment Period
Continuous 
descriptives
Patient-years of study 
treatment exposure 
(years)
Sum over participants of study treatment 
exposure
Treatment Period
—


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Parameter
Description
Timing
Methodology
Study treatment 
compliance (%)
Summary by visit interval and overall
100 ×
Number of capsules actually 
taken
Number of capsules expected 
to be taken

The total number of capsules 
actually taken during a specific 
period is calculated as the sum of 
the number of capsules taken 
during that interval. 

The number of capsules expected 
to be taken for a specific interval
will be calculated by multiplying 
the number of days in that period 
by the number of capsules to be 
taken per day.
Week 0 (Baseline)-
Week 1 visit (not 
inclusive), Week 1 
visit-Week 2 visit 
(not inclusive), 
Week 2 visit-Week 
4 visit (not 
inclusive), Week 4 
visit-Week 6 visit 
(not inclusive), and
Overall Treatment 
Period
Continuous 
descriptives
5.1.1.4.2
Adverse Events
The following adverse event (AE) terms are defined:
Table 5-16
AE Terms
Term
Description
Treatment-
emergent 
An event that initially occurs or increases in severity on or after the treatment start date, where:

Treatment start date ≤ event start date ≤ treatment end date + 30
Newly-
emergent
An AE occurring during the safety follow-up period will be considered a newly emergent adverse 
event if the AE was not present before the start of the safety follow-up period or was present 
before the start of the safety follow-up period and increased in severity during the safety follow-
up period.
On-therapy
An event where:

Treatment start date ≤ event start date ≤ treatment end date + 30
AEs, encompassing abnormalities and surgeries reported as occurring after the Screening Visit, 
will be coded using MedDRA version 19.1 or newer. Unique patients reporting AEs in the 
following AE categories will be summarized by treatment group for the Safety Population as 
follows:


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Table 5-17
AE Summaries
Parameter
Description
Timing
Methodology
Overall summary
Overall summary only for the following 
categories:

Deaths

Treatment-emergent AEs 
(TEAEs)

On-therapy Serious adverse 
events (SAEs)

AEs leading to discontinuation
Double-blind 
Treatment Period
Categorical 
descriptives
Overall summary only for the following 
categories:

Deaths

Serious adverse events (SAEs)

Newly emergent AEs
During the Safety 
Follow-up Period
and within 30 days 
after the last dose of 
double-blind 
treatment
Categorical 
descriptives
TEAEs
Overall summary and by SOC and PT
Double-blind 
Treatment Period
Categorical 
descriptives
NEAEs
Overall summary and by SOC and PT
During the Safety 
Follow-up Period 
and within 30 days 
after double-blind 
treatment
Categorical 
descriptives
Common TEAEs
Summary by SOC, PT, sorted by 
decreasing frequency for the test treatment

Includes TEAEs occurring in 
≥ 2.0% of participants in any 
treatment group.  Event rates will 
not be rounded prior to 
comparison with the 2.0% 
cutpoint.
Summary by PT, sorted by decreasing 
frequency for the test treatment
Double-blind 
Treatment Period
Categorical 
descriptives
TEAEs by severity
Overall summary and by SOC, PT, and 
severity

Participants categorized overall 
and within each SOC and PT for 
the most sever occurrence
Double-blind 
Treatment Period
Categorical 
descriptives
TEAEs by causality
Overall summary and by SOC, PT, and 
causality
Double-blind 
Treatment Period
Categorical 
descriptives
On-therapy SAEs1
Overall summary and by SOC and PT
Double-blind 
Treatment Period
and within 30 days 
after the last dose of 
double-blind 
treatment;
Categorical 
descriptives
On-therapy SAEs1
Overall summary and by SOC and PT
During the Safety 
Follow-up Period 
and within 30 days 
after the last dose of 
double-blind 
treatment
Categorical 
descriptives


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Parameter
Description
Timing
Methodology
AEs leading to 
discontinuation1
Overall summary and by SOC and PT, 
sorted by decreasing frequency for the 
highest dose test treatment
Double-blind 
Treatment Period
Categorical 
descriptives
AE of interest: Extra-
Pyramidal Symptoms 
(EPS) related TEAEs1
Overall summary and by PT. Include the 
below PT:
Akathisia, Bradykinesia, Cogwheel 
rigidity, Drooling, Dyskinesia, Dystonia, 
Extrapyramidal disorder, Hypokinesia, 
Masked facies, Muscle rigidity, Muscle 
tightness, Musculoskeletal stiffness, 
Oculogyric crisis, Oromandibular dystonia, 
Parkinsonism, Restlessness, Salivary 
hypersecretion, Tardive dyskinesia, 
Tongue spasm, Tremor, Trismus
Double-blind 
Treatment Period
Categorical 
descriptives
AE of interest:  Ocular 
events1
Overall summary and by Category and PT

Includes Categories and PTs, 
defined in Section 6.6.1.2
Double-blind 
Treatment Period
Categorical 
descriptives
1 Patients who report ≥ 1 AE in the AE category and all AEs for those patients will be listed.
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Description
Timing
Methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.1.5
Subgroup Analyses
Not applicable.
5.1.1.6
Interim Analyses
No interim analysis is planned for this study.
5.1.2
Determination of Sample Size
The primary efficacy endpoint is the change from baseline at Week 6 in MADRS total score. The 
secondary endpoint is the change from baseline at Week 6 in CGI-S score. For the comparison of 


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the primary endpoint, the sample size of 160 subjects per arm will provide approximately 82% 
statistical power to show statistically significantly higher effect in each dose of cariprazine 
versus placebo. The study has statistical power of 90% to show at least one of the two 
cariprazine doses is statistically significantly more efficacious than placebo in the primary 
endpoint. These calculations assumed an effect size of 0.36 (treatment group difference relative 
to SD). For a given successful (statistically significant) dose versus placebo with respect to the 
primary endpoint, its probability in detecting an effect size of 0.36 as statistically significant 
versus placebo with respect to the secondary endpoint is 88%. All statistical powers presented in 
this section were calculated adjusting for multiple comparisons using matched parallel 
gatekeeping procedure with the family-wise Type I error rate being controlled at a 0.05 level (2-
sided). The dropout rate is assumed to be 22% at Week 6. Within-person correlation for both 
primary and secondary endpoints is assumed to be 0.6, as well as correlation between the two 
endpoints (primary and secondary) to be 0.6. Assumptions of effect sizes, correlation 
coefficients, and drop-out rate are based on RGH-MD-56 study.
5.2
Changes in the Conduct of the Study or Planned Analyses
This analysis plan is consistent with the methods stated in the study protocol.  Changes in the 
conduct of the study or planned analyses, should they happen, will be documented in the clinical 
study report.  
5.2.1
Changes in the Conduct of the Study
Not applicable.
5.2.2
Changes to Analyses Prior to Database Lock
Not applicable.


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eek 6/Early Termination 
visit]


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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.6.1.2
AE Group of Interest
The following PTs are categorized as AE groups of special interest for Ocular Events:
Table 6-6
AE of Special Interest Terms:  Ocular Events
Category of 
Ocular 
Events
Verbatim
Preferred Terms
Cataract 
Category
Cataract
Atopic cataract, Cataract, Cataract cortical, Cataract diabetic, Cataract nuclear, 
Cataract subcapsular, Toxic cataract
Lens or lenticular 
abnormality
Acquired lenticonus, Aphakia, Lens disorder
Lens opacity, 
opacification or 
opalescence
Lens discolouration, Lenticular opacities, Posterior capsule opacification
Visual Acuity 
Change 
Category
Blindness
Amaurosis, Amaurosis fugax Blindness, Blindness day, Blindness transient, 
Blindness unilateral, Diabetic blindness, Sudden visual loss
Night blindness
Delayed dark adaptation, Night blindness
Visual acuity 
decreased, 
abnormality or 
change
Refraction disorder, Visual acuity reduced, Visual acuity reduced transiently
Vision decreased, 
abnormality or 
change
Accommodation disorder, Altered visual depth perception, Aniseikonia, 
Anisometropia, Antimetropia, Astigmatism, Hemianopia, Hemianopia 
heteronymous, Hypermetropia, Myopia, Pathologic myopia, Presbyopia, 
Pseudomyopia, Quadranopia, Tunnel vision, Visual field defect, Visual 
impairment
Visual acuity test 
abnormality or 
change
Visual acuity tests abnormal
Retinal 
Impairment 
Category
Retinal 
degeneration, 
abnormality or 
change
Pars plana cyst, Retinal cyst, Retinal degeneration, Retinal depigmentation, 
Retinal deposits, Retinal detachment, Retinal disorder, Retinal dystrophy, 
Retinal fibrosis, Retinal infiltrates, Retinal pallor, Retinal pigmentation, Retinal 
pigment epithelial tear, Retinal pigment epitheliopathy, Retinal tear, Retinal 
thickening Retinal toxicity, Retinoschisis, Subretinal fibrosis, Subretinal fluid
Macular 
degeneration, 
abnormality or 
change
Age-related macular degeneration, Dry age-related macular degeneration, 
Macular cyst, Macular degeneration, Macular hole, Macular opacity, Macular 
detachment, Macular rupture, Macular fibrosis, Macular pigmentation, Macular 
rupture, Maculopathy, Neovascular age-related macular degeneration, 
Vitreomacular interface abnormal
Optic nerve 
degeneration, 
abnormality or 
change
Myopic disc, Optic atrophy, Optic discs blurred, Optic disc disorder, Optic disc 
drusen, Optic nerve cupping, Optic nerve cup/disc ratio decreased, Optic nerve 
cup/disc ratio increased, Optic nerve disorder, Papilloedema, 
Pseudopapilloedema
Retinal pigment 
epithelium 
detachment, 
abnormality or 
change
Chorioretinal atrophy, Chorioretinal disorder, Chorioretinopathy, Detachment 
of macular retinal pigment epithelium, Detachment of retinal pigment 
epithelium, Retinal dystrophy
Color Vision 
Change 
Category
Color vision 
decrease, 
abnormality or 
change
Chloropsia, Chromatopsia, Colour blindness, Colour blindness acquired, 
Colour vision tests abnormal, Colour vision tests abnormal blue-yellow, Colour 
vision tests abnormal red-green, Cyanopsia, Erythropsia, Xanthopsia


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7.
References
Chen X et al. The application of enhanced parallel gatekeeping strategies. Statistics in Medicine, 
2005; 24 :1385-1397.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;  23:56–62.
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time dependence. 
Biometrika, 2003; 90(1): 53-71.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. J. Wiley & Sons, New York; 1987.
Rush JA, Trivedi MH, Ibrahim HM, et al. The 16-item Quick Inventory of Depressive 
Symptomatology (QIDS), Clinician Rating (QIDS-C), and Self-Report (QIDS-SR): A 
psychometric evaluation in patients with chronic major depression. Biol Psychiatry 2003;573-83.
SAS Institute Inc. SAS/STAT User’s Guide, Version 9.1. Cary, NC: SAS Institute Inc; 2004.
Wang C, Daniels MJ. A note on MAR, identifying restrictions, model comparison, and sensitivity 
analysis in pattern mixture models with and without covariates for incomplete data. Biometrics, 
2011; 67(3):810-818. 


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STATISTICAL ANALYSIS PLAN AMENDMENT                                                
SUMMARY OF CHANGES
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, 
Fixed-Dose Clinical Trial Evaluating the Efficacy, Safety and Tolerability of Cariprazine in 
Patients with Bipolar I Depression
Original SAP Date: 2017-03-30
Amendment #1: 2017-11-29
Protocol Number:
RGH-MD-54
Development Phase:
3
Product Name:
Cariprazine
Study Statistician:
Sponsor:
Forest Laboratories, LLC, an Allergan Affiliate
This document is the property of Forest Laboratories, LLC, an Allergan Affiliate, and may not, in 
full or part, be passed on, reproduced, published, distributed to any person, or submitted to any 
regulatory authority without the express written permission of Forest Laboratories, LLC, an 
Allergan Affiliate.


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1.
Introduction
Amendment #1 specifies the following changes to the original statistical analysis plan (SAP) for 
Study RGH-MD-54, dated March 30, 2017:

add a section for missing/imcomplete onset date of current episode of bipolar 1 disorder

make revision to 
-
update population for protocol deviation analysis
-
update imputation rules for missing items in efficacy parameter
-
update visits for analysis per design
-
include the weights for intersection tests in multiple comparison procedure
-
update analysis window for safety parameters to be consistent with previous studies
-
update lab PCS critiera
-
update lab parameters included in the summary analysis
-
update lab character value coding convention
-
make editorial updates that are necessary
These changes to the SAP are also reflected in the amended SAP. The page and section numbers 
in the headings of this amendment are those of the original SAP, dated March 30, 2017.


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2.
Global Changes
None


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4.
Deleted Sections
None


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5.
Revisions
5.1 SECTION 5.1.1.1.3, Statistical Methodology (Page 15)
Rational: This section has been amended to include details needed editorial updates of the 
MMRM model.
This section now reads as follows:
The methodologies defined below apply as specified to individual endpoints defined in this SAP. 
When indicated, 95.0% two-sided confidence intervals and two-sided p-values will be presented. 
Individual endpoint analyses may specify exceptions (additions or deletions) to these general 
definitions.
Table 5-2
Statistical Methodology
Methodology
Description
Categorical counts

Number of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
Categorical 
descriptives

Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
o
N1 = number of patients with non-missing baseline
o
For AE summary of sex-specific AEs, the percentage is based on the 
number of participants of the sex
PCS descriptives

Number and percentage of participants meeting potentially clinically significant 
(PCS) criteria
o
Participants with ≥ 1 qualifying event counted once per PCS category 

Percentage denominator = number of participants with non-missing baseline and 
>=1 non-missing postbaseline assessment
o
Unevaluable assessments considered missing

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
Shift analysis

Number and percentage of participants in individual baseline and postbaseline 
categories

Percentage denominator = number of participants in individual baseline categories

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
Continuous 
descriptives

N, mean, standard deviation (SD), median, minimum, maximum
CFB descriptives

Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values
 
 
 
 
 


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Methodology
Description
CFB MMRM

Continuous descriptives and SE for baseline, postbaseline, and CFB values at each 
analysis visit

Estimates derived from mixed model for CFB value controlling for fixed factors 
(treatment group, pooled study center, and visit), covariates (baseline value), and 
interactions (treatment group by visit, baseline value by visit), with an unstructured 
covariance matrix (compound symmetry if convergence fails).  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.
o
LS means and standard errors
o
LS mean differences, standard errors, and for comparisons of Cariprazine 
1.5 mg/day and Cariprazine 3.0 mg/day vs Placebo 
o
P-values from contrast t-test comparing Cariprazine 1.5 mg/day and 
Cariprazine 3.0 mg/day vs Placebo (Note that the nominal p-values for 
endpoints in primary and secondary endpoints will be adjusted through the 
matched parallel gatekeeping procedure, as described in Section 
5.1.1.3.2will be adjusted.)
 
 
 
 
 
 
 
 
 
 
CFB = change from baseline; ANCOVA = analysis of covariance; MMRM = mixed model for repeated measures; 
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document.
5.2 SECTION 5.1.1.2.2, Participant Disposition (Page 19)
Rational: This section has been amended to remove the disposition analysis for Randomized 
Population.
This section now reads as follows:
Participant disposition encompasses the distribution of participants who enter, complete, and 
discontinue each specified analysis period, along with eCRF-reported discontinuation reasons 
from each respective analysis period. Participant disposition will be summarized as follows:


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Table 5-5
Participant Disposition Summaries
Parameter
Description
Timing
Methodology
Screening disposition
Distribution in the Screened Population 
overall and within Study Center in total
Screening Period
Categorical 
descriptives
Double-blind 
disposition
Distribution in the Randomized, Safety
and ITT Population overall and within 
Study Center in total and by treatment 
group
Double-blind 
Treatment Period
Categorical 
descriptives
Double-blind 
disposition
Distribution by reason in the Randomized
and Safety Population in total and by 
treatment group
Double-blind 
Treatment Period
Categorical 
descriptives
5.3 SECTION 5.1.1.2.3, Protocol Deviations (Page 20)
Rational: This section has been amended to use Randomized Population for protocol deviation 
analysis.
This section now reads as follows:
Protocol deviations will be defined in Protocol Deviation Requirement Specification, including 
importance classification. Protocol deviations will be summarized as follows for the Randomized 
Population:
Table 5-6
Protocol Deviation Summary
Parameter
Description
Timing
Methodology
Important protocol 
deviations1
Distribution in the ITT Randomized
Population in total and by treatment group
—
Categorical 
descriptives
1Protocol deviations will be listed.
5.4 SECTION 5.1.1.3, Efficacy and Pharmacokinetic Analyses (Page 22)
Rational: This section has been amended 1) to add details in case of missing items, 2) to drop 
some visits in analysis per design, and 3) to include the weights for multiple comparison 
procedure.
This section now reads as follows:
5.1.1.3 Efficacy and Pharmacokinetic Analyses
Efficacy analyses will be based on the ITT Population.  Pharmacokinetic endpoints and analyses 
will not be described in this SAP.
The following efficacy assessments and terms are defined:


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Table 5-11
Efficacy Assessments
Assessment/Term
Description
Montgomery-Åsberg 
Depression Rating 
Scale (MADRS)
10-Item, clinician-rated scale to evaluate the patient’s depressive symptomatology.  Each 
item is scored on a 7-point scale, from 0 to 6 with a score of 0 reflecting no symptoms and a 
score of 6 reflecting symptoms of maximum severity. 
The MADRS total score is the sum of the 10 items from the MADRS at each visit if no item 
has missing score. If the number of missing items at a visit is 2 or less, the MADRS total 
score will be calculated as (sum of nonmissing items) × (total number of items) / (number 
of nonmissing items). If more than 2 items of the MADRS are missing, then the total score 
will be set to missing.
Clinical Global 
Impressions–
Severity (CGI-S)
Clinician-rated scale that measures the overall severity of a patient’s illness in comparison 
with the severity of other patients the physician has observed. The patient is rated on a scale 
from 1 to 7 with 1 indicating a “normal state”
and 7 indicating “among the most extremely ill patients.”.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Baseline assessments for applicable efficacy endpoints defined as follows:


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5.1.1.3.1   Efficacy Endpoint
The following efficacy variables will be analyzed as described below.
Table 5-13
Efficacy Analyses
Assessment
Parameter
Timing
Methodology
MADRS
Change from baseline in MADRS total 
score to Week 6
Treatment Period:  
Week 6
CFB MMRM
 
 
 
 
  
 
  
 
  
 
  
 
  
 
CGI-S
Change from baseline in CGI-S score by 
visit
Treatment Period:  
Weeks 1, 2, 4, and 6
CFB MMRM
 
  
 
  
 
 
  
 
 
  
 
 
  
 
  
 
  
 
  
1 Analysis visits defined in Section 6.2.1.


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5.1.1.3.2 Multiple Comparisons Procedure for Primary and Secondary Endpoints
Procedure:
To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo 
at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure 
will be implemented (Chen et al, 2005). 
Hypotheses:
The 4 null hypotheses will be grouped into 2 families denoted by F1 and F2, with F1 consisting 
of 2 null hypotheses for comparisons of the 2 active doses versus placebo in change from 
baseline to Week 6 in MADRS total score (i.e., F1 = {H11, H12}), and F2 consisting of 2 null 
hypotheses for comparisons of the 2 active doses versus placebo in change from baseline to 
Week 6 in CGI-S score (i.e., F2 = {H21, H22}).  Family F1 will serve as the parallel gatekeeper for 
F2. 
Testing:
The matched gatekeeping procedure utilizes the special logical relationship between the primary 
and the secondary parameters to enhance the power of statistical testing. The secondary efficacy 
parameter will be tested at a specific dose only if the corresponding primary efficacy parameter 
is statistically significant. The Simes test will be used to derive the local p-values for the 
interaction hypotheses. The adjusted p-values for the 4 elementary hypotheses will be calculated 
based on the closed testing principle. Statistical significance will be determined by comparing 
the adjusted p-values to α = 0.050.
Weights for Intersection Tests in the Matched Parallel Gatekeeping 
Procedure
Intersection hypothesis 
Weights 
H11
H12
H21
H22
H11∩H12∩H21∩H22
0.5
0.5
0
0
H11∩H12∩H21
0.5
0.5
0
0
H11∩H12∩H22
0.5
0.5
0
0
H11∩H12
0.5
0.5
0
0
H11 ∩H21∩H22
0.5
0
0
0.5
H11 ∩H21
1
0
0
0
H11 ∩H22
0.5
0
0
0.5
H11
1
0
0
0
H12∩H21∩H22
0
0.5
0.5
0
H12∩H21
0
0.5
0.5
0
H12 ∩H22
0
1
0
0
H12
0
1
0
0
H21∩H22
0
0
0.5
0.5
H21
0
0
1
0
H22
0
0
0
1


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PCS Criteria
 
 
 
 
Crystals


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