Clinical trial NCT03573297
Conditions: Bipolar I Disorder Mania Depression
Sponsor: AbbVie
Start date: 2018-06-15; Completion date: 2022-09-05
Enrollment: 901 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
1\) To evaluate the efficacy and safety of cariprazine at a target dose of 3.0 mg/day compared with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (i.e. index episode) is manic or depressive, with or without mixed features; 2) To evaluate the efficacy and safety of cariprazine at a target dose of 1.5 mg/day compared with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (i.e. index episode) is manic or depressive, with or without mixed features who were initially stabilized on a target dose of 3.0 mg/day

Detailed description:

Arms: arm 1: Participants randomized to receive cariprazine 3.0 mg once daily (QD) for up to 39 weeks. arm 2: Participants randomized to receive cariprazine 1.5 mg QD for up to 39 weeks. arm 3: Participants randomized to receive placebo QD for up to 39 weeks. arm 4: Participants started on cariprazine 1.5 mg QD, with a target dose of 3.0 mg QD, for up to 16 weeks.
Interventions: intervention 1: Cariprazine intervention 2: Placebo
Intervention descriptions: intervention 1: Cariprazine capsules, oral administration, once daily intervention 2: Matching placebo capsules, oral administration, once daily

Protocol documents:
Prot_000.pdf: 
AbbVie Confidential
Protocol RGH-MD-25 Amendment 5
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AbbVie – CONFIDENTIAL
The following contains confidential, proprietary information 
that is the property of AbbVie
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED WITHDRAWAL, 
MULTICENTER CLINICAL TRIAL EVALUATING THE EFFICACY, SAFETY, AND 
TOLERABILITY OF CARIPRAZINE IN A DOSE-REDUCTION PARADIGM IN THE 
PREVENTION OF RELAPSE IN BIPOLAR I DISORDER PATIENTS WHOSE 
CURRENT EPISODE IS MANIC OR DEPRESSIVE, WITH OR WITHOUT MIXED 
FEATURES
Protocol Number:  
RGH-MD-25
Phase:
3B
Name of Investigational 
Product:
Cariprazine
Sponsor:
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064-6148 USA
AbbVie Ltd.
1st Floor, Marlow International,
The Parkway, Marlow Buckinghamshire
SL7 1YL United Kingdom
AbbVie Deutschland GmbH & Co. KG
Knollstrasse, Ludwigshafen
67061, Germany
Emergency Telephone Number:
Refer to the Study Contacts List in the 
Investigator Site File or Trial Master File
Serious Adverse Event 
Reporting Fax Number:
+1-714-796-9504/ +1-714-246-5295 
IR-Clinical-SAE@abbvie.com
Medical Safety Physician:
Refer to study contacts list.
NCT03573297


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Protocol RGH-MD-25 Amendment 5
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AbbVie Signatory:
Vice President
Head, Development Neurosciences
Protocol Date:
Protocol Amendment 1 Date:
Protocol Amendment 2 Date:
12 December 2016
25 August 2017
28 March 2018
Protocol Amendment 3 Date:
20 November 2018
Protocol Amendment 4 Date:
17 December 2019
COVID-19 Global Protocol 
Addendum (incorporated in 
Amendment 5)
08 May 2020
Protocol Amendment 5 Date:
09 June 2022
The following information can be found on FDA Form 1572 (US) and/or study contacts list 
and/or Trial Master File: Name and contact information of AbbVie 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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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:

Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices, and all applicable laws and regulations.

Maintain all information supplied by AbbVie in confidence and, when this information is 
submitted to an institutional review board (IRB), independent ethics committee (IEC) or 
another group, it will be submitted with a designation that the material is confidential.

Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions.
I have read this protocol in its entirety and I agree to all aspects.
Investigator Printed Name
Investigator Signature
Date


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Table of Contents
Title Page ..............................................................................................................................1
Table of Contents ..................................................................................................................4
List of Tables.........................................................................................................................8
List of Figures.......................................................................................................................8
Protocol Summary.................................................................................................................9
1.
Background and Clinical Rationale...............................................................................19
2.
Study Objectives and Clinical Hypotheses....................................................................23
2.1
Study Objectives .................................................................................................23
2.2
Clinical Hypotheses ............................................................................................23
3.
Study Design................................................................................................................24
4.
Study Population and Entry Criteria .............................................................................26
4.1
Number of Patients..............................................................................................26
4.2
Study Population Characteristics .........................................................................26
4.3
Inclusion Criteria.................................................................................................27
4.4
Exclusion Criteria ...............................................................................................28
4.5
Remission and Stability Criteria During the OL Treatment Period.......................31
4.6
Randomization Criteria .......................................................................................32
4.7
Relapse Criteria in the Double-blind Treatment Period........................................32
4.8
Permissible and Prohibited Medications/Treatments............................................33
4.8.1
Permissible Medications/Treatments........................................................33
4.8.2
Prohibited Medications/Treatments..........................................................34
4.8.3
Rescue Medications.................................................................................35
5.
Study Treatments..........................................................................................................36
5.1
Study Treatments and Formulations.....................................................................36
5.2
Control Treatment ...............................................................................................36
5.3
Methods for Masking/Blinding............................................................................36
5.4
Method for Assignment to Treatment Groups/Randomization..............................36
5.5
Treatment Regimen and Dosing ..........................................................................37
5.6
Treatment Compliance ........................................................................................38
5.7
Storage of Study Medications/Treatments ...........................................................38


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6.
Response Measures and Summary of Data Collection Methods....................................38
6.1
Diagnostic Assessments ......................................................................................38
6.2
Efficacy Assessments ..........................................................................................38
6.2.1
Primary Efficacy Assessments .................................................................38
6.2.2
Additional Efficacy Assessments .............................................................39
6.3
Pharmacokinetics Measures.................................................................................40
6.4
Pharmacogenetic Sampling .................................................................................40
6.5
Medical Resource Utilization and Health Economics ..........................................41
6.6
Safety Measures..................................................................................................41
6.6.1
Adverse Events........................................................................................41
6.6.2
................................................42
6.6.3
Clinical Laboratory Determinations .........................................................42
6.6.4
Vital Signs...............................................................................................44
6.6.5
Electrocardiograms..................................................................................44
6.6.6
................................................................45
6.6.7
Other Safety Assessments........................................................................45
6.7
Summary of Methods of Data Collection.............................................................46
7.
Statistical Procedures....................................................................................................47
7.1
Analysis Populations...........................................................................................47
7.1.1
Screened Population ................................................................................47
7.1.2
Open-label Safety Population...................................................................47
7.1.3
Open-label Intent-to-Treat Population......................................................47
7.1.4
Open-label Safety-Follow-up Population .................................................47
7.1.5
Randomized Population...........................................................................47
7.1.6
Double-blind Safety Population...............................................................47
7.1.7
Double-blind Intent-to-Treat Population ..................................................47
7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments ........48
7.2.1
Primary Efficacy Variable........................................................................48
7.2.2
Secondary Efficacy Variable ....................................................................48
7.2.3
Other Efficacy Variables ..........................................................................48
7.3
Hypothesis and Methods of Analysis...................................................................49
7.3.1
Primary Efficacy Analyses.......................................................................49
7.3.2
Secondary Efficacy Analyses...................................................................51
7.3.3
Other Efficacy Analyses ..........................................................................51
7.3.4
Safety Analyses .......................................................................................52
7.3.5
Pharmacokinetic Analysis........................................................................57


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7.3.6
Medical Resource Utilization and Health Economics Analyses ................57
7.4
Subgroup Analyses..............................................................................................57
7.5
Sample Size Calculation......................................................................................57
7.6
Interim Analyses .................................................................................................58
8.
Study Visit Schedule and Procedures............................................................................58
8.1
Patient Entry Procedures .....................................................................................58
8.1.1
Overview of Entry Procedures.................................................................58
8.1.2
Informed Consent and Patient Privacy .....................................................58
8.2
Washout Intervals/Run-in....................................................................................59
8.3
Procedures for Final Study Entry.........................................................................59
8.4
Visits and Associated Procedures.........................................................................60
8.4.1
Screening/Visit 1 (Days -7 to -1)..............................................................60
8.4.2
Baseline (Visit 2).....................................................................................61
8.4.3
Open-label Treatment Period (Visits 3 to 11)............................................61
8.4.4
End of OL Period/Randomization Visit (Visit 12) ....................................62
8.4.5
Double-blind Treatment Period (Visits 13 to 30)......................................63
8.4.6
Final or Early Termination Visit (Visit 31) ...............................................64
8.4.7
Safety Follow-up Visits 32 and 33 ...........................................................65
8.5
Instructions for the Patients .................................................................................65
8.6
Unscheduled Visits..............................................................................................65
8.7
Compliance with Protocol...................................................................................66
8.8
Early Discontinuation of Patients ........................................................................66
8.9
Withdrawal Criteria.............................................................................................67
8.10 Study Termination...............................................................................................69
9.
Adverse Events.............................................................................................................69
9.1
Definitions ..........................................................................................................69
9.1.1
Adverse Event .........................................................................................69
9.1.2
Serious Adverse Event.............................................................................70
9.1.3
Severity ...................................................................................................70
9.1.4
Relationship to Study Drug or Study Procedure.......................................71
9.2
Procedures for Reporting Adverse Events............................................................71
9.3
Procedures for Reporting a Serious Adverse Event..............................................71
9.4
Reporting of Pregnancies Occurring During the Study ........................................72
9.5
Potential Hy’s Law Cases....................................................................................72


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9.6
Procedures for Unmasking of Study Medication..................................................73
10. Administrative Items ....................................................................................................73
10.1 Protection of Human Patients ..............................................................................73
10.1.1 Compliance with Informed Consent Regulations (US 21 CFR  Part 50) or 
Relevant Country Regulations .................................................................73
10.1.2 Compliance with IRB or IEC Regulations................................................74
10.1.3 Compliance with Electronic Records; Electronic Signatures Regulations 
(US 21CFR Part 11).................................................................................74
10.2 Changes to the Protocol.......................................................................................74
10.3 Patient Confidentiality.........................................................................................74
10.3.1 Patient Privacy.........................................................................................74
10.4 Documentation....................................................................................................75
10.4.1 Source Documents...................................................................................75
10.4.2 Case Report Form Completion.................................................................76
10.4.3 Study Summary.......................................................................................76
10.4.4 Retention of Documentation ....................................................................76
10.5 Labeling, Packaging, and Return or Disposal of Study Medications/Treatments..77
10.5.1 Labeling/Packaging .................................................................................77
10.5.2 Investigational Product Supply Inventory ................................................77
10.5.3 Return or Disposal of Study Medications/Treatments and/or Supplies......77
10.6 Monitoring by the Sponsor..................................................................................77
10.7 Handling of Biological Specimens ......................................................................78
10.8 Publications.........................................................................................................78
10.9 Coordinating Investigator....................................................................................78
11. References....................................................................................................................79
12. Attachments .................................................................................................................83
12.1 Elements of Informed Consent ............................................................................83
12.2 Young Mania Rating Scale ..................................................................................85
12.3 Montgomery-Åsberg Depression Rating Scale (MADRS) ...................................87
12.4 Clinical Global Impressions–Severity..................................................................93
12.5 Clinical Global Impressions–Improvement..........................................................94
12.6 Barnes Akathisia Rating Scale.............................................................................95
12.7 Abnormal Involuntary Movement Scale ..............................................................97
12.8 Simpson-Angus Scale .......................................................................................100


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12.9 Personal and Social Performance Scale .............................................................103
12.10
.........................................................................105
12.11 Columbia-Suicide Severity Rating Scale ...........................................................108
12.12Work Productivity and Activity Impairment Questionnaire: Bipolar Disorder 
(WPAI-BD).......................................................................................................116
12.13Protocol Modifications for COVID-19 ..............................................................117
12.13.1
Planned Changes in Research.....................................................117
12.13.2
Remote Assessment of Efficacy..................................................118
12.13.3
Remote Assessment of Health Outcome Measures .....................118
12.13.4
Remote Assessment of Safety.....................................................119
12.13.5
Visit 31/ET- End of Double-Blind and Early Termination Visit...122
12.13.6
Treatment Compliance ...............................................................122
12.14Package Insert...................................................................................................130
12.15Glossary of Abbreviations .................................................................................131
12.16Protocol Amendment #1 Summary....................................................................133
12.17Protocol Amendment #2 Summary....................................................................146
12.18Protocol Amendment #3 Summary....................................................................152
12.19Protocol Amendment #4 Summary....................................................................157
12.20Protocol Amendment #5 Summary....................................................................159
List of Tables
Table 1
Schedule of Visits and Procedures ................................................................14
Table 2
Treatment Regimen and Dosing....................................................................37
Table 3
Schedule of Clinical Laboratory Tests ..........................................................43
Table 4
Modified Schedule of Visits and Procedures-Open-Label Treatment Period 
(Applicable to active Patients who have completed visit 2).........................124
Table 5
Modified Schedule of Visits and Procedures-Double-Blind Treatment and 
Safety Follow-Up Periods ..........................................................................127
List of Figures
Figure 1
Study Schema...............................................................................................13


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Protocol Summary
Study Compound: Cariprazine
Phase: 3B
Study Objective(s): 1) To evaluate the efficacy and safety of cariprazine at a target dose of 3.0 mg/d compared 
with placebo in prevention of relapse in patients with bipolar I disorder whose current episode (ie, index 
episode) is manic or depressive, with or without mixed features; 2) To evaluate the efficacy and safety of 
cariprazine at a target dose of 1.5 mg/d compared with placebo in prevention of relapse in patients with bipolar I 
disorder whose current episode (ie, index episode) is manic or depressive, with or without mixed features, who 
were initially stabilized on a target dose of 3.0 mg/d 
Clinical Hypotheses: 1) In bipolar I disorder patients whose current episode (ie, index episode) is manic or 
depressive, with or without mixed features, cariprazine at 3.0 mg/d is safe and effective in preventing relapse 
when compared to placebo; 2) In bipolar I disorder patients whose current episode (ie, index episode) is manic 
or depressive, with or without mixed features and who were initially stabilized on a target dose of 3.0 mg/d, 
cariprazine at 1.5 mg/d is safe and effective in preventing relapse when compared to placebo.
Study Design
Structure: This is a multicenter, multinational, double-blind (DB), placebo-controlled, randomized withdrawal 
study evaluating the safety and efficacy of cariprazine compared with placebo in the prevention of relapse in 
bipolar I disorder patients whose current episode (ie, index episode) is manic or depressive, with or without 
mixed features. The study schema is presented in Figure 1.
Duration:
Screening/Washout period: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) criteria for bipolar I disorder whose current episode (ie, index episode) is manic or depressive, 
with or without mixed features will undergo a screening and washout period of up to 7 days, during which 
consent, eligibility assessment, and withdrawal of prior psychiatric and additional prohibited medications will 
occur. The length and timing of the washout of prior psychiatric medications during the 7 days allotted for the 
screening period is at the discretion of the investigator. Prior medications should be gradually withdrawn such 
that the washout is completed by Visit 2/Baseline. Please note that during the screening/washout period, 
psychotropic medications, other than those listed as rescue (Section 4.8.3), may not be newly initiated or 
reinstated. In order to ensure the safe transition of patients into the study, based upon the clinical judgment of 
the investigator, patients may be hospitalized during initiation of the study. This hospitalization can be for up to 
14 days during the screening and open-label (OL) periods (with the end of hospitalization no later than Visit 3 
[Day 8] of the OL treatment period). This 14-day allowance for hospitalization may include all or part of the 
screening period. Hospitalization beyond the initial 14 days allowed will require consultation with the AbbVie
medical monitor. Following the protocol-allowed 14 days of hospitalization (and any sponsor-allowed 
extension), patients should be treated as outpatients.
Open-label Treatment Period: Patients who continue to meet eligibility criteria at Visit 2/Baseline will enter 
an OL treatment period for up to 16 weeks. Note that, since patients need to respond to initial treatment and 
subsequently meet stability criteria and maintain it for 8 weeks before being randomized, there will be some 
patients who will meet the criteria earlier than others. 
Patients will be started on cariprazine 1.5 mg/d with a target dose of 3.0 mg/d. During the initial 8 weeks of the 
OL period, patients will be assessed for remission of symptoms, defined as Young Mania Rating Scale (YMRS) 
total score ≤ 12 and Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 and Clinical 
Global Impressions-Severity (CGI-S) ≤ 3. Per protocol, the earliest any patient can achieve remission is Day 15 
(Visit 4). This is to ensure all patients are on cariprazine 3.0 mg/d for at least one week. The patient is 
considered stabilized once remission (ie, YMRS and MADRS total scores are both ≤ 12 and CGI-S ≤ 3) has 
been established and maintained at the subsequent visit. The earliest any patient can achieve stability is Day 22 
(Visit 5). Stabilized patients will then be treated for an additional 8 weeks of OL cariprazine 3.0 mg/d. Patients 
who do not achieve remission by Week 6 (Visit 7) or stability by Week 8 (Visit 8) will be discontinued from the 


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study. Additionally, patients who require hospitalization (excluding protocol-specified allowed hospitalization) 
or who require the initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 2 mg/d of lorazepam 
equivalent or for more than 3 consecutive days) to treat worsening mood symptoms as judged by the clinical 
impression of the investigator at any time during the OL treatment period, will be discontinued.
Following the attainment of stability, YMRS total score ≤ 12 and MADRS total score ≤ 12 and CGI-S ≤ 3 must 
be maintained for an additional 8 weeks, with the exception of allowing 1 excursion (YMRS > 12 and/or 
MADRS > 12). If an excursion occurs, the YMRS and MADRS scores must return to the remission threshold 
(ie, ≤12) at the subsequent visit. The excursion (YMRS > 12 and/or MADRS > 12) may occur at any time 
during the 8-week stability period with the exception of Visit 12/End of OL, but must be followed by a return to 
remission threshold at the next visit. In the event the excursion occurs in the 8th week of stability but prior to 
Visit 12/End of OL, patients should be assessed at the following visit to confirm whether randomization criteria 
have been met. Previously stabilized patients whose efficacy scores increase to YMRS ≥ 17, MADRS ≥ 20, or 
CGI-S ≥ 4 during OL treatment will be discontinued from the study. Once stabilization has occurred and been 
maintained as described above, the patient will be randomized.
Randomization/Double-blind Treatment Period: OL patients who are able to maintain stability criteria for at 
least 8 weeks with no more than 1 excursion above the remission threshold will be randomized 1:1:1 to receive 
cariprazine at the same dose (3.0 mg/d), cariprazine at a reduced dose (1.5 mg/d), or placebo for up to 39 weeks. 
Patients will continue to receive study drug until a relapse event (manic or depressive) occurs or until 
completion of the 39 weeks of randomized treatment. Relapse will be defined as the occurrence of any 1 of the 
following:

YMRS total score ≥ 17

MADRS total score ≥ 20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 2 mg/d of 
lorazepam equivalent or for more than 3 consecutive days) to treat worsening mood symptoms as 
judged by the clinical impression of the investigator 

Psychiatric hospitalization

Exacerbation of illness as judged by clinical impression of the investigator (eg, clinically significant 
agitation, suicidal or homicidal ideations)
For patients who meet relapse criteria, the investigator will categorize the relapse event(s) as manic or 
depressive event(s), with or without mixed features.
Safety Follow-up (SFU) Period: Patients who complete the study, or who prematurely discontinue from either 
the OL or DB periods, will be followed for 4 more weeks and will have 2 evaluations for safety assessments at 
Visits 32 and 33 during the SFU period. During the SFU, patients will receive treatment as usual at the 
discretion of the investigator or designee. Patients will not receive investigational product (IP) during the SFU 
period.
Study Treatment Groups: Cariprazine 3.0 mg/d and 1.5 mg/d 
Controls: Matching placebo 
Dosage/Dose Regimen: Investigational product (IP) in the form of capsules packaged in blister packs will be 
provided by the sponsor. No IP will be administered during the screening/washout period or the SFU period. 
During the OL treatment period (up to 16 weeks), patients will take 1 capsule daily. All patients will begin with 
cariprazine 1.5 mg on Day 1. Patients diagnosed with bipolar I disorder, current episode (ie, index episode) 
manic, with or without mixed features, will receive cariprazine 3.0 mg/d on Day 2 and continue on 3.0 mg/d 
until the end of the OL treatment period. Patients diagnosed with bipolar I disorder, current episode (ie, index 
episode) depressive with or without mixed features, will continue to receive cariprazine 1.5 mg/d from Days 2 
to 7. On Day 8, the dose for these patients will be increased to 3.0 mg/d and continue until the end of the OL 
treatment period. For the 39-week DB treatment period, patients will be supplied with identically appearing 


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capsules of either cariprazine 3.0 mg, cariprazine 1.5 mg, or placebo. During the DB treatment period patients 
will take 1 capsule daily.
Randomization: After completing the OL treatment period, eligible patients will be randomized in a 1:1:1 ratio 
to cariprazine 3.0 mg/d, cariprazine 1.5 mg/d, or placebo. 
Visit Schedule: There are a total of up to 33 visits including screening/washout (up to 7 days), the OL treatment 
period (up to 16 weeks), the DB treatment period (up to 39 weeks), and the SFU period (4 weeks) as shown in 
Table 1.
Patients meeting remission and stability criteria and subsequent randomization criteria will be eligible for early 
randomization beginning at Week 12 (Visit 10) and will move forward to the DB treatment period without 
requiring all visits in the OL treatment period.
If no tolerability issues arise, all patients will receive at least 6 weeks of OL treatment. Some patients will be 
discontinued from the study after 6 or 8 weeks of OL treatment if remission or stability criteria, respectively, 
have not been achieved. 
Study Population Characteristics
Number of Patients: Approximately 378 patients are planned to be randomized (126 per treatment arm). It is 
anticipated that approximately 1245 patients will be screened and approximately 822 will enter the OL 
treatment period. In the event that screening or randomization failure rates are higher than projected, enrollment 
will continue until approximately 126 patients per treatment arm are randomized. Screened patients who have 
not reached the randomization visit at the time the randomization target is met, will not be discontinued from 
the study. These patients will be allowed to continue in the study until they either complete the study, 
prematurely discontinue, or otherwise fail to meet randomization criteria.
Condition/Disease: Bipolar I disorder patients whose current episode (ie, index episode) is manic or depressive, 
with or without mixed features.
Key Inclusion Criteria: Male or female 18 to 65 years of age; meeting DSM-5 criteria for bipolar I disorder, 
current episode manic, with or without mixed features; and having a total YMRS score ≥ 20 and a score of at 
least 4 on 2 of the following YMRS items: irritability, speech, content, and disruptive/aggressive behavior, or 
bipolar I disorder, current episode depressive, with or without mixed features; and having a MADRS total score 
≥ 23 and a score of at least 3 on 2 of the following MADRS items: apparent sadness, reported sadness, inner 
tension or inability to feel.
Key Exclusion Criteria: diagnosis of another psychiatric disorder other than bipolar disorder with the exception 
of specific phobias.
Efficacy Measures
Primary efficacy parameter: Time to first relapse of any mood episode during the DB treatment period. Time to 
first relapse is defined as number of days from randomization to the first relapse.
Relapse is defined as the occurrence of any 1 of the following:

YMRS total score ≥ 17

MADRS total score ≥ 20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 2 mg/d of 
lorazepam equivalent or for more than 3 consecutive days) to treat worsening mood symptoms as 
judged by the clinical impression of the investigator 

Psychiatric hospitalization

Exacerbation of illness as judged by the clinical impression of the investigator (eg, clinically 
significant agitation, suicidal or homicidal ideations)


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For patients who meet relapse criteria, the investigator will categorize the relapse event(s) as manic or 
depressive event(s), with or without mixed features.
Pharmacokinetics: Samples will be collected for determination of the plasma concentrations of cariprazine and 
its metabolites. A total of 12 blood samples will be collected at the visits shown in Table 1.
Pharmacogenetic Sampling: Blood samples will be collected at any time point between Visit 2/Baseline and 
Visit 7 (Week 6) to determine individual genotype status and for pharmacogenetic biobanking. Participation is 
optional.
Safety Assessments: Adverse event (AE) recording, clinical laboratory parameters (hematology, chemistry, 
urinalysis, prolactin), vital sign parameters (including orthostatic blood pressure, pulse rate), body mass index, 
weight, waist circumference, physical examinations, electrocardiograms, ophthalmological examinations, 
Columbia–Suicide Severity Rating Scale (C-SSRS), measures of extrapyramidal symptoms (EPS): Barnes 
Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), and Simpson-Angus Scale 
(SAS).
General Statistical Methods and Types of Analyses:
The OL safety population will consist of all screened patients who took at least 1 dose of cariprazine during the 
OL period of the study. The OL intent-to-treat (ITT) population will consist of all patients in the OL safety 
population who had at least 1 postbaseline assessment of the YMRS, MADRS, or CGI-S scores during the OL 
period of the study. The randomized population will consist of all patients in the OL safety population who 
were randomized to a treatment group during the DB treatment period of the study. The DB safety population 
will consist of all randomized patients who took at least 1 dose of DB IP. The DB ITT population will consist of 
all patients in the DB safety population who had at least 1 post-randomization assessment of the YMRS, 
MADRS, or CGI-S scores during the DB period of the study.
The primary efficacy analysis will compare the time to first relapse of any mood episode between each 
cariprazine group and the placebo group using the log-rank test stratified by modified index episode (manic or 
depressive) for the DB ITT Population. The modified index episode is derived as following: manic index 
episode(s) with or without mixed features will be classified as manic episode(s); depressive index episode(s) 
with or without mixed features will be classified as depressive episode(s). The comparison of cariprazine 
3.0 mg/d versus placebo will be tested first at the two-sided 0.05 significance level, only when it is significant, 
the comparison of cariprazine 1.5 mg/d versus placebo will be tested also at the two-sided 0.05 significance 
level. This testing strategy controls the overall Type I error rate at the 0.05 significance level. Estimates of the 
hazard ratio (HR) and 95% confidence intervals will be based on the Cox proportional hazards model, with 
treatment group as covariates stratified by modified index episode (manic or depressive). The Kaplan-Meier 
estimates for cumulative distribution function of relapse rate for each treatment group will be presented.
All safety parameters will be analyzed descriptively for the OL and DB safety populations.
Sample Size Calculation: The sample size is based on several considerations. Assuming that the relapse rate is 
approximately 35% in the placebo group and the relapse HR is assumed to be 0.42, the study would have to 
observe 75 events to have at least 85% statistical power to detect that at least 1 dose is significant. The 
statistical method for the power calculation is based on the log-rank 2-sided test at a 5% significance level to 
compare the difference of each of the 2 survival curves of the cariprazine treatment groups versus that of 
placebo. Based on the assumed event rates, and considering the 26% of patients who may discontinue early
from the DB treatment period for other reasons, approximately 378 patients should be randomized to 
cariprazine 3.0 mg/d, cariprazine 1.5 mg/d, and placebo, or approximately 126 patients per treatment group. It 
should be noted that this study is designed to test the 3.0 mg/d dose of cariprazine versus placebo first at the 
0.05 significance level and, if significant, then the 1.5 mg/d dose of cariprazine will be tested at the 
0.05 significance level. Given this sequential testing strategy, the higher dose of 3.0 mg/d has 85% statistical 
power to show significance versus placebo, and the 1.5 mg/d dose, if it is as effective as the 3.0 mg/d dose, and 
the 3.0 mg/d dose is statistically significant, would also have 85% statistical power at the 0.05 significance 
level.


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Figure 1
Study Schema
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 












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1.
Background and Clinical Rationale 
Bipolar disorder is a severe chronic mood disorder characterized by episodes of mania or 
hypomania alternating or commingling with episodes of depression (Vieta 2013). It affects more 
than 1% of the world’s population irrespective of nationality, ethnic origin, or socioeconomic 
status and represents one of the leading causes of disability among young people (Grande 2016). 
In the United States, it affects 5.7 million adults or about 2.6% of the population 18 years of age 
and older in any given year (Kessler 2005). Bipolar disorder causes substantial psychosocial 
morbidity that frequently affects the patient’s marriage, children, occupation, and other aspects of 
the patient’s life (Zarate 2000). The World Health Organization has ranked bipolar disorder as 
the seventh leading cause of worldwide nonfatal disease burden (World Health Organization 
2001). Bipolar disorder confers the highest risk of suicide among major psychological disorders 
(Costa 2015).
Bipolar mania accounts for 1 in 7 psychiatric emergencies. Acute manic and mixed episodes are 
frequently associated with severe behavioral, physical, functional, and cognitive disturbances, all 
of which can have important personal and social consequences. For the most part, bipolar mania 
constitutes a medical emergency requiring a hospital admission to ensure the immediate safety of 
the patient or others and rapid symptomatic relief (Keck 2003).
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 1997; Judd 2002; 
Judd 2003; Keller 1986; Post 2005; Post 2003). In addition, compared with bipolar mania, 
bipolar depression is associated with an increased risk of suicide and psychosocial impairment 
(Altshuler 2002; Calabrese 2003; Calabrese 2004; Dilsaver 1997; Leverich 2003; 
MacQueen 2001).
A variety of pharmacologic agents are currently available for the management of acute mania, 
including mood stabilizers, anticonvulsants, and antipsychotics, all of which can be used as 
monotherapy or in combination regimens. For bipolar depression, 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. Fewer treatment options are available for the maintenance of bipolar 
disorder, particularly as monotherapy.


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In recent years, atypical antipsychotics (eg, olanzapine, risperidone, quetiapine, ziprasidone, 
aripiprazole, cariprazine) have been approved for bipolar disorder. First- and 
second-generation antipsychotics are used in the acute setting in combination with mood 
stabilizers to achieve a more rapid control of symptoms in severely agitated patients whose 
treatment also necessitates hospitalization.
Only quetiapine and cariprazine have data demonstrating efficacy for the acute treatment of both 
mania and depressive episodes associated with bipolar I disorder.
Compared with conventional agents, the side-effect profile of atypical antipsychotics is more 
favorable. However, the atypicals have been associated with an increased risk of metabolic side 
effects, including weight gain, dyslipidemia, glucose intolerance, and type II diabetes mellitus. 
Due to this increased risk, the FDA requires a warning label for diabetes on all atypical 
antipsychotics. 
The optimum long-term treatment strategies for bipolar disorder I are not yet established. More 
effective therapies with improved side-effect profiles are still needed to enhance 
long-term, outcomes in these patients while preventing recurrences of mood episodes.
Cariprazine is an orally active and potent dopamine (DA) D3/D2 receptor functional antagonist 
developed by Gedeon Richter Plc., and AbbVie Sales, LLC. It is approved in the US for the 
treatment of schizophrenia and acute treatment of manic or mixed episodes associated with 
bipolar I disorder. For bipolar mania, the starting dose is 1.5 mg/d with a recommended dose of 3 
to 6 mg/d. In addition to efficacy in mania, cariprazine has also been shown to be effective in 
Bipolar I patients with most recent episode depressed. 
Study RGH-MD-54 was a randomized, double-blind, placebo-controlled, parallel-group, fixed-
dose study in 488 patients with bipolar depression. Two cariprazine treatment groups (1.5 or 3.0 
mg/day) were evaluated. This study met its primary endpoint, demonstrating a statistically 
significant improvement in change from baseline to Week 6 in MADRS total score in both the 
cariprazine 1.5 mg and cariprazine 3.0 mg groups compared with placebo in the treatment of 
patients with bipolar depression. For the key secondary efficacy endpoint of change from 
baseline to Week 6 in CGI-S, numerically larger reductions compared with placebo were 
observed in both cariprazine dose groups but these differences did not reach statistical 
significance after adjusting for multiplicity. 
Study RGH-MD-56 was an 8-week, randomized, double-blind, placebo-controlled, 
parallel-group, fixed-dose study in 578 patients with bipolar depression. Three cariprazine dose 
groups (0.75, 1.5, or 3.0 mg/day) were evaluated. For the primary efficacy parameter, the change 


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from baseline to the end of Week 6 in MADRS total score, statistically significant improvement 
was demonstrated for the cariprazine 1.5 mg dose relative to placebo. Nominally significant 
improvement was shown for cariprazine 3.0 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.
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. Desmethyl and 
didesmethyl cariprazine have been identified as circulating plasma metabolites. The 
receptor-binding profile of these 2 metabolites is similar to that of cariprazine.
A unique feature of cariprazine is that it binds with significantly higher affinity to D3 than to D2 
receptors. 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 and the degree of its apparent partial agonist 
activity is greater than aripiprazole.
Cariprazine also has considerable affinity for, and is a partial agonist and antagonist at, the 
serotonin 5-HT1A and 5-HT2B receptors, respectively. Antidepressant- 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, suggesting a lower potential for side effects such as extrapyramidal 
symptoms (EPS) and body weight gain. Cariprazine displays potent in vivo oral activity in 
various animal models of psychosis and mania and shows antidepressant- and anxiolytic-like 
activity as well as procognitive-like effects.
Discussion of Study Design, Including the Choice of Control Groups
 
 
 
 
 
 


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2.
Study Objectives and Clinical Hypotheses
2.1
Study Objectives
1) To evaluate the efficacy and safety of cariprazine at a target dose of 3.0 mg/d compared with 
placebo in prevention of relapse in patients with bipolar I disorder whose current episode (ie, 
index episode) is manic or depressive, with or without mixed features;
2) To evaluate the efficacy and safety of cariprazine at a target dose of 1.5 mg/d compared with 
placebo in prevention of relapse in patients with bipolar I disorder whose current episode (ie, 
index episode) is manic or depressive, with or without mixed features, who were initially 
stabilized on a target dose of 3.0 mg/d. 
2.2
Clinical Hypotheses
1) In bipolar I disorder patients whose current episode (ie, index episode) is manic or depressive 
with or without mixed features, cariprazine at 3.0 mg/d is safe and effective in preventing relapse 
when compared to placebo.
2) In bipolar I disorder patients whose current episode (ie, index episode) is manic or depressive, 
with or without mixed features, and who were initially stabilized on a target dose of 3.0 mg/d, 
cariprazine at 1.5 mg/d is safe and effective in preventing relapse when compared to placebo. 


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3.
Study Design
This is a multicenter, multinational, DB, placebo-controlled, randomized withdrawal study 
evaluating the safety and efficacy of cariprazine compared with placebo in the prevention of 
relapse in bipolar I disorder patients whose current episode (ie, index episode) is manic or 
depressive, with or without mixed features. 
Screening/Washout Period: Patients meeting Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria for bipolar I disorder whose current episode 
(ie, index episode) is manic or depressive, with or without mixed features will undergo a 
screening and washout period of up to 7 days, during which consent, eligibility assessment, and 
withdrawal of prior psychiatric and additional prohibited medications will occur. The length and 
timing of the washout of prior psychiatric medications during the 7 days allotted for the 
screening period is at the discretion of the investigator. Prior medications should be gradually 
withdrawn such that the washout is completed by Visit 2/Baseline. Please note that during the 
screening/washout period, psychotropic medications, other than those listed as rescue 
(Section 4.8.3), may not be newly initiated or reinstated. In order to ensure the safe transition of 
patients into the study, based upon the clinical judgment of the investigator, patients may be 
hospitalized during initiation of the study. This hospitalization can be for up to 14 days during 
the screening and OL periods (with the end of hospitalization no later than Visit 3 [Day 8] of the 
OL treatment period). This 14-day allowance for hospitalization may include all or part of the 
screening period. Hospitalization beyond the initial 14 days allowed will require consultation 
with the AbbVie medical monitor. Following the protocol-allowed 14 days of hospitalization 
(and any sponsor-allowed extension), patients should be treated as outpatients.
Open-label Treatment Period: Patients who continue to meet eligibility criteria at 
Visit 2/Baseline will enter an OL treatment period for up to 16 weeks. Note that, since patients 
need to respond to initial treatment and subsequently meet stability criteria and maintain it for 8 
weeks before being randomized, there will be some patients who will meet the criteria earlier 
than others.
Patients will be started on cariprazine 1.5 mg/d with a target dose of 3.0 mg/d. During the initial 
8 weeks of the OL treatment period, patients will be assessed for remission of symptoms, defined 
as Young Mania Rating Scale (YMRS) total score ≤ 12 and Montgomery-Åsberg Depression 
Rating Scale (MADRS) total score ≤ 12 and Clinical Global Impressions-Severity (CGI-S) ≤ 3. 
Per protocol, the earliest any patient can achieve remission is Day 15 (Visit 4). This is to ensure 
all patients are on cariprazine 3.0 mg/d for at least one week. The patient is considered stabilized 
once remission (ie, YMRS and MADRS total scores are both ≤12 and CGI-S ≤ 3) has been 
established and maintained at the subsequent visit. The earliest any patient can achieve stability 


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is Day 22 (Visit 5). Stabilized patients will then be treated for an additional 8 weeks of OL 
cariprazine 3.0 mg/d. Patients who do not achieve remission by Week 6 or stability by Week 8 
will be discontinued from the study. Additionally, patients who require hospitalization (excluding 
protocol-specified allowed hospitalization) or who require the initiation of treatment with a mood 
stabilizer, antidepressant, antipsychotic agent, or with a benzodiazepine that exceeds the 
protocol-specified allowance or duration (ie, more than 2 mg/d of lorazepam equivalent or for 
more than 3 consecutive days) to treat worsening mood symptoms as judged by the clinical 
impression of the investigator, at any time during the OL treatment period, will be discontinued.
Following the attainment of stability, YMRS total score ≤ 12 and MADRS total score ≤12 and 
CGI-S ≤ 3 must be maintained for an additional 8 weeks, with the exception of allowing 
1 excursion (YMRS > 12 and/or MADRS > 12). If an excursion occurs, the YMRS and MADRS 
scores must return to the remission threshold (ie, ≤ 12) at the subsequent visit. The excursion 
(YMRS > 12 and/or MADRS > 12) may occur at any time during the 8-week stability period 
with the exception of Visit 12/End of OL, but must be followed by a return to remission 
threshold at the next visit. In the event the excursion occurs in the 8th week of stability but prior 
to Visit 12/End of OL, patients should be assessed at the following visit to confirm whether 
randomization criteria have been met. Previously stabilized patients whose efficacy scores 
increase to YMRS ≥ 17, MADRS ≥ 20, or CGI-S ≥ 4 during OL treatment will be discontinued 
from the study. Once stabilization has occurred and been maintained as described above, the 
patient will be randomized.
Patients who meet remission and stability criteria and subsequent randomization criteria will be 
eligible for early randomization beginning at Week 12 (Visit 10) and will move forward to the 
DB treatment period without requiring all visits in the OL treatment period.
If no tolerability issues arise, all patients will receive at least 6 weeks of OL treatment. Some 
patients will be discontinued from the study after 6 or 8 weeks of OL treatment if remission or 
stability criteria, respectively, have not been achieved. 
Randomization/DB Treatment Period: OL patients who are able to maintain stability criteria 
for at least 8 weeks with no more than 1 excursion above the remission threshold will be 
randomized 1:1:1 to receive cariprazine at the same dose (3.0 mg/d), cariprazine at a reduced 
dose (1.5 mg/d), or placebo for up to 39 weeks. Patients will continue to receive study drug until 
a relapse event (manic or depressive) occurs or until completion of the 39 weeks of randomized 
treatment. Relapse will be defined as the occurrence of any 1 of the following:


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
YMRS total score ≥ 17

MADRS total score ≥ 20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with 
a benzodiazepine that exceeds the protocol-specified allowance or duration 
(ie, more than 2 mg/d of lorazepam equivalent or for more than 3 consecutive days) to 
treat worsening mood symptoms as judged by the clinical impression of the investigator,

Psychiatric hospitalization

Exacerbation of illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations)
For patients who meet relapse criteria, the investigator will categorize the relapse event(s) as 
manic or depressive event(s), with or without mixed features.
Safety Follow-up Period: Patients who complete the study, or who prematurely discontinue 
from either the OL or DB periods, will be followed for 4 more weeks and will have 2 evaluations 
for safety assessments at Visit 32 and 33 during the SFU period. During the SFU, patients will 
receive treatment as usual at the discretion of the investigator or designee. Patients will not 
receive IP during the SFU period.
4.
Study Population and Entry Criteria
4.1
Number of Patients
Approximately 378 patients are planned to be randomized (126 per treatment arm). It is 
anticipated that approximately 1245 patients will be screened and approximately 822 will enter 
the OL treatment period. In the event that screening or randomization failure rates are higher 
than projected, enrollment will continue until approximately 126 patients per treatment arm are 
randomized. Screened patients who have not reached the randomization visit at the time the 
randomization target is met, will not be discontinued from the study. These patients will be 
allowed to continue in the study until they either complete the study, prematurely discontinue, or 
otherwise fail to meet randomization criteria.
4.2
Study Population Characteristics
The study population will include bipolar I disorder patients whose current episode (ie, index 
episode) is manic or depressive, with or without mixed features. The diagnosis will be based 
upon Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, 
approached through a structured clinical interview (Structured Clinical Interview for 
DSM-5 [SCID-5]).


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4.3
Inclusion Criteria
The following are requirements for entry into the study: 
1. Written informed consent has been obtained.
2. Patients are male or female, 18 to 65 years of age, inclusive.
3. Patients meet DSM-5 criteria at both screening and baseline for one of the following:
a.
DSM-5 criteria for bipolar I disorder current episode manic with or without 
psychotic features; with or without mixed features, or 
b. DSM-5 criteria for bipolar I disorder current episode depressive with or without 
psychotic features; with or without mixed features 
4. Patients meet one of the following at both screening and baseline (note: the same 
criterion must be met at both visits):
a.
YMRS total score ≥ 20 and a score of at least 4 on 2 of the following YMRS 
items: irritability, speech, content, and disruptive/aggressive behavior, or
b. MADRS total score ≥ 23 and a score of at least 3 on 2 of the following MADRS 
items: apparent sadness, reported sadness, inner tension or inability to feel
5. Normal physical examination results, vital signs, clinical laboratory test results, and 
electrocardiogram (ECG) results or abnormal results that are judged not clinically 
significant by the investigator.
6. Written documentation has been obtained in accordance with the relevant country and 
local privacy requirements, where applicable (eg, written authorization for use and 
release of health and research study information [US sites] and written data protection 
consent [EU sites]).
7. Ability to follow study instructions, complete study assessment tools with minimal 
assistance and no alteration to the assessment tools, and likely to complete all required 
visits.
8. Continue to meet all Visit 1 (Screening) inclusion criteria at Visit 2 (Baseline); to be 
assessed at Visit 2.
9. Each patient must have an identified external contact person or an identified responsible 
person (eg, family member, friend, social worker, case worker, or nurse) who is 
considered reliable by the investigator and who will provide support to the patient and act 
as an external contact in the event the site is having difficulty reaching the patient during 
the trial and to ensure observation of patient’s wellbeing. 


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10. Male and female patients must agree to use a medically acceptable and highly effective 
method of birth control during the course of the entire study and for 12 weeks after the 
last dose of investigational product, as defined in Section 4.8.1.
11. Women of childbearing potential only must have a negative qualitative serum β-human 
chorionic gonadotropin (β-hCG) pregnancy test prior to enrollment.
4.4
Exclusion Criteria
The following are criteria for exclusion from participating in the study:
Psychiatric Criteria
1. Four or more episodes of a mood disturbance within the 12 months before Visit 1.
2. Another psychiatric disorder other than bipolar disorder with the exception of specific 
phobias.
3. Currently meeting DSM-5 criteria for any of the following:
a.
Major/minor neurocognitive disorder, amnestic, or other neurocognitive disorders
b. Schizophrenia, schizoaffective disorder, and other psychotic disorders
c.
Intellectual development disability
4. Known or suspected borderline o  antisocial personality disorder or other DSM-5 
personality disorders of sufficient severity to interfere with participation in this study.
5. History of meeting DSM-5 criteria for substance-related disorders (ie, use disorders 
except caffeine- and tobacco-related) within 3 months prior to Visit 1.
6. Positive result at Visit 1 from the urine drug screen (UDS). Patients with a positive UDS 
at Visit 1 for opiates, cannabinoids, amphetamines, barbiturates, or benzodiazepines may 
be enrolled if all of the following are satisfied:
a.
The drug was used for a legitimate medical purpose;
b. The drug can be discontinued prior to participation in the study (except for 
benzodiazepines which may be continued if the patient has been taking a stable 
dose [ie, lorazepam up to 2 mg/d or its benzodiazepine equivalent] for at least 
1 month prior to Visit 1 or if used as rescue during washout); and 
c.
A repeat UDS must be performed prior to Visit 2 and must be negative, except 
benzodiazepine use as described in 6(b).
7. History of intolerance or hypersensitivity to cariprazine or rescue medications.


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8. The patient is at imminent risk of injuring self or others or causing significant damage to 
property, as judged by the investigator.
9. The patient represents a suicide risk, as determined by meeting any of the following 
criteria:
a.
Patient made a suicide attempt within the past year before Visit 1
b. Patient had a score of 4 or greater on Item 10 of the MADRS at Visit 1 
(Screening) or Visit 2 (Baseline)
c.
Significant risk, as judged by the investigator, based on the psychiatric 
interview or information collected in the C-SSRS at Visit 1 (Screening) or 
Visit 2 (Baseline)
Treatment-Related Criteria:
10. Patient had electroconvulsive therapy in the 3 months prior to Visit 1.
11. Patient received treatment with depot antipsychotic within 6 months prior to Visit 1.
12. Patient received treatment with clozapine doses > 50 mg/d in the past 2 years.
13. Patients requiring concomitant treatment with moderate or strong cytochrome P450 
(CYP) 3A4 inhibitors or CYP3A4 inducers. If applicable, these drugs must be 
discontinued 7 days prior to Visit 2/Baseline.
14. Patient requires concomitant treatment with any prohibited medication, supplement, or 
herbal product including any psychotropic drug or any drug with psychotropic activity or 
with a potentially psychotropic component (for exceptions allowed for concomitant 
treatments, refer to Section 4.8).
15. Previous treatment with vagus nerve stimulation or transcranial magnetic stimulation 
within 6 months before Visit 1.
16. Initiation or termination of psychotherapy within the 3 months preceding Visit 1, or plans 
to initiate, terminate, or change such therapy during the course of the study.
17. Initiation or termination of phototherapy within the 2 weeks before Visit 1, or plans to 
initiate same during the course of the study.
18. Prior participation in any clinical trials involving experimental or investigational drugs 
within 6 months before Visit 1 or during the study.
Other Medical Criteria:
19. Female patients who are pregnant, planning to become pregnant during the course of the 
study, or are currently lactating.


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20. Any concurrent medical condition that, in the judgment of the investigator, might 
interfere with the conduct of the study, confounds the interpretation of the study results, 
or endangers the patient’s well-being. 
21. Any cardiovascular disease (eg, hypertension) or endocrinological disease 
(eg, thyroid disease/disorders) that is clinically unstable or decompensated based on the 
investigator's judgment.
22. Gastric bypass or any condition that would be expected to affect drug absorption (lap 
band procedures and gastric sleeve are acceptable if there is no problem with absorption).
23. History of seizure disorder (with the exception of febrile seizure), stroke, significant head 
injury, tumor of the central nervous system, or any other condition that predisposes 
toward a risk of seizure. 
24. Patients who meet any of the following ophthalmologic criteria:
a. A clinically significant finding of lens opacification(s) at the screening 
ophthalmologic examination that meets any of the following: 
1. Opacification ≥ AREDS standard photo #2
OR
2. Best-corrected visual acuity worse than LogMar 0.1 [20/25 Snellen 
equivalent]
OR
3. Cataract surgery is planned or expected at anytime during the trial, 
based upon the ophthalmological examination.
b. Any clinically significant ocular trauma or complications of ocular trauma, or 
history of retinal detachment, intraocular surgery (with the exception of 
cataract surgery to remove or replace lenses bilaterally) or laser treatment
c. History or current findings of ocular disease (open- or narrow-angle glaucoma, 
retinopathies, corneal diseases)
d. History of amiodarone or systemic corticosteroid use for ≥ 3 consecutive 
months in the past year
e. Intraocular pressure of > 21 mm Hg in either eye
f. Unable to dilate pupil to at least 5 mm in either eye 
25. Allergies to dilating drops, optic medications, or topical ocular anesthetics that are to be 
used in the ophthalmologic examination.


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26. Known human immunodeficiency virus infection.
27. Positive hepatitis C antibody on screening.
28. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody 
immunoglobulin M on screening.
29. Screening liver enzyme test (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT]) results > 2 × the upper limit of normal (ULN) or total bilirubin 
> 1 × ULN.
30. Absolute neutrophil count < 1000 per mm3 at screening.
31. Hemoglobin A1c (HbA1c) > 7% at screening.
32. Blood alcohol concentration ≥ 0.02 g/dL at Visit 1 as measured by breathalyzer.
Other Criteria:
33. Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or 
partners, or the study center.
34. Inability to speak, read, or understand the local language sufficiently to understand the 
nature of the study, to provide signed written informed consent, or to allow the 
completion of all study assessments.
35. Unable or unlikely to comply with the study protocol or unsuitable for any other reason, 
as judged by the investigator.
4.5
Remission and Stability Criteria During the OL Treatment Period 
Remission is defined as meeting all of the following on or after Visit 4: a YMRS total score ≤12 
and MADRS total score ≤ 12 and a CGI-S ≤ 3. Note: Patients who do not meet remission criteria 
by Visit 7 (Week 6) will be discontinued and undergo early termination (ET) procedures and 
subsequently complete the SFU period.
Stability is defined as confirmation of remission criteria at the visit following the study visit 
during which remission criteria were met. Note: If remission criteria are met, but stability criteria 
are not met at the subsequent visit, the patient must be reassessed for remission at the following 
visit. For this subset of patients only, discontinue patient if remission criteria are met at 
Visit 6, but stability criteria are not met at Visit 7. All other patients who do not meet criteria 
for stability by Visit 8 (Week 8) will be discontinued and undergo ET procedures and 
subsequently complete the SFU period.


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4.6
Randomization Criteria
Randomization requirement:

Ability to safely tolerate cariprazine 3.0 mg/d

Maintenance of stability criteria (ie, YMRS total score ≤ 12 and MADRS total score ≤ 12 and 
CGI-S ≤3 for 8 weeks)

During the 8 weeks, 1 excursion in YMRS and/or MADRS score (ie, YMRS > 12 [cannot 
meet or exceed 17] and/or MADRS > 12 [cannot meet or exceed 20]) is allowed. In the event 
the excursion occurs in the 8th week of stability, but prior to Visit 12/End of OL, patients 
should be assessed at the following visit to confirm whether randomization criteria have been 
met
o
If during the 8 weeks there is an excursion in YMRS ≥ 17 or MADRS ≥ 20 or CGI ≥ 
4, the patient should be discontinued from the study and have ET procedures 
performed and subsequently enter the SFU period
o
If the excursion occurs on Visit 12/end of OL, the patient is not eligible for 
randomization and should be discontinued from the study and have ET procedures 
performed and subsequently enter the SFU period
4.7
Relapse Criteria in the Double-blind Treatment Period
After randomization, relapse will be defined as the occurrence of any 1 of the following:

YMRS total score ≥ 17

MADRS total score ≥20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with 
a benzodiazepine that exceeds the protocol-specified allowance or duration
(ie, more than 2 mg/d of lorazepam equivalent or for more than 3 consecutive days) to 
treat worsening mood symptoms as judged by the clinical impression of the investigator,

Psychiatric hospitalization

Exacerbation of illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations)


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For patients who meet relapse criteria, the investigator will categorize the relapse event(s) as 
manic or depressive event(s), with or without mixed features.
4.8
Permissible and Prohibited Medications/Treatments
4.8.1
Permissible Medications/Treatments
Treatment considered necessary for the patient's welfare may be given at the discretion of the 
investigator. Prohibited and allowed rescue medications are detailed in Section 4.8.2 and
Section 4.8.3, respectively. If the permissibility of a specific medication/treatment is in question,
please contact the AbbVie medical monitor.
Definition of Females of (Non-)Childbearing Potential and/or Acceptable Contraceptive 
Methods:
For purposes of this study, females will be considered of childbearing potential unless they are 
naturally postmenopausal or permanently sterilized (eg, hysterectomy). Natural menopause is 
defined as the permanent cessation of menstrual periods, determined retrospectively after a 
woman has experienced 12 months of amenorrhea without any other obvious pathological or 
physiological cause. 
For women of childbearing potential who may participate in the study and are not exclusively 
homosexual, the following methods of contraception, if properly used, are generally considered 
reliable: hormonal contraceptives (ie, oral, patch, injection, implant, ring) with barrier method 
(eg, condom, diaphragm), or condom with intravaginal spermicide, diaphragm or cervical cap 
with spermicide, intrauterine device, surgical sterilization (bilateral tubal ligation, bilateral 
salpingectomy), vasectomized partner, or sexual abstinence. 
For males who may participate in the study, the following methods of contraception, if properly 
used, are generally considered reliable: post-bilateral vasectomy, barrier contraception, or sexual 
abstinence.
The investigator and each patient will determine the appropriate method of contraception for the 
patient during their participation in the study. The investigator must discuss with the participant 
the need to continue contraceptive use for 12 weeks after the last dose of study drug.
If a female becomes pregnant during the study, the investigator will notify the sponsor 
immediately after the pregnancy is confirmed and the patient will be exited from the study after 
appropriate safety follow-up. The investigator will (1) notify the patient’s physician that the 
patient was being treated with cariprazine, and (2) follow the progress of the pregnancy. The 


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investigator must document the outcome of the pregnancy and provide a copy of the 
documentation to AbbVie.
4.8.2
Prohibited Medications/Treatments
Medications that are moderate or strong CYP3A4 inhibitors or are CYP3A4 inducers are not 
allowed. Patients taking moderate (eg, erythromycin, fluconazole) or strong CYP3A4 inhibitors 
(eg, itraconazole, ketoconazole, clarithromycin) or CYP3A4 inducers 
(eg, rifampin, carbamazepine), will need to have medications discontinued 7 days prior to the 
start of open-label IP dosing with cariprazine. Patients who cannot or should not be taken off of 
the CYP 3A4 inhibitor or inducer should not be enrolled. If a patient requires sustained 
concomitant treatment with either a moderate or strong CYP3A4 inhibitor or with a CYP3A4 
inducer at any time during the study, he/she must be discontinued. 
Any psychotropic drug or any drug/treatment with psychotropic activity or with a potentially 
psychotropic component (including medications, supplements and herbal medications) is 
prohibited, other than what is listed under rescue medications.
Psychotropic medications include the following: 

Antipsychotics/neuroleptics

Antidepressants (including monoamine oxidase-B inhibitors)

Stimulants

Anticonvulsants/mood stabilizers

Sedative/hypnotics/anxiolytics

Dopamine-releasing drugs or dopamine agonists

Psychotropic drugs not otherwise specified (including herbal products)

Phenazepam
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. When possible, AbbVie should be notified before the 
prohibited medication/treatment is administered.
Patients will be asked to abstain from drinking alcohol during the study. 
Patients who have been taking stable doses of benzodiazepines (lorazepam up to 2 mg/d or 
equivalent) for at least 1 month before screening can continue use. 


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4.8.3
Rescue Medications 
Medically appropriate episodic use (up to 3 days) of narcotic analgesics for acute medical 
indications (eg, tooth extraction) is allowed during the study.
For insomnia, the following will be allowed but should not be prescribed prophylactically:

Zolpidem (maximum of 10 mg/d)

Zolpidem extended release (maximum of 12.5 mg/d)

Zaleplon (maximum of 20 mg/d)

Eszopiclone (maximum of 3.0 mg/d)

Zopiclone (maximum of 7.5 mg/d)

Chloral hydrate (maximum of 1000 mg/d) may be used acutely with approval from the 
AbbVie medical monitor

Suvorexant (maximum of 20 mg/d)
These medications must be administered before bedtime as recommended in their prescribing 
information. The medication must be documented on the relevant electronic case report form 
(eCRF). No such medication is permitted within 8 hours of psychiatric or neurological 
assessments.
For EPS or akathisia, the following will be allowed but should not be prescribed 
prophylactically:
For EPS or akathisia that emerge or worsen during the study, the rescue medications listed below 
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 be 
administered first to support the decision to dispense these rescue medications. The only 
exception to administering the EPS scales before dispensing rescue medication is medical 
urgency (eg, dystonia, severe akathisia, etc).

Benztropine

Diphenhydramine

Propranolol

Biperiden

Trihexyphenidyl
The need for continued use of these medications should be regularly assessed by the investigator 
and documented appropriately. 


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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/d (or equivalent benzodiazepine) and for up to 
3 consecutive days at a time is allowed for agitation, restlessness, and hostility. 
The medication use and the agitation, restlessness, or hostility must be documented on the 
relevant eCRF pages. 
Efficacy assessments should not be performed within 8 hours of administration of lorazepam or 
equivalent benzodiazepine or within 24 hours of administration of diazepam.
Abrupt discontinuation of benzodiazepines is not advised.
5.
Study Treatments 
5.1
Study Treatments and Formulations
Capsules containing 1.5 mg of cariprazine and 3.0 mg of cariprazine.
5.2
Control Treatment
Matching placebo capsules.
5.3
Methods for Masking/Blinding
There will be no blinding during the OL treatment period of the study. 
During the DB period, all study treatment will be provided in identical blister cards to maintain 
masking of the study. All patients will be instructed to take 1 capsule of IP once daily at 
approximately the same time each day.
5.4
Method for Assignment to Treatment Groups/Randomization
Prior to initiation of study treatment, each patient who provides informed consent will be 
assigned a patient number that will serve as the patient identification number (PID) on all study 
documents.
At the time of randomization, eligible patients will be randomly assigned to 1 of 3 treatment 
arms in a 1:1:1 ratio to receive cariprazine 3.0 or 1.5 mg/d, or placebo. Stratified randomization 
will be used for this study with strata defined by two factors: index episode (manic, manic with 
mixed features, depressive, depressive with mixed features) and region (US and non-US). 


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An automated interactive web response system (IWRS) will be used to manage IP dispensing 
during the OL period of the study. IWRS will also be used for randomization and DB treatment 
assignment. AbbVie Statistical Programming (randomization programmer) will prepare the 
randomization codes.
The IWRS system will also be used to ensure an appropriate distribution of bipolar types (manic 
or depressed). If the study begins to skew towards one bipolar pole, adjustments to allow 
enrollment of the other bipolar type may occur.
IP will be labeled with medication kit numbers. The IWRS will provide the site with the specific 
medication kit number(s) for each patient in the OL treatment period (cariprazine 3.0 mg/d or 
1.5 mg/d,) and for each randomized patient during the DB treatment period (cariprazine 3.0 or 
1.5 mg/d, or placebo). Sites will receive the IWRS confirmation notifications for each 
transaction. All notifications will be maintained with the study source documents.
5.5
Treatment Regimen and Dosing
Table 2
Treatment Regimen and Dosing
Drug/Dose
Investigational 
Product 
Frequency
Route of 
Administration
Open-Label Treatment Period (Week 1)
Index Episode: Manic (with or Without Mixed Features)
Cariprazine 1.5 mg Day 1 / Cariprazine 3.0 mg 
Days 2-7
Once daily
Oral (capsule)
Index Episode: Depressive (with or without Mixed Features)
Cariprazine 1.5 mg Days 1-7
Once daily
Oral (capsule)
Open-Label Treatment Period (Weeks 2 to 16)a
Cariprazine 3.0 mg
Once daily
Oral (capsule)
Double-Blind Treatment Period (Weeks 17 to 55)
Placebo
Once daily
Oral (capsule)
Cariprazine 1.5 mg
Once daily
Oral (capsule)
Cariprazine 3.0 mg
Once daily
Oral (capsule)
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.
a
Patients meeting randomization criteria (Section 4.6) on or after Week 12 (Visit 10) are eligible for early 
randomization and will skip any remaining visits in the OL period.


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5.6
Treatment Compliance
IP compliance will be closely monitored by counting the number of capsules dispensed and 
returned, and through patient interview. Before dispensing new IP, study center personnel will 
make every effort to collect all unused IP and empty blister cards. Patients who take less IP or 
more IP than the prescribed regimen, must be counseled on the importance of taking study 
medication as instructed. If a patient demonstrates poor compliance during the study (< 80% or 
> 120% overall), the investigator should evaluate whether the patient should be discontinued 
from the study.
Any patient who misses ≥ 4 consecutive doses of IP must be discontinued from the study.
The study centers will keep an accurate drug disposition record that specifies the amount of IP 
dispensed to each patient and the date of dispensing.
5.7
Storage of Study Medications/Treatments
All IP will be packaged in blister cards and provided by AbbVie Sales, LLC, and must be stored 
in an appropriate secure area (eg, a locked cabinet in a locked room) at room temperature (25°C 
or 77°F, with a permitted range of 15°C to 30°C or 59°F to 86°F) and must be protected from 
heat, moisture, and light. 
6.
Response Measures and Summary of Data Collection Methods
6.1
Diagnostic Assessments
The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for 
making the major DSM-5 diagnoses (formerly diagnosed on Axis I). This clinician-rated 
diagnostic assessment will be administered by the investigator, subinvestigator, or rater who has 
extensive professional training and experience in the diagnosis of mental illness. The SCID-5 
will be considered a source document for this study.
6.2
Efficacy Assessments
The primary efficacy parameter is the time to first relapse of any mood episode during the DB 
treatment period. Time to first relapse is defined as the number of days from randomization to 
the first relapse.
6.2.1
Primary Efficacy Assessments
Assessment and ratings of efficacy scales will be performed by a trained rater. Every effort 
should be made to have patients assessed by the same rater at each scheduled time point.


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6.2.1.1
Young Mania Rating Scale
The YMRS (Young 1978) is an 11-item scale that assesses manic symptoms based on the 
patient’s perception of his or her condition over the previous 48 hours, as well as the physician’s 
clinical observations during the interview. The 11 items are elevated mood, increased motor 
activity-energy, sexual interest, sleep, irritability, rate and amount of speech, language-thought 
disorder, content, disruptive-aggressive behavior, appearance, and insight. The severity of the 
abnormality is rated on a 5-point (0 to 4) or 9-point (0 to 8) scale; scoring between listed points 
is encouraged. Possible scores range from 0 to 60. 
This scale will be administered by a trained rater with expertise in evaluating manic patients. 
6.2.1.2
Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery 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. 
The MADRS will be administered by a trained rater with extensive professional training and 
experience in assessing mental illness.
6.2.1.3
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 a trained rater with extensive professional training and 
experience in assessing mental illness.
6.2.2
Additional Efficacy Assessments
6.2.2.1
Clinical Global Impressions–Improvement
The Clinical Global Impressions–Improvement (CGI-I) scale (Guy 1976) is a clinician-rated 
scale that in this study will be used to rate total improvement or worsening of mental illness 
relative to Visit 2, regardless of whether the investigator considers it to be a result of drug 
treatment or not. The patient will be rated on a scale from 1 to 7, with 1 indicating that the 
patient is very much improved and 7 indicating that the patient is very much worse. 


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The CGI-I will be administered by a trained rater with extensive professional training and 
experience in assessing mental illness.
6.2.2.2
Personal and Social Performance Scale
The Personal and Social Performance (PSP) scale is a 100-point, single-item, clinician-rated 
scale, which is subdivided into 10 equal intervals (Morosini 2000) (Attachment 12.9). The 
ratings are based mainly on the assessment of functioning in the following 4 domains: a) social 
useful activities; b) personal and social relationships; c) self-care; d) disturbing and aggressive 
behaviors. Ratings from 91 to 100 show excellent functioning in all 4 domains; from 71 to 90 
refer only to mild difficulties; from 70 to 31 to manifest disabilities of various degrees, while 
under 30 the person’s functioning is so poor that intensive support or supervision is needed.
The PSP will be administered by a trained rater with extensive professional training and 
experience in assessing mental illness.
6.3
Pharmacokinetics Measures 
Samples for determination of the plasma concentrations of cariprazine and its metabolites 
desmethyl cariprazine and didesmethyl cariprazine will be collected at 12 time points during the 
study: Visit 6 (Week 4), Visit 8 (Week 8), Visit 10 (Week 12), Visit 12 (Week 16), Visit 13 
(Week 18), Visit 14 (Week 20), Visit 17 (Week 26), Visit 20 (Week 32), Visit 23 (Week 38), Visit 
26 (Week 44), Visit 29 (Week 50), and Visit 31 (Week 55). 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 2 doses of IP. 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 omitted. In the event that a PK sample is missed, 
the reason must be recorded in the eCRF.
For details on blood sample collection, plasma separation, storage, and shipment, refer to 
instructions from the central laboratory.
6.4
Pharmacogenetic Sampling
Pharmacogenetic sampling is to be conducted only at study centers where the institutional review 
board (IRB)/independent ethics committee (IEC) has approved the pharmacogenetic portion of 
the study. Participation in the pharmacogenetic portion of the study is optional and will require a 
separate informed consent form (ICF). The pharmacogenetic ICF must be signed before the 
pharmacogenetic blood sample is taken. Pharmacogenetic consent may be obtained at any time 
between Visit 1/Screening and Visit 7 (Week 6). Pharmacogenetic sampling can be conducted at 
any time point between Visit 2 (Baseline) and Visit 7 (Week 6). Following consent, a single 


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blood sample will be collected to determine individual genotype status and for pharmacogenetic 
biobanking. The genetic material from the blood sample will be used to study factors which may 
influence how patients respond to a drug or may explain the pathophysiology of the disease. 
Blood samples will be stored to provide a resource for potential future trials conducted by 
AbbVie.
All pharmacogenetic samples collected will be sent to the designated central laboratory and later 
shipped to a biorepository for storage. Please refer to the laboratory manual for the 
pharmacogenetic blood sampling procedures, sample anonymization, shipping instructions, and 
contact information. Anonymized pharmacogenetic samples may be stored at the biorepository 
for potential analysis under separate protocols for up to 15 years. Samples may be stored for a 
longer time if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, such samples will be stored until these questions have 
been adequately addressed.
A patient who initially consents can withdraw that consent at any time and have his or her 
pharmacogenetic sample destroyed, including any by-products of the sample.
6.5
Medical Resource Utilization and Health Economics
Exploratory analyses of medical resource utilization and health economics data will include time 
to psychiatric hospitalization. Quality-of-life will be assessed via Work Productivity and Activity 
Impairment: Bipolar Disorder (Attachment 12.12; Reilly 1993), which is a 6-item patient-rated 
questionnaire used to quantify health-related work productivity loss for the employed population. 
It is used to evaluate patient’s employment status and productivity loss, as well as evaluate 
impairment in the domains of work and regular daily activities other than work. 
The scale (Attachment 12.12) will be administered at Visits 1, 12, 16, and 31/ET.
6.6
Safety Measures
Patients must be evaluated by a physician or an appropriately trained health care professional at 
every visit and the evaluation must be documented. The procedures discussed below will be 
completed at the designated visits shown in Table 1, (Schedule of Visits and Procedures).
6.6.1
Adverse Events
Adverse events (AEs) will be collected throughout the study. For all AEs, the investigator must 
provide an assessment of the severity, causal relationship to the IP, start and stop date, and 
seriousness of the event (eg, serious adverse event [SAE]), document all actions taken with 
regard to the IP, and detail any other treatment measures taken for the AE. For events noted as 




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Table 3
Schedule of Clinical Laboratory Tests
Category
Visit Number(s)
Parameter(s)
Hepatitis Screening
1
Hepatitis C virus antibody, hepatitis B 
surface antigen, and hepatitis B core antibody 
total. Reflex hepatitis B core antibody 
immunoglobulin M will be performed for all 
hepatitis B core antibody total positive or 
reactive results
Hematology
1, 7, 12, 18, 24, 31, or ET
Absolute and differential white blood cell 
count, erythrocyte count, hemoglobin, 
hematocrit, platelet count, and red blood cell 
indices (mean corpuscular volume, mean 
corpuscular hemoglobin, and mean 
corpuscular hemoglobin concentration)
Hemoglobin A1c
1, 12, 31, or ET
--
Chemistry
1, 7, 12, 18, 24, 31, or ET
Sodium, potassium, calcium, chloride, 
bicarbonate, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline phosphatase, 
albumin, total bilirubin, direct bilirubin, 
indirect bilirubin, AST, ALT, Free T3, free 
T4, TSH, lactate dehydrogenase, creatine 
phosphokinase, γ-glutamyl transpeptidase, 
uric acid, phosphate, lipid panel (total 
cholesterol, triglycerides, low density 
lipoproteins, high density lipoproteins), 
prolactin, insulin, and magnesium
Urine myoglobin
1, 7, 12, 18, 24, 31, or ET
Only in patients with creatine phosphokinase 
levels > 1000 U/L or as clinically indicated 
for any rise in creatine phosphokinase levels 
or as necessitated by symptoms.
Urinalysis
1, 7, 12, 18, 24, 31, or ET
Specific gravity, pH, protein, glucose, 
ketones, blood, nitrite, bilirubin, and 
microscopy (red blood cell count [high-
power field], white blood cell count [high-
power field], casts [low-power field], and 
crystals).
Serum β-hCG (women of 
childbearing potential only)
1, 7, 12, 18, 24, 31/ET, 33
--
Urine drug screen
1, 12
Benzoylecgonine (cocaine), barbiturates, 
amphetamines, benzodiazepines, 
cannabinoids, opiates, methadone, 
phencyclidine
Blood alcohol 
concentration as measured 
by breathalyzer
1, 12
--
Repeat urine drug screen, 
blood alcohol concentration 
as measured by 
breathalyzer, and serum 
pregnancy test
At random upon request from 
the investigator
--
ET = Early Termination; AST = aspartate aminotransferase; ALT = alanine aminotransferase; β-hCG = β-human 
chorionic gonadotropin; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.


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6.6.4
Vital Signs
Vital sign assessments will include radial pulse rate, systolic and diastolic BP, body weight, waist 
circumference and temperature. BP, pulse rate, temperature, and body weight will be measured at 
all visits. Whenever possible, the patient’s weight should be measured at the same time of day. 
Patients should wear their usual indoor clothing but remove their jackets and shoes.
Height (without shoes) will be measured at Visit 1 only.
Waist circumference will be measured at Visits 1, 7, 12, 18, 24, and 31/ET.
BP and radial pulse rate will be measured in the supine position followed by the standing 
position. The standing measurements must be measured after a sufficient amount of time has 
been given to allow the BP to equilibrate in the standing state. Radial pulse rate should be 
measured after BP measurements. BP and radial pulse may be measured manually or by 
machine.
All BP and radial pulse rate measurements will be recorded in the source documents and eCRF. 
Patients should be instructed not to wear clothing with tight sleeves when they come for clinic 
visits. Additionally, patients should be kept as calm and undisturbed as possible while BP and 
pulse rate measurements are taken (eg, there should be no talking while the BP is being 
measured). The same arm and BP cuff should be used for all BP measurements.
6.6.5
Electrocardiograms
A 12-lead ECG will be performed at Screening (Visit 1), Visit 12 and Visit 31 or ET using a 
standard paper speed of 25 mm/sec. ECGs will be electronically transmitted for analysis 
according to the instructions provided by the ECG central reader. Measurements (in msec) will 
be recorded for the following parameters in lead II or lead III (other leads may be used only if it 
is not possible to obtain good-quality tracings from lead II or lead III): PR interval, QRS interval, 
RR interval (preceding the QT), and uncorrected QT interval. Copies of the ECG waveforms will 
also be sent to the central reader, where the ECG parameters will be measured and evaluated. 
The ECG tracing and cardiology report will be retained as a source document.


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6.6.7
Other Safety Assessments
Assessment and ratings of safety scales will be performed by a trained rater. Every effort should 
be made to have patients assessed by the same rater at each scheduled time point.
6.6.7.1
Extrapyramidal Symptom Scales
The following 3 scales will be used to systematically assess EPS side effects at Visits 2, 3, 5, 7, 
9, 11, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 31, or at ET.
Abnormal Involuntary Movement Scale
The AIMS (Guy 1976) assesses abnormal involuntary movements, such as tardive dyskinesia, 
associated with antipsychotic drugs; it measures facial, oral, extremities, and trunk movements, 
as well as the patient’s awareness of abnormal movements. The first 10 items are rated on a none 
(0) to severe (4) scale. There are an additional 2 items on dental status that are answered yes or 
no. The AIMS will be administered by a trained and experienced rater. The same rater should 
assess the patient at each visit.
Barnes Akathisia Rating Scale
The BARS (Barnes 1989) is a 4-item rating scale used to assess drug-induced akathisia. The 
scale comprises items for rating the observable restless movements that characterize the 
condition, the subjective awareness of restlessness, and any distress associated with the akathisia 
(each on a 4-point scale from normal [0] to severe [3]). In addition, there is a global severity for 
akathisia rated on a 6-point scale (absent [0] to severe akathisia [5]). The BARS will be 
administered by a trained and experienced rater. The same rater should assess the patient at each 
visit.


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Simpson-Angus Scale
The SAS (Simpson 1970) is a 10-item rating scale for assessment of antipsychotic-induced 
parkinsonism in both clinical practice and research settings. Each item ranges from 0 (normal) to 
4 (extreme symptoms). The scale consists of 1 item measuring gait (hypokinesia), 6 items 
measuring rigidity, and 3 items measuring glabella tap, tremor, and salivation, respectively. The 
SAS will be administered by a trained and experienced rater. The same rater should assess the 
patient at each visit.
6.6.7.2
Columbia-Suicide Severity Rating Scale
The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and 
behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific 
active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to 
act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active 
suicidal ideation with specific plan and intent). The C-SSRS also captures information about the 
intensity of ideation, specifically the frequency, duration, controllability, deterrents, and reasons 
for the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no 
suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), 
and 4 (actual attempt). More than 1 classification can be selected provided they represent 
separate episodes. For actual attempts only, the actual or potential lethality is classified for the 
initial, most lethal, and most recent attempts. The C-SSRS will be completed at all study visits. 
At Visit 1 (Screening), the C-SSRS will be completed for the patient’s lifetime history of suicidal 
ideation and behavior. At all other visits the C-SSRS will be completed for ideation and behavior 
since the previous visit.
The C-SSRS will be completed by a trained rater with extensive professional training.
6.7
Summary of Methods of Data Collection
An IWRS will be used to dispense IP, randomize patients, and manage IP inventory. All other 
data for this study will be collected using eCRFs via an electronic data capture system, except for 
ECG and laboratory data.
A qualified central ECG reader will be used for the analysis of all ECGs and central laboratory 
for blood and urine samples. ECG and laboratory data will be transferred to AbbVie or its 
designee on a periodic basis throughout the study.


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7.
Statistical Procedures
7.1
Analysis Populations
Seven populations will be considered in the statistical analysis of this study.
7.1.1
Screened Population
The screened population will consist of all patients who underwent a Screening Visit and 
received a PID number.
7.1.2
Open-label Safety Population
The OL safety population will consist of all patients in the screened population who took at least 
1 dose of open-label cariprazine during the OL period of the study.
7.1.3
Open-label Intent-to-Treat Population
The OL intent-to-treat (ITT) population will consist of all patients in the OL safety population 
who had at least 1 postbaseline assessment of the YMRS, MADRS, or CGI-S scores during the 
OL period of the study.
7.1.4
Open-label Safety-Follow-up Population
The open-label safety-follow-up (OL SFU) population will consist of patients in the OL safety 
population who were not randomized.
7.1.5
Randomized Population
The randomized population will consist of all patients in the OL safety population who were 
randomized to a treatment group during the DB treatment period of the study.
7.1.6
Double-blind Safety Population
The DB safety population will consist of all patients in the randomized population who took at 
least 1 dose of DB IP.
7.1.7
Double-blind Intent-to-Treat Population
The DB ITT population will consist of all patients in the DB safety population who had at least 1 
post-randomization assessment of the YMRS, MADRS, or CGI-S scores during the DB period of 
the study.


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7.2
Collection and Derivation of Primary and Secondary Efficacy 
Assessments
7.2.1
Primary Efficacy Variable 
The primary efficacy parameter is the time to first relapse of any mood episode during the DB 
period. The time to first relapse is defined as the number of days from randomization to the first 
relapse.
Relapse criteria include any of the following:

YMRS total score ≥ 17

MADRS total score ≥ 20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 
2 mg/d of lorazepam equivalent or for more than 3 consecutive days) to treat worsening 
mood symptoms as judged by the clinical impression of the investigator,

Psychiatric hospitalization

Exacerbation of illness as judged by clinical impression of investigator (eg, clinically 
significant agitation, suicidal or homicidal ideations)
For patients who meet relapse criteria, the investigator will categorize the relapse event(s) as 
manic or depressive event(s), with or without mixed features.
7.2.2
Secondary Efficacy Variable
None.
7.2.3
Other Efficacy Variables
Additional efficacy parameters include:

Change from baseline in YMRS total score by visit during OL and DB period

Change from baseline in MADRS total score by visit during OL and DB period

Change from baseline in CGI-S score by visit during OL and DB period

CGI-I score by visit during OL and DB period

Change from baseline in PSP score by visit during OL and DB period


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Additional efficacy parameters only for the DB treatment period include:

Time to manic episode 

Time to depressive episode
Manic episode with mixed features or depressive episode with mixed features are classified as 
manic or depressive episodes, respectively.
7.3
Hypothesis and Methods of Analysis
All efficacy analyses for the OL will be performed using the OL ITT population, unless stated 
otherwise. Baselines for efficacy parameters in the OL period will be defined as the last non-
missing efficacy assessment before the first dose of OL IP. All efficacy analyses for the DB 
period will be performed using the DB ITT population, unless stated otherwise. Baselines for the 
additional efficacy parameters in the DB period will be defined as the last nonmissing efficacy 
assessment before the first dose of DB IP. All statistical tests will be 2-sided hypothesis tests 
performed at the 5% level of significance and all confidence intervals will be 2-sided 95% 
confidence intervals, unless stated otherwise.
7.3.1
Primary Efficacy Analyses
The primary efficacy analysis is to evaluate the time to first relapse of any mood episode in 
bipolar I disorder patients who responded to OL treatment with cariprazine. 
The primary null hypothesis is that the distribution of the time to first relapse for each of the 
cariprazine 3.0 mg/d and 1.5 mg/d treatment groups is not different from that for the placebo 
treatment group. The alternative primary hypothesis is that the distribution of the time to first 
relapse for each of the cariprazine 3.0 mg/d and 1.5 mg/d treatment group is different from that 
for the placebo treatment group. 
The hypothesis testing will compare the time to relapse between each cariprazine group and 
placebo group using the log-rank test stratified by modified index episode (manic or depressive) 
for the DB ITT population. To derive the modified index episode, the manic index episode(s) 
with or without mixed features will be classified as manic episode(s); depressive index 
episode(s) with or without mixed features will be classified as depressive episode(s). Estimates 
of the hazard ratio (HR) and 95% confidence intervals will be based on the Cox proportional 
hazards model with treatment group as covariates stratified by modified index episode (manic or 
depressive). The Kaplan-Meier estimates for the cumulative distribution of the relapse rate for 
each treatment group will be provided. 


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The primary hypotheses for cariprazine 3.0 mg/d and 1.5 mg/d treatment groups versus placebo 
will be tested sequentially in order to control the overall Type I error rate. The comparison of 
cariprazine 3.0 mg/d versus placebo will be tested first at the two-sided 0.05 significance level, 
only when it is significant, the comparison of cariprazine 1.5 mg/d versus placebo will be tested 
also at the two-sided 0.05 significance level. This testing strategy controls the overall Type I 
error rate at the 0.05 significance level.
Two sensitivity analyses will be performed to assess the robustness of the primary analysis 
results to the possible violation of the noninformative censoring assumption. The first sensitivity 
analysis will be based on the delta-adjusted method examined by Zhao et al. (2014), which 
specifies that the hazard of having an event for subjects who discontinued before the time point 
is increased relative to the hazard for subjects who continued beyond the time point for the 
experimental treatment group. The delta-adjustment will be gradually increased from zero until 
reaching the tipping point when the statistical significance of the primary efficacy endpoint is 
overturned, and the plausibility of the magnitude of delta-adjustment needed for reaching the 
tipping point will be subject to clinical scrutiny. 
The second sensitivity analysis is an extension of the placebo-based pattern mixture model 
(Lu 2014; Lu 2015). The placebo-based pattern mixture model assumes that patients who 
discontinued from the cariprazine treatment groups would have disease progression after 
discontinuation similar to that of placebo. The extended placebo-based pattern mixture model 
uses a sensitivity parameter to characterize the gradual deviation from the noninformative 
censoring underlying the primary analysis toward the informative censoring underlying the 
placebo-based pattern mixture model. The extended placebo-based pattern mixture model 
sensitivity analysis for time-to-event data is described as follows:
Let h0(t) denote the baseline hazard function associated with the placebo group. Let β1 and β2
denote the treatment effects in terms of log HRs under noninformative censoring for cariprazine 
1.5 mg/d versus placebo and cariprazine 3.0 mg/d versus placebo, respectively. The hazard 
functions associated with the cariprazine 1.5 and 3.0 mg/d groups under noninformative 
censoring are thus given by h1(t) = h0(t) exp(β1) and h2(t) = h0(t) exp(β2), respectively. Consider 
the extended placebo-based pattern mixture model sensitivity analysis. For the placebo group, we 
assume that patients with premature discontinuation would have comparable experience after 
discontinuation to their counterparts without premature discontinuation. For the cariprazine 
treatment groups, each dropout time point for cariprazine patients defines a missing data pattern, 
and we assume that patients with premature discontinuation would have disease progression after 
discontinuation somewhere between their counterparts without premature discontinuation and 
patients in the placebo group. Specifically, we assume that h1(t) = h0(t) exp((1- ϕ)β1) and h2(t) = 


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h0(t) exp((1- ϕ)β2) for t > C, where C denotes the time of premature discontinuation. The 
sensitivity parameter ϕ ϵ [0,1] characterizes the gradual deviation from the noninformative 
censoring with ϕ = 0 toward the informative censoring underlying the placebo-based pattern 
mixture model with ϕ = 1. A multiple imputation approach will be used to implement the 
extended placebo-based pattern mixture model.
7.3.2
Secondary Efficacy Analyses 
None.
7.3.3
Other Efficacy Analyses
The overall relapse rate, as well as the relapse rates for sub-categories of interest including manic 
episode and depressive episode will be presented. 
Time to early discontinuation for any reason during the DB treatment period for the ITT 
population will be analyzed.
These efficacy parameters will be analyzed using the same method used to analyze the primary 
efficacy variable.
The following continuous efficacy variables will be summarized by visit for the OL and DB 
treatment periods separately for the corresponding ITT populations. For the DB treatment period, 
the variables for YMRS, MADRS, CGI-S, and CGI-I will be analyzed by using a mixed-effects 
model for repeated measures (MMRM) with treatment group, region (US and non-US), modified 
index episode strata (manic or depressive), visit, and treatment group-by-visit interaction as fixed 
effects and the baseline value and baseline-by-visit interaction as the covariates. An unstructured 
covariance matrix will be used. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. 
Descriptive statistics will be provided at each assessment time point by treatment group for the 
change from baseline in PSP score.
For Open-label Treatment Period

Change from baseline in YMRS total score by visit

Change from baseline in MADRS total scores by visit

Change from baseline in CGI-S score by visit

CGI-I score by visit

Change from baseline in PSP score by visit


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For Double-blind Treatment Period

Change from DB baseline in YMRS total score by visit

Change from DB baseline in MADRS total score by visit

Change from DB baseline in CGI-S score by visit

CGI-I score by visit

Change from DB baseline in PSP score by visit
7.3.4
Safety Analyses
The safety analyses will be performed for the OL safety, OL SFU, and DB safety populations. 
The summarization will be overall for the OL period and the OL SFU period, and by treatment 
group for the DB period and the DB SFU period. The summarization for the OL treatment period 
will use the OL safety population as the denominator. The summarization for the OL SFU period 
will use the OL SFU population as the denominator. The summarization for the DB SFU period 
will use the DB safety population as the denominator. 
Safety parameters will include AEs, clinical laboratory parameters, vital signs, ECG parameters, 
, C-SSRS, EPS scales (AIMS, BARS, and SAS), and prolactin level. 
For each safety parameter, the last assessment made before the first dose of OL IP will be used as 
the baseline for all analyses of that safety parameter, unless stated otherwise.
7.3.4.1
Adverse Events
AEs will be coded by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 21.0 or newer.
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the first dose of OL IP.
The number and percentage of patients reporting TEAEs during the OL treatment period will be 
tabulated by system organ class and preferred term, by system organ class, preferred term, and 
severity, and by system organ class, preferred term, and relationship to IP. 
The number and percentage of patients reporting TEAEs during the DB treatment will be 
tabulated for each treatment group by system organ class and preferred term, by system organ 
class, preferred term, and severity, and by system organ class, preferred term, and relationship to 
IP. 


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The number and percentage of patients reporting TEAEs during the SFU period will be tabulated 
by system organ class, preferred term, and DB treatment group for the DB safety population and 
by system organ class and preferred term for the OL safety follow-up population. 
For the OL period, DB period, or SFU period, if more than 1 AE was coded to the same preferred 
term for the same patient, the patient will be counted only once for that preferred term using the 
most severe and most related occurrence for the summarization by severity and by relationship to 
IP. 
The total number and percentage of TEAEs during the DB treatment period will also be 
summarized by severity and relationship to IP for each treatment group.
The number and percentage of patients with common (≥ 2% of patients in any treatment group) 
TEAEs during the DB period will be summarized by preferred term and treatment group.
An AE that occurs more than 30 days after the last dose of IP will not be summarized.
A SAE that occurred between the date of the first dose of IP and 30 days after the date of the last 
dose of IP, inclusive, will be considered an on-therapy SAE. The number and percentage of 
patients who had on-therapy SAEs during the OL period and the OL SFU will be summarized by 
preferred term. The number and percentage of patients who had on-therapy SAEs during the DB 
period and the DB SFU period will be summarized by preferred term and DB treatment group.
The incidence of AEs leading to premature discontinuation of IP during the OL period will be 
summarized by preferred term. The incidence of AEs leading to premature discontinuation of IP 
during the DB period will be summarized by preferred term and treatment group.
For the Screening Population, listings will be presented for patients with SAEs, patients with 
AEs leading to discontinuation, and patients who died. All patients with SAEs, including SAEs 
reported during the screening period and the SFU period, and all patients discontinuing because 
of AEs, including AEs occurring during the screening period, will be included in these listings.
The number and percentage of patients with any EPS TEAEs during the OL period and DB 
period will be summarized separately. The number and percentage of patients with EPS SAEs, 
and the number and percentage of patients with EPS AEs leading to premature discontinuation of 
IP will also be summarized.
The number and percentage of patients reporting TEAEs of ocular AESIs will be summarized 
overall for the OL treatment period in the OL safety population and the OL SFU period in the OL 


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SFU population, and by treatment for the DB treatment period and the DB SFU period in the DB 
safety population. The listing of all reported ocular AESIs will be provided. 
7.3.4.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline values 
at each assessment time point will be presented for each clinical laboratory parameter, and for 
selected clinical laboratory parameters in conventional units.
The number and percentage of patients with potentially clinically significant (PCS) clinical 
laboratory values will be presented. The criteria for PCS laboratory values will be detailed in the 
statistical analysis plan. The percentages will be calculated relative to the number of patients 
with available non-PCS baseline values and at least 1 postbaseline assessment. The numerator 
will be the total number of patients with available non-PCS baseline values and at least 1 
postbaseline PCS value. A supportive listing of patients with postbaseline PCS value will be 
provided, including the PID number, study center number, and baseline and postbaseline values. 
A listing of all AEs for patients with PCS laboratory values will also be provided. 
7.3.4.3
Vital Signs
Descriptive statistics for vital signs (ie, supine radial pulse rate, supine systolic and diastolic BP, 
body weight, waist circumference, temperature, and body mass index) and changes from baseline 
values at scheduled postbaseline visits and at end of study will be presented.
Vital sign values will be PCS if they meet both the observed-value criteria and the change from 
baseline value criteria. The criteria for PCS vital sign values will be detailed in the Statistical 
Analysis Plan. The percentages will be calculated relative to the number of patients with baseline 
values and at least 1 postbaseline assessment. The numerator will be the total number of patients 
with available baseline values and at least 1 PCS postbaseline value. A supportive listing of 
patients with postbaseline PCS values will be provided, including the PID number, baseline and 
postbaseline values. A listing of all AEs occurring in patients who have PCS vital sign values 
will also be provided. The number and percentage of patients with orthostatic hypotension will 
be provided by treatment group. Orthostatic hypotension is defined as a reduction of ≥ 20 mm 
Hg in systolic BP or a reduction of ≥ 10 mm Hg in diastolic BP when the patient changes from 
the supine position to the standing position. A supportive listing will be provided including the 
PID number, study center number, and baseline and postbaseline systolic and diastolic BP values 
(supine and standing).


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7.3.4.4
Electrocardiogram
Descriptive statistics for ECG parameters (ie, heart rate, PR interval, QRS interval, RR interval, 
QT interval, QTcB, and QTcF) and changes from baseline values at each assessment time point 
in this study will be presented.
The number and percentage of patients with postbaseline PCS ECG values will be tabulated by 
treatment group for the DB treatment period. The criteria for PCS ECG values will be detailed in 
the statistical analysis plan. The percentages will be calculated relative to the number of patients 
with available non-PCS baseline values and at least 1 postbaseline assessment for the DB 
treatment period. The numerator will be the total number of patients with available non-PCS 
baseline values and at least 1 postbaseline PCS value for the DB treatment period. A supportive 
tabular display of patients with postbaseline PCS values will be provided, including the PID 
number, baseline, all postbaseline (including non-PCS) values, and change from baseline. In 
addition, a tabular display showing all AEs that occurred in patients who had postbaseline PCS 
ECG values will be provided.
A shift table from baseline to the end of study in the investigator’s overall interpretation of the 
ECG will be presented by treatment group for the following categories: normal; abnormal, not 
clinically significant; abnormal, clinically significant. A tabular display showing patients with 
postbaseline clinically significant ECG abnormalities according to the investigator’s overall 
interpretation will be provided.
The number and percentage of patients with a change from baseline QTc > 30 msec but not 
exceeding 60 msec and of patients with an increase > 60 msec will be tabulated by treatment 
group. A supportive listing that includes PID number, study center number, all QTc values 
(including change from baseline values), and all AEs will be provided for all patients with 
postbaseline QTc changes > 30 msec.
7.3.4.5
Other Safety Parameters
Other safety parameters include
 C-SSRS, and EPS scales (AIMS, 
BARS, and SAS scores).
 
 
 


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7.3.4.5.2
Columbia-Suicide Severity Rating Scale
For the C-SSRS, the number and percentage of patients with suicidal ideation or suicidal 
behavior, as recorded on the C-SSRS scale, will be presented. The distribution of response for 
most severe suicidal ideation and suicidal behavior during the lifetime history, the OL and the 
DB periods will be presented. Supportive listings will be provided, including the PID number, 
treatment group, visit number, lifetime history, and postbaseline values for each patient. Intensity 
of ideation, suicidal behavior type, and lethality of suicidal behavior will also be included in 
these listings.
7.3.4.5.3
Extrapyramidal Symptom Scales
A patient will be considered to have treatment-emergent parkinsonism if the patient’s SAS score 
was ≤ 3 at baseline and > 3 at any postbaseline assessment. A patient will be considered to have 
treatment-emergent akathisia if the patient’s BARS score was ≤ 2 at baseline and > 2 at any 
postbaseline assessment. The number and percentage of patients with treatment-emergent 
parkinsonism or akathisia will be tabulated. Listings of patients with treatment-emergent 
parkinsonism or akathisia will be provided, including the PID number, baseline and postbaseline 


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values. Listings of all AEs for patients with treatment-emergent parkinsonism or akathisia will 
also be provided.
7.3.5
Pharmacokinetic Analysis
Plasma concentrations of cariprazine, desmethyl cariprazine, and didesmethyl cariprazine will be 
listed for each subject with PK samples collected. Plasma concentration data will be used in 
population PK and/or PK-PD analyses to be reported separately. A detailed description of the 
population PK analysis and/or population PK-PD analysis will be specified in a separate 
prospective analysis plan.
7.3.6
Medical Resource Utilization and Health Economics Analyses
A detailed description of the analysis for the medical resource utilization and health economics 
assessments will be specified in a separate prospective analysis plan.
7.4
Subgroup Analyses
The analysis for the primary efficacy parameter will be performed within each category of the 
following: 

Age group (< 55 years, ≥ 55 years)

Sex (male, female)

Race (white, all other races)

Region (US, Non-US)

Modified index episode (manic or depressive)
7.5
Sample Size Calculation
The sample size and power calculations are based on the analysis of time to relapse of any mood 
episode in the DB treatment period to compare each cariprazine dose group versus placebo based 
on a log-rank test. The trial will have a fixed follow-up design. Patients are followed from 
randomization until dropout, relapse, or a fixed duration of 39 weeks. 
The relapse HR is assumed to be 0.42, supported by the final primary endpoint analysis result for 
the cariprazine maintenance study RGH-MD-06 in patients with schizophrenia (HR = 0.45) 
 
 
 
 The cumulative 
relapse rate at Week 39 for the placebo group is assumed to be 35%, 
 
 


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Using these assumptions, the study would observe approximately 75 events to have at least 85% 
statistical power to detect a significant treatment effect in at least 1 dose. The statistical method 
for the power calculation is based on the log-rank 2-sided test at the 5% significance level to 
compare the difference of each of the 2 survival curves of the cariprazine treatment groups 
versus that of placebo. Based on the assumed event rates and considering the 26% of patients 
who may discontinue early from the study due to other reasons, approximately 378 patients 
should be randomized to cariprazine 1.5 mg/d, cariprazine 3.0 mg/d, and placebo, or 
approximately 126 patients per treatment group. 
It should be noted that this study is designed to test 3.0 mg/d of cariprazine versus placebo first 
at the 0.05 significance level and, if the results are significant, then the 1.5 mg/d dose of 
cariprazine will be tested at the 0.05 significance level. Given this sequential testing strategy, the 
higher dose of 3.0 mg/d has 85% statistical power to show significance versus placebo and the 
1.5 mg/d dose, if as effective as the 3.0 mg/d dose, and the 3.0 mg/d dose is statistically 
significant, would also have 85% statistical power at the 0.05 significance level.
7.6
Interim Analyses
No formal interim analysis is planned.
8.
Study Visit Schedule and Procedures
See Table 1 for a schematic of the schedule of visits and procedures and Figure 1 for a schema of 
the study design.
8.1
Patient Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective patients as defined by the criteria in Section 4.3 and Section 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study.
8.1.2
Informed Consent and Patient Privacy
The study will be discussed with the patient and/or the patient's legally authorized representative, 
and a patient wishing to participate must give informed consent prior to any study-related 
procedures or change in treatment. The patient must also give authorization (US only), data 
protection consent (Europe only), and other written documentation in accordance with the 


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relevant country and local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment.
Each patient that provides informed consent will be assigned a patient number that will be used 
on patient documentation throughout the study.
Where applicable, a central vendor will be used to verify patients’ current and past research study 
status in order to mitigate safety concerns associated with duplicate enrollment and protocol 
deviations associated with multiple trial enrollment. Following proper informed consent and after 
issuing a patient number, each patient will be checked in the Verified Clinical Trials (VCT) 
database, indicated in the Schedule of Visits and Procedures (Table 1). Partial identifiers will be 
utilized. Patients who are identified as verification failures by VCT should not be enrolled 
without documented approval from the Sponsor.
8.2
Washout Intervals/Run-in
Patients will undergo a screening/washout period of up to 7 days. The length and timing of the 
washout of prior psychiatric medications during the 7 days allotted for the screening period is at 
the discretion of the investigator. Prior medications should be gradually withdrawn such that the 
washout is completed by Visit 2/Baseline. Please note that during the screening/washout period, 
psychotropic medications, other than those listed as rescue (Section 4.8.3), may not be newly 
initiated or reinstated. In order to ensure the safe transition of patients into the study, based upon 
the clinical judgment of the investigator, patients may be hospitalized during initiation of the 
study. This hospitalization can be for up to 14 days during the screening and OL periods (with 
the end of hospitalization no later than Visit 3 [Day 8] of the OL treatment period). This 14-day 
allowance for hospitalization may include all or part of the screening period. Hospitalization 
beyond the initial 14 days allowed will require consultation with the AbbVie medical monitor. 
Following the protocol-allowed 14 days of hospitalization (and any sponsor-allowed extension), 
patients should be treated as outpatients. 
8.3
Procedures for Final Study Entry 
Patients meeting all eligibility criteria to continue into the OL treatment period at Visit 2 
(Baseline) must meet the remission and stability criteria specified in Section 4.5 and 
randomization criteria specified in Section 4.6 to be eligible for randomization. Rescreening of 
screen failures is permitted in certain situations after consultation with the AbbVie medical 
monitor.
Also, all females of childbearing potential must have negative qualitative results on the serum 
pregnancy test at the Screening Visit (Visit 1).


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8.4
Visits and Associated Procedures
All assessments will be conducted at the appropriate visits as outlined in Table 1 and the timing 
of the visits should occur as close as possible to the specified day.
Visit 2/Baseline is expected to occur within 7 days of Visit 1; however, if required, it may be 
conducted up to 3 days after the scheduled visit. Visits 3 to 33 may be conducted up to 3 days 
before or after the scheduled visits. The visit windows for each scheduled visit are relative to 
Visit 2 for Visits 3 through 12, relative to Visit 12 for Visits 13 through 31/ET, and relative to 
Visit 31/ET for Visits 32 and 33.
The schedule of study procedures and assessments is displayed by visit in Table 1. The 
descriptions of the procedures to be performed at each visit are provided below.
8.4.1
Screening/Visit 1 (Days -7 to -1)
The following procedures will be carried out at Screening (Visit 1):

Obtain informed consent and patient privacy; consent for pharmacogenetic sampling may 
also be obtained 

Access IWRS to register the patient and assign a PID number

Verified Clinical Trials database check to be performed, where applicable

Assess inclusion/exclusion criteria

Collect and assess medical and psychiatric history

Administer and assess SCID-5

Collect blood sample for hepatitis screening

Collect samples for UDS; assess blood alcohol concentration via breathalyzer

Collect blood samples for serum pregnancy test (women of child-bearing potential only)

Collect blood samples for clinical laboratory determinations

Collect blood sample for Hemoglobin A1c

Review prior and concomitant medications

Assess YMRS, MADRS, CGI-S, and C-SSRS

Collect vital signs measurements, including weight, waist circumference, and height

Perform physical examination


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
Perform ECG

Have patient complete the WPAI-BD QoL questionnaire

 
 

Review and assess AEs and SAEs
8.4.2
Baseline (Visit 2)
The following procedures will be carried out at Baseline/Visit 2:

Assess inclusion/exclusion criteria

Review concomitant medications

Assess YMRS, MADRS, CGI-S, PSP, and C-SSRS

Evaluate EPS symptoms (AIMS/BARS/SAS)

Collect vital signs measurements (including weight)

Obtain consent for and/or collect blood for pharmacogenetic sampling (a single sample can 
be obtained any time between Visit 2 and Visit 7, inclusive)

Review and assess AEs and SAEs

Access IWRS to dispense IP
8.4.3
Open-label Treatment Period (Visits 3 to 11)
The following procedures will be carried out during the OL treatment period at every visit except 
as noted:

Collect blood samples for serum pregnancy test (women of child-bearing potential only) 
(Visit 7)

Collect blood samples for clinical laboratory determinations (Visit 7)

Obtain consent and/or collect blood for pharmacogenetic sampling (a single sample can be 
obtained any time between Visit 2 and Visit 7, inclusive)

Review concomitant medications

Assess CGI-I and C-SSRS

Assess YMRS, MADRS, and CGI-S


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
Assess PSP (Visit 6)

Evaluate remission criteria (Section 4.5; Visits 4 to 7)

Evaluate stability criteria (Section 4.5; Visits 5 to 8)

If remission and stability criteria (Section 4.5) have both been met at Visit 5, 6, 7, or 8, 
evaluate randomization criteria (Section 4.6) to determine whether patient qualifies for 
randomization (Visits 10 to 12)
Note: Patients meeting randomization criteria (Section 4.6) prior to Visit 12 are to undergo 
procedures specified for Visit 12/End of OL period (any remaining visits in the OL 
Treatment period will be skipped).
Patients who have not achieved remission by Visit 7 (Week 6) or stability by Visit 8 (Week 
8) are to be discontinued from the study and should undergo Visit 31/ET procedures and 
subsequently enter the SFU period.

Evaluate EPS symptoms (AIMS/BARS/SAS) (Visits 3, 5, 7, 9, 11)

Collect vital signs measurements (including weight at every visit)

Collect waist circumference measurement (Visit 7)

Review and assess AEs and SAEs

Collect blood for PK evaluation at any time during the visit (Visits 6, 8, and 10)

Collect IP blister card(s) and perform IP compliance and accountability

Access IWRS to dispense IP 
8.4.4
End of OL Period/Randomization Visit (Visit 12)
The following procedures will be carried out at Visit 12:

Collect samples for UDS; assess blood alcohol concentration via breathalyzer

Collect blood samples for serum pregnancy test (women of child-bearing potential only)

Collect blood samples for clinical laboratory determinations

Collect blood sample for Hemoglobin A1c

Review concomitant medications

Evaluate EPS symptoms (AIMS/BARS/SAS)

Collect vital signs measurements, including weight and waist circumference (not height)


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
Perform ECG

 
 
 
 

Review and assess AEs and SAEs

Collect blood for PK evaluation

Assess CGI-I, PSP, and C-SSRS

Have patient complete the WPAI-BD QoL questionnaire

Assess YMRS, MADRS, CGI-S and determine whether randomization criteria (Section 4.6) 
have been met
o
Eligible Patients: Access IWRS to randomize patient and dispense DB IP
o
Patients not meeting randomization criteria are to undergo procedures as for 
Visit 31/ET and be scheduled to return for 2 safety follow-up visits (Visit 32 
and Visit 33) 

Collect IP blister cards and perform drug compliance and accountability
8.4.5
Double-blind Treatment Period (Visits 13 to 30)
The following procedures will be carried out during the DB treatment period at every visit except 
as noted: 

Collect blood samples for serum pregnancy test (women of child-bearing potential only) 
(Visits 18 and 24)

Collect blood samples for clinical laboratory determinations (Visits 18 and 24)

Review concomitant medications

Assess YMRS, MADRS, CGI-S, CGI-I, and C-SSRS

Assess PSP (Visit 16 and Visit 22)

Have patient complete the WPAI-BD QoL questionnaire (Visit 16)

Evaluate EPS symptoms (AIMS/BARS/SAS) (Visits 14, 16, 18, 20, 22, 24, 26, 28, 30)

Assess patient for relapse (per Section 4.7)


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
Collect vital signs measurements (including weight)

Collect waist circumference measurement (Visits 18 and 24)

Review and assess AEs and SAEs

Collect blood for PK evaluation (Visits 13, 14, 17, 20, 23, 26, and 29)

Collect IP blister cards and perform drug compliance and accountability

Access IWRS to dispense IP
8.4.6
Final or Early Termination Visit (Visit 31)
The following procedures will be carried out at the Final Visit at the end of the DB treatment 
period (Visit 31) or at ET:

Collect blood sample for serum pregnancy test (women of child-bearing potential only)

Collect blood samples for clinical laboratory determinations

Collect blood sample for Hemoglobin A1c

Review concomitant medications

Assess YMRS, MADRS, CGI-S, CGI-I, PSP, C-SSRS

Assess patient for relapse (per Section 4.7)

Have patient complete the WPAI-BD QoL questionnaire

Evaluate EPS symptoms (AIMS/BARS/SAS)

Collect vital signs measurements, including weight and waist circumference

Perform physical examination

Perform ECG

 
 
 

Review and assess AEs and SAEs

Collect blood for PK evaluation 

Collect IP blister card(s) and perform drug compliance and accountability


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8.4.7
Safety Follow-up Visits 32 and 33
Patients who complete the study, and those who prematurely discontinue from either the OL or 
DB treatment periods, will enter a 4-week SFU period (2 visits, 1 at the end of every 2 weeks). 
During the SFU period, patients will be stabilized on appropriate medications, and additional 
evaluations (laboratory studies, ECG, etc) may be performed as deemed necessary by the 
investigator. This period may also be used for follow-up and management of all abnormal 
findings and AEs observed during OL or DB treatment periods. No IP will be administered 
during the SFU period. 

Collect blood sample for serum pregnancy test (women of child-bearing potential only 
[Visit 33 only])

Review concomitant medications

Collect vital signs measurements (including weight) 

 
 

Review and assess AEs and SAEs
8.5
Instructions for the Patients
Patients are to be instructed to take their study medication daily around the same clock time; 
study medication should not be taken with grapefruit juice. Patients are to be reminded to return 
used/partially used blister cards at every study visit. The investigator (or designee) is to ensure 
that concomitant medications are reviewed against the prohibited and allowed rescue 
medications detailed in Section 4.8.2 and Section 4.8.3 and patients are counseled accordingly. If 
the permissibility of a specific medication/treatment is in question, the investigator should 
consult the AbbVie medical monitor.
Patients are to be asked to abstain from drinking alcohol during the study. 
Patients are to be asked to fast for at least 10 hours before blood and urine samples are collected 
at Screening (Visit 1), Visits 7, 12, 18, 24, and 31 or at ET.
8.6
Unscheduled Visits
Additional examinations and laboratory assessments may be performed as necessary to ensure 
the safety and well-being of the patients during the study period. Unscheduled visit eCRF pages 


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will be completed for each unscheduled visit. For all parameters not measured, indicate “not 
done”. 
8.7
Compliance with Protocol
All assessments will be conducted at the appropriate visits as outlined in Table 1, and the timing 
of the visits should occur as close as possible to the specified day. Visit 2/Baseline is expected to 
occur within 7 days of Visit 1. If required, Visit 2/Baseline assessments may be conducted up to 
3 days after the scheduled visit. If necessary, Visits 3 to 33 may be conducted up to 3 days before 
or after the scheduled visits. 
The visit windows for each scheduled visit are relative to Visit 2 for Visits 3 through 12, relative 
to Visit 12 for Visits 13 through 31/ET, and relative to Visit 31/ET for Visit 32 and 33. Every 
attempt should be made to complete the postbaseline ophthalmological examinations (Visit 12 
and Visit 31/ET, and Visit 33 if required) on the same date as all other study procedures for that 
visit. 
At each visit, the patient will be asked if the patient changed the dose/regimen of any existing 
concomitant medications or initiated the use of any new concomitant medications since the last 
visit to ensure compliance with the protocol.
8.8
Early Discontinuation of Patients
Patients may discontinue from the study at any time for any reason. Discontinuation is 
permanent; once a patient is discontinued, he/she shall not be allowed to enroll again. 
Patients can be prematurely discontinued from the study for one of the following reasons:

AE

Noncompliance with protocol 

Noncompliance with IP dosing regimen

Withdrawal of consent (a clear reason must be documented when possible)

Lost to follow-up (every effort must be made to contact the patient; a certified/traceable letter 
must be sent)

Study terminated by sponsor

Site terminated by sponsor

Pregnancy

Other reasons


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Notification of early patient discontinuation from the study and the reason for discontinuation 
will be clearly documented on the appropriate eCRF page. Patients who take IP during the study
(OL treatment period or the DB treatment period) and who prematurely discontinue from the 
study, regardless of cause, should be seen for a final assessment. A final assessment will be 
defined as completion of the evaluations scheduled for Visit 31/ET. If the patient discontinues 
after IP is taken, the patient is also expected to return for 2 safety follow-up visits, Visit 32 
(2 weeks after completion of the ET visit) and Visit 33 (4 weeks after completion of the ET 
visit).
At a minimum, collect the following information when a patient discontinues:
1. The reason the patient discontinued;
2. The date of the last dose of test products from the trial;
3. The date of the last assessment and/or contact. A follow-up contact (telephone or visit) will be 
arranged as appropriate;
4. (S)AEs;
5. Compliance with the test product administration as specified in this protocol;
6. Final Assessments: Unless there is withdrawal of consent, every effort should be made to 
ensure that all procedures and evaluations scheduled for Visit 31/ET and subsequently Visits 32 
and 33 (SFU Period) are performed (Table 1, Schedule of Visits and Procedures).
7. Retrieve all IP(s) from the patient.
For all patients who discontinue as a result of being lost to follow-up, a determination must be 
noted in the eCRF as to whether the loss is related to an acute exacerbation of bipolar disorder.
8.9
Withdrawal Criteria
It is the right and the duty of the investigator or subinvestigator to stop treatment in any case in 
which emerging effects are of unacceptable risk to the individual patient. In addition, the 
investigator or subinvestigator is to stop treatment of any patient with unmanageable factors that 
may interfere significantly with the trial procedures and/or the interpretation of results. 
A patient must be discontinued from the study for any of the following reasons: 
1.
The patient fails to achieve remission by Week 6 or stability by Week 8 of the OL 
treatment period;


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2.
After stability criteria (Section 4.5) have been met, if there is a lack of ongoing stability 
as evidenced by an excursion event of YMRS total score of ≥ 17 and/or MADRS total 
score of ≥ 20, or CGI-S ≥ 4;
3.
The patient initiated treatment with a mood stabilizer, antidepressant, antipsychotic agent, 
or with a benzodiazepine that exceeds the protocol-specified allowance or duration (ie, 
more than 2 mg/d of lorazepam equivalent or for more than 
3 consecutive days) to treat worsening mood symptoms;
4.
The patient required or initiated hospitalization for his/her psychiatric symptoms 
(excluding the discretionary hospitalization stay which is to end no later than Visit 3 
[Day 8] of the OL treatment period or extension of the initial hospitalization described in
this protocol);
5.
At the end of the OL treatment period, the patient does not meet all criteria to enter the 
DB treatment period (eg, patient is unable to tolerate cariprazine 3.0 mg/d);
6.
Positive UDS after enrollment, confirmed by retest at next scheduled visit; for exceptions 
see Exclusion Criterion 6(b) and Section 4.8.3;
7.
The patient meets the criteria for relapse of a mood episode during the DB treatment 
period;
8.
The patient experiences 1 of the following elevated liver enzyme conditions, which is 
confirmed by repeat testing:

ALT or AST > 3× ULN and total bilirubin > 2 × ULN,

ALT or AST > 8 × ULN,

ALT or AST > 5 × ULN for more than 2 weeks,

ALT or AST > 3 × ULN with the appearance of jaundice, worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia.
9.
The patient has an absolute neutrophil count of < 1000 per mm3 and, after repeat testing 
within 24 hours of awareness, the values are not normalized or are not increasing;
10. A female patient becomes pregnant during treatment.


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8.10
Study Termination
The site investigator may stop the study at his/her study site at any time. AbbVie may stop the 
study (and/or the study site) for any reason with appropriate notification. A study may also be 
stopped by a regulatory authority.
9.
Adverse Events
Adverse events occurring during the study will be recorded on an adverse event eCRF. If adverse 
events occur, the first concern will be the safety of the study participants.
9.1
Definitions
9.1.1
Adverse Event
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. In addition, during the screening period, adverse events will be 
assessed regardless of the administration of a pharmaceutical product.
Note: Adverse events must be collected once informed consent has been obtained, regardless of 
whether or not the patient has been administered study drug.
Progression of treatment indication including new or worsening of anticipated clinical signs or 
symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course of 
the disease.
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained). At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, non-directed question such as 
“How have you been feeling since the last visit?” Directed questioning and examination will then 
be done as appropriate. All reported adverse events will be documented on the appropriate case 
report form.


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9.1.2
Serious Adverse Event
A SAE is any adverse event occurring at any dose that results in any of the following outcomes: 
death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
(See Section 9.3 for procedures for reporting a SAE.)
AbbVie considers all cancer adverse events as SAEs. Elective abortions and abnormal pregnancy 
outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) or genetic abnormalities (whether leading to an elective abortion or not) are 
considered SAEs.
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a SAE.
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the investigator or designee at the time of the patient’s entry into the study. If it 
has not been documented at the time of the patient’s entry into the study, then it should be 
documented as a SAE and reported to AbbVie.
9.1.3
Severity
A clinical determination will be made of the intensity of an adverse event. The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines:
Mild
Awareness of sign or symptom, but easily tolerated.
Moderate
Discomfort enough to cause interference with usual activity.
Severe
Incapacitating with inability to work or do usual activity.
Not applicable
In some cases, an adverse event may be an ‘all or nothing’ finding which 
cannot be graded.


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9.1.4
Relationship to Study Drug or Study Procedure
A determination will be made of the relationship (if any) between an adverse event and the study 
drug or study procedure, as applicable. A causal relationship is present if a determination is made 
that there is a reasonable possibility that the adverse event may have been caused by the drug or 
study procedure.
9.2
Procedures for Reporting Adverse Events
Any adverse event must be recorded on the appropriate case report form.
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current investigator's brochure) must be reported to the governing IRB/IEC as required by the 
IRB/IEC, local regulations, and the governing health authorities. Any adverse event that is 
marked ‘ongoing’ at the exit visit must be followed up as appropriate.
9.3
Procedures for Reporting a Serious Adverse Event
Any SAE occurring during the study period (beginning with informed consent) and for at least 
30 days after the last dose of study drug must be immediately reported but no later than 24 hours 
after learning of a SAE. SAEs must be reported to AbbVie (or agent of AbbVie eg, Contract 
Research Organization) as listed on the AbbVie study contacts list and recorded on the 
SAE/AESI form. All patients with a SAE must be followed up and the outcomes reported. The 
investigator must supply the sponsor and the IRB/IEC with any additional requested information 
(eg, autopsy reports and discharge summaries).
In the event of a SAE, the investigator must:
1. Notify AbbVie immediately using the SAE/AESI form (contact details can be found on 
page 1 of the SAE/AESI form); phone numbers and relevant AbbVie personnel contacts 
are also on the front page of protocol and study contacts list.
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
patient.
3. Provide AbbVie with a complete, written description of the adverse event(s) on the 
SAE/AESI form describing the event chronologically, including any treatment given 
(eg, medications administered, procedures performed) for the adverse event(s). 
Summarize relevant clinical information about the event: signs, symptoms, diagnosis, 
clinical course and relevant clinical laboratory tests, etc. Include any additional or 


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alternative explanation(s) for the causality which includes a statement as to whether the 
event was or was not related to the use of the investigational drug.
4. Promptly inform the governing IRB/IEC of the SAE as required by the IRB/IEC, local 
regulations, and the governing health authorities.
9.4
Reporting of Pregnancies Occurring During the Study
Study site personnel must report every pregnancy from the time the patient signs the ICF until 
12 weeks following the last dose of IP. Within 24 hours of learning of the pregnancy, the study 
site personnel must report the event to the sponsor’s Global Patient Safety department on the 
clinical trial pregnancy form and fax/email it to the following SAE/pregnancy fax number/email 
address, even if no AE has occurred: 
Fax number: +1-714-796-9504 (back-up fax number: +1-714-246-5295)
Email: IR-Clinical-SAE@abbvie.com.
Pregnancies in female partners of male patients occurring during the time frame described above 
must also be reported.
The pregnancy must be followed to term and the outcome reported by completing a follow-up 
clinical trial pregnancy form. If the pregnancy is associated with an SAE (eg, if the mother is 
hospitalized for hemorrhage), a separate SAE/AESI form for clinical trials must be filed with the 
appropriate serious criterion (eg, hospitalization) indicated in addition to the pregnancy form.
9.5
Potential Hy’s Law Cases
Criteria for potential Hy’s Law cases are as follows:

ALT or AST ≥ 3 × ULN AND

Total bilirubin ≥ 2 × ULN AND

Alkaline phosphatase < 2 × ULN
Study site personnel must report every patient who meets these 3 criteria. Typically, all
3 analytes will be obtained from the same sample, but they may come from multiple samples 
taken within a 24-hour period. This requirement applies from the time the patient signs the ICF 
for the trial until 30 days after the final protocol-defined study visit or the last known dose of IP 
(if the final visit does not occur).


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A lab alert for potential Hy’s Law cases will be in place, and will notify investigators and the 
sponsor immediately when the above criteria have been met. A potential Hy’s Law case must be 
faxed to the sponsor on the SAE/AESI form as soon as possible (within 24 hours of learning of 
the potential Hy’s Law) to the following SAE/pregnancy fax number/email address even if no 
AE has occurred: 
Fax number: +1-714-796-9504 (back-up fax number: +1-714-246-5295)
Email: IR-Clinical-SAE@abbvie.com
The eCRF pages for potential Hy’s Law cases must be completed within 7 calendar days. Every 
effort to determine the cause of the liver enzyme abnormalities must be made, and close 
monitoring must be initiated in conjunction with the study physician and in accordance with the 
FDA “Guidance for Industry: Drug-Induced Liver Injury-Pre-Marketing Clinical Evaluation” 
July 2009.
9.6
Procedures for Unmasking of Study Medication
When necessary for the safety and proper treatment of the patient, the investigator can unmask 
the patient’s treatment assignment to determine which treatment has been assigned and institute 
appropriate follow-up care. When possible, the sponsor (AbbVie medical safety physician) 
should be notified prior to unmasking study medication. The investigator should inform the 
sponsor (AbbVie medical safety physician) of the unmasking if there is no notification prior to 
the unmasking.
The treatment assignment for the patient can be determined by designated site personnel logging 
into the IWRS system via password protected access. The reason for breaking the code must be 
recorded in the patient’s source documents.
10.
Administrative Items
This protocol is to be conducted in accordance with the applicable Good Clinical Practice (GCP) 
regulations and guidelines, eg, the International Conference on Harmonisation (ICH) Guideline 
on GCP.
10.1
Protection of Human Patients
10.1.1
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) or Relevant Country Regulations
Written informed consent is to be obtained from each patient prior to any study-related activities 
or procedures in the study, and/or from the patient's legally authorized representative. 


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10.1.2
Compliance with IRB or IEC Regulations
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) or 
applicable IEC regulations. The investigator must obtain approval from a properly constituted 
IRB/IEC prior to initiating the study and re-approval or review at least annually. AbbVie is to be 
notified immediately if the responsible IRB/IEC has been disqualified or if proceedings leading 
to disqualification have begun. Copies of all IRB/IEC correspondence with the investigator 
should be provided to AbbVie.
10.1.3
Compliance with Electronic Records; Electronic Signatures 
Regulations (US 21CFR Part 11)
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature.
10.2
Changes to the Protocol
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.
10.3
Patient Confidentiality
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed, but the patient’s name will 
not be disclosed in these documents. The patient's name may be disclosed to the sponsor of the 
study, AbbVie, or the governing health authorities or the FDA if they inspect the study records. 
Appropriate precautions will be taken to maintain confidentiality of medical records and personal 
information.
10.3.1
Patient Privacy
Written authorization (US sites only), data protection consent (European sites only), and other 
documentation in accordance with the relevant country and local privacy requirements (where 
applicable) is to be obtained from each patient prior to enrollment into the study, and/or from the 
patient's legally authorized representative in accordance with the applicable privacy requirements 


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(eg, the Health Insurance Portability and Accountability Act Standards for Privacy of 
Individually Identifiable Health Information (“HIPAA”), European Union Data Protection 
Directive 95/46/EC [“EU Directive”]).
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study.
10.4
Documentation
10.4.1
Source Documents
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator's patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and ECG. The investigator's copy of the case report forms serves as part of the 
investigator's record of a patient’s study-related data.
The following information should be entered into the patient's medical record:

Patient’s name.

Patient’s contact information.

The date that the patient entered the study, patient number, and patient randomization [or 
medication kit] number.

The study title and/or the protocol number of the study and the name of AbbVie.

A statement that informed consent was obtained (including the date). A statement that 
written authorization (US sites only), data protection consent (EU sites only), or other 
country and local patient privacy required documentation for this study has been obtained 
(including the date).

Dates of all patient visits.

All concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment. At each subsequent visit, changes to the list of 
medications should be recorded.).

Occurrence and status of any adverse events.

The date the patient exited the study, and a notation as to whether the patient completed 
the study or reason for discontinuation.


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
The results of laboratory tests performed by the site (eg, results of urine pregnancy tests). 

Key study variables.
Source documentation practices must follow ALCOA-C principles (ie, records must be 
Attributable, Legible, Contemporaneous, Original, Accurate, and Complete).
10.4.2
Case Report Form Completion
All patient data relating to the study will be recorded on eCRFs to be provided by the sponsor 
through the electronic data capture 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 electronic data capture system for 
source document verification and possible regulatory inspection.
10.4.3
Study Summary
An investigator's summary will be provided to AbbVie within a short time after the completion 
of the study, or as designated by AbbVie. A summary is also to be provided to the responsible 
IRB/IEC.
10.4.4
Retention of Documentation
All study-related correspondence, patient records, consent forms, patient privacy documentation, 
records of the distribution and use of all IPs, and copies of case report forms should be 
maintained on file.
For countries falling within the scope of the ICH guidelines, the sponsor-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the IP. These documents should be retained for a longer period, however, 
if required by the applicable regulatory requirement(s) or if needed by the sponsor.
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation.
AbbVie requires that it be notified in writing if the investigator wishes to relinquish ownership of 
the data so that mutually agreed-upon arrangements can be made for transfer of ownership to a 
suitably qualified, responsible person.


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10.5
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments
10.5.1
Labeling/Packaging
IP will be supplied in blister cards and will be labeled with the protocol number, storage 
information, warning language, and instructions to take the capsules as directed. The card will 
also include the medication number. Immediately before dispensing the blister card, the 
investigator or designee will write the study center number, patient’s initials (if applicable), 
patient number, visit number, and dispensing date on the blister card.
10.5.2
Investigational Product Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units 
received from AbbVie, dispensed or administered to the patients, the number of units returned to 
the investigator by the patient (if applicable), and the number of units returned to AbbVie during 
and at the completion of the study. A detailed inventory must be completed for all IP. IP must be 
dispensed or administered only by an appropriately qualified person to patients in the study. The 
medication is to be used in accordance with the protocol. 
10.5.3
Return or Disposal of Study Medications/Treatments and/or 
Supplies
All IP and/or supplies will be returned to AbbVie or AbbVie designee for destruction.
10.6
Monitoring by the Sponsor
A representative of the sponsor will monitor the study on a periodic basis. The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.
Authorized representatives of AbbVie or regulatory authority representatives will conduct on-site 
visits to review, audit and copy study-related documents. These representatives will meet with 
the investigator(s) and appropriate staff at mutually convenient times to discuss study-related 
data and questions.


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10.7
Handling of Biological Specimens 
Blood and urine samples for evaluation of hematology, chemistries, and urinalysis will be 
analyzed at a central clinical laboratory with certification from a recognized accreditation agency 
(eg, College of American Pathology [CAP] or Clinical Laboratory Improvement Amendments 
[CLIA] certification).
Blood samples obtained for analysis of plasma concentrations of cariprazine and its metabolites 
(desmethyl cariprazine and didesmethyl cariprazine) will be stored at the central clinical 
laboratory until ready for analysis by the Sponsor's bioanalytical Clinical Research Organization 
using validated bioanalytical methods. All samples not used for analyses will be destroyed by the 
Sponsor's bioanalytical Clinical Research Organization. AbbVie shall have full ownership rights 
to any biological specimens/samples derived from the study.
Patients consenting to participate in pharmacogenetic sampling will have a single blood sample 
collected to determine individual genotype status and for pharmacogenetic biobanking. The 
genetic material from the blood sample will be used to study factors which may influence how 
patients respond to a drug or may explain the pathophysiology of the disease. Blood samples will 
be stored to provide a resource for potential future trials conducted by AbbVie.
All pharmacogenetic samples collected will be sent to the designated central laboratory and later 
shipped to a biorepository for storage.
10.8
Publications
AbbVie as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple Investigators and sites and AbbVie
personnel. Authorship will be established prior to the writing of the manuscript. As this study 
involves multiple centers, no individual publications will be allowed prior to completion of the 
final report of the multicenter study except as agreed with AbbVie.
10.9
Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report.


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11.
References
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impairment in patients with bipolar disorder. J Clin Psychiatry. 2002;63:807-811.
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Bowden CL, Vieta E, Ice KS, et al. Ziprasidone plus a mood stabilizer in subjects with bipolar I 
disorder: a 6-month, randomized, placebo controlled, double-blind trial. J Clin Psychiatry. 2010 
Feb;71(2):130-7.
Calabrese JR, Hirschfeld RM, Reed M, et al. Impact of bipolar disorder on a U.S. community 
sample. J Clin Psychiatry. 2003;64:425-432.
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;65:1499-1504.
Costa LDS, Alencar AP, Neto PJN, et al. Risk factors for suicide in bipolar disorder: A systematic 
review [review]. Journal of Affective Disorder. 2015;170:237–254.
Dilsaver SC, Chen YW, Swann AC, et al. Suicidality, panic disorder and psychosis in bipolar 
depression, depressive-mania and pure-mania. Psychiatry Res. 1997;73:47-56. 
Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of relapse in 
patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Schizophrenia 
Res. 2016;176:264–271.
Grande I, Berk M, Birmaher B, et al. Bipolar Disorder [seminar]. Lancet. 2016;387:1561-1572.
Guy W. ECDEU assessment manual for psychopharmacology. Revised. DHEW publication no. 
(ADM) 76-338. Rockville, MD: U.S. Department 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. p. 534-537.
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;59:530-537.


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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-
269.
Kane LA, Mackle M, Snow-Adami Linda, et al. A randomized placebo-controlled trial of 
Asenapine for the prevention of relapse of schizophrenia after long-term treatment. J Clin 
Psychiatry. 2011;72(3):349-355. 
Keck PE. The management of acute mania [editorial]. BMJ. 2003;327(7422):1002-1003.
Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized, placebo-controlled, 26-week trial 
of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67:626-
637.
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;255:3138-3142.
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(6):617-627.
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;64:506-515.
Lu K. An extension of the placebo-based pattern-mixture model. Pharmaceut Statis. 
2014;13:103-109.
Lu K, Li D, Koch GG. Comparison between two controlled multiple imputation methods for 
sensitivity analyses of time-to-event data with possibly informative censoring. American 
Statistical Association—Statistics in Biopharmaceutical Research. 2015;7(3):199213.
MacQueen GM, Young LT, Joffe RT. A review of psychosocial outcome in patients with bipolar 
disorder. Acta Psychiatr Scand. 2001;103:163-170.
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry. 1979;134:382-389.
Morosini P, Magliano L, Brambilla L, et al. Development, reliability and acceptability of a new 
version of the DSM-IV Social and Occupational Functioning Assessment Scale
(SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101:323-329.


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Pigott TA, Carson William H, Saha AR, et al. Aripiprazole for the Prevention of Relapse in 
Stabilized Patients With Chronic Schizophrenia: A Placebo-Controlled 26-Week Study. J Clin 
Psychiatry. 2003;64(9):1048-1056. 
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year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry. 
2003;64:680-690.
Post RM. The impact of bipolar depression. J Clin Psychiatry. 2005;66(Suppl 5):5-10.
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activity impairment instrument. PharmacoEconomics 1993;4(5):353-365.
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Suppl. 1970;212:11-19. 
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from a north American study of quetiapine in combination with lithium or divalproex (trial 127). 
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Szegedi A, Durgam S, Mackle M, et al. Randomized, Double-Blind, Placebo-Controlled Trial of 
Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed Episode Associated 
With Bipolar I Disorder. Am J Psychiatry. 2018 Jan 1;175(1):71-79.
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Yatham LN, Fountoulakis KN, Rahman Z, et al. Efficacy of aripiprazole versus placebo as 
adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I 
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sensitivity. Brit J Psychiat. 1978;33:429-435.
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Disorder. Psychiatric Quarterly. 2000;71;4:309-329.
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2014;24(2):229-253.


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12.
Attachments
12.1
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 (eg , “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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12.2
Young Mania Rating Scale 
1.
ELEVATED MOOD
0
Absent
1
Mildly or possibly increased on questioning
2
Definite subjective elevation; optimistic, self-confident; cheerful; appropriate to content
3
Elevated, inappropriate to content; humorous
4
Euphoric; inappropriate laughter; singing
2.
INCREASED MOTOR ACTIVITY - ENERGY
0
Absent
1
Subjectively increased
2
Animated; gestures increased
3
Excessive energy; hyperactive at times; restless (can be calmed)
4
Motor excitement; continuous hyperactivity (cannot be calmed)
3.
SEXUAL INTEREST
0
Normal; not increased
1
Mildly or possibly increased
2
Definite subjective increase on questioning
3
Spontaneous sexual content; elaborates on sexual matters; hypersexual by self-report
4
Overt sexual acts (toward patients, staff, or interviewer)
4.
SLEEP
0
Reports no decrease in sleep
1
Sleeping less than normal amount by up to one hour
2
Sleeping less than normal by more than one hour
3
Reports decreased need for sleep
4
Denies need for sleep
5.
IRRITABILITY
0
Absent
2
Subjectively increased
4
Irritable at times during interview; recent episodes of anger or annoyance on ward
6
Frequently irritable during interview; short, curt throughout
8
Hostile, uncooperative; interview impossible


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6.
SPEECH (RATE AND AMOUNT)
0
No increase
2
Feels talkative
4
Increased rate or amount at times, verbose at times
6
Push; consistently increased rate and amount; difficult to interrupt
8
Pressured; uninterruptible, continuous speech
7.
LANGUAGE -THOUGHT DISORDER
0
Absent
1
Circumstantial; mild distractibility; quick thoughts
2
Distractible; loses goal of thought; changes topics frequently; racing thoughts
3
Flight of ideas; tangentiality; difficult to follow; rhyming, echolalia
4
Incoherent; communication impossible
8.
CONTENT
0
Normal
2
Questionable plans, new interests
4
Special project(s); hyperreligious
6
Grandiose or paranoid ideas; ideas of reference
8
Delusions; hallucinations
9.
DISRUPTIVE - AGGRESSIVE BEHAVIOUR
0
Absent, co-operative
2
Sarcastic; loud at times, guarded
4
Demanding; threats on ward
6
Threatens interviewer; shouting; interview difficult
8
Assaultive; destructive; interview impossible
10.
APPEARANCE
0
Appropriate dress and grooming
1
Minimally unkempt
2
Poorly groomed; moderately disheveled; overdressed
3
Disheveled; partly clothed; garish make-up
4
Completely unkempt; decorated; bizarre garb
11.
INSIGHT
0
Present; admits illness; agrees with need for treatment
1
Possibly ill
2
Admits behavior change, but denies illness
3
Admits possible change in behavior, but denies illness
4
Denies any behavior change


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12.3
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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12.4
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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12.5
Clinical Global Impressions–Improvement
GLOBAL IMPROVEMENT
Rate total improvement whether or not, in your judgment, it is due entirely to drug treatment.
Compared to his/her condition at Visit 2 (Baseline), how much has the patient changed?
Check one:
1 = Very much improved
2 = Much improved
3 = Minimally improved
4 = No change
5 = Minimally worse
6 = Much worse
7 = Very much worse


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12.6
Barnes Akathisia Rating Scale
Rating scale for drug-induced akathisia (Barnes Akathisia Rating Scale)
Patient name:
Patient research no.:
Hospital No.:
Ward:
Rater:
Instructions
Patient should be observed while they are seated, and then standing while engaged in neutral 
conversation (for a minimum of two minutes in each position). Symptoms observed in other 
situations, for example while engaged in activity on the ward, may also be rated. Subsequently, 
the subjective phenomena should be elicited by direct questioning.
Objective
0
Normal, occasional fidgety movements of the limbs
1
Presence of characteristic restless movements: shuffling or tramping movements of the 
legs/feet, or swinging of one leg while sitting, and/or rocking from foot to foot or 
“walking on the spot” when standing, but movements present for less than half the time 
observed
2
Observed phenomena, as described in (1) above, which are present for at least half the 
observation period
3
Patient is constantly engaged in characteristic restless movements, and/or has the inability 
to remain seated or standing without walking or pacing, during the time observed
Subjective
Awareness of restlessness
0
Absence of inner restlessness
1
Non-specific sense of inner restlessness
2
The patient is aware of an inability to keep the legs still, or a desire to move the legs, 
and/or complains of inner restlessness aggravated specifically by being required to stand 
still
3
Awareness of intense compulsion to move most of the time and/or reports strong desire to 
walk or pace most of the time


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Distress related to restlessness
0
No distress
1
Mild
2
Moderate
3
Severe
Global clinical assessment of akathisia
0
Absent. No evidence of awareness of restlessness. Observation of characteristic 
movements of akathisia in the absence of a subjective report of inner restlessness or 
compulsive desire to move the legs should be classified as pseudoakathisia
1
Questionable. Non-specific inner tension and fidgety movements
2
Mild akathisia. Awareness of restlessness in the legs and/or inner restlessness worse when 
required to stand still. Fidgety movements present, but characteristic restless movements 
of akathisia not necessarily observed. Condition causes little or no distress
3
Moderate akathisia. Awareness of restlessness as described for mild akathisia above, 
combined with characteristic restless movements such as rocking from foot to foot when 
standing. Patient finds the condition distressing
4
Marked akathisia. Subjective experience of restlessness includes a compulsive desire to 
walk or pace. However, the patient is able to remain seated for at least five minutes. The 
condition is obviously distressing
5
Severe akathisia. The patient reports a strong compulsion to pace up and down most of 
the time. Unable to sit or lie down for more than a few minutes. Constant restlessness 
which is associated with intense distress and insomnia
Reproduced from: A rating scale for drug-induced akathisia. T.R.E. Barnes, British Journal of 
Psychiatry (1989), 154, 672-676.
© 1989 The Royal College of Psychiatrists.


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12.7
Abnormal Involuntary Movement Scale
EXAMINATION PROCEDURE
Either before or after completing the Examination Procedure, observe the patient unobtrusively, 
at rest (eg , in waiting room). The chair to be used in this examination should be hard, firm 
without arms.
1. Ask patient whether there is anything in his/her mouth (ie, gum, candy, etc.) and if there is, to 
remove it.
2. Ask patient about the current condition of his/her teeth. Ask patient if he/she wears dentures. 
Do teeth or dentures bother patient now?
3. Ask patient whether he/she notices any movements in mouth, face, hands or feet. If yes, ask 
to describe and to what extent they currently bother patient or interfere with their activities.
4. Have patient sit in chair with hands on knees, leg slightly apart, and feet flat on floor. (Look 
at entire body for movements while in this position.)
5. Ask patient to sit with hands hanging unsupported. If male, between legs, if female and 
wearing a dress, hanging over knees. (Observe hands and other body areas.)
6. Ask patient to open mouth. (Observe tongue at rest within mouth.) Do this twice.
7. Ask patient to protrude tongue. (Observe abnormalities of tongue movement.) Do this twice.
8. Ask patient to tap thumb, with each finger, as rapidly as possible for 10-15 seconds; 
separately with right hand. (Observe facial and leg movements.)*
9. Flex and extend patient’s left and right arms (one at a time).
10. Ask patient to stand up. (Observe profile. Observe all body areas again, hips included.)
11. Ask patient to extend both arms outstretched in front with palms down. (Observe trunk, legs 
and mouth.) *
12. Have patient walk a few paces, turn, and walk back to chair. (Observe hands and gait.) Do 
this twice. *
* Activated movements






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12.8
Simpson-Angus Scale
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 








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Occasional is defined as occurring three or more times in the reference period or occurring even less than three times 
but in circumstances and/or with such a previous history to convince the rater that there is a risk of recurrence in the 
near future. If the aggressive behavior has been present occasionally, the rating may be decreased by one degree, eg, 
from severe to marked.
*Main areas: a=socially useful activities, including work and study; b=personal and social relationships; 
c=self-care; d=disturbing and aggressive behaviors.
Guidelines for PSP Total Score

Ratings from 71-100 reflect only mild difficulties.

Ratings from 31-70 reflect manifest disabilities of various degrees.

Ratings from 1-30 reflect functioning so poor that intensive support or supervision is 
needed.
The levels of functioning in other areas should be taken into account to adjust the rating inside 
the decimal level (for instance, from 31 to 40). Suicidal risk is not included in the scale.
10-point
Intervals
PSP Descriptions
100 – 91
Excellent function in all four main areas*. He/she is held in high consideration for his/her 
qualities, copes adequately with life problems, is involved in a wide range of interests and 
activities
90 – 81
Good functioning in all four main areas, presence of only common problems or difficulties
80 - 71 
Mild difficulties in 1 or more areas of a-c
70 – 61
Manifest, but not marked difficulties in 1 or more areas of a-c or mild difficulties in d
60 - 51
Marked difficulties in 1 of areas a-c, or manifest difficulties in d
50 – 41
Marked difficulties in 2 or more, or severe difficulties in 1 of areas a-c, with or without manifest 
difficulties in d
40 - 31
Severe difficulties in 1 and marked difficulties in at least 1 of areas a-c, or marked difficulties in d
30 - 21
Severe difficulties in 2 of areas a-c, or severe difficulties in d, with or without impairment in areas 
a-c
20 - 11
Severe difficulties in all areas a-d or very severe in d with or without impairment in general areas 
a-c. If the person reacts to external prompts the suggested score are 20-16, if not, the suggested 
scores are 15-11
10 - 1
Lack of autonomy in basic functioning with extreme behaviours but without survival risk (ratings 
6-10) or with survival risk, eg, death risk due to malnutrition, dehydration, infections, inability to 
recognize situations of manifest dander (ratings 5-1)


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12.11
Columbia-Suicide Severity Rating Scale
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Baseline Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended for use by trained clinicians. The questions contained in the 
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of 
the presence of suicidality depends on clinical judgment.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia-
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu


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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 
is “yes,” ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
Lifetime:
Time He/She 
Felt Most 
Suicidal 
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe: 
Yes No
□ □
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (eg, “I’ve thought about killing myself”) without 
thoughts of ways to kill oneself/associated methods, intent, or plan.
Have you actually had any thoughts of killing yourself?
If yes, describe: 
Yes No
□ □
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different 
than a specific plan with time, place or method details worked out (eg, thought of method to kill self but not a specific plan). 
Includes person who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or 
how I would actually do it…..and I would never go through with it”.
Have you been thinking about how you might do this?
If yes, describe: 
Yes No
□ □
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I 
have the thoughts but I definitely will not do anything about them”.
Have you had these thoughts and had some intention of acting on them?
If yes, describe: 
Yes No
□ □
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
If yes, describe: 
Yes No
□ □
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (ie,1-5 from above, with 
1 being the least severe and 5 being the most severe ). Ask about time he/she was feeling the most suicidal.
_____ _________________________________________________
Most Severe Ideation:
Type # (1-5) Description of Ideation 
Most Severe 
Frequency
How many times have you had these thoughts?
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day 
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____
Controllability
Could /can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty (5) Unable to control thoughts
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts 
____
Deterrents
Are there things - anyone or anything (eg, family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide (4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you (5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the 
pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you 
were feeling) or was it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others. (4) Mostly to end or stop the pain (you (2) Mostly to 
get attention, revenge or a reaction from others. couldn’t go on living with the pain or how you were feeling).
(3) Equally to get attention, revenge or a reaction from others (5) Completely to end or stop the pain and to end/stop the 
pain. (you couldn’t go on living with the (0) Does not apply pain or how you were feeling).
____


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as 
method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can 
be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. 
If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred 
(eg, gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that 
what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel 
better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes No
□ □
Total # of
Attempts
Yes No
□ □ 
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, 
actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather 
than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow 
prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is 
poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang 
- is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped 
you before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of 
interrupted
 
Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in 
any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, 
instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself 
before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of
aborted


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Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or 
thought, such as assembling a specific method (eg, buying pills, purchasing a gun) or preparing for one’s death by suicide (eg, 
giving things away, writing a suicide note).
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting 
pills, getting a gun, giving valuables away or writing a suicide note)?
If yes, describe: 
Yes No
□ □ 
Suicidal Behavior:
Suicidal behavior was present during the assessment period? 
Yes No
□ □ 
Answer for Actual Attempts Only 
Most Recent
Attempt
Date:
Most Lethal
Attempt
Date:
Initial/First
Attempt
Date:
Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (eg, surface scratches).
1. Minor physical damage (eg, lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (eg, conscious but sleepy, somewhat 
responsive; second-degree burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required 
(eg, comatose with reflexes intact; third-degree burns less than 20% of body; extensive 
blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (eg, comatose 
without reflexes; third-degree burns over 20% of body; extensive blood loss with unstable 
vital signs; major damage to a vital area).
5. Death 
Enter Code
______ 
Enter Code
______ 
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no 
actual medical damage, had potential for very serious lethality: put gun in mouth and pulled the 
trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but 
pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
______ 
Enter Code
______ 
Enter Code
______


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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
Since Last Visit Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended for use by trained clinicians. The questions contained in the Columbia-
Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence 
of suicidality depends on clinical judgment.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia-
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu


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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is 
“yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” 
section below. 
Since Last 
Visit 
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe: 
Yes No
□ □
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (eg , “I’ve thought about killing myself”) without 
thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period.
Have you actually had any thoughts of killing yourself?
If yes, describe: 
Yes No
□ □
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (eg , thought of method to kill self but not a specific plan). Includes 
person who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would 
actually do it…and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe: 
Yes No
□ □
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe: 
Yes No
□ □
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
If yes, describe: 
Yes No
□ □
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (ie, 1-5 from above, with 1 
being the least severe and 5 being the most severe).
_____ _________________________________________________
Most Severe Ideation:
Type # (1-5) Description of Ideation 
Most Severe 
Frequency
How many times have you had these thoughts?
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day 
____ 
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____ 
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty (5) Unable to control thoughts
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts 
____ 
Deterrents
Are there things - anyone or anything (eg , family, religion, pain of death) - that stopped you from wanting to die 
or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide (4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you (5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you (0) Does not apply 
____ 
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others (4) Mostly to end or stop the pain (you couldn’t go on)
(2) Mostly to get attention, revenge or a reaction from others living with the pain or how you were feeling
(3) Equally to get attention, revenge or a reaction from others (5) Completely to end or stop the pain (you couldn’t go on and 
to end/stop the pain living with the pain or how you were feeling)
(0) Does not apply 
____


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as 
method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be 
considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If 
person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. 
For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (eg, gunshot to head, 
jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be 
lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel 
better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes No
□ □
Total # of
Attempts
Yes No
□ □ 
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual 
attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than 
an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow 
prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised 
to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is 
stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of 
interrupted
 
Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any 
self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of 
being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped 
yourself before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of
aborted
 
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought,
such as assembling a specific method (eg, buying pills, purchasing a gun) or preparing for one’s death by suicide (eg, giving 
things away, writing a suicide note).
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)?
If yes, describe: 
Yes No
□ □ 
Suicidal Behavior:
Suicidal behavior was present during the assessment period? 
Yes No
□ □ 
Completed Suicide: 
Yes No
□ □
Answer for Actual Attempts Only 
Most Lethal 
Attempt
Date:


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Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (eg, surface scratches).
1. Minor physical damage (eg, lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (eg, conscious but sleepy, somewhat responsive; second-degree burns; 
bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (eg, comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (eg, comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area).
5. Death 
Enter Code
______ 
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on 
train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
______ 


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12.12
Work Productivity and Activity Impairment Questionnaire:
Bipolar Disorder (WPAI-BD)
The following questions ask about the effect of your bipolar disorder on your ability to work and perform 
regular activities. Please fill in the blanks or circle a number, as indicated. 
1) Are you currently employed (working for pay)? ____NO ___YES 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
2) During the past seven days, how many hours did you miss from work because of problems associated 
with your bipolar disorder? Include hours you missed on sick days, times you went in late, left early, etc. 
because of bipolar disorder. Do not include time you missed to participate in this study. 
______HOURS 
3) During the past seven days, how many hours did you miss from work because of any other reason, 
such as vacation, holidays, time off to participate in this study? 
______HOURS 
4) During the past seven days, how many hours did you actually work? 
______HOURS (If “0”, skip to question 6) 
5) During the past seven days, how much did bipolar disorder affect your productivity while you were 
working? Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual. If 
bipolar disorder affected your work only a little, choose a low number. Choose a high number if bipolar 
disorder affected your work a great deal. 
CIRCLE A NUMBER
6) During the past seven days, how much did bipolar disorder affect your ability to do your regular
daily activities, other than work at a job? By regular activities, we mean the usual activities you do,
such as work around the house, shopping, child care, exercising, studying, etc. Think about times you 
were limited in the amount or kind of activities you could do and times you accomplished less than you 
would like. If bipolar disorder affected your activities only a little, choose a low number. Choose a high 
number if bipolar disorder affected your activities a great deal.
CIRCLE A NUMBER
Bipolar disorder
had no effect on my
Bipolar disorder
completelyprevented
work
0
1
2
3
4
5
6
7
8
9
10
me from working
Bipolar disorder
had no effect on
Bipolar disorder
completelyprevented
my daily activities
0
1
2
3
4
5
6
7
8
9
10
me from doing my daily
activities


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12.13
Protocol Modifications for COVID-19
The following modifications to the Global Protocol are being instituted in response to the novel 
coronavirus disease (COVID-19) pandemic and are intended to provide guidance for the safe 
conduct of Study RGH-MD-25 in light of the restrictions imposed on patients and clinical sites 
during the COVID-19 pandemic. These measures can be followed for active patients in Study 
RGH-MD-25, who have completed all assessments through Visit 2 (inclusive) per the Global 
Protocol and are continuing in the study. The instructions and procedures specified herein will 
supersede those specified in the Global Protocol only in local, regional or national circumstances 
that limit the conduct of the Global Protocol as a direct result of the COVID-19 pandemic 
(including any potential re-emergence of this coronavirus). Please refer to the Global Protocol 
(or country-specific protocol, if applicable) for the visit assessments and procedures required at 
Visit 1 and Visit 2, including the full inclusion and exclusion criteria to be evaluated. The 
following procedures apply in cases where patients are either unable or unwilling to attend study 
visits as a result of the pandemic.
12.13.1
Planned Changes in Research
In response to the impact of COVID-19 to study patients and site staff, the Sponsor is proposing 
a change in research to Study RGH-MD-25 that would allow the following options for sites and 
patients facing extenuating circumstances:

Allowing wider visit windows when necessary 

Replacing protocol mandated in-person study visits with one or more of the following:
o
home visits
o
telemedicine virtual visits
o
telephone/video calls (no recording will be performed)

Allowing blood draws at alternative or commercial laboratories (where available)

Study sites shipping investigational products (IP) to research patients (where permissible 
by local/statutory or country law) and where approved by Sponsor

Extending the window for consecutive missed doses of IP specifically resulting from 
COVID-19-related circumstances from 4 or more days to more than 7 days, prior to 
requiring withdrawal of the patient from the study
Any procedures completed in accordance with this addendum should be clearly denoted in the 
source document(s) and in the electronic case report forms (eCRFs) as having been completed 
remotely due to COVID-19.


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12.13.2
Remote Assessment of Efficacy
Efficacy assessments must always be conducted by a rater that has been certified by Signant 
Health to rate that assessment for this study. Every effort should be made to have patients 
assessed by the same rater at each scheduled timepoint. For efficacy assessments that are 
conducted remotely (eg, by telephone, telemedicine virtual visit, video call) or in-home by 
qualified site staff, the following assessments are required to be completed in the course of the 
remote visit. Note: The source documents and eCRF should clearly denote which assessments 
have been completed remotely.

Young Mania Rating Scale (YMRS)

Montgomery-Åsberg Depression Rating Scale (MADRS)

Clinical Global Impression-Severity scale (CGI-S)

Clinical Global Impression-Improvement scale (CGI-I)

Personal and Social Performance scale (PSP)
For patients in the Open-label Period (OLP) of the study, the following assessments are also 
required:

Visits 4 through 7 (as applicable): Assessment of remission criteria (Global Protocol 
Section 4.5)

Visits 5 through 8 (as applicable): Assessment of stability criteria (Global Protocol 
Section 4.5)

Visits 6 through 12 (as applicable): Maintenance of stability (Global Protocol Section 4.6)

Visits 10 through 12 (as applicable): Assessment of randomization criteria (Global 
Protocol Section 4.6)
For patients in the Double-blind Period (DBP) of the study (Visits 13 through 31/ET), the 
following assessment is also required:

Assess relapse criteria (Global Protocol Section 4.7)
12.13.3
Remote Assessment of Health Outcome Measures
In the event that visits 12, 16, or 31/Early Termination (ET) are being conducted remotely (eg, by 
telephone, telemedicine virtual visit, video call), study staff should verbally administer the Work 
Productivity and Activity Impairment: Bipolar Disorder (WPAI-BD) questionnaire to the patient 
and record the patient’s responses in the source. The source document should capture the name 


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of study personnel administering the WPAI-BD, the date and time of administration, as well as 
clearly document that the responses were obtained verbally due to COVID-19. For in-home 
visits, study staff should have patient complete the WPAI-BD per the Global Protocol.
12.13.4
Remote Assessment of Safety
For safety assessments that are conducted remotely (eg, by telephone, telemedicine virtual visit, 
video call), the following assessments are required to be completed in the course of the remote 
visit. Note: The source documents and eCRF should clearly denote which assessments have been 
completed remotely.

Adverse Events/Serious Adverse Event Assessment 

Concomitant medication assessment

Columbia–Suicide Severity Rating Scale (C-SSRS)- Must be conducted by a certified 
rater. Every effort should be made to have patients assessed by the same rater at each 
scheduled timepoint. In the event the rater certified for this study is unavailable, a rater 
certified on the C-SSRS for another Allergan trial may conduct the assessment.

Movement scales (Abnormal Involuntary Movement Scale (AIMS); Barnes Akathisia 
Rating Scale (BARS); Simpson-Angus Scale (SAS)) – Telemedicine virtual visits or 
video calls (without recording) are the preferred methods of remote assessment. If a scale 
item cannot be assessed, the item may be skipped and the source should indicate the item 
could not be assessed. Every effort should be made to have patients assessed by the same 
rater at each scheduled timepoint.
12.13.4.1In-Home Study Visits
Where possible via in-home visits by study personnel or contracted vendor (where applicable), 
the following safety assessments should also be completed, in addition to the safety assessments 
above. Note: For any clinical laboratory determinations, specimen collection, handling and 
processing must be carried out in accordance with the central laboratory manual. If specimen 
processing cannot be completed within the time specified in the central laboratory manual for 
any samples, collection of those samples should be omitted.

Collection of samples for clinical laboratory assessments (in accordance with Table 3-
Schedule of Clinical Laboratory Tests of the Global Protocol (Amendment #5) or 
Country-Specific Protocol, if applicable.)

Serum pregnancy testing

Urine drug screen/blood alcohol concentration assessment

Electrocardiogram (ECG)

Vital signs (with or without weight)

Physical examination


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12.13.4.2Clinical Laboratory Assessments
All attempts should be made to complete clinical laboratory assessments, including pregnancy 
testing, in accordance with Table 3- Schedule of Clinical Laboratory Tests of the Global Protocol 
(Amendment #5) or Country-Specific Protocol, if applicable. As an alternative to patients having 
laboratory assessments on-site, or conducted via an in-home visit by study personnel, laboratory 
assessments may also be conducted at an alternate laboratory facility, if necessary (eg, general 
practitioner’s office, commercial laboratory etc.). In this case, the data is intended to facilitate the 
safety oversight of the patient and will be filed in the source document only and not recorded in 
the eCRF. If a patient is unable or unwilling to travel to an alternate laboratory facility, the 
laboratory assessment at the scheduled timepoint may be omitted. The Principal Investigator (PI) 
must determine whether the patient can safely continue in the study if a laboratory assessment is 
not completed. For women of childbearing potential, study sites may provide urine pregnancy 
test kits for at-home testing. Study personnel should document the patient’s verbal confirmation 
of pregnancy test results in the source document. Results of at-home urine pregnancy tests will 
not be recorded in the eCRF. For patients allowed to continue in the study, all attempts should be 
made to have patients complete laboratory assessments at the next scheduled timepoint, or 
earlier, at an Unscheduled Visit.
12.13.4.3Electrocardiogram (ECG)
If visit is being performed remotely, this assessment may be omitted at the protocol-specified 
timepoint. The PI must determine whether the patient can safely continue in the study if an ECG 
is not performed. For patients allowed to continue in the study, all attempts should be made to 
have patients undergo an ECG at the next scheduled timepoint, or earlier, at an Unscheduled 
Visit. Clinical findings upon termination must be followed until the condition returns to prestudy 
status or can be explained as unrelated to investigational product. If necessary, an additional 
follow-up visit should be scheduled.
12.13.4.4Physical Examination
If visit is being performed remotely, this assessment may be omitted at the protocol-specified 
timepoint. Every attempt should be made to have patient complete as an unscheduled assessment 
during the Safety Follow-up (SFU) period. Clinical findings upon termination must be followed 
until the condition returns to prestudy status or can be explained as unrelated to investigational 
product. If necessary, an additional follow-up visit should be scheduled.


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12.13.4.5Vital Signs
If visit is being performed remotely, this assessment may be omitted at the protocol-specified 
timepoint. Vital signs should be obtained at the next scheduled in-home or in-person visit.
 
 
 
 
 
 
 
 


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12.13.5
Visit 31/ET- End of Double-Blind and Early Termination Visit
Every attempt should be made to complete the Visit 31/ET efficacy and safety assessments on 
the same date. In the event that a remote visit for Visit 31/ET is not possible at the scheduled 
timepoint, all Visit 31/ET efficacy assessments should be completed within 2 weeks of last dose 
of IP. If Visit 31/ET is completed as a remote visit without the assessment of clinical laboratory 
parameters (including pregnancy testing, if applicable), physical examination and/or ECG, the 
patient should be brought back for safety assessments during the SFU period. Patients who have 
missed the safety assessments scheduled for Visit 31/ET and are unable to return for these 
assessments during the SFU period should be encouraged to return to the site for a final
assessment of safety when possible. All attempts should be made to make a final assessment of 
safety even if it falls beyond the end of the Safety Follow-up period. If Visit 31/ET procedures 
are being completed more than 2 weeks after the last dose of IP, efficacy assessments should be 
omitted.
12.13.6
Treatment Compliance
Investigational Product compliance is to be assessed at every visit. Wherever possible, IP 
compliance will be closely monitored by counting the number of capsules dispensed and 
returned, and through patient interview. For remote visits where a pill count by site staff may not 
be possible, patient reported compliance is to be documented. If a remote visit is occurring 
through a video/telemedicine virtual call, study staff should make every effort to visually verify 
number of capsules remaining in the blister card. Otherwise, patient reported verification of IP 
capsules remaining should be documented in the source.
To minimize undue burden on the patient, IP return may be less frequent during the time that 
visits are being conducted remotely but should occur no less frequently than monthly.
Patients who take less IP or more IP than the prescribed regimen must be counseled on the 
importance of taking study medication as instructed. If a patient demonstrates poor compliance 
during the study (< 80% or > 120% overall), the investigator should evaluate whether the patient 
should be discontinued from the study. It is recognized that patients may miss doses due to 
circumstances related to COVID-19 (eg, unanticipated study window extension, delay in receipt 
of IP shipment from site to patient). There will be an allowance of up to 7 consecutive missed 
doses before requiring that a patient be discontinued from the study. The PI must ensure that the 
reason for missed doses is adequately assessed and determined to be related to logistical 
challenges related to COVID-19 and not that the reason is related to a causally-related adverse 
event, general non-adherence with the protocol, etc.


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The study centers will continue to keep an accurate drug disposition record that specifies the 
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Note: If necessary, Visits 13 to 33 may be conducted up to 3 days before or after the scheduled visits. The visit windows for each scheduled visit are relative to 
Visit 12 for Visits 13 through 31/ET, and relative to Visit 31/ET for Visits 32 and 33. In extenuating circumstances, the visit window for Visits 14 to 33 
(inclusive) may be extended an additional 4 days (ie, + 7 days from the scheduled visit). All attempts should be made to conduct the visit within the pre-
defined ± 3 day window as well as to avoid a potential lapse in IP during the extension of a visit window.
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-I = Clinical Global Impressions-
Improvement scale; CGI-S = Clinical Global Impressions-Severity; C-SSRS = Columbia–Suicide Severity Rating Scale; ECG = electrocardiogram; ET = Early 
Termination; HbA1c = glycated hemoglobin; IP = investigational product; IWRS = interactive web response system; MADRS = Montgomery-Åsberg 
Depression Rating Scale; OP = Open-label; PI = Principal Investigator; PK = pharmacokinetic; PSP = Personal and Social Performance scale; SAE = serious 
adverse event; SAS = Simpson-Angus Scale; WOCBP = women of childbearing potential; WPAI-BD = Work Productivity and Activity Impairment: Bipolar 
Disorder questionnaire; YMRS = Young Mania Rating Scale.
a
Clinical laboratory assessments, including serum pregnancy testing (WOCBP only) and HbA1c, may be performed at an off-site laboratory facility if needed. 
If patient is unable or unwilling to travel to an alternate laboratory facility, the laboratory assessment at the scheduled timepoint may be omitted. For 
WOCBP, study sites may provide urine pregnancy test kits for at-home testing. Study personnel should document the patient’s verbal confirmation of 
pregnancy test results in the source document. For all omitted laboratory assessments, the PI must determine whether the patient can safely continue in the 
study if a laboratory assessment is not completed. For patients allowed to continue in the study, patient should have laboratory assessments performed at the 
next scheduled timepoint, or earlier, at an Unscheduled Visit.
b
Clinical laboratory assessments scheduled for Visit 31/ET, including serum pregnancy testing (WOCBP only) may be performed at an off-site laboratory 
facility if needed. If patient is unable or unwilling to travel to an alternate laboratory facility, the laboratory assessment at the scheduled timepoint may be 
omitted. For WOCBP, study sites may provide urine pregnancy test kits for at-home testing. Study personnel should document the patient’s verbal 
confirmation of pregnancy test results in the source document. Patient should have clinical laboratory testing performed as an Unscheduled assessment 
during the Safety Follow-up period. Clinical findings upon termination must be followed until the condition returns to prestudy status or can be explained as 
unrelated to investigational product. If necessary, an additional follow-up visit should be scheduled.
c
As an alternative to in-person drug dispensing, IP may be dispensed via a secure delivery method (where permissible by local, statutory, country law) and 
after approval by Sponsor.
d
Assessment of compliance should be performed at each visit during the Double-blind Treatment period. For remote visits where a pill count by site staff may 
not be possible, patient reported compliance is to be documented. Patient reported verification of IP capsules remaining should be documented.
e
To minimize undue burden on the patient, IP return may be less frequent during the time that visits are being conducted remotely, but should occur no less 
frequently than monthly.
f
C-SSRS may be assessed remotely, if needed, by a certified rater. Clinicians with a valid C-SSRS certification for another Allergan study may rate C-SSRS 
in the event the study-certified rater is unavailable to complete the assessment.
g
If visit is being performed remotely, study staff should verbally administer the WPAI-BD questionnaire to the patient and record the patient’s responses in 
the source.
h
Movement scales may be conducted remotely if needed. Where possible, telemedicine virtual visits or video calls (without recording) should be used to 
conduct this assessment remotely. If a scale item cannot be assessed, the item may be skipped and the source should indicate the item could not be assessed. 
Movement scales may only be conducted by raters certified on the scale. In the event a rater is not available, these assessments may be omitted and assessed 
at the next scheduled timepoint, or earlier, at an Unscheduled Visit.
i
Blood pressure and pulse rate will be measured both standing and supine. If visit is being performed remotely, this assessment may be omitted at this 
timepoint; however, vital signs, including weight, should be obtained at the next scheduled in-home (where possible) or in-person visit. 




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12.14
Package Insert 
The appropriate package insert will be supplied to investigators in countries where the product is 
marketed.


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12.15
Glossary of Abbreviations
Term/Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
AIMS
Abnormal Involuntary Movement Scale
ALT
AREDS
alanine aminotransferase
Age-Related Eye Disease Study
AST
aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
β-hCG
BCVA
β-human chorionic gonadotropin
best-corrected visual acuity
BP
blood pressure
CGI-I
Clinical Global Impressions-Improvement scale
CGI-S
Clinical Global Impressions-Severity
CRF
case report form
C-SSRS
Columbia–Suicide Severity Rating Scale
DA
dopamine
DB
double-blind
DSM-5
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition
ECG
electrocardiogram
eCRF
electronic CRF
EPS
extrapyramidal symptoms
ET
ETDRS
Early Termination
Early Treatment Diabetic Retinopathy Study
GCP
Good Clinical Practices
HIPAA
Health Insurance Portability and Accountability Act
HR
Hazard ratio
HRR
Hardy Rand Rittler
ICD-10
International Classification of Diseases, Tenth Revision
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
IOP
Independent Ethics Committee
intraocular pressure
IP
investigational product
IRB
Institutional Review Board
ITT
intent-to-treat


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Term/Abbreviation
Definition
IWRS
interactive web response system
MADRS
Montgomery-Åsberg Depression Rating Scale
NEAE
newly emergent adverse event
OL
open-label
OL SFU
open-label safety-follow-up 
PCS
potentially clinically significant
PID
patient identification number
PSC
posterior subcapsular
PSP
Personal and Social Performance scale
PK
pharmacokinetic
SAE
serious adverse event
SAS
Simpson-Angus Scale
SCID-5
Structured Clinical Interview for DSM-5
SFU
safety-follow-up
TEAE
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal
WPAI-BD
YMRS
Work Productivity and Activity Impairment: Bipolar Disorder
Young Mania Rating Scale


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SAP_001.pdf: 
Cariprazine
RGH-MD-25 – Statistical Analysis Plan
Amendment #3 – 23 Nov 2022
1
1.0
TITLE PAGE
ABBVIE – CONFIDENTIAL
The following contains confidential, proprietary information, 
which is the property of AbbVie
RGH-MD-25
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED WITHDRAWAL, 
MULTICENTER CLINICAL TRIAL EVALUATING THE EFFICACY, SAFETY, 
AND TOLERABILITY OF CARIPRAZINE IN A DOSE-REDUCTION PARADIGM 
IN THE PREVENTION OF RELAPSE IN BIPOLAR I DISORDER PATIENTS 
WHOSE CURRENT IS MANIC OR DEPRESSIVE, WITH OR WITHOUT MIXED 
FEATURES
STATISTICAL ANALYSIS PLAN
Final: 11 October 2017
Amendment #1:  28 February 2019
Amendment #2: 13 June 2022
Amendment #3: 23 Nov 2022
Confidentiality Statement
This document is the property of AbbVie 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 AbbVie.
 
NCT03573297


Cariprazine
RGH-MD-25 – Statistical Analysis Plan
Amendment #3 – 23 Nov 2022
2
2.0
TABLE OF CONTENTS
1.0
Title Page.................................................................................................................................... 1
2.0
Table of Contents........................................................................................................................ 2
2.1
List of In-Text Tables.................................................................................................... 3
3.0
List of Abbreviations................................................................................................................... 5
4.0
Introduction ................................................................................................................................ 6
5.0
Objectives................................................................................................................................. 15
6.0
Patient Populations.................................................................................................................... 16
6.1
Screened Population.................................................................................................... 16
6.2
Open-Label Safety Population ..................................................................................... 16
6.3
Open-Label Intent-to-Treat Population......................................................................... 16
6.4
Open-Label Safety-Follow-Up Population ................................................................... 16
6.5
Randomized Population............................................................................................... 16
6.6
Double-Blind Safety Population................................................................................... 16
6.7
Double-Blind Intent-to-Treat Population...................................................................... 16
7.0
Study Patients ........................................................................................................................... 17
7.1
Patient Disposition ...................................................................................................... 17
7.2
Protocol Deviations..................................................................................................... 18
8.0
Demographics and Other Baseline Characteristics ..................................................................... 19
9.0
Extent of Exposure and Treatment Compliance.......................................................................... 21
9.1
Extent of Exposure...................................................................................................... 21
9.2
Measurement of Treatment Compliance....................................................................... 21
10.0
Efficacy Analyses ..................................................................................................................... 23
10.1
Primary Efficacy Parameter......................................................................................... 23
10.2
Secondary Efficacy Parameter ..................................................................................... 26
10.3
Additional Efficacy Parameters.................................................................................... 26
11.0
Safety Analyses ........................................................................................................................ 28
11.1
Adverse Events ........................................................................................................... 28
11.2
Clinical Laboratory Parameters.................................................................................... 30
11.3
Vital Signs .................................................................................................................. 34
11.4
Electrocardiogram....................................................................................................... 36
11.5
Other Safety Parameters .............................................................................................. 37
11.5.1
Ophthalmologic Parameters ........................................................................... 37
11.5.2
Columbia-Suicide Severity Rating Scale ........................................................ 38
11.5.3
Extrapyramidal Symptom Scales.................................................................... 38
12.0
Health Outcomes Analyses........................................................................................................ 40
13.0
Interim Analysis........................................................................................................................ 42


Cariprazine
RGH-MD-25 – Statistical Analysis Plan
Amendment #3 – 23 Nov 2022
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14.0
Determination of Sample Size ................................................................................................... 43
15.0
Statistical Software ................................................................................................................... 45
16.0
Data Handling Conventions....................................................................................................... 46
16.1
Visit Time Windows.................................................................................................... 46
16.2
Derived Efficacy Variables and Safety Variables ......................................................... 52
16.3
Repeated or Unscheduled Assessments of Safety Parameters........................................ 53
16.4
Missing Date of the Last Dose of Investigational Product............................................. 53
16.5
Missing Severity Assessment for Adverse Events......................................................... 53
16.6
Missing Causal Relationship to Investigational Product for Adverse Events.................. 54
16.7
Missing Date Information for Adverse Events.............................................................. 54
16.8
Missing Date Information for Prior or Concomitant Medications.................................. 55
16.8.1
Incomplete Start Date .................................................................................... 55
16.8.2
Incomplete Stop Date..................................................................................... 56
16.9
Character Values of Clinical Laboratory Parameters..................................................... 57
17.0
Covid-19 Related Analysis........................................................................................................ 58
17.1
Efficacy Evaluation ..................................................................................................... 58
17.2
Safety and Other Evaluations....................................................................................... 58
18.0
Changes to Analyses Specified in Protocol ................................................................................ 60
19.0
References ................................................................................................................................ 61
20.0
Appendices ............................................................................................................................... 62
Appendix I.
SAS Program for Primary Efficacy Analysis .................................................. 63
Appendix II.
SAS Program for Sensitivity Analyses I and II ............................................... 64
Appendix III.
Reporting Selected Laboratory Parameters in Conventional Units................... 73
Appendix IV.
SAP Amendment Summary ........................................................................... 74
2.1
LIST OF IN-TEXT TABLES
Table 4-1.
Treatment Regiment and Dosing............................................................................. 9
Table 4-2.
Schedule of Visits and Procedures......................................................................... 10
Table 11.2-1.
Criteria for Potentially Clinically Significant Laboratory Tests.............................. 32
Table 11.2-2.
Criteria for Treatment-emergent Significant Changes in Glucose........................... 33
Table 11.2-3.
Criteria for Treatment-emergent Significant Changes in Lipids.............................. 34
Table 11.3-1.
Criteria for Potentially Clinically Significant Vital Signs....................................... 35
Table 11.4-1.
Criteria for Potentially Clinically Significant Electrocardiograms.......................... 37
Table 16.1-1.
Visit Time Windows for the Open-label Treatment Period (for Assessments 
Performed at Each Visit)....................................................................................... 46
Table 16.1-2.
Visit Time Windows for the Open-label Treatment Period (for Clinical 
Laboratory and Waist Circumference)................................................................... 47
Table 16.1-3.
Visit Time Windows for the Open-label Treatment Period (for Personal and 
Social Performance Scale) .................................................................................... 47
Table 16.1-4.
Visit Time Windows for the Open-label Treatment Period (for Extrapyramidal 
Symptoms)........................................................................................................... 48


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RGH-MD-25 – Statistical Analysis Plan
Amendment #3 – 23 Nov 2022
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Table 16.1-5.
Visit Time Windows for the DB Treatment Period (for Assessments Performed at 
Each Visit) ........................................................................................................... 49
Table 16.1-6.
Visit Time Windows for the DB Treatment Period (for Clinical Laboratory and 
Waist Circumference)........................................................................................... 50
Table 16.1-7.
Visit Time Windows for the DB Treatment Period (for Personal and Social 
Performance Scale)............................................................................................... 50
Table 16.1-8.
Visit Time Windows for the DB Treatment Period (for WPAI-BD) ....................... 50
Table 16.1-9.
Visit Time Windows for the DB Treatment Period (for Extrapyramidal 
Symptoms)........................................................................................................... 51
Table 16.1-10.
Visit Time Windows for the SFU period ............................................................... 52
Table 16.9-1.
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters............................................................................................................ 57
Table 20-1.
List of Selected Parameters to be Reported in Conventional Units ......................... 73


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Amendment #3 – 23 Nov 2022
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3.0
LIST OF ABBREVIATIONS
Term/Abbreviation
Definition
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BCVA
Best corrected visual acuity
BMI
Body mass index
BP
Blood pressure
CGI-I
Clinical Global Impressions-Improvement scale
CGI-S
Clinical Global Impressions-Severity
CI
Confidence interval
CRF
Case report form
C-SSRS
Columbia–Suicide Severity Rating Scale
DB
Double-blind
DBTP
Double-blind treatment period
DSM-5
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition
ECG
Electrocardiogram
eCRF
Electronic CRF
EPS
Extrapyramidal symptoms
ET
Early Termination
HR
Hazard Ratio
ICH
International Conference on Harmonisation
IOP
Intraocular pressure
IP
Investigational product
ITT
Intent to treat
IWRS
Interactive web response system
LOCF
Last-observation-carried forward
MADRS
Montgomery-Åsberg Depression Rating Scale
MMRM
Mixed-effects model for repeated measures
OC
Observed cases
OL
Open-label
OLTP
Open-label treatment period
PCS
Potentially clinically significant
PID
Patient identification
PK
Pharmacokinetic
PSP
Personal and Social Performance scale
SAE
Serious adverse event
SAS
Simpson-Angus Scale
SFU
Safety follow-up
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WPAI-BD
Work Productivity and Activity Impairment: Bipolar Disorder
YMRS
Young Mania Rating Score


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RGH-MD-25 – Statistical Analysis Plan
Amendment #3 – 23 Nov 2022
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4.0
INTRODUCTION
This statistical analysis plan (SAP) describes the methodology that will be used to 
summarize the statistical analyses of the efficacy and safety data for the final protocol of
Study RGH-MD-25 (version dated 12 Dec 2016) and its most recent amendment #5 dated
09 June 2022.
This is a Phase 3B, multicenter, multinational, double-blind (DB), placebo-controlled, 
randomized withdrawal study evaluating the efficacy, safety and tolerability of 
cariprazine in a dose-reduction paradigm in the prevention of relapse in bipolar I disorder 
patients whose current episode is manic or depressive, with or without mixed features.
The study is designed with four periods:
Screening/Washout Period: Patients meeting Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar I disorder whose current 
episode (ie, index episode) is manic or depressive, with or without mixed features will 
undergo a screening and washout period up to 7 days, during which consent, eligibility 
assessment, and withdrawal of prior psychiatric and additional prohibited medications 
will occur. The length and timing of the washout of prior psychiatric medications during 
the 7 days allotted for the screening period is at the discretion of the investigator. Prior
medications should be gradually withdrawn such that the washout is completed by 
Visit 2/Baseline. During the screening/washout period, psychotropic medications, other 
than those listed as rescue (Protocol Section 4.8.3), may not be newly initiated or 
reinstated. In order to ensure the safe transition of patients into the study, based upon the 
clinical judgment of the investigator, patients may be hospitalized during initiation of the 
study. This hospitalization can be for up to 14 days during the screening and open-label 
(OL) periods (with the end of hospitalization no later than Visit 3 [Day 8] of the 
open-label treatment period [OLTP]). This 14-day allowance for hospitalization may 
include all or part of the screening period. Hospitalization beyond the initial 14 days 
allowed will require consultation with the AbbVie medical monitor. Following the 
protocol-allowed 14 days of hospitalization (and any sponsor-allowed extension), patients 
should be treated as outpatients.
Open-label Treatment Period: Patients who continue to meet eligibility criteria at 
Visit 2/Baseline will enter an OLTP for up to 16 weeks. Note that, since patients need to 
respond to initial treatment and subsequently meet stability criteria and maintain it for 
8 weeks before being randomized, there will be some patients who will meet the criteria 
earlier than others.


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RGH-MD-25 – Statistical Analysis Plan
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Patients will be started on cariprazine 1.5 mg/d with a target dose of 3.0 mg/d. During the 
initial 8 weeks of the OLTP, patients will be assessed for remission of symptoms, defined 
as Young Mania Rating Score (YMRS) total score ≤ 12 and Montgomery-Åsberg 
Depression Rating Scale (MADRS) total score ≤ 12 and Clinical Global 
Impressions-Severity (CGI-S) ≤ 3. Per protocol, the earliest any patient can achieve 
remission is Visit 4 (Day 15). This is to ensure all patients are on cariprazine 3.0 mg/d for 
at least one week. The patient is considered stabilized once remission (ie, YMRS and 
MADRS total scores are both ≤ 12 and CGI-S ≤ 3) has been established and maintained 
at the subsequent visit. The earliest any patient can achieve stability is Visit 5 (Day 22). 
Stabilized patients will then be treated for an additional 8 weeks of OL cariprazine 
3.0 mg/d. Patients who do not achieve remission by Visit 7 (Week 6) or stability by 
Visit 8 (Week 8) will be discontinued from the study. Additionally, patients who require 
hospitalization (excluding protocol-specified allowed hospitalization) or who require the 
initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with 
a benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 
2 mg/d of lorazepam equivalent or for more than 3 consecutive days) to treat worsening 
mood symptoms as judged by the clinical impression of the investigator at any time 
during the OLTP, will be discontinued.
Following the attainment of stability, YMRS total score ≤ 12 and MADRS total 
score ≤12 and CGI-S ≤ 3 must be maintained for an additional 8 weeks, with the 
exception of allowing 1 excursion (YMRS > 12 and/or MADRS > 12). If an excursion 
occurs, the YMRS and MADRS scores must return to the remission threshold (ie, ≤ 12) 
at the subsequent visit. The excursion (YMRS > 12 and/or MADRS > 12) may occur at 
any time during the 8-week stability period with the exception of Visit 12 (Week 16)/End 
of OL, but must be followed by a return to remission threshold at the next visit. In the 
event the excursion occurs in the 8th week of stability but prior to Visit 12
(Week 16)/End of OL, patients should be assessed at the following visit to confirm 
whether randomization criteria have been met. Previously stabilized patients whose 
efficacy scores increase to YMRS ≥ 17, MADRS ≥ 20, or CGI-S ≥ 4 during OLTP will 
be discontinued from the study. Once stabilization has occurred and been maintained as 
described above, the patient will be randomized.
Randomization/Double-blind Treatment Period (DBTP): OL patients who are able to 
maintain stability criteria for at least 8 weeks with no more than 1 excursion above the 
remission threshold will be randomized 1:1:1 to receive cariprazine at the same dose 
(3.0 mg/d), cariprazine at a reduced dose (1.5 mg/d), or placebo for up to 39 weeks. 
Patients will continue to receive study drug until a relapse event (manic or depressive) 
occurs or until completion of the 39 weeks of randomized treatment. Relapse will be 
defined as the occurrence of any 1 of the following:


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
YMRS total score ≥ 17

MADRS total score ≥ 20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, 
or with a benzodiazepine that exceeds the protocol-specified allowance or 
duration 
(ie, more than 2 mg/d of lorazepam equivalent or for more than 3 consecutive 
days) to treat worsening mood symptoms as judged by the clinical impression of 
the investigator

Psychiatric hospitalization

Exacerbation of illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations)
For patients who meet relapse criteria, the investigator will categorize the relapse event(s) 
as manic or depressive event(s), with or without mixed features.
Safety Follow-up (SFU) Period: Patients who complete the study, or who prematurely 
discontinue from either the OLTP or DBTP, will be followed for 4 more weeks and will 
have 2 evaluations for safety assessments at Visit 32 (Week 57) and Visit 33 (Week 59)
during the SFU period. During the SFU, patients will receive treatment as usual at the 
discretion of the investigator or designee. Patients will not receive investigational product 
(IP) during the SFU period.
IP in the form of capsules packaged in blister packs will be provided by the sponsor. No 
IP will be administered during the screening/washout period or the SFU period. During 
the OLTP (up to 16 weeks), patients will take 1 capsule daily. All patients will begin with 
cariprazine 1.5 mg on Day 1. Patients diagnosed with bipolar I disorder, current episode 
(ie, index episode) manic with or without mixed features, will receive cariprazine 
3.0 mg/d on Day 2 and continue on 3.0 mg/d until the end of the OLTP. Patients 
diagnosed with bipolar I disorder, current episode (ie, index episode) depressive with or 
without mixed features, will continue to receive cariprazine 1.5 mg/d from Day 2 to 7. On 
Day 8, the dose for these patients will be increased to 3.0 mg/d and continue until the end 
of the OLTP. For the 39-week DBTP, patients will be supplied with identically appearing 
capsules of either cariprazine 3.0 mg, cariprazine 1.5 mg, or placebo. During the DBTP, 
patients will take 1 capsule daily. The dosing regimen is presented in the Table 4-1.


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Table 4-1.
Treatment Regiment and Dosing 
Drug/Dose
Investigational 
Product 
Frequency
Route of 
Administration
Open-Label Treatment Period (Week 1)
Index Episode: Manic (with or Without Mixed Features)
Cariprazine 1.5 mg Day 1 / Cariprazine 3.0 mg Days 2-7
Once daily
Oral (capsule)
Index Episode: Depressive (with or without Mixed Features)
Cariprazine 1.5 mg Days 1-7
Once daily
Oral (capsule)
Open-Label Treatment Period (Weeks 2 to 16)a
Cariprazine 3.0 mg
Once daily
Oral (capsule)
Double-Blind Treatment Period (Weeks 17 to 55)
Placebo
Once daily
Oral (capsule)
Cariprazine 1.5 mg
Once daily
Oral (capsule)
Cariprazine 3.0 mg
Once daily
Oral (capsule)
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.
a Patients meeting randomization criteria on or after Visit 10 (Week 12) are eligible for early randomization and will 
skip any remaining visits in the OL period. 
The schedule of evaluations is presented in Table 4-2.
Specifications of tables, figures, and data listings are contained in a separate document. 
The SAP for pharmacokinetic/pharmacodynamic parameters is prepared separately.








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Double-blind Treatment Period
Trial Period
Double-blind Treatment Period
Safety 
Follow-up
Period
Visit Number/
Visit Title
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31/ET
32
33
End of Trial Week 
(Day) 
18
(127)
20
(141)
22
(155)
24
(169)
26
(183)
28
(197)
30
(211)
32
(225)
34
(239)
36
(253)
38
(267)
40
(281)
42
(295)
44
(309)
46
(323)
48
(337)
50
(351)
52
(365)
55
(386)
57
(400)
59
(414)
Visit Window 
(Days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Serum Pregnancy 
test
X
X
X
X
Clinical Laboratory 
X
X
X
Hemoglobin A1c
X
IP Dispensing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP Return 
(Compliance and 
Accountability)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
YMRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MADRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGI-S 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGI-I 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PSP
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-BD
X
X
Extrapyramidal 
Symptoms 
(AIMS/BARS/SAS)
X
X
X
X
X
X
X
X
X
X
Assess relapse 
criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weighta
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist Circumference
X
X
X
Physical examination
X
ECG
X




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5.0
OBJECTIVES
1) To evaluate the efficacy and safety of cariprazine at a target dose of 3.0 mg/d 
compared with placebo in prevention of relapse in patients with bipolar I disorder whose 
current episode (ie, index episode) is manic or depressive, with or without mixed 
features;
2) To evaluate the efficacy and safety of cariprazine at a target dose of 1.5 mg/d 
compared with placebo in prevention of relapse in patients with bipolar I disorder whose 
current episode (ie, index episode) is manic or depressive, with or without mixed 
features, who were initially stabilized on a target dose of 3.0 mg/d.


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6.0
PATIENT POPULATIONS
6.1
SCREENED POPULATION
The Screened Population will consist of all patients who signed informed consent and 
received a Patient identification (PID) number.
6.2
OPEN-LABEL SAFETY POPULATION
The OL Safety Population will consist of all patients in the screened population who took 
at least 1 dose of OL cariprazine during the OLTP of the study.
6.3
OPEN-LABEL INTENT-TO-TREAT POPULATION
The OL Intent-to-treat (ITT) Population will consist of all patients in the OL Safety 
Population who had at least 1 postbaseline assessment of the YMRS, MADRS or CGI-S 
scores during the OLTP of the study.
6.4
OPEN-LABEL SAFETY-FOLLOW-UP POPULATION
The OL SFU population will consist of patients in the OL safety population who were not 
randomized. 
6.5
RANDOMIZED POPULATION
The Randomized Population will consist of all patients in the OL Safety Population who 
were randomized to a treatment group during the DBTP of the study.
6.6
DOUBLE-BLIND SAFETY POPULATION
The DB Safety Population will consist of all patients in the Randomized Population who 
took at least 1 dose of DB IP.
Patients will be included in the treatment group corresponding to the DB IP they actually 
received regardless of the treatment they were randomized to.
6.7
DOUBLE-BLIND INTENT-TO-TREAT POPULATION
The DB ITT Population will consist of all who took at least 1 dose of DB IP and had at 
least 1 post-randomization assessment of the YMRS, MADRS, or CGI-S scores during 
the DBTP of the study, or had a relapse event.
Patients will be included in the randomized treatment group for the DB ITT population.


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7.0
STUDY PATIENTS
7.1
PATIENT DISPOSITION
The OLTP starts with the first dose of OLTP and ends with one of the following: the last
scheduled assessment at Visit 12 (Week 16) or early termination (ET) before Visit 12 for 
patients who do not enter the DBTP; or 1 day before the date of the first dose of DBTP
(or the date of the first dose of the DB IP if the last scheduled assessment date in the 
OLTP is on the date of the first dose of the DBTP) for patients who enter the DBTP.
The DBTP starts with the first day of randomization and ends with the last scheduled 
assessment at Visit 31 (Week 55) or ET.
The SFU period starts one day after the end of the previous period and ends with the last 
available assessment. For patients without Visit 32 (Week 57) or Visit 34 (Week 59)
assessment, the SFU period would not be derived.
Screen-failure patients (ie, patients screened but not included in the OL Safety 
Population) and the associated reasons for failure will be tabulated overall for the 
Screened Population.
The number and percentage of patients in the Screened, OL Safety and OL ITT 
Populations will be summarized overall and by study center. The number and percentage 
of patients in the Randomized, DB Safety, and DB ITT Populations will be summarized 
overall by treatment group and by treatment group and study center.
The number and percentage of patients in the OL Safety Population, who prematurely 
discontinued from the OLTP, who completed the OLTP, who entered the DBTP, and who 
entered the SFU period will be summarized overall and by reasons for premature 
discontinuation as recorded on the OL disposition page of the electronic case report 
forms (eCRF).
Similarly, the number and percentage of patients in the DB Safety Population who 
completed the DBTP, who prematurely discontinued from the DBTP, and who entered 
the SFU period will be summarized overall, by DBTP treatment group and by reasons for 
premature discontinuation as recorded on the DB disposition page of the eCRF. Patients 
who relapse during the DBTP will also be summarized as completing the study.


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7.2
PROTOCOL DEVIATIONS
The number and percentage of patients with important protocol deviations will be 
summarized overall for the OLTP, and by treatment group for the DBTP. Supportive 
listings will also be provided. At a minimum, deviations related to the following 
categories will be included:

Inclusion or exclusion criteria

Withdrawal criteria

Treatment or dose

Concomitant medications
These and any additional important protocol deviations will be reviewed and documented 
before database lock and unblinding of treatment codes.


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8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters, including age; age group; region; race; ethnicity; sex; weight; 
height; and body mass index (BMI), calculated as weight [kg]/(height [m])2 will be 
summarized descriptively overall for the OL Safety and OL ITT Populations and by 
treatment group for the DB Safety and DB ITT populations.
The baseline efficacy variables for OLTP, which is defined as the last available 
assessment at or prior to the first dose of OL IP, will be summarized descriptively overall 
for the OL ITT Population. The baseline efficacy variables for DBTP, which is defined at 
the last available assessment at or prior to the first dose of DB IP, will be summarized by 
treatment for the DB ITT Population.
The medical and surgical history, psychiatric disorders, and nondrug psychiatric 
treatment, will be summarized descriptively overall for the OL Safety Populations and by 
treatment group for the DB Safety Populations.
Continuous variables will be summarized by number of patients and mean, SD, median, 
Q1, Q3, minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of patients.
Prior medication is defined as any medication started before the date of the first dose of 
OL IP. Concomitant medication during the OLTP is defined as any medication taken on 
or after the date of the first dose of OL IP during the OLTP. Concomitant medication
during the DBTP is defined as any medication taken on or after the date of the first dose 
of DB IP during the DBTP.
The use of prior and concomitant medications during the OLTP will be summarized by 
the number and percentage of patients receiving each medication within each therapeutic 
class for the OL Safety Population. The use of concomitant medications during the DBTP
and SFU period will be summarized by treatment group by the number and percentage of 
patients receiving each medication within each therapeutic class for the DB Safety 
Population. Multiple medication use by a patient will only be counted once.
The use of rescue medications during the OLTP and during the DBTP will be 
summarized by treatment group and generic terms for the following rescue medication 
categories in the safety population:

Insomnia

Extrapyramidal symptoms (EPS) or akathisia

Agitation, Restlessness, and Hostility


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The WHO Drug Dictionary Enhanced, version March 2017 or newer, will be used to 
classify prior and concomitant medications by therapeutic class and drug name.


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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to the OL IP for the OL Safety Population will be summarized for treatment 
duration, calculated as the number of days from the date of the first dose of OL
cariprazine taken to the date of the last dose taken during the OLTP, inclusive. 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) will be presented.
Exposure to the DB IP for the DB Safety Population during the DBTP will be 
summarized for treatment duration, calculated as the number of days from the date of the 
first dose of DB IP to the date of the last dose of DB IP, inclusive. Descriptive statistics 
(n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) will be 
presented by treatment group.
Exposure to cariprazine during the entire study (OLTP and DBTP) will be summarized 
by intervals for the OL Safety Population. Descriptive statistics (n, mean, standard 
deviation, median, Q1, Q3, minimum, and maximum) will be presented.
By design, patients will take a fixed dose of cariprazine and there is no titration period 
during the DBTP. Mean daily dose, final dose will not be provided during the DBTP.
Patient-years, defined as exposure to the IP in years, will be summarized for the OLTP
for the OL Safety Population. Patient-years will also be summarized by treatment group 
for the DBTP for the DB Safety Population. Patient years of exposure to cariprazine 
during the entire study (OLTP and DBTP) will also be summarized for the OL Safety 
Population.
9.2
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
prescribed 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. This information will be obtained from the IP record of the 
patient’s eCRF. Descriptive statistics for IP compliance will be presented by treatment 
for each period between 2 consecutive visits, as well as for the period from the first dose 
of DB IP actually taken to the last dose of DB IP actually taken from the Safety 
Population.


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Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) for 
OL IP compliance will be presented overall for each period between 2 consecutive visits, 
as well as for the entire OLTP for the OL Safety Population. Descriptive statistics
(n, mean, standard deviation, median, minimum and maximum) for DB IP compliance 
will be presented by treatment group for each period between 2 consecutive visits, as well 
as for the entire DBTP for the DB Safety Population.


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10.0
EFFICACY ANALYSES
All efficacy analyses for the OLTP will be performed using the OL ITT Population, 
unless stated otherwise. Baselines for efficacy parameters in the OLTP will be defined as 
the last nonmissing efficacy assessment before the first dose of OL IP.
All efficacy analyses for the DBTP will be performed using the DB ITT Population, 
unless stated otherwise. Baselines for the additional efficacy parameters in the DBTP will
be defined as the last nonmissing efficacy assessment before the first dose of DB IP.
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance and all confidence intervals (CIs) will be 2-sided 95% CIs, unless stated 
otherwise.
To accommodate the flexible duration of the OLTP, the derived visits in the DBTP will 
be named as Week i post randomization (or DB Week i) for a specific Week i after the 
first dose of the DB study medications. The total exposure to IPs for patients in Week i
post randomization will vary because of the flexible OLTP. The detailed week-mapping 
windows is provided in Section 16.1.
10.1
PRIMARY EFFICACY PARAMETER
The primary efficacy parameter is the time to first relapse of any mood episode during 
the DBTP. The time to first relapse is defined as the number of days from the 
randomization date to the first relapse date. Relapse during the DBTP will be defined as 
meeting 1 or more of the following criteria:

YMRS total score ≥ 17

MADRS total score ≥ 20

CGI-S ≥ 4

Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, 
or with a benzodiazepine that exceeds the protocol-specified allowance or 
duration (ie, more than 2 mg/d of lorazepam equivalent or for more than 
3 consecutive days) to treat worsening mood symptoms as judged by the clinical 
impression of the investigator

Psychiatric hospitalization

Exacerbation of illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations)
For patients who meet the above relapse criteria will categorize the relapse event(s) as 
manic or depressive event(s), with or without mixed features. Patients who did not meet 
the above relapse criteria will be censored at the time of completion or discontinuation 
from the DBTP.


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The primary efficacy analysis is to evaluate the time to first relapse of any mood episode 
in bipolar I disorder patients who responded to OLTP with cariprazine.
The primary null hypothesis is that the distribution of the time to first relapse for each of 
the cariprazine 3.0 mg/d and 1.5 mg/d treatment groups is not different from that for the 
placebo treatment group. The alternative primary hypothesis is that the distribution of the 
time to first relapse for each of the cariprazine 3.0 mg/d and 1.5 mg/d treatment group is 
different from that for the placebo treatment group.
The hypothesis testing will compare the time to relapse between each cariprazine group 
and placebo group using the log-rank test stratified by modified index episode (manic or 
depressive) and region (US, non-US) for the DB ITT population. To derive the modified 
index episode, the manic index episode(s) with or without mixed features will be 
classified as manic episode(s); depressive index episode(s) with or without mixed 
features will be classified as depressive episode(s). Estimates of the hazard ratio (HR)
and 95% confidence intervals will be based on the Cox proportional hazards model with 
treatment group as the covariate stratified by modified index episode (manic or 
depressive) and region (US, non-US). The Kaplan-Meier estimates for the cumulative 
distribution of the relapse rate for each treatment group will be provided.
Per the protocol, relapses are collected within a double-blind treatment period that lasts 
with a maximum of 39 weeks (or 273 days + 3 days visit time window), hence all 
survival analyses will censor data at 276 days.
The primary hypotheses for cariprazine 3.0 mg/d and 1.5 mg/d treatment groups versus 
placebo will be tested sequentially in order to control the overall Type I error rate. The 
comparison of cariprazine 3.0 mg/d versus placebo will be tested first at two-sided 
0.05 significance level, and only when it is significant, the comparison of cariprazine 
1.5 mg/d versus placebo will be tested also at the two-sided 0.05 significance level. This 
testing strategy controls the overall Type I error rate at 0.05 significance level.
Two sensitivity analyses will be performed to assess the robustness of the primary 
analysis results to the possible violation of the noninformative censoring assumption.
The first sensitivity analysis will be based on the delta-adjusted method examined by 
Zhao et al. (2014), which specifies that the hazard of having an event for subjects who 
discontinued before the time point is increased relative to the hazard for subjects who 
continued beyond the time point for the experimental treatment group. The 
delta-adjustment will be gradually increased from zero until reaching the tipping point 
when the statistical significance of the primary efficacy endpoint is overturned, and the 
plausibility of the magnitude of delta-adjustment needed for reaching the tipping point 
will be subject to clinical scrutiny.


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The second sensitivity analysis is an extension of the placebo-based pattern mixture 
model proposed by Lu (2014, 2015). The placebo-based pattern mixture model assumes 
that patients who discontinued from the cariprazine treatment groups would have disease 
progression after discontinuation similar to that of placebo. The extended placebo-based 
pattern mixture model uses a sensitivity parameter to characterize the gradual deviation 
from the noninformative censoring underlying the primary analysis toward the 
informative censoring underlying the placebo-based pattern mixture model. The extended 
placebo-based pattern mixture model sensitivity analysis for time-to-event data is 
described as follows:
Let h0(t) denote the baseline hazard function associated with the placebo group. Let β1
and β2 denote the treatment effects in terms of log HRs under noninformative censoring 
for cariprazine 1.5 mg/d versus placebo and cariprazine 3.0 mg/d versus placebo, 
respectively. The hazard functions associated with the cariprazine 1.5 and 3.0 mg/d 
groups under noninformative censoring are thus given by h1(t) = h0(t) exp(β1) and 
h2(t) = h0(t) exp(β2), respectively. Consider the extended placebo-based pattern mixture 
model sensitivity analysis. For the placebo group, we assume that patients with premature 
discontinuation would have comparable experience after discontinuation to their 
counterparts without premature discontinuation. For the cariprazine treatment groups, 
each dropout time point for cariprazine patients defines a missing data pattern, and we 
assume that patients with premature discontinuation would have disease progression after 
discontinuation somewhere between their counterparts without premature discontinuation 
and patients in the placebo group. Specifically, we assume that h1(t) = h0(t) exp((1- ϕ)β1) 
and h2(t) = h0(t) exp((1- ϕ)β2) for t > C, where C denotes the time of premature 
discontinuation. The sensitivity parameter ϕ ϵ [0,1] characterizes the gradual deviation 
from the noninformative censoring with ϕ = 0 toward the informative censoring 
underlying the placebo based pattern mixture model with ϕ = 1. A multiple imputation 
approach will be used to implement the extended placebo-based pattern mixture model.
Sample SAS programs for primary efficacy analysis and sensitivity analyses are provided 
in Appendix I and Appendix II.
The analysis for primary efficacy parameter will be performed within each category of 
the following, and the corresponding Kaplan-Meier curves will be provided:

Age group (< 45 years, ≥ 45 years).

Sex (male, female)

Race (white, all other races)

Region (US, Non-US)

Modified index episode (manic or depressive)
Manic episode with mixed features or depressive episode with mixed features is 
classified as manic or depressive episodes, respectively. 


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Kaplan-Meier curves of cumulative rate of first relapse with manic episode with or 
without mixed features during the DBTP, and Kaplan-Meier curves of cumulative rate of 
first relapse with depressive episode with or without mixed features during the DBTP
will be generated.
Additional sensitivity analysis for the primary endpoint, time to first relapse of any mood 
episode, will be conducted for the DB ITT population, censoring ongoing participants in 
Russia and Ukraine as of 24Feb2022, and will be analyzed using the log-rank test 
stratified by modified index episode and region. Any relapse events in Russia and 
Ukraine on or after 24Feb2022 will not be included and all ongoing participants in those 
two countries will be considered ‘lost’ as of that date.
10.2
SECONDARY EFFICACY PARAMETER
None.
10.3
ADDITIONAL EFFICACY PARAMETERS
The overall relapse rate, as well as the relapse rates for sub-categories of interest 
including modified manic episode and modified depressive episode will be presented.
Time to early discontinuation with any reason (including relapse) during the DBTP for 
the DB ITT population will be analyzed using the same method used to analyze the 
primary efficacy variable.
For the following continuous efficacy variables, the change from baseline refers to the 
change from OL baseline during the OLTP, and the change from DB baseline during the 
DBTP, unless stated otherwise.
For Open-label Treatment Period

Change from baseline in YMRS total score by visit

Change from baseline in MADRS total scores by visit

Change from baseline in CGI-S score by visit

CGI-I score by visit

Change from baseline in PSP total score and sub-domain score by visit
For Double-blind Treatment Period

Change from DB baseline in YMRS total score by visit

Change from DB baseline in MADRS total score by visit

Change from DB baseline in CGI-S score by visit

CGI-I score by visit

Change from DB baseline in PSP total score and sub-domain score by visit


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Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) for additional efficacy parameters will be provided by visit for the OL ITT 
population and the DB ITT population using both last-observation-carried forward 
(LOCF) and observed cased (OC) approaches. LOCF approach will be used to impute 
missing postbaseline values. Imputation of missing values will be done for the OLTP and 
the DBTP separately.
For the DBTP, the additional efficacy parameters will be analyzed by using a mixed-
effects model for repeated measures (MMRM) with treatment group, region (US and 
non-US), modified index episode strata (manic or depressive), visit, and treatment 
group-by-visit interaction as fixed effects and the baseline value and baseline-by-visit 
interaction as the covariates. An unstructured covariance matrix will be used. The 
Kenward-Roger approximation (Kenward and Roger, 1997) will be used to estimate 
denominator degrees of freedom. The analysis will be performed based on post-DB 
baseline scores using only the OC without imputation of missing values. Least squares 
mean and their standard errors based on the MMRM analysis will be plotted by treatment 
group and visit.
The analysis for change from baseline in YMRS and MADRS total scores by visit will 
also be performed within modified index episode (manic or depressive).
Sub-domains for PSP are socially useful activities, personal and social relationships, 
self-care, disturbing and aggressive behaviors.


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11.0
SAFETY ANALYSES
The safety analyses will be performed for the OL safety, OL SFU and DB safety 
Population. The summarization will be overall for the OLTP in the OL safety population 
and OL SFU period in the OL SFU population, and by treatment group for the DB period 
and the DB SFU period in the DB safety population. The summarization for the OLTP 
will use the OL safety population as the denominator. The summarization for the DBTP 
will use the DB safety population as the denominator. The summarization for the OL
SFU period or DB SFU period will use the OL SFU Safety Population or the DB safety 
population as the denominator respectively. 
Safety parameters will include adverse events (AEs), clinical laboratory parameters, vital 
signs, Electrocardiogram (ECG) parameters, ophthalmology parameters, Columbia–
Suicide Severity Rating Scale (C-SSRS), EPS scales, including Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus 
Scale (SAS), and prolactin level. 
For each safety parameter, the last assessment made before the first dose of OL IP will be 
used as the baseline for all analyses of that safety parameter, unless stated otherwise.
Continuous variables will be summarized by number of patients and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number 
and percentage of patients.
The derived visits in the DBTP will use the same strategy as described in Section 10.0. 
The detailed week mapping windows is provided in Section 16.1.
11.1
ADVERSE EVENTS
Aes will be coded by system organ class and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 21.0 or newer.
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date of the first dose of 
OL IP. Per eCRF instructions, a new AE record will be created with a new AE onset date 
for any AE that worsens. Therefore, TEAEs can simply be identified as those Aes with 
recorded onset date (and time, if known) on or after the date of the first dose of IP.
The number and percentage of patients reporting TEAEs during the OLTP will be 
tabulated by system organ class and preferred term; by system organ class, preferred 
term, and severity; and by system organ class, preferred term, and relationship to IP.
The number and percentage of patients reporting TEAEs during the DBTP will be 
tabulated for each treatment group by system organ class and preferred term; by system 
organ class, preferred term, and severity; and by system organ class, preferred term, and 
relationship to IP. The total number and percentage of TEAEs during the DBTP will also 
be summarized by severity and relationship to IP for each treatment group.


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The number and percentage of patients reporting TEAEs during the OL SFU period will 
be tabulated by system organ class and preferred term for the OL Safety Population. The 
number and percentage of patients reporting TEAEs during the DB SFU period will be 
tabulated by system organ class, preferred term, and DB treatment group for the DB 
Safety Population.
For OLTP, DBTP, or SFU period, if more than 1 AE was coded to the same preferred 
term for the same patient, the patient will be counted only once for that preferred term 
using the most severe and most related occurrence for the summarization by severity and 
by relationship to IP.
An AE that occurs more than 30 days after the date of the last dose of DB IP or occurs 
after the last SFU visit (whichever comes last) will not be summarized except for Aes 
related to reported pregnancies. Aes associated with pregnancies reported in the 
protocol-required timeframe up to approximately 12 weeks following the last dose of DB 
IP will be summarized.
The number and percentage of patients with common (≥ 2% of patients in any treatment 
group) TEAEs will be summarized by preferred term for OLTP and be summarized by 
preferred term and treatment group for DBTP.
The number and percentage of TEAEs leading to premature discontinuation of IP during 
the OLTP will be summarized by preferred term. The incidence of Aes leading to 
premature discontinuation of IP during the DBTP will be summarized by preferred term 
and treatment group.
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a 
TEAE that additionally meets any serious adverse event (SAE) criterion.
Summary tables will be provided for patients with TESAEs if these occurred in 5 or more 
patients. The number and percentage of patients with TESAEs will be summarized for 
OLTP, DBTP, and SFU period.
For the Screened Population, listings will be presented for patients with SAEs, patients 
with Aes leading to premature discontinuation, and patients who die (if any). All patients 
with SAEs, including SAEs reported during the screening period and the SFU period, and 
patients discontinuing because of Aes occurring before the start of OLTP will be included 
in these listings.
The number and percentage of patients with EPS TEAEs, EPS SAEs, and EPS Aes 
leading to premature discontinuation of IP will be summarized overall for the OLTP in 
the OL safety population and by treatment for the DBTP in the DB safety population 
separately.


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The number and percentage of patients reporting TEAEs of ocular events of special 
interest will be summarized overall for the OLTP in the OL safety population and OL 
SFU period in the OL SFU population, by treatment for the DBTP and DB SFU in the 
DB safety population. A listing of all reported ocular events of special interest will be 
provided.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values and change from baseline values at 
each assessment timepoint will be presented for the OLTP and by treatment group for the 
DBTP in International System of Units (SI units). There is a central lab transition (from 
Q2 to Covance) during the clinical trial. In addition, descriptive statistics for clinical 
laboratory values and changes from baseline values at each assessment timepoint will 
also be presented by central lab for the OLTP and by treatment group for the DBTP in SI 
units.
The descriptive statistics will be provided for the following laboratory parameters:
Hematology
Absolute and differential white blood cell count, 
erythrocyte count, hemoglobin, hematocrit, platelet count, 
and red blood cell indices (mean corpuscular volume, mean 
corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration)
Fasting serum chemistry
Sodium, potassium, calcium, chloride, bicarbonate, 
glucose, blood urea nitrogen, creatinine, total protein, 
alkaline phosphatase, albumin, total bilirubin, direct 
bilirubin, indirect bilirubin, AST, ALT, Free T3, free T4, 
TSH, lactate dehydrogenase, creatine phosphokinase, 
γ-glutamyl transpeptidase, uric acid, phosphate, lipid panel 
(total cholesterol, triglycerides, low density lipoproteins, 
high density lipoproteins), prolactin, insulin, and 
magnesium
Urinalysis
Specific gravity, pH, protein, glucose
Hemoglobin A1c
In addition, descriptive statistics for values and changes from the baseline values in 
conventional units at each assessment time point will be presented for selected clinical 
laboratory parameters listed in Appendix III. A description of reporting the lab values in 
conventional units in patient narratives (along with the standard reporting in SI units) is 
presented at the end of Appendix III. Only patients with selected clinical laboratory data 
at baseline and at least one postbaseline visit during the OLTP and DBTP will be 
included in the summary. 


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Clinical laboratory test values will be considered potentially clinically significant (PCS) 
if they meet either the lower-limit or higher-limit PCS criteria listed in Table 11.2-1. The 
number and percentage of patients who have PCS postbaseline clinical laboratory values 
will be tabulated overall for the OLTP, and by treatment group for the DBTP. The 
percentages will be calculated relative to the number of patients with available non-PCS 
baseline values and at least 1 postbaseline assessment for the corresponding treatment 
periods (OLTP or DBTP). The numerator will be the total number of patients with 
available non-PCS baseline values and at least 1 PCS postbaseline value for the 
corresponding treatment periods (OLTP or DBTP). A supportive tabular display of 
patients with PCS postbaseline values will be provided, including the PID number, study 
center number, and baseline and all postbaseline (including non-PCS) values.
In addition, a tabular display showing all Aes that occurred in patients who had PCS 
postbaseline clinical laboratory values will be provided.
Potential Hy’s Law criteria within a 24-hour window is defined by a post baseline 
elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥3x ULN, along with total bilirubin (TBL) ≥ 2x ULN and a non-elevated alkaline 
phosphatase (ALP) < 2x ULN, all based on blood draws collected within a 24-hour
period.
Patients who meet the potential Hy’s Law criteria during the OLTP will be summarized 
for the OL Safety Population. Patients who meet the potential Hy’s Law criteria from the 
first dose of DB IP to within 30 days after the last dose of DB IP will be summarized for 
the DB Safety Population. Supportive tabular displays will also be provided.
The number and percentage of patients with treatment-emergent significant changes in 
lipids parameters (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) 
and glucose will be tabulated by treatment group for the OLTP and the DBTP. The 
criteria for treatment-emergent significant changes in lipids and glucose are specified in 
Table 11.2-2 and Table 11.2-3. Percentages will be calculated relative to the number of 
patients with baseline values meeting the specified baseline criteria and with at least one 
postbaseline assessment during the specific period. The change in lipids and glucose from 
baseline to the highest (lowest for HDL cholesterol) postbaseline measurement during the 
specific period will be summarized. Supportive listings of patients with treatment-
emergent changes in lipids and glucose values will be provided.


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11.3
VITAL SIGNS
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) for 
vital signs (supine systolic and diastolic blood pressures, supine pulse rate, weight, BMI, 
waist circumference, and temperature) and changes from baseline values at each visit and 
at the end of study will be presented overall for the OLTP and OL SFU period, and by 
treatment group for the DBTP and DB SFU period.


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Vital sign values will be considered as PCS if they meet both the observed-value criteria 
and the change-from-baseline criteria listed in Table 11.3-1. The number and percentage 
of patients with PCS postbaseline values will be tabulated overall for the OLTP and by 
treatment group for the DBTP. The percentages will be calculated relative to the number 
of patients with available baseline values and at least 1 postbaseline assessment for the 
corresponding periods (OLTP or DBTP). The numerator will be the total number of 
patients with available baseline values and at least 1 PCS postbaseline value for the 
corresponding periods (OLTP or DBTP). A supportive tabular display of patients with 
PCS postbaseline values will be provided, including the PID number, study center 
number, and baseline and all postbaseline (including non-PCS) values.
In addition, a tabular display showing all Aes that occurred in patients who had PCS 
postbaseline vital sign values will be provided.
The number and percentage of patients with orthostatic hypotension will be provided for 
OLTP and DBTP. Orthostatic hypotension is defined as a reduction of ≥20 mm Hg in 
systolic blood pressure or a reduction of ≥10 mm Hg in diastolic blood pressure while 
changing from the supine to standing position. A supportive listing of patients with 
orthostatic hypotension will be provided. A listing of all AEs for patients with orthostatic 
hypotension will also be provided. 
Table 11.3-1.
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Supine systolic blood 
pressure, mm Hg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Supine diastolic blood 
pressure, mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Supine pulse rate, bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
a A postbaseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria.
bpm = beats per minute.
As specified in the Seventh Report for the Joint National Committee on prevention, 
detection, evaluation and treatment of high blood pressure (NIH Publication No. 04-5230, 
2004), hypertension status is defined in the following texts.

Normotensive: systolic BP < 120 mm Hg and diastolic BP < 80 mm Hg.


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
Prehypertension: systolic BP 120 to 139 mm Hg or diastolic BP 80 to 89 mm Hg

Stage I Hypertension: systolic BP 140 to 159 mm Hg or diastolic BP 90 to 
99 mm Hg

Stage II Hypertension: systolic BP ≥ 160 mm Hg or diastolic BP ≥100 mm Hg
The number and percentage of patients with hypertension status changes from baseline 
will be provided for

Shift of hypertension status from baseline to end of the OLTP in the OL Safety 
Population

Shift of hypertension status from baseline to highest category during the OLTP in 
the OL Safety Population

Shift of hypertension status from baseline to end of the DBTP in the DB Safety 
Population

Shift of hypertension status from baseline to highest category during the DBTP in 
the DB Safety Population
Supportive listings of patients who have a shift in hypertension status from 
normotensive/prehypertension at Baseline to stage I/stage II hypertension will be 
provided.
11.4
ELECTROCARDIOGRAM
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) for 
ECG parameters (heart rate, RR interval, PR interval, QRS duration, QT interval, and
QTc) and changes from baseline values at each assessment time point to the end of study 
will be presented overall for the OLTP and by treatment group for the DBTP. The QTc 
will be calculated using both the Bazett and Fridericia corrections.
ECG parameter values are considered PCS if they meet or exceed the higher-limit PCS 
criteria listed in Table 11.4-1. The number and percentage of patients with PCS 
postbaseline ECG values will be tabulated overall for the OLTP and by treatment group 
for the DBTP. The percentages will be calculated relative to the number of patients with 
available non-PCS baseline values and at least 1 postbaseline assessment for the 
corresponding periods (OLTP or DBTP). The numerator is the total number of patients 
with available non-PCS baseline values and at least 1 PCS postbaseline value for the 
corresponding periods (OLTP or DBTP). A supportive tabular display of patients with 
PCS postbaseline values will be provided, including the PID number, study center 
number, baseline, all postbaseline (including non-PCS) values, and change from baseline.
In addition, a tabular display showing all AEs that occurred in patients who had 
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Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) for 
the total scores and the changes from baseline values at every assessment timepoint for 
each EPS scale (AIMS, BARS, and SAS) will be presented overall for the OLTP and by 
treatment group for the DBTP.


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12.0
HEALTH OUTCOMES ANALYSES
Work Productivity and Activity Impairment Questionnaire Bipolar Disorder 
(WPAI-BD)
The Health Outcome endpoint is change from baseline in percent work time missed, 
percent impairment while working, percent overall impairment, and percent activity 
impairment due to bipolar disorder at Week 16 for OLTP, and at Double-blind Weeks 8
and 39 for DBTP, as assessed by the WPAI-BD.
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) will be provided by visit for the OL ITT population and the DB ITT 
populations.
Baseline for this HEOR endpoint during the DB treatment period for the DB ITT 
population will be defined as the last nonmissing efficacy assessment before the first dose 
of DB IP.
The change from baseline will be analyzed during the DB treatment period for the DB 
ITT population, by using an MMRM with treatment group, region (US and non-US), 
modified index episode strata (manic or depressive), visit, and treatment group-by-visit 
interaction as fixed effects, and the baseline value and baseline-by-visit interaction as the 
covariates. An unstructured covariance matrix will be used. The analysis will be 
performed based on post-DB baseline using only the OC without imputation of missing 
values.
WPAI:BIPOLAR DISORDER Related Endpoints Derivation
WPAI outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes, as follows:
Questions:

Q1 = Currently employed (working for pay).

Q2 = During past 7 days, missed work hours because of problems associated with 
your bipolar disorder

Q3 = During past 7 days, missed work hours due to other reason, such as vacation, 
holidays, time off to participate in this study

Q4 = During past 7 days, how many hours actually worked

Q5 = During past 7 days, how much bipolar disorder affected productivity while 
working


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
Q6 = During past 7 days, how much bipolar disorder affected regular daily 
activity.
Scores:
Multiply scores by 100 to express in percentages.

Percent work time missed due to bipolar disorder (absenteeism): Q2/(Q2 + Q4)

Percent impairment while working due to bipolar disorder (presenteeism): Q5/10

Percent overall work impairment due to bipolar disorder (overall work 
productivity loss): Q2/(Q2 + Q4) + (1- (Q2/(Q2 + Q4))) × (Q5/10)

Percent activity impairment due to bipolar disorder (regular activity impairment): 
Q6/10
If the response to Q1 (“Currently employed?”) is No or missing, absenteeism, 
presenteeism, and overall work productivity loss will all be set to missing.


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13.0
INTERIM ANALYSIS
No interim analysis is planned for this study.


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14.0
DETERMINATION OF SAMPLE SIZE
The sample size and power calculations are based on the analysis of time to relapse of 
any mood episode in the DBTP to compare each cariprazine dose group versus 
placebo-based on a log-rank test. The trial will be a fixed follow-up design. Patients are 
followed from randomization until dropout, relapse or a fixed duration of 39 weeks.
The relapse HR is assumed to be 0.42 based on cariprazine maintenance study in patients 
with schizophrenia (Durgam 2016) 
 
compounds (asenapine and aripiprazone) in bipolar I disorder trials and schizophrenia 
maintenance trails were similar (Pigott 2003; Keck 2006; Kane 2011; Szegedi 2018). The 
cumulative relapse rate at Week 39 for the placebo group is assumed to be 35%, which is 
the average of the relapse rate in the placebo arm at Week 39 for the asenapine bipolar 
mania maintenance trial (Kane 2011) and the quetiapine bipolar I disorder maintenance 
trial (Suppes 2009). 
Using these assumptions, the study would have to observe approximately 75 events to 
have 85% statistical power to detect that at least 1 dose is significant. The statistical 
method for the power calculation is based on the log-rank 2-sided test at the 
5% significance level to compare the difference of each of the 2 survival curves of the 
cariprazine treatment groups versus that of placebo. Based on the assumed event rates, 
and considering the 26% of patients who may discontinue early from the study due to 
other reasons, approximately a total of 378 patients should be randomized to cariprazine 
3.0 mg/d, cariprazine 1.5 mg/d, and placebo, or approximately 126 patients per treatment 
group.
It should be noted that this study is designed to test the 3.0 mg/d dose of cariprazine 
versus placebo first at the 0.05 significance level and, if the results are significant, then 
the 1.5 mg/d dose of cariprazine will be tested at the 0.05 significance level. Given this 
sequential testing strategy, the higher dose of 3.0 mg/d has 85% statistical power to show 
significance versus placebo, and the 1.5 mg/d dose, if it is as effective as the 3.0 mg/d 
dose, and the 3.0 mg/d dose is statistically significant, would also have 85% statistical 
power at the 0.05 significance level. 
With the expectation that approximately 46% of patients will complete the OLTP period 
and will meet the randomization criteria, approximately 882 patients would be expected 
to enter and be treated with cariprazine in the OLTP.


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With the expectation of a 34% screening failure rate, approximately 1245 patients are 
expected to be screened. In the event that screening and/or randomization failure rates are 
higher than projected, enrollment will continue until approximately 126 patients per 
treatment arm are randomized. At the time the randomization target has been met, 
patients who have been screened, but are not yet randomized will be allowed to continue 
in the study until they complete the study, prematurely discontinue, or otherwise fail to 
meet randomization criteria.


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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux 
operating system.


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16.0
DATA HANDLING CONVENTIONS


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16.2
DERIVED EFFICACY VARIABLES AND SAFETY VARIABLES
If only a few item scores are missing, the total score will be calculated based on available 
item scores using the following formula: (total number of items in the scale) × (sum of 
nonmissing items / number of items with nonmissing values). The maximum number of 
missing items allowed for the total scores imputation is specified below.

MADRS total score is the sum of the 10 items from the MADRS. If more than 
2 items of the MADRS are missing, then the total score will be set to missing

YMRS total score is the sum of the 11 items of the YMRS. If more than 1 item of 
the YMRS are missing, then the total score will be set to missing

AIMS total score is the sum of the first 7 items of the AIMS. Possible range is 
0 to 28, with each item ranging from 0 to 4.  If more than 1 item of the first 
7 AIMS items is missing, then the total score will be set to missing. Items 8 
through 12 will be summarized separately (items 8-10 also range from 0-4 each, 
while items 11-12 are yes/no).

SAS total score is the sum of the 10 items of the SAS. Possible range is 0 to 40, 
with each item ranging from 0 to 4.  If more than 1 item for the SAS are missing, 
then the total score will be set to missing.

BARS total score is the sum of the first 3 items (Q1, Q2a and Q2b) of the BARS. 
Possible range is 0 to 9, with each item ranging from 0 to 3.  If any of these
3 BARS items is missing, then the total score will be set to missing. Q3 will be 
summarized separately as a single value score with possible range 0 to 5.


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For the LOCF analysis, if a patient misses a postbaseline visit or if the postbaseline visit 
occurs outside the visit time window, a record for the scheduled visit will be imputed 
using the last nonmissing value immediately before the missing value. If the missing 
value occurs at Week 1, the baseline value will be carried forward for Week 1, provided 
that at least 1 subsequent postbaseline assessment is available. For a composite scale such 
as MADRS total score, individual items of a rating scale will not be carried forward. 
Only total scores will be carried forward using the last-observation-carried-forward 
approach.
Several ophthalmologic examinations were performed later than the visit dates of OLTP, 
hence the data will be reported by the examination dates within in the derived visit 
windows in the DBTP. Similarly, for the examination dates performed after the visit 
dates of DBTP, data will be reported in the SFU period according to the derived visit 
windows.
16.3
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a patient has repeated assessments before the start of OLTP, the results from the final 
nonmissing assessment made before the start of the OL IP will be used as baseline. If 
end-of-study assessments are repeated or if unscheduled visits occur, the last nonmissing
postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics. However, all postbaseline assessments will be used for PCS value 
determinations, and all assessments will be presented in the data listings.
16.4
MISSING DATE OF THE LAST DOSE OF INVESTIGATIONAL 
PRODUCT
When the date of the last dose of OL IP is missing for a patient in the OL Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all 
efforts are made it is still missing, the last visit date during the corresponding period will 
be used as the last dose date for the corresponding period.
When the date of the last dose of DB IP is missing for a patient in the DB Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all 
efforts are made it is still missing, the last visit date will be used as the last dose date.
16.5
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of OL IP, an 
intensity of mild will be assigned. If severity is missing for an AE that started on or after 
the date of the first dose of OL IP, an intensity of severe will be assigned. The imputed 
values for severity assessment will be used for the incidence summary; the values will be 
shown as missing in the data listings.


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16.6
MISSING CAUSAL RELATIONSHIP TO INVESTIGATIONAL 
PRODUCT FOR ADVERSE EVENTS
If the causal relationship to the IP is missing for an AE that started on or after the date of 
the first dose of OL IP, a causality of yes will be assigned. The imputed values for causal 
relationship to OL or DB treatment will be used for the incidence summary; the values 
will be shown as missing in the data listings.
16.7
MISSING DATE INFORMATION FOR ADVERSE EVENTS
The following imputation rules only apply to cases in which the start date for Aes is 
incomplete (ie, partly missing).
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of 
OL IP, the month and day of the first dose of OL IP will be assigned to the 
missing fields

If the year of the incomplete start date is before the year of the first dose of OL IP, 
December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of OL IP, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the 
month and the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and 
year of the first dose of OL IP, the day of the first dose of OL IP will be assigned 
to the missing day

If either the year of the incomplete start date is before the year of the date of the 
first dose of OL IP or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of OL IP, the last day of 
the month will be assigned to the missing day


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
If either the year of the incomplete start date is after the year of the date of the 
first dose of OL IP or if both years are the same but the month of the incomplete 
start date is after the month of the date of the first dose of OL IP, the first day of 
the month will be assigned to the missing day
If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following 
algorithm will be used to impute the start date:

If the stop date is after the date of the first dose of OL IP, the date of the first dose 
of OL IP will be assigned to the missing start date

If the stop date is before the date of the first dose of OL IP, the stop date will be 
assigned to the missing start date
16.8
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS
For prior or concomitant medications, including rescue medications, incomplete 
(ie, partly missing) start dates and/or stop dates will be imputed. When the start date and 
the stop date are both incomplete for a patient, the start date will be imputed first.
16.8.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, the start date will be imputed 
using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of 
OL IP, the month and day of the first dose of OL IP will be assigned to the 
missing fields

If the year of the incomplete start date is before the year of the first dose of OL IP, 
December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of OL IP, 
January 1 will be assigned to the missing fields


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Missing month only

If only the month is missing, the day will be treated as missing and both the 
month and the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and 
year of the first dose of OL IP, the day of the first dose of OL IP will be assigned 
to the missing day

If either the year of the incomplete start date is before the year of the date of the 
first dose of OL IP or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first dose of OL IP, the last day of 
the month will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the 
first dose of OL IP or if both years are the same but the month of the incomplete 
start date is after the month of the date of the first dose of OL IP, the first day of 
the month will be assigned to the missing day
16.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date for a patient in the respective safety 
population (OL Safety Population or DB Safety Population). If the date of the last dose of 
IP in one of the periods is missing, replace it with the last visit date during the 
corresponding period in the imputations described below. If the imputed stop date is 
before the start date (imputed or nonimputed start date), the imputed stop date will be 
equal to the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of 
IP, the month and day of the last dose of IP will be assigned to the missing fields

If the year of the incomplete stop date is before the year of the last dose of IP, 
December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of IP, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the 
month and the day will be replaced according to the above procedure


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Missing day only

If the month and year of the incomplete stop date are the same as the month and 
year of the last dose of IP, the day of the last dose of IP will be assigned to the 
missing day

If either the year of the incomplete stop date is before the year of the date of the 
last dose of IP or if both years are the same but the month of the incomplete stop 
date is before the month of the date of the last dose of IP, the last day of the 
month will be assigned to the missing day

If either the year of the incomplete stop date is after the year of the date of the last 
dose of IP or if both years are the same but the month of the incomplete stop date 
is after the month of the date of the last dose of IP, the first day of the month will 
be assigned to the missing day
16.9
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table because, for example, a character string is reported for a parameter of the 
numeric type, a coded value must be appropriately determined for use in the statistical 
analyses. The actual values, however, as reported in the database will be presented in the 
data listings.
Table 16.9-1 shows examples of how some possible laboratory results should be coded 
for the analysis.
Table 16.9-1.
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters
Laboratory Test,
SI Unit
Possible Laboratory Results
Coded Value for Analysis
URINALYSIS
Glucose, mmol/L
= OR > 55, ≥ 55, > 0
Positive
≤ 0, negative
Negative
pH
> 8.0, ≥ 8.0
8.0
≥ 8.5
8.5
Protein
= OR > 3.0, ≥ 3.0, > 0
Positive
≤ 0
Negative
SI = Le Système International d’Unités (International System of Units).


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17.0
COVID-19 RELATED ANALYSIS
To eliminate immediate potential hazards to patients and study staff due to the 
COVID-19 pandemic while ensuring participant safety and maintaining data integrity, the 
protocol clarification letter and corresponding protocol amendment were sent to sites 
during the pandemic to allow remote visits. 
This section specifies analyses for evaluating the impact of COVID-19. 
17.1
EFFICACY EVALUATION
For the assessment that are conducted remotely (eg, by telephone, telemedicine virtual 
visits, and video call) or in-home, the following assessments are required to be completed 
in the course of the remote visit: YMRS, MADRS, CGI-S, CGI-S, and PSP. 
For patients in the OLTP of the study, the following assessments are also required:

Visits 4 through 7 (as applicable): assessment of remission criteria

Visit 5 through 8 (as applicable): assessment of stability criteria

Visit 6 through 12 (as applicable): maintenance of stability

Visits 10 through 12 (as applicable): assessment of randomization criteria
For patients in the DBTP of the study (Visit 13 through Visit 31/ET), assessment of 
relapse criteria is also required. 
Minimal disruption is expected for the primary endpoint. To evaluate the missing rate for 
the additional endpoints at the end of OLTP and DBTP, the number of patients who 
missed the assessments due to COVID-19 will be summarized at each visit in the OL ITT
or DB ITT population.
17.2
SAFETY AND OTHER EVALUATIONS
This section specifies analyses related to COVID-19 pandemic from the following 
aspects:

Disposition

Study visit (missing entire visit due to COVID-19 or missing assessments due to 
COVID-19)

Protocol deviation

Study drug disruption due to COVID-19


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
TEAEs related with COVID-19 and supplemental signs and symptoms

COVID-19 status (COVID-19 testing results or contact with a COVID-19 positive 
person)
OL Safety Population or DB Safety Population will be used for the planned analyses 
described above. The number of participants impacted by COVID-19 during the OLTP 
will be summarized overall and the number of participants impacted by COVID-19 
during the DBTP will be summarized by treatment group and overall. In addition, the 
number of patients impacted by COVID-19 and their corresponding disposition status in 
the OLTP and DBTP will be summarized respectively.
The number of patients who missed at least one entire visit due to COVID-19 will be 
summarized overall for the OLTP and by treatment group and overall for the DBTP. 
Furthermore, the number of patients who missed at least one assessment due to 
COVID-19 will be summarized by assessment category (laboratory, C-SSRS, urine 
pregnancy test, vital signs, ECG, and ophthalmological assessments) and overall. Similar 
summaries will be provided by visit.
The number of patients with significant protocol deviation due to COVID-19 will be 
provided. The number of patients with study drug disruption due to COVID-19 will be 
provided as well. The number of participants with TEAEs related to coronavirus infection 
or coronavirus test positive will be provided. Supporting listings for the described 
analyses above will also be provided. 


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18.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
1. The definition of the DB ITT population in this document Section 6.7 was updated and 
overwrites the one specified in the Protocol Amendment 5, and reads as follows:
The DB ITT Population will consist of all who took at least 1 dose of DB IP and had at 
least 1 post-randomization assessment of the YMRS, MADRS, or CGI-S scores during 
the DBTP of the study, or had a relapse event.
2. The cutoff for the Age group in the SAP Section 7.4 was updated from 55 to 45 years 
old, due to imbalance between <55 and >=55 years based on the blinded data review.
Now it reads as:

Age group (< 45 years, ≥ 45 years).


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19.0
REFERENCES
Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of 
relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled 
trial. Schizophrenia Res. 2016;176:264–271.
Kane LA, Mackle M, Snow-Adami Linda, et al. A randomized placebo-controlled trial of 
Asenapine for the prevention of relapse of schizophrenia after long-term treatment. 
J Clin Psychiatry. 2011 ;72(3) :349-355. 
Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized, placebo-controlled, 
26-week trial of aripiprazole in recently manic patients with bipolar I disorder. 
J Clin Psychiatry. 2006;67:626-637.
Lu K. An extension of the placebo-based pattern-mixture model. Pharmaceutical 
Statistics 2014; 13: 103-109.
Lu K., Li D., Koch, G. Comparison between two controlled multiple imputation methods 
for sensitivity analysis of time-to-event data with possibly informative censoring. 
Statistics in Biopharmaceutical Research, 2015; 7: 199-213.
National Institutes of Health, National Heart, Lung, and Blood Institute, National High 
Blood Pressure Education Program. The Seventh Report of the Joint National Committee 
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 
NIH Publication No. 04-5230,2014
Pigott TA, Carson William H, Saha AR, et al. Aripiprazole for the Prevention of Relapse 
in Stabilized Patients With Chronic Schizophrenia: A Placebo-Controlled 26-Week 
Study. J Clin Psychiatry. 2003;64(9):1048-1056.
Suppes T, Vieta E, Liu S, et al. Maintenance treatment for patients with bipolar I 
disorder: results from a north american study of quetiapine in combination with lithium 
or divalproex (trial 127). Am J Psychiatry. 2009 Apr;166(4):476-488.
Szegedi A, Durgam S, Mackle M, et al. Randomized, Double-Blind, Placebo-Controlled 
Trial of Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed 
Episode Associated With Bipolar I Disorder. Am J Psychiatry. 2018 Jan 1;175(1):71-79.
Zhao, Y., Herring, A. H., Zhou, H., Ali, M.W., and Koch, G. G. A multiple imputation 
method for sensitivity analyses of time-to-event data with possibly informative 
censoring,” Journal of Biopharmaceutical Statistics, 2014; 24: 229–253.


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20.0
APPENDICES


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APPENDIX I.
SAS PROGRAM FOR PRIMARY EFFICACY ANALYSIS
The primary efficacy analysis for time to relapse include (1) the log-rank test and (2) the 
Cox proportional hazards model with treatment group and modified index episode (manic 
or depressive) as the covariate. The sample SAS code for these analyses are provided 
below. Note in the dataset adtte (DB ITT population), variables trt02pn and trt02p are for 
the double-blind treatment group, episode is for the modified index episode, aval is for 
the time (days) to censor/relapse, and cnsr is for the status of censored (=0) or relapsed 
(=1).
(1) SAS program for log-rank test comparing treatment groups trt02pn=0 and =1:
proc lifetest data=adtte method=km;
  strata episode region/test=logrank group=trt02p diff=control(‘Placebo’);
   time aval * cnsr(0);
   run;
(2) SAS program for Cox proportional hazard model:  
proc phreg data=adtte;
   class trt02p (ref= ‘Placebo’) episode(ref=’depressive’) region;
   model aval * cnsr(0)= episode region trt02p/rl;
   contrast ‘ cariprazine 1.5 mg/d vs placebo Episode=depressive’    trt02p 1 0  episode 0/ 
estimate=exp e; 
   contrast ‘ cariprazine 3.0 mg/d vs placebo Episode=depressive’    trt02p 0 1  episode 0/ 
estimate=exp e;
   contrast ‘ cariprazine 1.5 mg/d vs placebo Episode=manic’    trt02p 1 0  episode 1/ estimate=exp e;
   contrast ‘ cariprazine 3.0 mg/d vs placebo Episode=manic’    trt02p 0 1  episode 1/ estimate=exp e; 
   ods output parameterestimates=pvval;
   run;


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APPENDIX II.
SAS PROGRAM FOR SENSITIVITY ANALYSES I AND II
The SAS program for Sensitivity Analyses II (delta-adjusted method) and III (placebo 
based pattern-mixed model) are presented as below. Note the program is for comparison 
of two treatment groups (eg. Dose1 vs. placebo):
/*****************************************************************************************************
Name:            Sensi.sas
Date:            18April2019
Description:     This analysis program performs the below sensitivity analyses for the primary 
                 Efficacy parameter (time to relapse):
                
                 1. Delta-adjusted method (Zhao 2014)
                 2.  Placebo-based pattern mixture model (Lu, 2014 and 2015)
              
Datasets used:   (Note: This SAS program is for comparison between two treatment groups.) 
                 adsl(AdaM), with the below variables: 
                 Variable    Type    Len    Format       Informat    Label
                 -------------------------------------------------------------------------------------
                 AP02EDT     Num       8    YYMMDD10.                Period 02 End Date - DB                 
                 AP02SDT     Num       8    YYMMDD10.                Period 02 Start Date - DB               
                 -
                 EOPH3STT    Char     20                             End of DB status             
                 ITTDBFL     Char      1                             DB Intent-To-Treat Population 
                 RANDDT      Num       8    YYMMDD10.                Date of Randomization                   
                 SUBJID      Char     20                 $7.         Subject Identifier for the Study 
                 RELAPSE     Char      8                             Relapse event     
                 EPISODE     Char     20                             Index episode  
                 
                 adtte(AdaM), with the below variables:
                 Variable    Type    Len    Format       Informat    Label
                 ------------------------------------------------------------------------------------
                 AVAL        Num       8                             Analysis Value, time to event
                 CNSR        Num       8                             Censor                                  
                 PARAMN      Num       8                             Parameter (N)                           
                 SUBJID      Char     20                 $7.         Subject Identifier for the Study        
                 TRT02PN     Num       8                             Planned Treatment for DB 
                 EPISODE     Char     20                             Index episode
Macro(s) called: (none)
Output files:    (none)
Revision:      
              
*****************************************************************************************************/
libname ad ‘/sasdata/rgh/rgh25’;
%let fllow=39;  ***planned minimum follow-up time***;
%let flhigh=39; ***planned maximum follow-up time***;
* obtain the planned follow-up time for each subject;
data a1;
set ads.adsl(keep=subjid randdt tr02sdt tr02edt eoph3stt relapse ittdbfl episode region 
where=(ittdbfl=’Y’));
durdb=tr02edt-randdt+1;
if index(upcase(EOPH3STT), ‘COMPLETE’)>0 then COMPDBFL=”Y”;
else COMPDBFL=”N”;
run;
proc freq data=a1;
    tables compdbfl*eoph3stt/list missing;    *patient disposition status;
run;
proc univariate data=a1 noprint;
    where COMPDBFL=”N”;
    var durdb;
    output out=b1 max=maxdurb;  *max duration for discontinued;
run;


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proc sort data=a1 out=a2;
    by randdt;
run;
data b2;
    set a2 end=eof;
    retain franddt;
    format franddt yymmdd10.;
    if _n_=1 then do;
        franddt = randdt;
        set b1;
    end;
    if eof then do;
        lranddt = randdt;
        ta = lranddt - franddt; * duration of enrollment period;
        tfmin = %eval(&fllow.*7);
        tfmax = %eval(&flhigh.*7);
        output;
    end;
    keep franddt ta tfmin tfmax;
    label franddt=”Randomization Date for First Randomized Subject”
          ta=”Duration of Enrollment Period (days)”
          tfmin=”Minimum Follow-up Time (days)”
          tfmax=”Maximum Follow-up Time (days)”;
run;
proc print data=b2 label;
    var franddt ta tfmin tfmax;
run;
data a3;
    set a1;
    if _n_=1 then set b2;
    e = randdt - franddt;   * enrollment time for the current subject;
    *if compynfl=”Y” or index(upcase(trmspc),”26 WEEK”)>0 then do; /* completed the study */
    if compdbfl=”Y” then do; 
        tf = durdb; 
        complete=1; 
    end;
    else do;   * relapsed or discontinued for other reasons;
        tf = min(ta - e + tfmin, tfmax);
        complete=0;
    end;
run;
data raw1;
    merge a3 
          ad.adtte(keep=aval cnsr paramn subjid trt03pn where=(paramn=0));    ***paramn=0 corresponds 
to time to relapse***;
    by subjid;
    status=(cnsr=0);
    rename subjid=subj trt03pn=treated aval=time tf=followup;
    keep subjid trt03pn cnsr status aval complete tf episode;
run;
* check number of events per treatment group;
proc freq data=raw1;
    tables treated*status/norow nocol nopercent;
run;
ods listing close;
* examine Bayesian analysis results to determine thinning;
proc phreg data=raw1;
    class episode;
    model time*status(0)=episode region treated;
    bayes piecewise=hazard;
run;
* ==> thin=10 is enough to achieve approx. indep. posterior samples;
%let thin=10; * thinning;
%let ninterval=8; * number of time intervals for piecewise exponential;
%let nimps=200; * number of imputations;
%let seed=314;


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* obtain sample size in raw data;
proc sql noprint;
    select count(*) into :n from raw1;
quit;
data raw;
    set raw1(drop=subj);
    subj = _n_;
run;
options nonotes nosource;
ods noresults;
ods html close;
ods graphics off;
data bootid;    * dummy data set to store bootstrapped subject numbers;
    seed=123;
    do boot=0 to 100;
    do i=1 to &n;
        if boot=0 then subj=i;
        else do;
            call ranuni(seed, u);
            subj=ceil(&n*u); * bootstrapped subject number;
        end;
        output;
    end;
    end;
    call symput(“seed”, strip(put(seed,12.)));
    keep boot subj;
run;
* match the subject number to retrieve other subject-specific data;
proc sql noprint;
    create table bootsamp as
    select b.boot, a.subj, a.treated, a.followup, a.time, a.status a.complete a.episode
    from raw as a, bootid as b
    where a.subj=b.subj 
    order by boot, subj;
quit;
* obtain posterior draws of model parameters from bootstrap samples;
proc phreg data=bootsamp;
by boot;
class episode region treated(ref=’1’);
    model time*status(0)=episode region treated;
    bayes nmc=%eval(&nimps*&thin) piecewise=hazard seed=314;
    ods output Partition=partitio PosteriorSample=postsamp;
run;
ods output close;
* Bootsamp data for both treatments
data bootsamp1;
set bootsamp;
if treated in (1,2); * Placebo Vs 1.5mg;
run;
data bootsamp2;
set bootsamp;
if treated in (1,3); * Placebo Vs 3.0;
if treated=3 then treated=2;
run;
/*Delta-Adjusted Method*/
%macro delta(postsamp=, bootsamp=, trt=, dataout=);
data postsam2;
    set &postsamp.;
    temp = (Iteration - 2000 - 1)/&thin + 1;
    _imputa_ = floor(temp);
    if _imputa_ = temp;
    rename &trt.=beta;
    keep boot _imputa_ lambda1-lambda&ninterval &trt.;
run;


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*merge with raw data;
proc sql noprint;
    create table raw2 as
    select a.*, b.subj, b.treated, b.followup, b.time, b.status, b.complete, b.episode
    from postsam2 as a, &bootsamp. as b
    where a.boot=b.boot
    order by boot, _imputa_, subj;
quit;
* obtain maximum follow-up;
proc univariate data=&bootsamp. noprint;
    by boot;
    var time;
    output out=maxtime max=maxtime; * maximum survival time;
run;
* organize partition information;
proc transpose data=partitio out=partitit(drop=_name_ _label_) 
    prefix=a;
    by boot;
    var UpperTime;
run;
data partitit;
    merge partitit maxtime;
    by boot;
    a&ninterval = maxtime+1;  * a large number to represent infinity;
    drop maxtime;
run;
data raw2;
    merge raw2 partitit;
    by boot;
run;
* impute censored event times for early dropouts;
data raw4;
    set raw2 end=eof;
    if _n_=1 then seed=789;
    retain seed;
    array a{&ninterval};
    array lambda{&ninterval};
    call ranuni(seed, u);
    do delta=0 to 2 by 0.147;
    nlogu = -log(u)/exp(treated*(beta+delta)); * MNAR;
    
    * no imputation needed for subjects with events or for completers;
    if status=1 or (status=0 and time=followup) then do; 
        time3 = time; 
        status3 = status;
    end;
    else do; * impute censored event time;
        * locate the time interval that contains the censoring time; 
        j1 = 1;
        do while (time >= a[j1]);
            j1 = j1 + 1;
        end;
       * locate the time interval containing the censored event time;
        * cumulative hazard in the first interval;
        v = lambda[j1]*(a[j1] - time); 
        j2 = j1;
        do while (nlogu > v and j2 < &ninterval);
            j2 = j2 + 1;    * cumulative hazard in current interval;
            v = v + lambda[j2]*(a[j2] - a[j2-1]); 
        end;
        * obtain the event time;
        if j2 = j1 then
            u3 = nlogu/lambda[j1] + time; * event in interval j1;
        else
            u3 = a[j2] - (v - nlogu)/lambda[j2]; * event in interval j2;


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        time3 = min(u3, followup);
        status3 = (u3 <= followup); 
    end;
    output;
    end;
    if eof then call symput(“seed”, strip(put(seed,12.)));
    keep boot _imputa_ subj episode treated delta time3 status3;
run;
proc sort data=raw4;
    by boot _imputa_ delta;
run;
* perform log-rank test for each imputed data set;
proc lifetest data=raw4;
    by  boot _imputa_ delta;
    time time3*status3(0);
    strata episode region /test=logrank group=treated;
    ods output HomStats=lrdiff2 LogrankHomCov=vlrdiff2; 
run;
ods output close;
data vlrdiff2;
set vlrdiff2;
new=input(treated, 8.);
drop treated;
rename new=treated;
run;
* combine numberator and denominator of the log-rank test;
data lrtest2;
    merge lrdiff2(where=(treated=1)) vlrdiff2(where=(treated=1));
    by boot _imputa_ delta;
    stderr = sqrt(_1);  * standard error of log-rank test statistic;
run;
proc sort data=lrtest2;
    by boot delta _imputa_;
run;
* use Rubin rule to make multiple imputation inference based on log-rank test;
proc mianalyze data=lrtest2;
    by boot delta;
    modeleffects logrank ;
    stderr stderr;
    ods output ParameterEstimates=milrtes2;
run;
ods output close;
* fit Cox model to each imputed data set;
proc phreg data=raw4;
    class episode;
    by  boot _imputa_ delta;
    model time3*status3(0)=episode treated;
    ods output ParameterEstimates=phest2;
run;
ods output close;
proc sort data=phest2;
   by boot delta _imputa_;
run;
* use Rubin rule to make multiple imputation inference based on Cox model;
proc mianalyze data=phest2(where=(parameter=”treated”));
    by boot delta;
    modeleffects estimate;
    stderr stderr;
    ods output ParameterEstimates=miphest2;
run;
ods output close;
data miout2a;
    merge milrtes2(keep=boot delta probt)
          miphest2(keep=boot delta estimate stderr lclmean uclmean);


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    by boot delta;
    plogrank = probt;
    hazardra = exp(estimate);
    hrlowerc = exp(lclmean);
    hrupperc = exp(uclmean);
    *drop probt estimate lclmean uclmean;
run;
proc sort data=miout2a out=miout2b;
    by delta boot;
    where boot>0;
run;
proc univariate data=miout2b noprint;
    by delta;
    var estimate;
   output out=miout2c std=StdErrbo;
run;
data miout2;
    merge miout2a(where=(boot=0)) miout2c;
    by delta;
    bhrlower = exp(estimate - 1.96*stderrbo);
    bhrupper = exp(estimate + 1.96*stderrbo);
    label stderrbo=” “;
run;
data &dataout.;
    format Analysis $20.;
    set miout2(in=b);
    analysis=”Sensitivity”;
    drop boot probt lclmean uclmean;
    format estimate stderr stderrbo bhrlower bhrupper 8.3;
run;
%mend;
%delta(postsamp=postsamp, bootsamp=bootsamp1, trt=treated2, dataout=sensi3);
%delta(postsamp=postsamp, bootsamp=bootsamp2, trt=treated3, dataout=sensi4);
* /*placebo-based pattern mixture model*/
%macro pattern(postsamp=, bootsamp=, trt=, dataout=);*;
data postsam2;
    set &postsamp.;
    *set postsamp;
    temp = (iteration - 2000 - 1)/&thin + 1;
    _imputa_ = floor(temp);
    if _imputa_ = temp;
    rename &trt.=beta;
*rename treated2=beta;
    keep boot _imputa_ lambda1-lambda&ninterval &trt.;
run;
* merge with raw data;
proc sql noprint;
    create table raw2 as
    select a.*, b.subj, b.treated, b.followup, b.time, b.status, b.episode
    from postsam2 as a, &bootsamp. as b
    where a.boot=b.boot
    order by boot, _imputa_, subj;
quit;
* obtain maximum follow-up;
proc univariate data=&bootsamp. noprint;
    by boot;
    var time;
    output out=maxtime max=maxtime; * maximum survival time;
run;
* organize partition information;
proc transpose data=partitio out=partitit(drop=_name_ _label_) prefix=a;
    by boot;
    var uppertime;
run;


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data partitit;
    merge partitit maxtime;
    by boot;
    a&ninterval = maxtime+1;  * a large number to represent infinity;
    drop maxtime;
run;
data raw2;
    merge raw2 partitit;
    by boot;
run;
* impute censored event times for early dropouts;
data raw3;
    set raw2 end=eof;
    if _n_=1 then seed=789;
    retain seed;
    array a{&ninterval};
    array lambda{&ninterval};
    call ranuni(seed, u);
    do phi=0 to 1 by 0.2;
    nlogu = -log(u)/exp(treated*(1-phi)*beta ); * MNAR;
    
    * no imputation needed for subjects with events or for completers;
    if status=1 or (status=0 and time=followup) then do; 
        time3 = time; 
        status3 = status;
    end;
    else do; * impute censored event time;
        * locate the time interval that contains the censoring time; 
        j1 = 1;
        do while (time >= a[j1]);
            j1 = j1 + 1;
        end;
        * locate the time interval containing the censored event time;
        * cumulative hazard in the first interval;
        v = lambda[j1]*(a[j1] - time); 
        j2 = j1;
        do while (nlogu > v and j2 < &ninterval);
            j2 = j2 + 1;    * cumulative hazard in current interval;
            v = v + lambda[j2]*(a[j2] - a[j2-1]); 
        end;
        * obtain the event time;
        if j2 = j1 then
            u3 = nlogu/lambda[j1] + time; * event in interval j1;
        else
            u3 = a[j2] - (v - nlogu)/lambda[j2]; * event in interval j2;
        time3 = min(u3, followup);
        status3 = (u3 <= followup); 
    end;
    output;
    end;
    if eof then call symput(“seed”, strip(put(seed,12.)));
    keep boot _imputa_ subj treated phi time3 status3 episode;
run;
proc sort data=raw3;
    by boot _imputa_ phi;
run;
* perform log-rank test for each imputed data set;
proc lifetest data=raw3;
    by boot _imputa_ phi;
    time time3*status3(0);
    strata episode region /test=logrank group=treated;
    ods output HomStats=lrdiff LogrankHomCov=vlrdiff; 
run;


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data vlrdiff;
set vlrdiff;
new=input(treated, 8.);
drop treated;
rename new=treated;
run;
* combine numberator and denominator of the log-rank test;
data lrtest1;
    merge lrdiff(where=(treated=1)) vlrdiff(where=(treated=1));
    by boot _imputa_ phi;
    stderr = sqrt(_1);  * standard error of log-rank test statistic;
run;
proc sort data=lrtest1;
    by boot phi _imputa_;
run;
* use Rubin rule to make multiple imputation inference based on log-rank test;
proc mianalyze data=lrtest1;
    by boot phi;
    modeleffects logrank ;
    stderr stderr;
    ods output ParameterEstimates=milrtest;
run;
* fit Cox model to each imputed data set;
proc phreg data=raw3;
    class episode;
    by boot _imputa_ phi;
    model time3*status3(0)=episode treated;
    ods output ParameterEstimates=phest1;
run;
proc sort data=phest1;
    by boot phi _imputa_;
run;
* use Rubin rule to make multiple imputation inference based on Cox model;
proc mianalyze data=phest1(where=(Parameter=”treated”));
    by boot phi;
    modeleffects estimate ;
    stderr stderr;
    ods output ParameterEstimates=miphest;
run;
data miout1a;
    merge milrtest(keep=boot phi probt)
          miphest(keep=boot phi estimate stderr lclmean uclmean);
    by boot phi;
    plogrank = probt;
    hazardra = exp(estimate);
    hrlowerc = exp(lclmean);
    hrupperc = exp(uclmean);
    *drop probt estimate lclmean uclmean;
run;
proc sort data=miout1a out=miout1b;
    by phi boot;
    where boot>0;
run;
proc univariate data=miout1b noprint;
    by phi;
    var estimate;
    output out=miout1c std=StdErrbo;
run;
data miout1;
    merge miout1a(where=(boot=0)) miout1c;
    by phi;
    bhrlower = exp(estimate - 1.96*stderrbo);
    bhrupper = exp(estimate + 1.96*stderrbo);
    label stderrbo=” “;
run;


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data &dataout.;
    format Analysis $20.;
    set miout1(in=b);
    Analysis=”Sensitivity”;
    drop boot probt lclmean uclmean;
    format estimate stderr stderrbo bhrlower bhrupper 8.3;
run;
%mend;
/*Placebo Vs 3.0mg/day*/
%pattern(postsamp=postsamp, bootsamp=bootsamp1, trt=treated2, dataout=sensi1);
/*Placebo Vs 1.5mg/day*/
%pattern(postsamp=postsamp, bootsamp=bootsamp2, trt=treated3, dataout=sensi2);
data placebo;
set sensi1(in=a) sensi2(in=b);
if a then compare=”Placebo Vs Cariprazine 1.5mg/day”;
if b then compare=”Placebo Vs Cariprazine 3.0mg/day”;
run;
title ‘Placebo-based pattern mixture model (Lu, 2014, 2015)’;
proc print data=placebo label;
    var analysis phi plogrank hazardra hrlowerc hrupperc;
    format plogrank  6.4;
run;
data delta;
set sensi3(in=a) sensi4(in=b);
if a then compare=”Placebo Vs Cariprazine 1.5mg/day”;
if b then compare=”Placebo Vs Cariprazine 3.0mg/day”;
run;
title ‘Delta-adjusted Method (Zhao, 2014)’;
proc print data=delta label;
    var analysis delta plogrank hazardra hrlowerc hrupperc;
    format plogrank  6.4;
run;


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APPENDIX III.
REPORTING SELECTED LABORATORY PARAMETERS 
IN CONVENTIONAL UNITS
All clinical laboratory parameters will be reported in the International System (SI) units 
as standard practice. In addition, descriptive statistics for values and changes from 
baseline in conventional units at all assessed visits will be reported for selected laboratory 
parameters as listed in Table 20-1 below.
Table 20-1.
List of Selected Parameters to be Reported in Conventional Units
Number
Laboratory Parameter
Conventional Unit
1
Alanine Aminotransferase (SGPT)
U/L
2
Albumin
G/dL
3
Alkaline Phosphatase
U/L
4
Aspartate Aminotransferase (SGOT)
U/L
5
Bilirubin, Direct (Conjugated)
mg/dL
6
Bilirubin, Indirect (Unconjugated)
mg/dL
7
Bilirubin, Total
mg/dL
8
Blood Urea Nitrogen
mg/dL
9
Calcium
mg/dL
10
Cholesterol, HDL
mg/dL
11
Cholesterol, LDL
mg/dL
12
Cholesterol, LDL direct and calculated (combined)
(This lab parameter could be the same as #11) 
mg/dL
13
Cholesterol, Total
mg/dL
14
Creatine Kinase
U/L
15
Creatinine
mg/dL
16
Glucose
mg/dL
17
Insulin
uIU/mL
18
Triglycerides
mg/dL
19
Uric Acid
mg/dL
20
Hemoglobin
G/dL
Patients narratives will also include the values in conventional units for the selected lab 
parameters. That might be accomplished by presenting the values in conventional units 
within the parentheses next to the values in SI units.


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APPENDIX IV.
SAP AMENDMENT SUMMARY
Title: A Double-blind, Placebo-Controlled, Randomized Withdrawal, Multicenter Clinical 
Trial Evaluating the Efficacy, Safety, and Tolerability of Cariprazine in a Dose-reduction 
Paradigm in the Prevention of Relapse in Bipolar I Disorder Patients Whose Current 
Episode is Manic or Depressive, With or Without Mixed Features
Study RGH-MD-25 SAP Amendment #1 (28 February 2019)
Study RGH-MD-25 SAP Amendment #2 (13 June 2022)
Study RGH-MD-25 SAP Amendment #3 (23 November 2022)
Amendment Summary
This summary includes changes made to SAP RGH-MD-25 (11 October 2017).
Minor editorial and document formatting revisions have not been summarized. The 
following is a summary of the major changes that were made to each section of the SAP, 
and a brief rational for these changes. 
SAP 
Amendment
Section
Major Revision
Rationale
#1
Global
Depressive with or without mixed 
feature as one more current Episode 
was added.
To align with Protocol 
Amendment #3. Depressive 
episodes have been included 
as potential index episodes 
following proven efficacy in 
bipolar I depression 
(RGH-MD-56 and 
RGH-MD-54).
#1
Global
Doses (Open-Label Period –
Changed from 4.5 mg to 3.0 mg; DB 
Period: 2 Cariprazine Dose arms are 
now: 3.0 mg and 1.5 mg) were 
changed.
To align with Protocol 
Amendment #3. Depressive 
episodes have been included 
as potential index episodes, so 
OL dose was adjusted to 
reflect efficacy dose range in 
both bipolar I manic and 
bipolar I depressed patients.
#1
Section 4.0, 
Table 4-2
Visit schedule was changed. Day 4 
and Day 10 study visits were deleted 
and a Day 22 visit was added. Study
Visits have been renumbered 
throughout entire amendment 2. 
Study days have been renumbered to 
allow 1 full week of dosing before 
Visit 3 (Day 8).
Day 22 Visit was added to 
improve the potential to 
capture remission/stability 
criteria during the first weeks 
of OL treatment.


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SAP 
Amendment
Section
Major Revision
Rationale
#1
Table 4-2
Symbol Digit Coding 
(SDC) – additional efficacy 
assessment was deleted.
Operational concerns, and 
clinical decision to remove 
cognitive battery 
#1
Table 4-2
Visit windows of +3 days for 
Visit 2/Baseline and ± 3 days for 
Visits 3 through 33 to the table 
header were added.
For clarity
#1
Table 4-2
“Blood Alcohol Level” was changed 
to “Blood Alcohol Concentration by 
Breathalyzer”.
To expedite turnaround time 
for blood alcohol 
concentration results
#1
Table 4-2
Serum pregnancy tests at Visits 7, 18, 
24, and 33 were added.
For clarity and for consistency 
with approved labeling
#1
Table 4-2
Text to clarify the timing of visits was 
added.
For clarity
#1
Section 4.0,
Section 10.1 
MADRS total score was changed 
from MADRS total score ≥ 17 to 
≥20.
To align MADRS 
discontinuation score with 
moderate depression. 
MADRS ≥ 17 is considered 
mild depression and may not 
be suggestive of a true 
depressive episode
#1
Section 6.4 
OL SFU population was added.
For analysis clarity
#1
Section 6.6
One paragraph “patients will be 
included in the treatment group 
corresponding to the DB IP they 
actually received regardless of the 
treatment they were randomized to” 
was added.  
For clarity
#1
Section 6.7 
One paragraph “patients will be
included in the randomized treatment 
group for the DB ITT population” 
was added. 
For clarity
#1
Section 8.0
The rescue medication categories 
were added.
For clarity




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SAP 
Amendment
Section
Major Revision
Rationale
#1
Section 11.2
The analysis on some lab parameters 
in conventional units was added.
To reflect current sponsor 
standards
#1
Section 14.0
Sample size was changed.
Sample size was modified for 
the following reasons
1. As the study population 
changed due to inclusion 
criteria changes, related 
assumptions were modified. 
The assumed probability of 
relapse in the placebo arm at 
Week 39 was updated to 50%.
2. The assumed hazard ratio 
was updated to reflect 
modified relapse data based on 
feedbacks from FDA review 
of maintenance filing for study 
RGH-MD-06.
#1
Table 16.1-1, 
Table 16.1-2, 
Table 16.1-3
Analysis windows were changed.
To align with updated visit 
schedule. 
#1
Section 17.0
Paragraphs to describe the changes 
to analyses specified in protocol were
added.
To align with Protocol 
Amendment #3.
#2
Table 4-2
Updated table.
To align with COVID-19 
Global Protocol Addendum 
and Protocol Amendment #5
#2
Section 7.1
Added summary of number and 
percentage of patients in each 
analysis population.
For completeness
#2
Section 8.0
Defined baseline efficacy variables 
for OLTP and DBTP
For clarity
#2
Section 10.1
Added subgroup analyses for primary 
efficacy parameter by age group, sex, 
race, region and modified index 
episode.
Evaluate the efficacy in 
different subgroups
#2
Section 10.3
Listed additional efficacy parameters 
for OLTP and DBTP
For clarity
#2
Section 11.1
Added summary of TEAEs during 
the OL SFU period and DB SFU 
period
Evaluate safety in safety 
follow-up periods
#2
Section 11.2
Added summary for potential Hy’s 
Law cases during the OLTP and 
DBTP.
Evaluate liver function tests
#2
Section 11.2
Added Table 11.2-2
Define criteria for treatment-
emergent significant changes 
in glucose


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SAP 
Amendment
Section
Major Revision
Rationale
#2
Section 11.2
Added Table 11.2-3
Define criteria for treatment-
emergent significant changes 
in lipids
#2
Section 14.0
Revised assumptions for sample size 
determination
To align with protocol 
Amendment #5
#2
Section 16.1
Added Table 16.1-2
Define analysis windows in 
OLTP for lab and waist 
circumference parameters
#2
Section 16.1
Added Table 16.1-3
Define analysis windows in 
OLTP for PSP
#2
Section 16.1
Added Table 16.1-4
Define analysis windows in 
OLTP for EPS
#2
Section 16.1
Added Table 16.1-6
Define analysis windows in 
DBTP for lab and waist 
circumference parameters
#2
Section 16.1
Added Table 16.1-7
Define analysis windows in 
DBTP for PSP
#2
Section 16.1
Added Table 16.1-8
Define analysis windows in 
DBTP for WPAI-BD
#2
Section 16.1
Added Table 16.1-9
Define analysis windows in 
DBTP for EPS
#2
Section 17.0
New section specifying analyses for 
evaluating the impact of COVID-19
Evaluate impact of COVID-19
#3
Section 6.7
Updated the DB ITT population
definition by including patients with 
relapse event but no efficacy 
assessments.
To account for relapses during 
the double-blind treatment 
period for patients without any
efficacy assessments.
#3
Sections 10.1
and 10.3 and 
SAS codes in 
Appendices
Added ‘region’ to the models.
The study was stratified by 
region as well.
#3
Section 10.1
Updated age cutoff from 55 to
45 years.
Due to imbalance of age 
categories for 55 cutoff based 
on blinded data review.
#3
Section 10.1
New sensitivity analysis of primary 
endpoint, censoring ongoing Russian 
and Ukrainian participants after 
24Feb2022.
Due to Russian-Ukrainian 
conflict that began on 
24Feb2022.
#3
Section 10.1
Added 2 Kaplan-Meier figures.
To explore data further.
#3
Section 12.0
Updated text in WPAI.
WPAI description was 
missing.