Conditions: Major Depressive Disorder
Keywords: MDD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 752
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the efficacy, safety and tolerability of cariprazine as an adjunctive treatment to antidepressant therapy (ADT) in patients with MDD who have had an inadequate response to antidepressants alone.

Detailed description:

Arms:
arm 1: Cariprazine matching placebo capsules, orally, once daily in addition to their ongoing antidepressant therapy (ADT) \[same antidepressant and dose of ADT they were on at the Baseline\] during the Double-blind Treatment Period, up to Week 6. arm 2: Cariprazine 1.5 mg capsules, orally, once daily in addition to their ongoing ADT (same antidepressant and dose of ADT they were on at the Baseline) during the Double-blind Treatment Period, up to Week 6. arm 3: Cariprazine 1.5 mg capsules, orally, once daily for 2 weeks starting at the Baseline, titrated to 3.0 mg capsules, orally, once daily from Week 2 through Week 6 in addition to their ongoing ADT (same antidepressant and dose of ADT) during the Double-blind Treatment Period, up to Week 6.

Interventions: intervention 1: Cariprazine intervention 2: Placebo intervention 3: Antidepressant Therapy (ADT)
Intervention descriptions: intervention 1: Cariprazine supplied in capsules intervention 2: Placebo supplied in capsules intervention 3: ADT as prescribed by the physician per standard of care in clinical practice.

Protocol document:
Prot_000.pdf: 


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 3
July 2020
Amendment 2 (not implemented)
March 2020 (not implemented)
Amendment 1
December 2018
Original Protocol
July 2018
The following information can be found on FDA Form 1572 (US) and/or in the study 
contacts list in the Investigator site file and/or Trial Master File: Name and contact 
information of Allergan 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.


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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Protocol Amendment #3 Summary
Title: A Double-Blind, Placebo-Controlled Study of Cariprazine as an Adjunct to 
Antidepressants in the Treatment of Patients With Major Depressive Disorder who Have had 
an Inadequate Response to Antidepressants Alone
Amendment Summary
Protocol 3111-302-001 Amendment #2 was approved by the Sponsor in March 2020, but not 
implemented due to a change in strategy; pertinent changes from amendment #2 that will be 
implemented are summarized in the table below.  This summary includes the complete list of 
changes made from Protocol 3111-302-001 Amendment #1 (19 Dec 2018) to Amendment #3.
Following is a summary of changes that were made to each section of the protocol, and a 
brief rationale for these changes.
Minor editorial and document formatting revisions, including updates to abbreviations have 
not been summarized.
Section 
Revision
Rationale
Protocol Summary,
Study Design: Structure
Protocol Summary,
Study Design: Duration, 
Visit Schedule
Protocol Summary, 
Study Population 
Characteristics: 
Number of Patients
Protocol Summary, 
Study Population 
Characteristics: 
Key Inclusion Criteria
General Statistical 
Methods and Types of 
Analyses: Sample Size 
Calculation
Revised text to clarify expectation around 
inadequate response to 1-3 ADTs in the current 
episode.
Added text to extend the screening period an 
additional 7 days if needed with Sponsor 
approval.
Increased potential screening pool from 
approximately 1125 to approximately 1700.
Revised text to clarify expectation around 
inadequate response to 1-3 ADTs in the current 
episode.
Increased potential screening pool from 
approximately 1125 to approximately 1700.
For clarity
To facilitate enrollment
To account for a higher than 
expected screen failure rate
For clarity
To account for a higher than 
expected screen failure rate
Figure 1 Study
Schema
Figure 1 was revised to add text to extend the 
screening period up to an additional 7 days if 
necessary as approved by the Sponsor.
To facilitate enrollment


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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Section 
Revision
Rationale
Schedule of Visits and 
Procedures, Table 1
Footnote d, blood alcohol removed
Footnote e, clarified that blood alcohol 
concentration is assessed by Breathalyzer;
statement that blood alcohol concentration was to 
be assessed at Visit 1 only was deleted.  
Footnote e, was also added to serum pregnancy 
test.
Footnote k “May be up to an additional 7 days 
(up to 21 days) if necessary with Sponsor 
approval” was added to indicate extended 
screening period.
For consistency
Footnote streamlined for 
clarity 
For consistency
To facilitate enrollment
Section 3 Study Design: 
Study Duration,
Screening/Washout 
Period
Added text to extend the screening period up to 
an additional 7 days if needed with Sponsor 
approval.
To facilitate enrollment
Section 4.1 Number of 
Patients
Increased potential screening pool from
approximately 1125 to approximately 1700.
To account for an increased 
screen failure rate
Section 4.2 Study 
Population Characteristics  
and Section 4.3 Inclusion 
Criteria: Inclusion 
criterion number 5.
Extended the maximum duration of current major 
depressive episode at screening from “not 
exceeding 18 months” to “less than 24 months”.
Window for depressive 
episode has been widened to 
facilitate recruitment while 
still excluding potential cases 
of dysthymia.
Section 4.3 Inclusion 
Criteria: Inclusion 
criterion number 8.
Text was changed/added:
8. In the current depressive episode, patients must 
have an inadequate response (< 50% 
improvement) to 1 to 3 antidepressants of 
adequate dose and adequate duration, as 
measured by the modified ATRQ. Adequate dose 
is defined as a dose above the minimum labeled 
dose (per package insert). Adequate duration is 
defined as continuous ADT treatment for at least 
6 weeks, with a minimum of 3 of 6 weeks above 
the minimal dose.
Text amended for clarity.
Section 4.4 Exclusion 
Criteria: Exclusion 
Criterion 12
Added text to also exclude “treatment with 
esketamine”.
Exclusion expanded to 
account for recent approval of 
esketamine
Section 4.4 Exclusion 
Criteria: Exclusion 
Criterion 15
Lowered restriction of participation in another
study from within 6 months to within 3 months of 
Visit 1.
To enhance enrollment
Section 4.4 Exclusion 
Criteria: Exclusion 
Criterion 25
Added text to except patients with negative reflex 
HCV RNA titer test from being excluded.
Criterion is being amended to 
facilitate recruitment of 
otherwise eligible patients, 
without increasing safety risk.
Section 4.4 Exclusion 
Criteria: Exclusion 
Criterion 30
Changed exclusion criterion on Hemoglobin A1c 
to > 8% (instead of > 7%).
Criterion is being amended to 
facilitate recruitment of 
otherwise eligible patients, 
without increasing safety risk.


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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Section 
Revision
Rationale
Section 4.5.1.1 Definition 
of Females of (Non-) 
Childbearing Potential 
and/or Acceptable 
Contraceptive Methods
Additional permitted hormonal contraceptive 
(ring) added.
To reflect current available 
contraceptive products
Section 4.5.2 Prohibited 
Medications and 
Treatments
Text revised to clarify that the concomitant study 
ADT is excluded from this restriction.
Text revised to clarify the expectation around 
alcohol consumption during the study.
For clarity
For clarity
Section 6.1.2 SAFER 
Criteria Inventory
Added text to clarify that phone interviews 
should not occur on-site.
For patient comfort and data 
quality
Section 6.6.2 Ocular 
Events of Special Interest 
Added text to clarify that the ocular events to 
report to the Sponsor are ocular adverse events of 
special interest.
For clarity
Section 6.6.3: Table 3
Added text to reflect the amended Exclusion 
Criterion 25: Reflex HCV RNA titer test will be 
performed for all Hepatitis C virus antibody 
positive or reactive results.
Added Absolute Neutrophil Count (ANC) to the 
table.
To facilitate recruitment of 
otherwise eligible patients, 
without increasing safety risk.
For consistency
Section 7.4 Other
Analyses
Added text to clarify that any additional analyses 
related to COVID-19 that might be needed, 
would be detailed in the SAP.
To account for potential 
analyses that may be needed in 
light of COVID-19. 
Section 8.2
Washout Interval
Added text to extend the screening period up to 
an additional 7 days if needed with Sponsor 
approval.
To facilitate enrollment
Section 8.3 Procedures 
for Final Study Entry 
Added text to permit rescreening of screen 
failures in certain situations after consultation 
with the Allergan Medical Monitor.
To facilitate enrollment
Section 8.4 Visits and 
Associated Procedures
Added text to address modifications to study 
visits during COVID-19.
For consistency with COVID-
19 protocol addendum – dated 
29-APR-2020
Section 8.5 Instructions
for the Patients
Text revised to clarify the expectation around 
alcohol consumption during the study.
For clarity
Section 8.9 Withdrawal 
Criteria 
Deleted withdrawal criterion #2 regarding using 
prohibited medications.
To facilitate patient retention 
when appropriate
Section 9.4 Reporting of 
Pregnancies Occurring 
During the Study
Added text to clarify that serum pregnancy tests 
can be done at any time if a pregnancy is 
suspected by the investigator. Also added 
statement that if a serum pregnancy test comes 
back as borderline, it should be repeated and 
consultation with the Allergan Medical Monitor 
is required.
For clarity and patient safety


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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Section 
Revision
Rationale
Section 12.2 Protocol 
Modifications for 
COVID-19
Purpose of Protocol 
Addendum
Section 12.2.1. Planned 
Changes in Research
Section 12.2.4.1 In-Home 
Study Visits and Section 
12.2.4.2 Clinical 
Laboratory Assessments
Global Protocol Amendment #1 COVID-19 
addendum (dated 29-APR-2020) was wholly 
incorporated as Section 12.2 with the following 
modifications:
-Heading deleted and introductory text revised to 
reflect its incorporation into the global protocol
-Introductory text revised and criterion regarding 
withdrawal due to 4 or more missed doses of IP 
or ADT revised to state patients should be 
withdrawn if more than 7 doses of IP or ADT are 
missed due to COVID-related reasons
-References to Amendment #1 were updated to 
Amendment #3.
For completeness
To improve readability
Text revised to provide 
specific guidance around 
missed consecutive doses
To reflect latest protocol 
version


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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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 Allergan in confidence and, when this information 
is submitted to an Institutional Review Board, Independent Ethics Committee, 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
Signature
Date


Allergan Confidential
Protocol 3111-302-001 Amendment 3
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Table of Contents
Title Page .................................................................................................................................. 1
Protocol Amendment Summary of Changes Table................................................................... 2
Protocol Amendment #3 Summary........................................................................................... 3
Table of Contents ...................................................................................................................... 8
List of Tables........................................................................................................................... 12
List of Figures......................................................................................................................... 12
Protocol Summary .................................................................................................................. 13
1
Background and Clinical Rationale ............................................................................ 19
2
Study Objectives and Clinical Hypotheses................................................................. 22
2.1
Study Objective............................................................................................... 22
2.2
Clinical Hypotheses ........................................................................................ 22
3
Study Design............................................................................................................... 22
4
Study Population and Entry Criteria........................................................................... 24
4.1
Number of Patients ......................................................................................... 24
4.2
Study Population Characteristics.................................................................... 24
4.3
Inclusion Criteria ............................................................................................ 25
4.4
Exclusion Criteria ........................................................................................... 26
4.5
Permissible and Prohibited Medications/Treatments...................................... 30
4.5.1
Permissible Medications/Treatments .................................................. 30
4.5.1.1 Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods........................................ 30
4.5.2
Prohibited Medications/Treatments .................................................... 31
4.5.3
Rescue Medications ............................................................................ 32
5
Study Treatments ........................................................................................................ 33
5.1
Study Treatments and Formulations ............................................................... 33
5.2
Control Treatment ........................................................................................... 33
5.3
Methods for Masking/Blinding....................................................................... 34
5.4
Method for Assignment to Treatment Groups/Randomization....................... 34
5.5
Treatment Regimen and Dosing ..................................................................... 34
5.6
Treatment Compliance.................................................................................... 35
5.6.1
IP Compliance..................................................................................... 35


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Protocol 3111-302-001 Amendment 3
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5.6.2
ADT Compliance................................................................................ 35
5.7
Storage of Study Medications/Treatments...................................................... 36
6
Response Measures and Summary of Data Collection Methods................................ 36
6.1
Diagnostic Assessments.................................................................................. 36
6.1.1
The Structured Clinical Interview for DSM-5 (SCID-5).................... 36
6.1.2
SAFER Criteria Inventory .................................................................. 36
6.1.3
The Modified Antidepressant Treatment Response Questionnaire..... 37
6.2
Efficacy Endpoints.......................................................................................... 37
6.2.1
Primary Efficacy................................................................................. 37
6.2.1.1 Montgomery-Åsberg Depression Rating Scale ...................... 38
6.2.2
Additional Efficacy Variables ............................................................. 38
6.2.2.1 The Hamilton Anxiety Rating Scale ....................................... 38
6.2.2.2 Clinical Global Impressions–Severity .................................... 38
6.2.2.3 Clinical Global Impressions–Improvement ............................ 38
6.2.2.4 Hamilton Depression Rating Scale–17 Items ......................... 39
6.3
Health Outcome Measures.............................................................................. 39
6.4
Pharmacokinetics Measures............................................................................ 39
6.5
Pharmacogenetic Sampling............................................................................. 40
6.6
Safety Measures.............................................................................................. 40
6.6.1
Adverse Events ................................................................................... 40
6.6.2
Ocular Events of Special Interest........................................................ 41
6.6.3
Clinical Laboratory Determinations ................................................... 41
6.6.4
Vital Signs........................................................................................... 43
6.6.5
Electrocardiograms ............................................................................. 43
6.6.6
Other Safety Assessments................................................................... 44
6.6.6.1 Extrapyramidal Symptoms Scales .......................................... 44
6.6.6.2 Columbia–Suicide Severity Rating Scale............................... 44
6.6.6.3 Young Mania Rating Scale ..................................................... 45
6.7
Summary of Methods of Data Collection....................................................... 45
7
Statistical Procedures.................................................................................................. 46
7.1
Analysis Populations....................................................................................... 46
7.1.1
Patient Populations.............................................................................. 46
7.1.1.1 Screened Population................................................................ 46
7.1.1.2 Randomized Population.......................................................... 46
7.1.1.3 Safety Population.................................................................... 46
7.1.1.4 Modified Intent-to-Treat Population....................................... 46


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Protocol 3111-302-001 Amendment 3
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7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments 46
7.2.1
Primary Efficacy Variable................................................................... 46
7.2.2
Additional Efficacy Variables ............................................................. 46
7.3
Hypothesis and Methods of Analysis.............................................................. 47
7.3.1
Primary Efficacy Analyses.................................................................. 47
7.3.2
Other Efficacy Analyses ..................................................................... 50
7.3.3
Safety Analyses................................................................................... 51
7.3.3.1 Adverse Events ....................................................................... 51
7.3.3.2 Clinical Laboratory Parameters .............................................. 52
7.3.3.3 Vital Signs............................................................................... 53
7.3.3.4 Electrocardiogram................................................................... 54
7.3.3.5 Other Safety Parameters ......................................................... 54
7.4
Other Analyses................................................................................................ 55
7.4.1
Pharmacokinetic Parameters............................................................... 55
7.4.2
Health Outcome Measure Analyses.................................................... 56
7.5
Subgroup Analyses.......................................................................................... 56
7.6
Interim Analyses ............................................................................................. 56
7.7
Sample Size Calculation ................................................................................. 56
8
Study Visit Schedule and Procedures.......................................................................... 57
8.1
Patient Entry Procedures................................................................................. 57
8.1.1
Overview of Entry Procedures............................................................ 57
8.1.2
Informed Consent and Patient Privacy ............................................... 57
8.2
Washout Interval ............................................................................................. 57
8.3
Procedures for Final Study Entry.................................................................... 58
8.4
Visits and Associated Procedures.................................................................... 58
8.4.1
Screening (Visit 1) .............................................................................. 58
8.4.2
Baseline (Visit 2)................................................................................. 59
8.4.3
Double-blind Treatment Period (Visits 3 to 6/ET).............................. 60
8.4.4
Safety Follow-up (Visit 7) .................................................................. 61
8.5
Instructions for the Patients ............................................................................ 61
8.6
Unscheduled Visits.......................................................................................... 62
8.7
Compliance with Protocol............................................................................... 62
8.8
Early Discontinuation of Patients ................................................................... 62
8.9
Withdrawal Criteria......................................................................................... 64
8.10
Study Termination........................................................................................... 65


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Protocol 3111-302-001 Amendment 3
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9
Adverse Events ........................................................................................................... 65
9.1
Definitions....................................................................................................... 65
9.1.1
Adverse Event..................................................................................... 65
9.1.2
Serious Adverse Event ........................................................................ 66
9.1.3
Severity ............................................................................................... 66
9.1.4
Relationship to Study Drug................................................................. 67
9.2
Procedures for Reporting Adverse Events ...................................................... 67
9.3
Procedures for Reporting a Serious Adverse Event........................................ 67
9.4
Reporting of Pregnancies Occurring During the Study.................................. 68
9.5
Potential Hy’s Law Cases............................................................................... 68
9.6
Procedures for Unmasking of Study Medication............................................ 69
10
Administrative Items................................................................................................... 69
10.1
Protection of Human Patients ......................................................................... 70
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 50) 
and Relevant Country Regulations ..................................................... 70
10.1.2 Compliance With IRB or IEC Regulations......................................... 70
10.1.3 Compliance With Good Clinical Practice........................................... 70
10.1.3.1
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11)........................................... 70
10.2
Changes to the Protocol .................................................................................. 70
10.3
Patient Confidentiality.................................................................................... 70
10.3.1 Patient Privacy .................................................................................... 71
10.4
Documentation................................................................................................ 71
10.4.1 Source Documents .............................................................................. 71
10.4.2 Case Report Form Completion ........................................................... 72
10.4.3 Study Summary................................................................................... 72
10.4.4 Retention of Documentation............................................................... 73
10.5
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments.................................................................................. 73
10.5.1 Labeling/Packaging............................................................................. 73
10.5.2 Investigational Product Supply Inventory .......................................... 73
10.5.3 Return or Disposal of Study Medications/Treatments........................ 74
10.6
Monitoring by the Sponsor ............................................................................. 74
10.7
Handling of Biological Specimens ................................................................. 74
10.8
Publications..................................................................................................... 75
10.9
Coordinating Investigator ............................................................................... 75


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Protocol 3111-302-001 Amendment 3
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11
References................................................................................................................... 75
12
Attachments ................................................................................................................ 79
12.1
Scales and Questionnaires............................................................................... 79
12.2
Protocol Modifications for COVID-19........................................................... 80
12.2.1 Planned changes in research ............................................................... 80
12.2.2 Remote Assessment of Efficacy.......................................................... 80
12.2.3 Remote Assessment of Health Outcome measures............................. 81
12.2.4 Remote Assessment of Safety............................................................. 81
12.2.4.1
In-Home Study Visits......................................................... 82
12.2.4.2
Clinical Laboratory Assessments ....................................... 82
12.2.4.3
Electrocardiogram (ECG) .................................................. 83
12.2.4.4
Physical Examination......................................................... 83
12.2.4.5
Vital Signs .......................................................................... 83
12.2.5 Visit 6/ET- End of Double-Blind and Early Termination Visit........... 83
12.2.6 Treatment compliance......................................................................... 84
12.3
Glossary of Abbreviations............................................................................... 88
12.4
Protocol Amendment #1 Summary................................................................. 90
List of Tables
Table 1
Schedule of Visits and Procedures............................................................ 16
Table 2
Treatment Regimen and Dosing ............................................................... 35
Table 3
Schedule of Clinical Laboratory Tests...................................................... 42
Table 4
COVID-19 Modified Schedule of Visits and Procedures (Applicable to 
Randomized Patients who have completed Visit 2).................................. 85
List of Figures
Figure 1
Study Schema............................................................................................ 15


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Protocol 3111-302-001 Amendment 3
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Protocol Summary
Study Compound: Cariprazine
Phase: 3
Study Objective: To evaluate the efficacy, safety, and tolerability of cariprazine 1.5 mg/day and 3 mg/day
compared with placebo as an adjunctive treatment to ongoing antidepressant therapy (ADT) in patients with 
major depressive disorder (MDD) who have had an inadequate response to antidepressants alone.
Clinical Hypotheses: In the treatment of patients with MDD who have had an inadequate response to ADT 
alone, cariprazine as an adjunctive treatment to ADT is safe and more effective than placebo + ADT.
Study Design
Structure: This is a global, multicenter, randomized, double-blind (DB), placebo-controlled, parallel-group, 
fixed-dose study comparing cariprazine 1.5 mg/day and cariprazine 3 mg/day with placebo as an adjunctive 
treatment to ongoing ADT in outpatients with a diagnosis of MDD (via the Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition [DSM-5]) who have an inadequate response, as measured by the modified 
Antidepressant Treatment Response Questionnaire (ATRQ), to 1 to 3 antidepressants administered during the 
current episode at an adequate dose and adequate duration.  Adequate dose is defined as a dose above the 
minimum labeled dose (per package insert). Adequate duration is defined as continuous ADT treatment for at 
least 6 weeks, with a minimum of 3 of 6 weeks above the minimal dose. The study schema is presented in
Figure 1.
Duration: The study will consist of up to 14 days of screening (with up to an additional 7 days if needed with 
Sponsor approval) and washout of prohibited medications followed by 6 weeks of DB treatment followed by a 
4-week safety follow-up. At the end of the screening period, patients meeting the entry criteria for this study 
will be randomized (1:1:1) to 1 of 3 DB treatment groups:

cariprazine 1.5 mg/day + ADT

cariprazine 3 mg/day + ADT

placebo + ADT
Study Treatment Groups: cariprazine 1.5 mg/day + ADT and cariprazine 3 mg/day + ADT
Controls: matching placebo + ADT
Dosage/Dose Regimen: Investigational product (cariprazine or placebo) in the form of capsules packaged in 
blister packs will be provided by the Sponsor. No investigational product will be administered during the 
screening/washout period; patients will continue the same antidepressant and dose they were on at Screening.
Patients who are taking more than one antidepressant at Screening, regardless of the indication, will need to 
discontinue all other antidepressants prior to Baseline (Visit 2). During the DB treatment period (6 weeks), 
patients will take 1 capsule orally per day in addition to their ongoing ADT. Patients in the 1.5 mg/day + ADT 
arm will take 1.5 mg + ADT starting at Visit 2 (Week 0). Patients in the 3 mg/day + ADT arm will take 
1.5 mg + ADT starting at Visit 2 (Week 0) for 2 weeks and then titrate to 3 mg/day + ADT starting at Visit 4
(Week 2). Patients will be supplied with identically appearing capsules of either cariprazine 1.5 mg, cariprazine 
3 mg, or placebo. After completion of the DB treatment period, patients will continue as outpatients during the 
safety follow-up period and will receive treatment as usual at the discretion of the investigator or designee; no 
investigational product will be administered.
Randomization/Stratification: After the screening period, eligible patients will be randomized in a 1:1:1 ratio to 
cariprazine 1.5 mg/day + ADT, cariprazine 3 mg/day + ADT, or placebo + ADT.
Visit Schedule: There are 7 visits including screening/washout (up to 14 days, with up to an additional 7 days if
needed with Sponsor approval), the DB treatment period (6 weeks), and the safety follow-up visit (4 weeks) as 
shown in Table 1.


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Protocol 3111-302-001 Amendment 3
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Study Population Characteristics
Number of Patients: The study will screen approximately 1700 patients to randomize 750 patients in a 1:1:1 
ratio to cariprazine 1.5 mg/day + ADT, cariprazine 3 mg/day + ADT, and placebo + ADT groups. In the event 
that screen failure rates are higher than projected, enrollment will continue until approximately 250 patients per 
treatment arm are randomized.
Condition/Disease: Major depressive disorder
Key Inclusion Criteria: Male or female 18 to 65 years of age; meeting DSM-5 criteria for MDD; having a total 
score ≥ 22 on the Hamilton Depression Rating Scale–17 items (HAMD-17) and having an inadequate response, 
as measured by the modified ATRQ, to 1-3 antidepressants administered during the current episode at an
adequate dose and adequate duration. Adequate dose is defined as a dose above the minimum labeled dose (per 
package insert). Adequate duration is defined as continuous ADT treatment for at least 6 weeks, with a 
minimum of 3 of 6 weeks above the minimal dose.
Key Exclusion Criteria: Any current psychiatric diagnosis other than MDD (including those with current 
intellectual development disability) with the exception of specific phobias. History of meeting DSM-5 for any 
substance-related disorders (ie, use disorders except caffeine- and tobacco-related) and addictive disorders 
within the 6 months before Visit 1.
Response Measures
Primary Efficacy Parameter: Montgomery-Åsberg Depression Rating Scale (MADRS).
Pharmacokinetics: Samples will be collected for determination of the plasma concentrations of cariprazine and 
its metabolites. A total of 3 blood samples will be collected during the study, as shown in Table 1.
Pharmacogenetic Sampling: One blood sample will be collected from randomized patients at any time point 
between Visit 2/Baseline (Week 0) and Visit 6/ET (Week 6) for pharmacogenetic biobanking. Participation is 
optional.
Safety: Adverse event recording, clinical laboratory parameters (hematology, chemistry, urinalysis, prolactin), 
vital sign parameters (including blood pressure, pulse rate), body mass index, weight, waist circumference, 
physical examinations, electrocardiograms, Columbia–Suicide Severity Rating Scale, Young Mania Rating 
Scale, and measures of extrapyramidal symptoms: Barnes Akathisia Rating Scale, Abnormal Involuntary 
Movement Scale, and Simpson-Angus Scale.
General Statistical Methods and Types of Analyses: Efficacy analyses will be based on the modified 
intent-to-treat population, consisting of all randomized patients with ≥ 1 postbaseline assessment of the 
MADRS total score.
The primary efficacy parameter will be the change from baseline to Week 6 in the MADRS total score. The 
primary analysis will be performed using a mixed-effects model for repeated measures with treatment group, 
country, ADT failure category (one ADT failure, more than one ADT failure), visit, and treatment 
group-by-visit interaction as fixed effects, and the baseline value and baseline-by-visit interaction as covariates. 
An unstructured covariance matrix will be used to model the covariance of within-patient scores. The Hochberg 
procedure will be used to control the overall type I error rate at a 0.05 level (2-sided) for multiple comparisons 
of 2 active doses with placebo for the primary endpoint.
Safety analyses will be based on the safety population consisting of all randomized patients who received at 
least 1 dose of DB investigational product. All safety parameters will be summarized descriptively.
Sample Size Calculation: The study will screen approximately 1700 patients to randomize 750 patients in a 
1:1:1 ratio to cariprazine 1.5 mg/day + ADT, cariprazine 3 mg/day + ADT, and placebo + ADT groups. A 
sample size of 250 patients per arm will provide approximately 90% statistical power to show at least 1 of the 
2 cariprazine doses is statistically significantly more efficacious than placebo in the primary endpoint, assuming 
an effect size of 0.286 and a dropout rate of 15% at Week 6. The sample size and power were calculated 
adjusting for multiple comparisons using the Hochberg procedure.




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Protocol 3111-302-001 Amendment 3
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Table 1
Schedule of Visits and Procedures
Study Period
Screening
Baseline
Double-blind Treatment
Safety 
Follow-up
Visit
1
2
3
4
5
6/ET
7
Study Week
Up to -2 k
0
1
2
4
6a,b
10
Study Day
Up to -14k
1
8
15
29
43
71
Visit Windows 
(within 14 
days of start 
of screening 
procedures)k
± 3 Days
± 3 Days
± 3 Days
± 3 Days
± 3 Days
Informed Consent
X
Verified Clinical Trials Checkc
X
Medical and Psychiatric Histories
X
Prior Medication History
X
Inclusion/Exclusion Criteria
X
X
Randomization
X
Clinical Laboratory Testsd,e
X
X
Serum Pregnancy Testd,e
X
X
X
Hepatitis Serology
X
Hemoglobin A1c
X
Urine Drug Screene
X
Blood Alcohol Concentration (by 
Breathalyzer)e
X
Vital Signsf
X
X
X
X
X
X
X
Electrocardiogram
X
X
Physical Examination
X
X
SCID-5
X
SAFER Remote Telephone Interviewg
X
Evaluate SAFER Score Qualificationg
X
Modified ATRQ
X
HAMD-17
X
X
X
YMRS
X
X
X
MADRS
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
CGI-I
X
X
X
X


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Study Period
Screening
Baseline
Double-blind Treatment
Safety 
Follow-up
Visit
1
2
3
4
5
6/ET
7
Study Week
Up to -2 k
0
1
2
4
6a,b
10
Study Day
Up to -14k
1
8
15
29
43
71
Visit Windows 
(within 14 
days of start 
of screening 
procedures)k
± 3 Days
± 3 Days
± 3 Days
± 3 Days
± 3 Days
HAM-A
X
X
X
SF-12
X
X
BARS/AIMS/SAS
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
Drug Return and Compliance
X
X
X
X
ADT Compliance
X
X
X
X
X
Pharmacogenetic Consenth
X
X
Pharmacogenetic Samplei
X
Pharmacokinetic Samplej
X
X
X
Note: After completion of Visit 6/ET, patients will be treated at the discretion of the investigator or designee.
ADT = antidepressant therapy; AIMS = Abnormal Involuntary Movement Scale; ATRQ = Antidepressant Treatment Response Questionnaire; BARS = Barnes 
Akathisia Rating Scale; CGI-I = Clinical Global Impressions–Improvement; CGI-S = Clinical Global Impressions–Severity; C-SSRS = Columbia–Suicide 
Severity Rating Scale; ET = early termination; HAM-A = Hamilton Anxiety Rating Scale; HAMD-17 = Hamilton Depression Rating Scale–17 items;
IP = investigational product; MADRS = Montgomery-Åsberg Depression Rating Scale; SAS = Simpson-Angus Scale; SF-12 = Short Form-12 v2 Health Survey; 
YMRS = Young Mania Rating Scale.
a Performed for all patients, including those prematurely discontinued after randomization (Visit 2).
b 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 Verified Clinical Trials database check to be performed, where applicable.
d Clinical laboratory tests include hematology, serum chemistry, urinalysis (including urine myoglobin 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), as well as serum pregnancy test in women of 
childbearing potential.
e Urine drug screen, blood alcohol concentration (by Breathalyzer), and serum pregnancy test can be repeated at random at request of investigator.
f Height will be measured only at Visit 1 (Screening). Waist circumference will be measured at Visits 2 and 6/ET.


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g SAFER/remote telephone interview will be scheduled and implemented before Visit 2 (Baseline) for patients who meet the screening criteria at Visit 1. The 
patient’s SAFER evaluation score should be reviewed before Visit 2 to confirm eligibility.
h Pharmacogenetic consent may be obtained at any time between Visit 1 (Screening) and Visit 6 (Week 6).
i Pharmacogenetic sample (1 per patient for the entire study) may be obtained from randomized patients at any time between Visit 2 (Baseline) and Visit 6 
(Week 6).
j Can be taken at any time during visits 4, 5 and 6/ET.
k May be up to an additional 7 days (up to 21 days) if needed with Sponsor approval.


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1
Background and Clinical Rationale
Major depressive disorder (MDD) is a highly disabling, serious condition that is associated 
with significant morbidity and mortality. MDD manifests as a major depressive episode 
(which may be singular or recurrent) in which the affected individual experiences 
1) depressed mood, or 2) loss of interest or pleasure (as well as other symptoms) for most of 
the day, nearly every day, for at least 2 weeks. MDD affects approximately 14.8 million 
American adults, or about 6.7% of the US population 18 years of age and older, in a given 
year (Kessler et al, 2005). Worldwide, about 15% of the adult population is at lifetime risk of 
developing MDD (Kessler et al, 1994).
Depression may cause serious, long-lasting symptoms and often disrupts a person’s ability to 
perform routine tasks. According to the World Health Organization, depression is one of the 
leading causes of disability, measured as years lived with disability, in the world today 
among persons age 5 years and older and is the fourth most important contributor to the 
global burden of disease, measured as disability-adjusted life years (Mathers and Loncar, 
2006). In 2010, mental and substance use disorders accounted for nearly 184 million 
disability-adjusted life years worldwide; depressive disorders accounted for 40.5% of this 
total burden (Whiteford et al, 2013). The total economic burden of treating depression in the 
United States was $83.1 billion, with workplace costs, including missed days and lack of 
productivity due to illness, accounting for most of the total economic burden (62%). Other 
economic burdens in 2000 included $26.1 billion (31%) for treatment costs and $5.4 billion 
(7%) for suicide-related costs (Greenberg et al, 2003).
MDD is a leading cause of disability in the United States (Murray et al, 2013). Moreover,
MDD is known to be a significant risk factor for suicide and ischemic heart disease, as it
accounted for 16 million of the disability-adjusted life years associated with suicide and 
4 million of the disability-adjusted life years associated with ischemic heart disease. 
Research has shown that untreated depression has both a functional (social and work role) as 
well as a neuroanatomical (hippocampal shrinkage) effect on the patient (Videbech and
Ravnkilde, 2004). Given the disease burden and link to suicidality as well as increased 
mortality with other comorbid conditions, MDD is a serious and life-threatening condition 
that is a leading cause of disability in the world.
Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors in 
Major Depressive Disorder
Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors 
currently represent the first line of treatment of depression in the United States. 


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Unfortunately, a large number of patients do not experience therapeutic benefit from these 
first-line agents (Rosenzweig-Lipson et al, 2007). Lack of sufficient response to adequate 
treatment remains a critical problem in the management of patients with MDD. Up to two 
thirds of patients treated with first-line antidepressant monotherapy do not reach full 
remission, and as many as a third become treatment resistant (Fava and Davidson, 1996; 
Trivedi et al, 2006). Not achieving remission has been shown to be predictive of poorer 
psychosocial functioning, higher rates of relapse, and higher rates of rehospitalization 
(McIntyre and O’Donovan, 2004). The results of the STAR*D study suggest that with 
successive failures of treatment, patients are less and less likely to respond to subsequent 
treatment, and those who do respond are more likely to relapse (Rush et al, 2006). Present 
strategies available to treat patients who do not respond to first-line antidepressant 
monotherapy include switching of antidepressant (either within or between classes); 
combination therapy in which multiple antidepressants are used simultaneously; 
augmentation of ongoing antidepressant monotherapy with adjunctive use of drugs such as 
mood stabilizers or atypical antipsychotics (Boland and Keller, 2006); and the use of 
nonpharmacologic treatments including psychotherapy and phototherapy, vagus nerve 
stimulation, transcranial magnetic stimulation, and electroconvulsive therapy.
Atypical Antipsychotics as Adjunctive Therapy in Major Depressive Disorder
The drugs currently approved for use as adjunctive therapy to antidepressants for the 
treatment of MDD—namely, the atypical antipsychotics—are Abilify® (aripiprazole; Abilify®
Package Insert, 2017), Seroquel XR® (quetiapine fumarate; Seroquel XR® Package Insert, 
2017), and Rexulti® (brexpiprazole; Rexulti® Package Insert, 2018). Abilify (aripiprazole) 
was approved in 2007 for adjunctive treatment in adult patients meeting Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, criteria for MDD who had had an 
inadequate response to prior antidepressant therapy (ADT). Aripiprazole and brexpiprazole 
are both dopamine partial agonists like cariprazine. Both have shown efficacy in the 
treatment of depression as an adjunctive treatment to ADT. Seroquel XR was approved in 
2009 for adjunctive treatment in adult patients meeting Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition, criteria for MDD. Quetiapine is an atypical antipsychotic 
with relatively high affinity for D2 and 5-HT2a receptors and an active metabolite that has 
inhibitory affects at the norepinephrine transporter. Olanzapine in combination with 
fluoxetine has been shown to be effective in the treatment of treatment-resistant depression 
and is currently marketed for that indication as Symbyax® (Symbyax® Package Insert).


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Cariprazine is an orally active and potent partial agonist at central dopamine D3/D2 and 
serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors developed by 
Gedeon Richter PLC and Allergan Sales, LLC. 
On 17 September 2015, cariprazine (Vraylar®) was approved by the US FDA for the 
treatment of schizophrenia (1.5 mg to 6 mg/day) and for the acute treatment of manic or 
mixed episodes associated with bipolar I disorder in adults (3 mg to 6 mg/day) (Vraylar®
Package Insert 2017). On 13 July 2017, Allergan’s development partner, Gedeon Richter, 
was granted marketing authorization in the European Union for cariprazine (Reagila®) 
(Reagila® Package Insert 2017) for the treatment of schizophrenia in adult patients (1.5 to 6
mg/day). 
Cariprazine has also demonstrated efficacy in the treatment of bipolar depression in three 
studies (RGH-MD-53, RGH-MD-54 and RGH-MD-56). Cariprazine doses of 1.5 and 3 mg 
have demonstrated efficacy in the treatment of bipolar depression. 
The mechanism of action of cariprazine in schizophrenia and bipolar I disorder has not been 
fully elucidated. However, the efficacy of cariprazine could be mediated through a 
combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A
receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms 2 major 
metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that 
have in vitro receptor binding profiles similar to the parent drug. 
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 than 
aripiprazole, and the degree of its apparent partial agonist activity is greater than 
aripiprazole’s. 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.


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2
Study Objectives and Clinical Hypotheses 
2.1
Study Objective
The objective of this study is to evaluate the efficacy, safety, and tolerability of cariprazine 
1.5 mg/day and 3 mg/day compared with placebo as an adjunctive treatment to ADT in 
patients with MDD who have had an inadequate response to antidepressants alone.
2.2
Clinical Hypotheses
In the treatment of patients with MDD who have had an inadequate response to ADT alone, 
cariprazine as an adjunctive treatment to ADT is safe and more effective than placebo as an 
adjunctive treatment to ADT.
3
Study Design
This is a global, multicenter, randomized, double-blind (DB), placebo-controlled, 
parallel-group, fixed-dose study comparing cariprazine 1.5 mg/day and cariprazine 3 mg/day 
with placebo as an adjunctive treatment to ongoing ADT in outpatients with a diagnosis of 
MDD (via the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
[DSM-5]) who have had an inadequate response to ADT in the current episode as measured 
by the modified Antidepressant Treatment Response Questionnaire (ATRQ). The study 
schema is presented in Figure 1.
Dose Selection and Rationale: Cariprazine has been evaluated as an adjunctive treatment to 
ADT in three flexibly-dosed clinical trials (RGH-MD-71, RGH-MD-72, and RGH-MD-75) 
in patients who have had an inadequate response to ADT alone. In those trials, the dose of 
cariprazine ranged from 0.1 mg to 4.5 mg. In one trial (RGH-MD-75), cariprazine 2 mg to 
4.5 mg + ADT was found to be superior to placebo + ADT, as measured by the change from 
baseline to Week 6 on the MADRS total score. In this patient population, cariprazine doses 
lower than 2 mg did not demonstrate efficacy as an adjunctive treatment to ADT. However, in 
3 monotherapy fixed-dose trials conducted in patients with depressive episodes associated 
with bipolar I disorder (RGH-MD-53, RGH-MD-54, and RGH-MD-56) cariprazine 1.5 mg 
was shown to be superior to placebo as a monotherapy treatment of depression. Cariprazine 
1.5 and 3 mg/day have both demonstrated superior efficacy in the monotherapy treatment of 
bipolar depression.
The bipolar depression studies utilized a different titration schedule than previously 
employed for bipolar mania. This alternate dosing regimen and lower dose contributed to 


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improvements in tolerability. In the phase III bipolar depression program, all patients were 
started on cariprazine 1.5 mg. Patients assigned to 1.5 mg remained on dose for the 
remainder of the study, whereas, patients assigned to cariprazine 3 mg remained on 
cariprazine 1.5mg for 14 days before being uptitrated to 3 mg for the remainder of the study. 
Accordingly, based on the above-mentioned studies in MDD and bipolar depression, the 
doses for investigation in Study 3111-302-001 will be 1.5 mg/day and 3 mg/day as an 
adjunctive treatment to ADT.
Another area to consider is dopamine D2/D3 receptor occupancy. Cariprazine 1.5 mg/day D2 
occupancy is 59% while its D3 occupancy is 83%. At 3 mg/day, D2 occupancy for 
cariprazine is 72% and D3 is 90% (Study RGH-PK-15). While no specific occupancy data 
are available to guide a dosing decision for adjunctive use of an antipsychotic agent with 
antidepressants, we do know that 2 other dopamine partial agonists with approved indications 
as an adjunctive treatment to antidepressants (aripiprazole 5 to 15 mg/day and brexpiprazole 
2 mg/day to 4 mg/day) have rates of D2 receptor occupancy ranging from 60% to 90% 
(aripiprazole 80% to 90%; brexpiprazole 60% to 67%). The low D2 occupancy of cariprazine 
at 1.5 mg/day and 3 mg/day may provide enough receptor blockade to affect mood without 
adversely affecting movement. The occupancy of D3 and 5HT1A receptors may also play an 
important role in the antidepressant efficacy of cariprazine.
Study Duration: The study will consist of up to 14 days of screening (with up to an 
additional 7 days if needed with Sponsor approval) and washout of prohibited medications 
followed by 6 weeks of DB treatment followed by a 4-week safety follow-up.
Screening/Washout Period: Patients with MDD with inadequate response to ongoing ADT 
in the current episode will undergo a screening period where consent, eligibility assessment, 
and withdrawal of prohibited medications will occur for up to 14 days (with up to an 
additional 7 days if needed with Sponsor approval). During the screening period, the patients 
will continue to take the ADT at the same dose to which they are having an inadequate 
response. Patients who are taking more than one antidepressant at Screening, regardless of 
the indication, will need to discontinue all other antidepressants prior to Baseline (Visit 2). 
The length and timing of the washout of prior psychiatric medications during the 14 days 
allotted for the screening period is at the discretion of the investigator (with up to an 
additional 7 days if needed with Sponsor approval). Prior medications should be gradually 
withdrawn such that the washout is completed by Baseline (Visit 2). Please note that during 
the washout period psychotropic medications other than those listed as rescue (Section 4.5.3) 
may not be newly initiated or reinitiated.


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Randomization/DB Treatment Period: 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 
1.5 mg/day + ADT or 3 mg/day + ADT, or placebo + ADT. Investigational product (IP) will 
be administered orally once daily for 6 weeks.
Dosage and Dosing Regimen: Investigational product (cariprazine or placebo) in the form 
of capsules packaged in blister packs will be provided by the Sponsor. No investigational 
product will be administered during the screening/washout period; patients will continue on 
the ADT they were on at Screening. During the DB treatment period (6 weeks), patients will 
take 1 capsule orally per day in addition to their ongoing ADT. Patients in the 1.5 mg/day + 
ADT arm will take 1.5 mg + ADT starting at Visit 2 (Week 0). Patients in the 3 mg/day + 
ADT arm will take 1.5 mg + ADT starting at Visit 2 (Week 0) for 2 weeks and then 3 mg/day 
+ ADT starting at Visit 4 (Week 2). Patients will be supplied with identically appearing 
capsules of either cariprazine 1.5 mg, cariprazine 3 mg, or placebo. After completion of the 
DB treatment period, patients will continue as outpatients during the safety follow-up period 
and will receive treatment as usual at the discretion of the investigator or designee; no 
investigational product will be administered.
4
Study Population and Entry Criteria
4.1
Number of Patients
The study will screen approximately 1700 patients to randomize approximately 750 patients 
in a 1:1:1 ratio to cariprazine 1.5 mg, cariprazine 3 mg, and placebo groups. In the event that 
screen failure rates are higher than projected, enrollment will continue until approximately 
250 patients per treatment arm are randomized. 
When the randomization target has been met, patients who have been screened, but who are 
not yet randomized, will be allowed to continue in the study until they fail to meet 
randomization criteria, prematurely discontinue, or complete the study.
4.2
Study Population Characteristics
The study population will include patients meeting criteria for MDD with a current major 
depressive episode of at least 8 weeks to less than 24 months in duration and an inadequate 
response to ongoing ADT in the current episode.
The diagnosis will be based upon Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria (American Psychiatric Association, 2013), approached 


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through a structured clinical interview (Structured Clinical Interview for DSM-5 [SCID-5]),
and the ADT inadequate response will be determined using the modified ATRQ.
4.3
Inclusion Criteria
The following are requirements for entry into the study:
1. Written informed consent has been obtained
2. 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])
3. Patient is male or female 18 to 65 years of age, inclusive, at the time of consent
4. Patient must be an outpatient at the time of Visit 1 (Screening)
5. Patient meets the DSM-5 criteria for MDD based on SCID-5, with a current major 
depressive episode of at least 8 weeks to less than 24 months in duration at 
Visit 1/Screening. A diagnosis of MDD with psychotic features will be acceptable
6. Diagnosis of MDD confirmed through a formal adjudication process (see Section 6.1)
7. Patient demonstrates ability to follow study instructions and likely to complete all 
required visits
8. In the current depressive episode, patient must have an inadequate response (< 50% 
improvement) to 1 to 3 antidepressants of adequate dose and adequate duration, as 
measured by the modified ATRQ. Adequate dose is defined as a dose above the minimum 
labeled dose (per package insert). Adequate duration is defined as continuous ADT 
treatment for at least 6 weeks, with a minimum of 3 of 6 weeks above the minimal dose. 
9. Only one antidepressant (of sufficient dose per package insert and taken for at least 
6 weeks) will be allowed at randomization and patients must agree to continue taking the 
same ADT dosing regimen through completion of Visit 6/ET. Patients who are taking 
more than one antidepressant at Screening, regardless of the indication, will need to 
discontinue all other antidepressants prior to Baseline (Visit 2)
10. Patient must have a minimum score of 22 on the rater-administered Hamilton Depression 
Rating Scale–17 items (HAMD-17) at both Screening (Visit 1) and Baseline (Visit 2)


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11. Patient has a score of 2 or higher on Item 1 of the HAMD-17 rating scale at Visits 1 and 2
12. Patient has normal physical examination findings, clinical laboratory test results, and
electrocardiogram (ECG) results from Screening (Visit 1), or abnormal results that are
judged to be clinically insignificant by the investigator
13. 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 4.5.1.1
14. Women of childbearing potential (only) must have a negative qualitative serum β-human
chorionic gonadotropin pregnancy test prior to Visit 2
4.4 Exclusion Criteria
The following are criteria for exclusion from participating in the study:
1. Diagnosis of any current psychiatric diagnosis other than MDD (including those with 
current intellectual development disability) with the exception of specific phobias
2. History of manic or hypomanic episodes
3. Patients with a YMRS score ≥ 12 
4. Patient has a history of meeting DSM-5 diagnosis for any substance-related disorders 
(ie, use disorders except caffeine- and tobacco-related) within the 3 months before Visit 1 
(Screening)
5. Patient had a positive result at Visit 1 (Screening) from the urine drug screen (UDS) for 
any prohibited drugs. Exception: patients with a positive UDS at Visit 1 for opiates, 
cannabinoids, amphetamines, barbiturates, or benzodiazepines may be allowed in the 
study provided:
a. The drug was used for a legitimate medical purpose;
b. The drug can be discontinued prior to further 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/day or its benzodiazepine equivalent] for at 
least 1 month prior to Visit 1 (Screening) or if used as rescue during washout); 
and 


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c. A repeat UDS must be performed prior to Visit 2 and must be negative, except 
benzodiazepine use as described in 4(b) and Section 4.5.3
6. 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 prior to Visit 1 (Screening)
b. Patient had a score of 4 or greater on Item 10 of the MADRS at Visit 1
(Screening) or Visit 2 (Baseline)
c. Patient had a score of 3 or greater on Item 3 of the HAMD-17 at Visit 1 
(Screening) or Visit 2 (Baseline)
d. Patient is at significant risk, as judged by the investigator, based on the 
psychiatric interview or information collected in the Columbia–Suicide Severity 
Rating Scale (C-SSRS) at Visit 1 (Screening) or Visit 2 (Baseline)
7. Patient is at imminent risk of injuring self or others or causing significant damage to
property, as judged by the investigator
8. Patient has a history of intolerance or hypersensitivity to cariprazine or other drugs of the 
same class or to rescue medications
Treatment-Related Criteria:
9. Per ATRQ, patient failed to respond to > 3 trials of ADTs given at an adequate dose (as 
defined by the ADT package insert) and duration of ≥6 weeks during the present episode
10. Patient was treated with monoamine oxidase inhibitors in the current episode
11. Patient has history of treatment with clozapine > 50 mg/day or any depot antipsychotic at 
any time prior to Visit 1 (Screening)
12. Patient has history of treatment with esketamine, electroconvulsive therapy, vagus nerve 
stimulation, transcranial magnetic stimulation, or any experimental central nervous 
system treatment during the current episode or in the 6 months before Visit 1 (whichever 
is longer) or previous lack of response to treatment with esketamine, electroconvulsive 
therapy, vagus nerve stimulation, or transcranial magnetic stimulation


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13. Patients who require concomitant treatment with moderate or strong cytochrome P450 
3A4 (CYP3A4) inhibitors or any CYP3A4 inducers. If applicable, these treatments must 
be discontinued at least 10 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 Sections 4.5.2 and 4.5.3)
15. Participation in any clinical study, involving experimental or investigational drugs or 
devices during the study or within 3 months before Visit 1 (or at least 5 half-lives of the 
drug, whichever is longer)
16. Initiation or termination of psychotherapy for depression within the 3 months preceding 
Visit 1 (Screening), or plans to initiate, terminate, or change such therapy during the
course of the study 
Other Medical Criteria:
17. Female patients who are pregnant, planning to become pregnant during the course of the 
study, or are currently lactating
18. Any concurrent medical condition that, in the judgment of the investigator, might 
interfere with the conduct of the study, confound the interpretation of the study results, or 
endanger the patient’s well-being
19. Any cardiovascular disease that is clinically significant, unstable, or decompensated 
including history of congenital QTc prolongation or QTc prolongation (screening ECG 
with QTcF ≥ 450 msec for men and QTcF ≥ 470 msec for women)
20. Any disease (eg, hypertension) that is clinically unstable or decompensated, based on the 
investigator’s judgment
21. Newly diagnosed or clinically uncontrolled hypo- or hyperthyroidism as evident on 
clinical laboratory test results at Visit 1 (Screening). Patients diagnosed previously with 
hypo- or hyperthyroidism have to be stabilized on appropriate pharmacotherapy with no 
change in dosage for at least 1 month before Visit 1 (Screening)
22. Psychiatric symptoms possibly secondary to any other general medical condition


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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 to 
seizure
24. Known human immunodeficiency virus infection
25. Positive hepatitis C antibody on screening, with the exception of patients for whom the 
reflex HCV RNA titer test is negative
26. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody
immunoglobulin M on screening
27. Screening liver enzyme test (aspartate aminotransferase [AST] and/or alanine
aminotransferase [ALT]) results > 2 times the upper limit of normal (ULN), or bilirubin 
> 1 time the ULN
28. Absolute neutrophil count (ANC) < 1000 per mm3 at Visit 1 (Screening)
29. Blood alcohol concentration ≥ 0.02 g/dL at Visit 1 (Screening) as measured by 
breathalyzer
30. Hemoglobin A1c > 8% at Visit 1 (Screening)
31. History of tardive dyskinesia, serotonin syndrome, or neuroleptic malignant syndrome
32. Known history of cataracts or retinal detachment 
33. History of amiodarone or systemic corticosteroid use for ≥ 3 consecutive months in the 
past year
Other Criteria:
34. Patient is an employee, or immediate relative of an employee, of Allergan, any of its 
affiliates or partners, or the study center
35. Patient demonstrates an inability to speak, read, or understand the local language 
sufficiently to understand the nature of the study, to provide written informed consent, or 
to allow the completion of all study assessments
36. Patient is unable or unlikely to comply with the study protocol or unsuitable for any other
reason, including other conditions that might indicate that the patient is unsuitable for the 
study as judged by the investigator


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Eligibility Criteria to be Assessed at Visit 2
37. Not meeting the Visit 1 (Screening) inclusion criteria or meeting any of the Visit 1 
exclusion criteria
4.5
Permissible and Prohibited Medications/Treatments
4.5.1
Permissible Medications/Treatments
Treatment considered necessary for the patient’s welfare may be given at the discretion of the
Investigator. Prohibited and allowed escape medications are detailed in Sections 4.5.2 and
4.5.3, respectively. If the permissibility of a specific medication/treatment is in question, 
please contact the Allergan Medical Monitor.
4.5.1.1
Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods
For the 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: postbilateral vasectomy, barrier 
contraception, or sexual abstinence.
The investigator and each patient will determine the appropriate method of contraception for 
the patient during his or her participation in the study. The investigator must discuss with the 
patient the need to continue contraceptive use for 12 weeks after the last dose of study drug.
If a female patient 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 


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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 investigator must document the outcome of the pregnancy and provide a 
copy of the documentation to Allergan.
4.5.2
Prohibited Medications/Treatments
Medications that are moderate or strong CYP3A4 inhibitors or are CYP3A4 inducers, with 
the exception of the concomitant study ADT, 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 10 days prior to the start of treatment with DB IP. Patients who 
cannot or should not be taken off the CYP3A4 inhibitor or inducer should not be enrolled. If 
a patient requires concomitant treatment with either a moderate or strong CYP3A4 inhibitor 
or a CYP3A4 inducer at any time during the study, he or 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 inhibitors) except the ongoing ADT

Stimulants

Anticonvulsants/mood stabilizers

Sedatives/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 patient as the primary consideration. When possible, Allergan should be notified before 
the prohibited medication/treatment is administered.


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Patients will be asked to limit drinking alcohol and abstain from using illicit drugs during the 
study.
Patients who have been taking stable doses of benzodiazepines (lorazepam up to 2 mg/day or
equivalent, with the exception of phenazepam) for at least 1 month before screening can 
continue use.
4.5.3
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/day)

Zolpidem extended release (maximum of 12.5 mg/day)

Zaleplon (maximum of 20 mg/day)

Eszopiclone (maximum of 3.0 mg/day)

Zopiclone (maximum of 7.5 mg/day)

Chloral hydrate (maximum of 1000 mg/day) may be used acutely with approval from the 
Allergan Medical Monitor

Suvorexant (maximum of 20 mg/day)
These medications for insomnia 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 extrapyramidal symptoms (EPS) or akathisia, the following will be allowed but should 
not be prescribed prophylactically:
For EPS or akathisia that emerges or worsens 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


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only exception to administering the EPS scales before dispensing rescue medication is
medical urgency (eg, dystonia, severe akathisia, etc.).

Benztropine 

Biperiden

Diphenhydramine

Trihexyphenidyl

Propranolol. Daily dose of propranolol depends on heart rate and blood pressure (BP).
The need for continued use of these medications should be regularly assessed by the 
investigator and documented appropriately.
Injectable agents are not allowed, except for the treatment of an acute dystonic reaction if
deemed necessary.
For agitation, restlessness, and hostility:
Episodic use of lorazepam up to 2 mg/day (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.


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5.3
Methods for Masking/Blinding
During the DB period, all IP (cariprazine or placebo) will be provided in identical blister 
cards to maintain masking throughout the study. All patients will be instructed to take 
1 capsule of IP once daily at approximately the same time each day, in addition to the 
background ADT.
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 via an automated interactive web response system (IWRS) that 
will serve as the patient identification number 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 1.5 mg/day or 3 mg/day, or placebo. Stratified 
randomization will be used for this study with strata defined by two factors: ADT failure 
category (one ADT failure, more than one ADT failure) and country. 
An IWRS will be used for patient randomization and to manage all aspects of IP during the 
study. Allergan Statistical Programming (randomization programmer) will prepare the 
randomization codes.
IP will be labeled with medication kit numbers. The IWRS will provide the site with the
specific medication kit number(s) for each randomized patient during the DB treatment 
period (cariprazine 1.5 mg/day and 3 mg/day, 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
No IP will be administered during the screening/washout period or the safety follow-up 
period. Patients will continue on their background ADT during the screening/washout period.
During the safety follow-up period, the investigator may initiate alternative treatment as 
clinically necessary. 
During the DB treatment period (6 weeks), patients will take 1 capsule of IP, orally, per day
in addition to their ongoing ADT as shown in Table 2.


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Table 2
Treatment Regimen and Dosing
Drug/Dose
Investigational Product 
Frequency
Route of Administration
Double-Blind Treatment Period (Visit 2 through Visit 6)
Placebo
Once daily
Oral (capsule)
Cariprazine 1.5 mg
Once daily
Oral (capsule)
Cariprazine 3 mg (1.5 mg/day for 2 weeks, 
starting at Visit 2 [Baseline]; 3 mg/day from 
Visit 4 [Week 2] through Visit 6 [Week 6])
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.
5.6
Treatment Compliance
5.6.1
IP Compliance
IP compliance will be closely monitored by counting the number of capsules dispensed and 
returned, and through patient interviews at study visits. 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, measured by capsule counts and 
patient interviews), the Investigator should evaluate whether the patient should be 
discontinued from the study. 
The study centers will monitor patient compliance at every visit and maintain an accurate 
drug disposition record which specifies the amount of IP administered to each patient and the 
date of administration. The site’s drug disposition record will be considered source 
documentation. 
Any patient who misses ≥ 4 consecutive doses of IP and/or ongoing ADT must be 
discontinued from the study. 
5.6.2
ADT Compliance
Background ADT medication compliance will also be closely monitored. Patients will 
continue on the same antidepressant and dose of ADT they were on at baseline. Patients 
should be questioned to determine if there were any missed doses or changes in dose between 
visits. Every effort should be made to have patients bring their background ADT to study 


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Visits 2, 3, 4, 5, and 6 for verification of patient-reported compliance by pill/capsule count 
(to the extent possible) and patient interviews at study visits. Patients who take less ADT or 
more ADT than the prescribed regimen, must be counselled on the importance of taking ADT 
as instructed. If a patient demonstrates poor compliance with their ongoing ADT during the 
study (< 80% or > 120% overall, measured by pill/capsule count and patient interview), the 
Investigator should evaluate whether the patient should be discontinued from the study. Any 
patient who misses ≥ 4 consecutive doses of IP and/or ongoing ADT must be discontinued 
from the study. Patients, who in the current episode, have had an inadequate response to at 
least 1 ADT given at a dose above the minimum and for at least 6 weeks, can be enrolled. 
5.7
Storage of Study Medications/Treatments
IP (cariprazine and placebo) will be packaged in blister cards and provided by Allergan, and 
must be stored in an appropriate secure area (eg, a locked cabinet in a locked room) at room 
temperature (20°C to 25°C or 68°F to 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
6.1.1
The Structured Clinical Interview for DSM-5 (SCID-5)
The 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 an 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. 
6.1.2
SAFER Criteria Inventory
The SAFER criteria inventory (Targum et al, 2008) is a clinician-rated scale that is used to 
facilitate the identification of appropriate and valid patients for clinical trials. The scale will 
confirm that the identified patients have acute symptoms that reflect the current state of 
illness and that these symptoms can be assessed with the appropriate rating instruments. The 
scale will be administered to the patients remotely via telephone by clinicians from the 
Massachusetts General Hospital Clinical Trial Network and Institute (MGH CTNI) at Visit 1 
(Screening). In addition, the MGH CTNI SAFER raters will also remotely administer the 
HAMD-17 and the modified ATRQ. After the assessments are evaluated, MGH CTNI will 


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notify the study center, indicating whether the patient meets eligibility criteria to continue in 
the study. MGH CTNI will only perform the SAFER, HAMD-17, and modified ATRQ 
interviews at Visit 1 and only for patients who have already met the inclusion and exclusion 
criteria assessed at Visit 1. To ensure the highest quality and for patient comfort, these calls 
should not be conducted while the patient is on-site, unless approved by the Sponsor.
Study center staff will schedule the telephone assessment (SAFER interview) with raters 
from MGH CTNI. Patients who do not meet the SAFER criteria will be screen failed. The 
information collected by MGH CTNI will be copied and transmitted to the study centers to 
retain as source documentation. Sites will acknowledge receipt of the SAFER scale, 
HAMD-17 and modified ATRQ interview results via a check-box in an eCRF.
6.1.3
The Modified Antidepressant Treatment Response Questionnaire
The ATRQ (Fava 2003) is a clinician-administered questionnaire that will be used to 
determine whether the patient meets inclusion criteria for prior ADT treatment and response 
requirements. A modified ATRQ, completed by a clinician at the study site who has been 
certified in administration of the ATRQ, will be used to assess prior antidepressant exposure 
and response within the current depressive episode. The clinician will identify the 
antidepressants the patient had previously taken within the current episode; indicating the 
dose range and duration. The clinician will then select the level of response the patient had to 
the antidepressant which resulted in the greatest response.
The number of ADTs in the current episode to which the patient had an inadequate response 
will include any ADT with < 50% reduction in depressive symptoms if given at adequate 
doses (as defined by the ADT package insert; with at least 1 ADT having been escalated 
above the minimum dose) and with a duration of at least 6 weeks during the present episode. 
6.2
Efficacy Endpoints
6.2.1
Primary Efficacy
The primary efficacy parameter will be the change from baseline to Week 6 in the MADRS 
total score.
Assessment and ratings of the primary efficacy scale will be performed by a trained rater. 
Every effort should be made to have patients assessed by the same rater at each scheduled 
timepoint.


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6.2.1.1
Montgomery-Åsberg Depression Rating Scale
The MADRS (Montgomery and Åsberg, 1979) is a 10-item, clinician-rated scale that
evaluates the patient’s depressive symptomatology during the past week. Patients are rated 
on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, 
reduced sleep or appetite, difficulty in concentration, and lack of interest. Each item is scored 
on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting 
symptoms of maximum severity.
6.2.2
Additional Efficacy Variables
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 timepoint.
6.2.2.1
The Hamilton Anxiety Rating Scale
The Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1959) is a clinician-rated scale 
which consists of 14 items, each rated on a 5-point scale ranging from 0 (not present) to 
4 (very severe). The highest possible score is 56, which represents the most severe form of 
anxiety; the lowest possible score is 0, which represents an absence of anxiety. This 
instrument will be administered by an experienced rater meeting the training requirements 
and qualifications set by the Sponsor.
6.2.2.2
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 in 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 an investigator, 
subinvestigator or rater with extensive professional training and experience in assessing 
mental illness.
6.2.2.3
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
from 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. The 


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CGI-I will be administered by an investigator, subinvestigator or rater with extensive 
professional training and experience in assessing mental illness.
6.2.2.4
Hamilton Depression Rating Scale–17 Items
The HAMD-17 (Hamilton 1960; Hamilton 1967; Miller et al, 1985) is a clinician-rated, 
17-item scale used to rate the patient’s depressive state based on feelings of depression, guilt, 
suicidality, anxiety, agitation, level of insight, patterns of insomnia, loss of interest in work 
and other activities, weight loss, hypochondriasis, and degree of psychomotor retardation. It 
also can be used to identify genital and somatic symptoms. This instrument will be 
administered by an experienced rater meeting the training requirements and qualifications set 
by the Sponsor.
6.3
Health Outcome Measures
The 12-item Short Form (SF)-12v2 health survey, a shortened version of the 36-item Short 
Form (SF-36) survey, is a generic assessment of health-related quality of life from the 
patient’s perspective. It measures 8 concepts: physical functioning, role limitations due to 
physical health problems, bodily pain, general health, vitality (energy/fatigue), social 
functioning, role limitations due to emotional problems, and mental health (physiologic 
distress and physiologic well-being) (Ware et al, 1996). The 8 scales are aggregated into 
2 summary measures: the Physical Component Summary (PCS-12) and the Mental 
Component Summary (MCS-12) scores, which range from 0 to 100, with higher scores 
indicating better quality of life.
6.4
Pharmacokinetics Measures
Samples for determination of the plasma concentrations of cariprazine and its metabolites
DCAR and DDCAR will be collected at 3 timepoints during the study, Visit 4 (Week 2), 
Visit 5 (Week 4) and Visit 6 (Week 6). 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 
pharmacokinetic (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.


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6.5
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 6 (Week 6). Pharmacogenetic 
sampling (one sample per patient) can be conducted at any time point between Visit 2 
(Baseline) and Visit 6 (Week 6). Following consent, a single 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 studies conducted by Allergan. 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.
6.6
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, the schedule of visits and procedures.
6.6.1
Adverse Events
Subjective 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.
Treatment for an AE is entered as a concomitant medication on the AE CRF. For events noted 


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as SAEs, Allergan must be notified immediately to meet their reporting obligations to 
appropriate regulatory authorities (see Section 9.3).
6.6.2
Ocular Events of Special Interest 
The Sponsor is required to inform worldwide regulatory authorities of ocular events of 
special interest. Therefore, the Sponsor must be notified immediately regarding any ocular 
adverse events of special interest that occur after informed consent is obtained.
The following are considered ocular AEs of special interest, whether serious or nonserious,
and require immediate notification:

cataract, lens, or lenticular abnormality or change, opacity, opacification or opalescence

blindness, night blindness, visual acuity or vision decrease, abnormality or change, visual 
acuity test abnormality or change

retinal, macular, or optic nerve degeneration, abnormality or change; retinal pigment 
epithelium detachment, abnormality or change

color vision decrease, abnormality or change
Within 24 hours of learning of any ocular event of special interest, the study site personnel 
must report the event, whether serious or nonserious, on the SAE/AESI form.
All ocular events of special interest are to be followed by the study staff until resolution or 
until the ocular event of special interest is deemed stable. The Sponsor may contact the study 
site to solicit additional information or follow up on the event.
6.6.3
Clinical Laboratory Determinations
Clinical laboratory tests will be performed according to the schedule in Table 3. Patients will
be asked to fast for at least 10 hours prior to any visit requiring clinical laboratory testing.


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Table 3
Schedule of Clinical Laboratory Tests
Category
Visit Number(s)
Parameter(s)
Hepatitis Serology
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. Reflex 
HCV RNA titer test will be performed for 
all Hepatitis C virus antibody positive or 
reactive results.
Screening Hemoglobin A1c
1
Hemoglobin A1c
Hematology
1 and Visit 6/ET
Absolute and differential white blood cell 
count, Absolute Neutrophil Count (ANC), 
erythrocyte count, hemoglobin, hematocrit, 
platelet count, and red blood cell indices 
(mean corpuscular volume, mean 
corpuscular hemoglobin, and mean 
corpuscular hemoglobin concentration)
Chemistry
1 and Visit 6/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 drug screen
1 
Benzoylecgonine (cocaine), barbiturates, 
amphetamines, benzodiazepines, 
cannabinoids, opiates, methadone, 
phencyclidine
Urine myoglobin
1 and Visit 6/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 and Visit 6/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
Blood alcohol concentration
1 
Blood alcohol concentration by 
Breathalyzer
Serum β-hCG (women of
childbearing potential only)
1, Visit 6/ET, and Visit 7 
Safety Follow-up Visit
—
Repeat urine drug screen, 
blood alcohol level, and 
serum pregnancy test
At random upon request 
from the Investigator
—


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ET = early termination; AST = aspartate aminotransferase; ALT = alanine aminotransferase; β-hCG = β-human 
chorionic gonadotropin; HCV = Hepatitis C virus; RNA = ribonucleic acid; T3 = triiodothyronine; 
T4 = thyroxine; TSH = thyroid-stimulating hormone.
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 (Screening) only.
Waist circumference will be measured at Visits 2 and 6/early termination (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 Visit 1 (Screening) and Visit 6 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. Sites will transmit all ECGs to the ECG central reader. 


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6.6.6
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.
6.6.6.1
Extrapyramidal Symptoms Scales
The following 3 scales will be used to systematically assess extrapyramidal side effects at
Visits 2, 3, 4, 5, 6, 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. 
Barnes Akathisia Rating Scale
The BARS (Barnes 1989) is a 4-item rating scale used to assess drug-induced akathisia. The
scale comprises 3 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 item rated on a 6-point scale (absent [0] to severe akathisia [5]).
Simpson-Angus Scale
The SAS (Simpson and Angus, 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.
6.6.6.2
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 


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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, 
including a 12-month lookback. At all other visits the C-SSRS will be completed for ideation 
and behavior since the previous visit.
The C-SSRS must be completed by an investigator, subinvestigator or trained rater, all of 
whom must have extensive professional training.
6.6.6.3
Young Mania Rating Scale
The YMRS (Young et al, 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.
Possible scores range from 0 to 60. 
This scale will be administered by a trained rater with expertise in evaluating manic patients. 
6.7
Summary of Methods of Data Collection
An IWRS will be used to screen patients, 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 and central laboratory vendor will be used for the analysis of all 
ECGs and blood and urine samples. ECG and laboratory data will be transferred to Allergan 
or its designee on a periodic basis throughout the study.


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7
Statistical Procedures
7.1
Analysis Populations
7.1.1
Patient Populations
Four populations will be considered in the statistical analysis of the study.
7.1.1.1
Screened Population
The screened population will consist of all screened patients who sign informed consent.
7.1.1.2
Randomized Population
The randomized population will consist of all patients in the screened population who were 
randomized to a treatment group.
7.1.1.3
Safety Population
The safety population will consist of all patients in the randomized population who took at 
least 1 dose of DB IP.
7.1.1.4
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population will consist of all randomized patients with 
≥1 postbaseline assessment of the MADRS total score.
7.2
Collection and Derivation of Primary and Secondary Efficacy
Assessments
7.2.1
Primary Efficacy Variable 
The primary efficacy parameter is the change from baseline to Week 6 in the MADRS total 
score.
7.2.2
Additional Efficacy Variables
Additional efficacy parameters will include the following at postbaseline visits described in 
Table 1:


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
Change from baseline in the CGI-S score

CGI-I score

CGI-I response (CGI-I score ≤ 2)

MADRS response (≥ 50% reduction from baseline in MADRS total score)

MADRS remission (MADRS total score ≤ 10)

Change from baseline in the HAMD-17 total score

Change from baseline in the HAM-A total score
7.3
Hypothesis and Methods of Analysis
All efficacy analyses will be based on the mITT population. Baseline for efficacy is defined 
as the last nonmissing efficacy assessment before the date of the first dose of DB IP. All 
statistical hypothesis tests will be 2-sided 5%-level of significance tests for main effects. All 
confidence intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise.
To compare with historic studies, some analyses based on the imputed data using the 
last-observation-carried-forward (LOCF) approach, will be presented for all efficacy 
parameters. Only the postbaseline total score of a parameter will be imputed; individual item 
scores will not be carried forward. The baseline value will be carried forward only for the 
intermittent missing values immediately after baseline. If all the postbaseline values are 
missing, the baseline value will not be carried forward.
7.3.1
Primary Efficacy Analyses
The primary estimand is provided below through specification of the population, the variable, 
the handling of intercurrent events, and the population-level summary. 
Population
The target population are patients with MDD who have had an inadequate response to 
antidepressant therapy in the current episode and who satisfy the inclusion and exclusion 
criteria as specified in the protocol.
The analysis population is defined to be the mITT population consisting of all randomized 
patients with ≥ 1 postbaseline assessment of the MADRS total score as specified in protocol 
Section 7.1.1.4.


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Variable
The variable is the same as the primary efficacy endpoint, which is the change from baseline 
to Week 6 in the MADRS total score.
Accounting of Intercurrent Events
Intercurrent events and their handling rules are described as follows:

Regardless of whether allowed rescue medications are taken or not, data are included 
in the analysis. Patients are still taking assigned drugs as specified in the protocol 
while taking allowed rescue medications. The clinical objective is to assess the 
efficacy of the treatment regardless of allowed rescue medication use. 

To evaluate the efficacy at Week 6 in the mITT population, patients are assumed to 
adhere to the assigned treatment for the duration of the study. As a result, data after 
the discontinuation from the study treatment due to all reasons will not be included in 
the primary analysis and they will be assumed as missing at random. 
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between each cariprazine group and placebo.
To address the primary hypotheses that each dose of cariprazine is superior to placebo in the 
reduction of MADRS total score after 6 weeks of treatment, the change from baseline in 
MADRS total score will be analyzed using a mixed-effects model for repeated measures 
(MMRM) with treatment group, country, ADT failure category, 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 to model the 
covariance of within-patient scores. The Kenward-Roger approximation (Kenward and
Roger, 1997) will be used to estimate denominator degrees of freedom. In the event of 
non-convergence of the model using unstructured covariance matrix, a structured covariance 
matrix will be used in combination with empirical variance estimate (ie, sandwich estimator) 
to address the potential mis-specified situation. The following sequence of alternative 
covariance structures (First-order antedependence [ANTE (1)], Toeplitz [TOEP], First-order 
autoregressive [AR(1)] and compound symmetry[CS]) will be considered in the MMRM 
until convergence.
The analysis will be performed based on all postbaseline scores using only the observed 
cases without imputation of missing values. The treatment difference in the primary endpoint 


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at Week 6 for each active treatment group versus placebo in the mITT population will be 
estimated and reported along with the corresponding 95% CI and the p-value.
The Hochberg procedure (Hochberg 1988) will be used to control the overall type I error rate 
at a 0.05 level (2-sided) for multiple comparisons of 2 active doses with placebo for the
primary endpoint. Statistical significance will be determined by comparing the adjusted 
p-values to α = 0.050.
The study will be considered positive if at least 1 dose arm of cariprazine is statistically 
superior to placebo for change from baseline in MADRS total score at Week 6 after 
multiplicity adjustment.
A sensitivity analysis using a pattern-mixture model based on non–future-dependent missing 
value restrictions (Kenward et al, 2003) will be performed to assess the robustness of the 
primary MMRM results to the possible violation of the missing-at-random assumption. The 
details of this sensitivity analyses are as follows:
The pattern for the pattern-mixture model will be defined by the patient’s last visit with an 
observed value. The observed MADRS total score at a visit is assumed to have a linear 
relationship with the patient’s prior measurements. The missing values will be imputed under 
the assumption that the distribution of a missing observation differs from the observed only 
by a shift parameter value Δ. The dataset with missing values imputed will be analyzed using 
an analysis-of-covariance (ANCOVA) model with treatment group, country, and ADT failure 
category, as factors and baseline MADRS total score as a covariate for between–treatment-
group comparison at Week 6. The imputation of missing values and the analysis will be 
performed multiple times, and the inference of this sensitivity analysis will be based on the 
combined estimates using the standard multiple imputation technique. The values for Δ will 
be selected as 0 to 6, inclusively. This range is selected because the mean reduction of 
MADRS score from baseline within a treatment group at Week 6 is likely to be within 
15 points (Bauer et al, 2009; El-Khalili et al, 2010), and a Δ value of 6 accounts for 40% of 
treatment efficacy.
The second sensitivity analysis will consider dropout reasons while imputing missing values 
after the discontinuation. Patients who discontinued due to lack of efficacy in the cariprazine 
arms are assumed to have no treatment effect after the discontinuation. These patients are 
assumed to copy the profile of placebo arm and missing values are imputed based on the 
distribution estimated from the placebo group under the MAR using copy-reference approach 
(Carpenter et al, 2013). The rest of missing values in the placebo arm and cariprazine arms 


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will be imputed using the observed data in their respective group under the MAR 
assumption.
Mean treatment difference (raw mean difference ± standard error) in change in primary 
endpoint between each cariprazine dose and placebo with missing values imputed using the 
LOCF approach will be plotted against country. In addition, summary statistics will be 
provided by center to examine the consistency of treatment effect across the study centers. 
The impact of dropouts on the efficacy outcomes will be explored graphically by plotting the 
time courses of mean changes by dropout reason.
Results of analyses from MMRM and from ANCOVA models will also be reported for each 
visit between baseline and Week 6. 
To compare with historic studies, the LOCF approach will be used with an ANCOVA model 
that has treatment group, country and ADT failure category as factors and the baseline value 
as the covariate.
7.3.2
Other Efficacy Analyses
Additional quantitative efficacy parameters will be analyzed in the following way:
Analysis of CGI-I score, change from baseline in HAMD-17 total score, change from 
baseline in HAM-A total score, and change from baseline in CGI-S will be performed using a 
similar MMRM to that used for the primary analysis. Baseline CGI-S score will be used as a 
covariate for the analysis of change in CGI-I score. In addition, these parameters will be 
analyzed using ANCOVA (with LOCF imputation) as used for the analysis of primary 
efficacy parameters.
Additional categorical efficacy parameters will be analyzed in the following way:
Rates for categorical parameters (response and remission) will be reported by treatment 
group and by visit; a logistic regression model (with LOCF imputation) will be used to model 
the probability of a response or the probability of a remission as a function of a treatment 
group and the corresponding baseline score (CGI-S for the analysis of the CGI-I response) as 
explanatory variables.


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7.3.3
Safety Analyses
The safety analysis will be performed using the safety population. The safety parameters will 
include AEs, clinical laboratory parameters, vital signs, ECG parameters, EPS scales, the 
C-SSRS and the YMRS. For each safety parameter, the last assessment made before the first 
dose of DB IP will be used as the baseline for all analyses of that safety parameter. The 
summarization will be by treatment group for both double-blind and safety follow-up 
periods.
7.3.3.1
Adverse Events
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 DB IP. 
For the DB treatment, the number and percentage of patients reporting TEAEs in each 
treatment group 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 the IP. If more than 1 AE is coded to the same preferred term for the same 
patient, the patient will be counted only once for that preferred term using the most severe 
and most related occurrence for the summarization by severity and by relationship to the IP.
The distribution of TEAEs by severity and relationship to the IP will be summarized by 
treatment group.
The TEAEs during the safety follow-up period will be summarized by body system, 
preferred term, and treatment group for the safety population.
An AE that occurs more than 30 days after the date of the last dose of DB IP will not be 
summarized.
The number and percentage of patients with common (≥ 2% of patients in any treatment 
group) TEAEs, on-therapy SAEs, and AEs leading to premature discontinuation of IP will be 
summarized by preferred term and treatment group and sorted by decreasing frequency for 
the test treatment. An SAE will be defined as an on-therapy SAE if it occurred on or after the 
date of the first dose of DB IP and within 30 days of the date of the last dose of DB IP.
Listings will be presented for patients with SAEs, patients with AEs leading to 
discontinuation, and patients who die (if any). All patients with SAEs, including SAEs 
reported during the screening period and the safety follow-up period, and patients 


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discontinuing because of AEs occurring before the start of DB IP will be included in these 
listings.
The number and percentage of patients reporting TEAEs of ocular events of special interest 
will be summarized. A listing of all reported ocular events of special interest will be 
provided.
7.3.3.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each assessment time point will be presented by treatment group for each clinical 
laboratory parameter. 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; these will be detailed in the statistical analysis plan 
(SAP).
The number and percentage of patients with potentially clinically significant (PCS) 
postbaseline clinical laboratory values will be tabulated by treatment group. The criteria for 
PCS laboratory values will be detailed in the SAP. 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 PCS postbaseline value. A supportive listing of patients with 
PCS postbaseline values will be provided, including the patient identification number, study 
center number, and baseline and postbaseline values. A listing of all AEs occurring in patients 
who have PCS laboratory values will also be provided. 
The number and percentage of patients with treatment-emergent significant changes in lipid 
parameters (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein 
cholesterol, and triglycerides) and glucose will be tabulated by treatment group for the DB 
treatment period. The criteria for treatment-emergent significant changes in lipids and 
glucose will be detailed in the SAP. Percentages will be calculated relative to the number of 
patients with baseline values meeting the specified baseline criteria and with at least 
1 postbaseline assessment. The change in lipids and glucose from baseline to the highest 
(lowest for high-density lipoprotein cholesterol) postbaseline measurement will be 
summarized. Supportive listings of patients with treatment-emergent changes in lipids and 
glucose values will be provided.


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The number and percentage of patients meeting potential Hy’s Law criteria will be tabulated 
by DB treatment group starting from the first dose of DB IP to within 30 days after the last 
dose of DB IP for the safety population. A supportive listing will be provided. 
7.3.3.3
Vital Signs
Descriptive statistics for vital signs and changes from baseline values at each visit and at the 
end of the DB treatment period will be presented by treatment group.
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 SAP. 
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 patient identification 
number, study center number, and 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 measured after the patient stands up after 
resting in the supine position. Standing measurements should be taken after a sufficient 
amount of time has passed to allow the BP to equilibrate in the standing state. A supportive 
listing will be provided including the patient identification number, study center number, and 
baseline and postbaseline systolic and diastolic BP values (supine and standing).
The definition of different hypertension status will be detailed in the SAP. 
Tabulations showing 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 DB treatment period

Shift of hypertension status from baseline to highest category during the DB treatment 
period
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.


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7.3.3.4
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 
timepoint will be presented by treatment group. 
The number and percentage of patients with PCS postbaseline ECG values will be tabulated 
by treatment group. The criteria for PCS ECG values will be detailed in the SAP. 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 PCS postbaseline 
value. A supportive listing of patients with PCS postbaseline values will be provided, 
including the patient identification number, study center number, and baseline and 
postbaseline values.
In addition, a listing of all AEs occurring in patients who have PCS ECG values and a listing 
of patients with clinically significant postbaseline ECG abnormalities, as reported by the 
Investigator and/or the central ECG laboratory, will also 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 the patient identification number, study center 
number, all QTc values (including change from baseline values), and all AEs will be provided 
for all patients who have postbaseline QTc changes > 30 msec.
7.3.3.5
Other Safety Parameters
Other safety parameters include YMRS, EPS scales (AIMS, BARS, and SAS scores) and 
C-SSRS.
The number and percentage of patients with treatment-emergent mania will be presented by 
treatment group. Treatment-emergent mania will be defined as an YMRS total score of 16 or 
greater at any postbaseline visit. Descriptive statistics for YMRS total score and change from 
baseline values at each assessment time point will be presented by treatment group.
A patient will be considered to have treatment-emergent parkinsonism if the patient’s SAS 
score was ≤ 3 at baseline and > 3 at any DB 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 
DB assessment. The number and percentage of patients reporting treatment-emergent 
parkinsonism or treatment-emergent akathisia will be tabulated by treatment group. Listings 


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of patients with treatment-emergent parkinsonism and patients with treatment-emergent 
akathisia will be provided and will include the patient identification number, study center 
number, and baseline and postbaseline values. Listings of all AEs occurring in patients who 
have treatment-emergent parkinsonism or treatment-emergent akathisia will also be provided.
Descriptive statistics for EPS scale parameters (AIMS, BARS, and SAS) and changes from 
baseline values at each assessment timepoint in this study will be presented.
The number and percentage of patients with suicidal ideation or suicidal behavior as recorded 
on the C-SSRS will be summarized by treatment group. The distribution of responses for 
most severe suicidal ideation and most severe suicidal behavior during the patient’s lifetime, 
during the DB treatment period, and during the safety follow-up period will also be presented
by treatment group for the safety population. Supportive listings will be provided and will 
include the patient identification number, study center number, lifetime history, and 
postbaseline values. Intensity of suicidal ideation, suicidal behavior type, and lethality of 
suicidal behavior will also be included in these listings. A listing of all AEs occurring in 
patients who have suicidal ideation or suicidal behavior will also be provided.
7.4
Other Analyses 
Patient disposition, demographics and other baseline characteristics, prior and concomitant 
medication, extent of exposure and treatment compliance will be summarized and described 
in detail in the SAP. 
Any potential additional analyses of efficacy and safety data due to the impact of COVID-19, 
(infection or disruption) on patient treatment (discontinuation or interruptions) and follow-up 
(data collection via alternative modality, missing or late visits, or complete lost-to-follow-up) 
will be described in the SAP.
7.4.1
Pharmacokinetic Parameters
Plasma samples will be analyzed for the concentrations of cariprazine and its metabolites 
DCAR and DDCAR using a validated bioanalytical method. A population PK approach will 
be used to estimate individual-level drug-exposure parameters (eg, steady-state area-under-
the-curve [AUC], steady-state maximum concentration [Cmax], steady-state minimum 
concentration [Cmin]) for each of the 3 analytes. This will be performed via the use of 
appropriate nonlinear mixed-effects modeling software. The relationship, if any, between 
effectiveness and drug-exposure parameters will be explored. These analyses will be reported 
separately. 


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7.4.2
Health Outcome Measure Analyses
The SF-12 will be administered at Visit 2 and Visit 6/ET. 
Analysis of change from baseline in the PCS-12 and MCS-12 score at Week 6 will be 
conducted using the ANCOVA model that has treatment group and study center as factors 
and the baseline value as the covariate.
7.5
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a 95% CI) for each cariprazine dose 
versus placebo for the primary efficacy variable will be estimated within each category of the 
following classification variables:

ADT failure category (one ADT failure, more than one ADT failure)

Region (US, NonUS)
7.6
Interim Analyses
No interim analysis is planned for this study.
7.7
Sample Size Calculation
The study will randomize approximately 750 patients in a 1:1:1 ratio to cariprazine 
1.5 mg/day, cariprazine 3 mg/day, and placebo groups. A sample size of 250 patients per arm 
will provide approximately 84% statistical power to show statistically significantly higher 
effect in each dose of cariprazine versus placebo based on the mITT analysis set. The study 
has approximately 90% statistical power to show that at least 1 of the 2 cariprazine doses is 
statistically significantly more efficacious than placebo in the primary endpoint. These 
calculations assumed an effect size of 0.286. All statistical powers presented in this section 
were calculated adjusting for multiple comparisons using the Hochberg procedure with the 
family-wise type I error rate being controlled at a 0.05 level (2-sided). The dropout rate is 
assumed to be 15% at Week 6. Within-person correlation for the primary endpoint is assumed 
to be 0.58. This value is used in the sample size calculation to calculate an inflation factor 
that accounts for information loss due to the missing data at Week 6 for longitudinal data 
collection.


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Assumptions of effect size, intracorrelation and dropout rate are based on cariprazine 
Study RGH-MD-75.
8
Study Visit Schedule and Procedures
Please see Table 1 for a schematic of the schedule of visits and procedures, and Section 6 for 
details of tests and rating scales.
8.1
Patient Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective patients as defined by the criteria in Sections 4.3 and 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 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 (United States only), data protection consent (Europe only), and 
other written documentation in accordance with the 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 reviewed 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 continue participation without documented approval from the Sponsor.
8.2
Washout Interval
Patients with MDD with inadequate response to ongoing ADT in the current episode will 
undergo a washout of prohibited medications for up to 14 days during the screening period, 
with up to an additional 7 days if needed with Sponsor approval (see Section 4.5.2). During 
the washout, the patients will continue to take the ADT that they are not responding to.


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The length and timing of the washout of prior psychiatric medications during the 14 days 
allotted for the screening period is at the discretion of the investigator (with up to an 
additional 7 days if needed with Sponsor approval). Prior medications should be gradually 
withdrawn such that the washout is completed by Baseline (Visit 2). Please note that during 
the washout period psychotropic medications other than those listed as rescue (Section 4.5.3) 
may not be newly initiated or reinitiated.
8.3
Procedures for Final Study Entry
Final study eligibility, for patients meeting SAFER criteria, will be determined at Visit 2 
(Baseline Visit). Patients should continue to meet the inclusion and exclusion criteria as 
specified in Sections 4.3 and 4.4.
A patient is considered to have entered the study at the time of randomization to treatment at 
Visit 2 (Baseline).
Rescreening of screen failures is permitted in certain situations after consultation with the 
Allergan Medical Monitor.
See Section 5.4 for the method for assignment to treatment groups/randomization.
8.4
Visits and Associated Procedures
The schedule of study procedures and assessments is tabulated by visit in the schedule of 
visits and procedures in (Table 1). A description of individual procedures is provided in 
Sections 6.1, 6.2, 6.3, 6.4, 6.5, and 6.6. Evaluations should be performed by the same 
evaluator throughout the study whenever possible. During the study, every effort should be 
made to perform the study procedures as indicated in (Table 1). The descriptions of the 
procedures to be performed at each visit are provided below.
As a result of the ongoing COVID-19 pandemic, some in-person study visits may not be 
possible due to public health concerns.  When these public health concerns interfere with the 
conduct of in-person clinic visits, site visits may be conducted via an alternative format.  
Refer to Section 12.2 for allowable protocol modifications during the COVID-19 pandemic.
8.4.1
Screening (Visit 1)
The following procedures will be carried out at Screening (Visit 1):


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
Obtain informed consent and patient privacy authorization/consent; consent for 
pharmacogenetic sampling may also be obtained

Access IWRS to register the patient and assign a patient identification number

Perform Verified Clinical Trials check

Assess inclusion/exclusion criteria

Collect and assess medical and psychiatric history

Administer and assess SCID-5

Collect blood samples for hepatitis serology 

Collect samples for UDS

Perform blood alcohol concentration assessment with Breathalyzer

Collect blood samples for serum pregnancy test (women of childbearing potential only)

Collect blood samples for clinical laboratory tests

Collect blood sample for hemoglobin A1c

Review prior and concomitant medications

Assess modified ATRQ, MADRS, HAMD-17, CGI-S, C-SSRS and YMRS

Collect vital signs measurements, including weight and height

Perform physical examination

Perform ECG and transmit to central reader 

Review and assess AEs and SAEs

For patients meeting initial inclusion/exclusion criteria, schedule and ensure the SAFER 
interview is conducted prior to Visit 2 (Baseline Visit)
8.4.2
Baseline (Visit 2)
The following procedures will be carried out at Baseline (Visit 2):


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
Evaluate results from SAFER interview to confirm patient eligibility to continue in study 

Assess all other inclusion/exclusion criteria

Review concomitant medications and assess ADT compliance

Assess MADRS, HAMD-17, HAM-A, YMRS, CGI-S and C-SSRS

Evaluate EPS (AIMS/BARS/SAS)

Administer SF-12

Collect vital signs measurements (including weight and waist circumference)

If not already obtained at Screening (Visit 1), obtain consent for and collect blood for the 
pharmacogenetic sample. Consent for pharmacogenetic sampling may be obtained any 
time between Visit 1 and Visit 6/ET, inclusive. A single sample can be obtained any time 
between Visit 2 and Visit 6/ET, inclusive

Review and assess AEs and SAEs

Access IWRS to randomize patient and then dispense IP
8.4.3
Double-blind Treatment Period (Visits 3 to 6/ET)
The following procedures will be carried out during the DB treatment period at every visit 
except as noted: 

Review concomitant medications and assess ADT compliance

Collect IP blister cards, perform drug accountability and assess IP compliance

Assess MADRS, CGI-S, CGI-I, and C-SSRS; HAM-A (Visits 4 and 6/ET only), YMRS 
(Visit 6/ET only) and HAMD-17 (Visit 6/ET only)

Evaluate EPS (AIMS/BARS/SAS)

Administer SF-12 (Visit 6/ET only)

Collect vital signs measurements (including weight)

Collect waist circumference measurement (Visit 6/ET only)


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
Review and assess AEs and SAEs

Collect blood sample for serum pregnancy test for women of childbearing potential 
(Visit 6/ET only)

Collect blood samples for clinical laboratory determinations (Visit 6/ET only)

Collect blood for PK evaluation (any time during Visits 4, 5 and 6/ET)

If not already obtained previously, obtain consent for and collect blood for the 
pharmacogenetic sample. A single sample can be obtained at any time between Visit 2
and Visit 6/ET, inclusive

Perform ECG (Visit 6/ET only)

Perform physical examination (Visit 6/ET only)

Access IWRS to dispense IP (Visit 3 through Visit 5), and register patient completing 
Visit 6/ET
Note: After completion of Visit 6/ET, patients will receive treatment for their MDD as 
deemed necessary by the Investigator or designee.
8.4.4
Safety Follow-up (Visit 7)
The following procedures will be carried out at the Safety Follow-up Visit (Visit 7/Week 10):

Review concomitant medications

Collect vital signs measurements (including weight)

Collect blood sample for serum pregnancy test (women of childbearing potential only)

Review and assess AEs and SAEs

Assess C-SSRS
8.5
Instructions for the Patients

Patients are to be instructed to take their study medication daily around the same clock 
time, with or without food; study medication should not be taken with grapefruit juice


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
Patients are to continue to take their ADT as instructed throughout the study and to bring 
their ADT to visits for compliance review

Patients are to be reminded to return used/partially used IP 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 Sections 4.5.2 and 
4.5.3; patients are to be advised accordingly. If the permissibility of a specific 
medication/treatment is in question, the Investigator should consult the Allergan Medical 
Monitor.

Patients are to be asked to limit alcohol consumption and abstain from using illicit drugs 
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) and Visit 6/ET
8.6
Unscheduled Visits
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
Investigator. Additional examinations may be performed as necessary to ensure the safety 
and well-being of patients during the study. An eCRF will be completed for each 
unscheduled visit.
8.7
Compliance with Protocol
Participating patients should be able to adhere to the completion of required questionnaires 
and testing parameters as described in this protocol.
Data will be recorded on the appropriate eCRF supported by appropriate source 
documentation. At each visit, patients should be asked if any concomitant medications had 
been used, if they had undergone any concurrent procedures (nonstudy procedures), and if 
they had been in compliance with the protocol since the previous visit.
For compliance with IP and ADT see Sections 5.6.1 and 5.6.2, respectively.
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. 


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Patients can be prematurely discontinued from the study and subsequently enter the safety 
follow-up period for one of the following reasons:

AE

Noncompliance with protocol 

Noncompliance with IP dosing regimen and/or ongoing ADT dosing regimen

Withdrawal of consent (a clear reason must be documented when possible)

Patient decision to not continue in the study

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
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 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 6/ET. If the patient discontinues after IP is taken, the patient is also 
expected to return for the Safety Follow-up Visit (Visit 7) 4 weeks after completion of the ET
Visit.
At a minimum, the following information should be collected when a patient is discontinued:
1. The reason the patient discontinued
2. The date of the last dose of IP taken by the patient. All IP should also be retrieved from the 
patient. 
3. The date of the last study assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate


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4. (S)AEs
5. Compliance with the IP 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 6/ET and subsequently 
Visit 7 (Safety Follow-up Visit) are performed (Table 1, and Section 8.4).
Discontinued patients will not be replaced, and re-screening will not be allowed.
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 misses ≥ 4 consecutive doses of IP and/or ongoing ADT
2.
The patient required or initiated hospitalization for his/her psychiatric symptoms
3.
The patient decompensates psychiatrically (becomes acutely suicidal, homicidal or 
psychotic) and in the judgment of the Investigator cannot be safely managed in the 
study
4.
The patient has a positive UDS at any time during the study; for exceptions see 
Exclusion Criterion 4 and Section 4.5.3
5.
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


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
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
6.
The patient has an absolute neutrophil count (ANC) of < 1000 per mm3 and, after 
repeat testing within 24 hours of awareness, the values are not normalized or are not 
increasing
7.
A female patient becomes pregnant during treatment
8.10
Study Termination
The study may be stopped at a study site at any time by the site investigator. The Sponsor
may stop the study (and/or the study site) for any reason with appropriate notification.
9
Adverse Events
AEs occurring during the study will be recorded on an AE eCRF. If AEs occur, the first 
concern will be the safety of the study patients.
9.1
Definitions
9.1.1
Adverse Event
An AE 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 AE 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, AEs will be assessed 
regardless of the administration of a pharmaceutical product.
Note: AEs must be collected once informed consent has been obtained, regardless of whether 
or not the patient has been administered IP.
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 
AEs unless the disease progression is greater than anticipated in the natural course of the 
disease.


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AEs 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 AEs 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 AEs will be documented on the appropriate eCRF.
9.1.2
Serious Adverse Event
An SAE is any AE occurring at any dose that results in any of the following outcomes: death, 
is life-threatening, 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 an 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 SAEs).
Allergan considers all cancer AEs as SAEs. In addition, Allergan considers any abortion 
(spontaneous or nonspontaneous) as an SAE.
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as an SAE.
Any preplanned 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 screening visit (Visit 1), then it should 
be documented as an SAE and reported to Allergan.
9.1.3
Severity
A clinical determination will be made of the intensity of an AE. The intensity assessment for 
an AE must be completed using the following definitions as guidelines:
Mild
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living
Moderate
A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of 
daily living, causing discomfort but poses no significant or permanent 
risk of harm to the research patient.


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Severe
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
9.1.4
Relationship to Study Drug
A determination will be made of the relationship (if any) between an AE 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 AE may have been caused by the drug or study 
procedure.
9.2
Procedures for Reporting Adverse Events
Any AE must be recorded on the appropriate eCRF.
All AEs 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 AE that is marked ‘ongoing’ at the last 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 DB IP must be immediately reported but no later than 
24 hours after learning of an SAE. SAEs must be reported to Allergan (or agent of Allergan) 
as listed on the Allergan Study Contacts List and recorded on the SAE/AESI Form. All 
patients with an SAE must be followed and the outcomes reported. The Investigator must 
supply the Sponsor and the IRB/IEC with any additional requested information (eg, autopsy 
reports, discharge summaries).
In the event of an SAE, the Investigator must:
1. Notify Allergan immediately using the SAE/AESI Form (contact details can be found 
on page 1 of the SAE/AESI Form); phone numbers and relevant Allergan personnel 
contacts are also on the front page of the 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


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3. Provide Allergan with a complete, written description of the AE(s) on the SAE/AESI 
Form describing the event chronologically, including any treatment given 
(eg, medications administered, procedures performed) for the AE(s). Summarize 
relevant clinical information about the event: signs, symptoms, diagnosis, clinical 
course and relevant clinical laboratory tests, etc. Include any additional or 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 after the last dose of IP. Serum pregnancy tests are scheduled at screening and 
at Visit 6/ET and Visit 7 (EOS). If a pregnancy is suspected at any other time, an unscheduled 
serum pregnancy test should be performed. If any β-hCG test comes back as borderline, it 
should be repeated and consultation with the Allergan Medical Monitor is required. Within 
24 hours of learning of the pregnancy, the study site personnel must report the event to 
Allergan’s Global Patient Safety department on the clinical trial pregnancy form and 
fax/email it to the SAE fax number/email address on the cover page of this protocol, even if 
no AE has occurred. 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 
reported 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


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Study site personnel must report every patient who meets these 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 study until 30 days after last known dose of study treatment. 
A laboratory alert for potential Hy’s laws cases will be in place, and the laboratory must 
notify Investigators and the Sponsor (Allergan) immediately when the above criteria have 
been met. A potential Hy’s law case must be reported to Allergan on an SAE/AESI Form as 
soon as possible (within 24 hours of learning of the potential Hy’s law case) to the 
SAE/Pregnancy fax number, even if no AE has occurred. The eCRF 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 should be initiated in 
conjunction with the Allergan Medical Monitor and in accordance with the FDA Guidance 
for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009. The 
patient should return to the study site and be evaluated as soon as possible, preferably within 
48 hours from the time the Investigator becomes aware of the abnormal results. This 
evaluation should include laboratory tests, detailed history, and physical assessment.
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 (Allergan Medical 
Safety Physician) should be notified prior to unmasking study medication. The Investigator 
should inform the Sponsor (Allergan 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 
calling 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 GCP regulations and 
guidelines, eg, ICH Guideline on GCP.


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10.1
Protection of Human Patients
10.1.1
Compliance With Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study.
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 reapproval or review at least annually
(US sites). Allergan 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 Allergan.
10.1.3
Compliance With Good Clinical Practice
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.
10.1.3.1 Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR 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
The Investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the
study (eg, change of telephone numbers).
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 IP may ultimately be marketed, but the patient’s name 


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or other personal identifying information will not be disclosed in these documents. The 
patient’s name may be disclosed to the Sponsor of the study, Allergan, 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 in accordance with the applicable privacy requirements 
(eg, HIPAA [United States]; European Union Data Protection Directive 95/46/EC [EU]).

Patients will be assigned a unique identifier. Any patient records or datasets that are 
transferred to the Sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred. 

The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient. 

The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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 ECGs. 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


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
A statement that informed consent was obtained (including the date). A statement that 
written authorization (US sites only), data protection consent (European sites only), or 
other country and local patient privacy required documentation for this study has been 
obtained (including the date)

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 Allergan

Dates of all patient visits

All concurrent medications (list all prescription and nonprescription medications being 
taken at the time of screening. At each subsequent visit, changes to the list of medications 
should be recorded)

Occurrence and status of any AEs

The date the patient exited the study, and a notation as to whether the patient completed 
the study or reason for discontinuation

Key study variables
Source documentation practices must follow ALCOA principles, ie, records must be 
attributable, legible, contemporaneous, original, and accurate.
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 Allergan within a short time after the 
completion of the study, or as designated by Allergan. A summary is also to be provided to 
the responsible IRB/IEC, as required.


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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 electronic copies of CRFs
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.
Allergan 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.
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, instructions to take the capsules as directed, and any other 
required information. 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 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 product 
units received from Allergan, dispensed or administered to the patients, returned to the 
Investigator by the patient, and returned to Allergan during and at the completion of the
study. A detailed inventory must be completed for all IP. IP must be dispensed or 


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administered to patients in the study only by an appropriately qualified person. The 
medication is to be used in accordance with the protocol.
10.5.3
Return or Disposal of Study Medications/Treatments
It is the Investigator’s responsibility to ensure that patients return all unused IP, and all empty 
blister packs, to the site. All IP will be returned to Allergan or Allergan designee for 
destruction. All unused IP must be returned to Allergan during the course of the study when a 
patient discontinues from the study, upon drug expiration, and at the end of the study. 
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 Allergan 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.
10.7
Handling of Biological Specimens
Samples of blood and urine for evaluation of hematology, chemistry and urinalysis, will be 
analyzed at a centralized clinical laboratory with certification from a recognized accreditation 
agency (eg, College of American Pathology or Clinical Laboratory Improvement 
Amendments certification). 
Blood samples obtained for analysis of cariprazine and its metabolites DCAR and DDCAR 
will be stored by the central clinical laboratory until ready for analysis. Analysis will be 
performed using a validated method and a laboratory that meets Good Laboratory Practice 
requirements. Allergan 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 that 
may influence how patients respond to a drug or may explain the pathophysiology of the 


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disease. These blood samples will be stored to provide a resource for potential future trials 
conducted by Allergan.
All pharmacogenetic samples collected will be sent to the designated central laboratory and 
later shipped to a biorepository for storage.
10.8
Publications
Allergan, as the Sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan 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 Allergan.
10.9
Coordinating Investigator
A signatory Coordinating Investigator will be designated prior to the writing of the clinical 
study report.
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Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
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DSM-IV disorders in the National Comorbidity Survey. Arch Gen Psychiatry 
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McIntyre RS, O’Donovan C. The human cost of not achieving full remission in depression. 
Can J Psychiatry. 2004;49(suppl 1):10S-16S.


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Mathers CD, Loncar D. Projections of Global Mortality and Burden of Disease from 2002 to 
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diseases, injuries, and risk factors. JAMA. 2013;310(6):591-608.
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future: efficacy and safety. Pharmacol Ther. 2007;113(1):134-153.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry.
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12 Attachments
12.1
Scales and Questionnaires
Please refer to the Study Scales and Questionnaire Binder for reference copies of 
questionnaires and scales.


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12.2
Protocol Modifications for COVID-19
As a result of the novel coronavirus disease 2019 (COVID-19) pandemic, the following
protocol modifications can be followed for active patients in Study 3111-302-001, who have 
completed all assessments through Visit 2 (inclusive) per Table 1, Schedule of Visits and 
Procedures and have been randomized via the Interactive Web Response System (IWRS). 
The instructions and procedures specified herein will supersede those specified in the 
Schedule of Visits and Procedures 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 Table 1 of 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 prior to randomization. The following procedures apply in cases where 
patients are either unable or unwilling to attend study visits as a result of the pandemic.
12.2.1
Planned changes in research
In response to the impact of COVID-19 to study patients and site staff, the following
modifications to the study plan are allowable 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 (preferred method if/when home visits are not 
feasible)
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 (see Section 12.2.6.)
12.2.2
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 


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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.

Montgomery-Åsberg Depression Rating Scale (MADRS)

Hamilton Anxiety Rating Scale (HAM-A)

Clinical Global Impression-Severity scale (CGI-S)

Clinical Global Impression-Improvement scale (CGI-I)

Hamilton Depression Rating Scale–17 Items (HAMD-17)
12.2.3
Remote Assessment of Health Outcome measures
In the event that Visit 6/Early Termination (ET) is being conducted remotely (eg, by 
telephone, telemedicine virtual visit, video call), study staff should verbally administer the 
Short-Form 12 (SF-12) to the patient and record the patient’s responses in the source.  The 
source document should capture the name of study personnel administering the SF-12, 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 
SF-12 per protocol.
12.2.4
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 (as applicable) 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.

Young Mania Rating Scale (YMRS)

Movement scales (BARS/AIMS/SAS) – Must be conducted by a certified rater.  
Telemedicine virtual visits (where available) or video calls (without recording) are the 
preferred method 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.


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12.2.4.1 In-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.  Due to considerations of the processing time required, pharmacokinetic 
(PK) samples should not be collected during in-home visits.  If processing cannot be 
completed within the time specified in the central laboratory manual for any other 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 #3) or 
Country-Specific Protocol, if applicable.)  

Serum pregnancy testing 

Electrocardiogram (ECG)

Vital signs (with or without weight)

Physical examination
12.2.4.2 Clinical 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 #3) 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.  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.  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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12.2.4.3 Electrocardiogram (ECG)
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. 
12.2.4.4 Physical 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 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.
12.2.4.5 Vital 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.
12.2.5
Visit 6/ET- End of Double-Blind and Early Termination Visit
Every attempt should be made to complete the Visit 6/ET efficacy, safety and health outcome 
assessments on the same date.  In the event that a remote visit for Visit 6/ET is not possible at 
the scheduled timepoint, all Visit 6/ET efficacy assessments should be completed within 2 
weeks of the last dose of IP.  If Visit 6/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 
6/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 6/ET procedures are being completed more than 2 weeks 
after the last dose of IP, efficacy assessments should be omitted.


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12.2.6
Treatment compliance
Investigational Product compliance is to be assessed at every visit during the Double-Blind 
Treatment period.  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.  
Background ADT medication compliance is also to be assessed at every visit. Patients should 
be questioned to determine if there were any missed doses or changes in dose between visits. 
Every effort should be made to have patients bring their background ADT to in-person study 
visits for verification of patient-reported compliance by pill/capsule count (to the extent 
possible) and patient interviews. For remote visits where a pill count by site staff may not be 
possible, patient reported compliance is to be documented. 
Patients who take less IP or ADT or more IP or ADT than the prescribed regimen must be
counseled on the importance of taking study medications 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 of investigational product or his/her ADT 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.  Given the aforementioned 
concession, patients missing 4 or more doses should not be automatically withdrawn from the 
study treatment and the study as a result of the pandemic.
The study centers will continue to keep an accurate drug disposition record that specifies the 
amount of IP dispensed to each patient and the date of dispensing.




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*Note: If necessary, Visits 3 to 7 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 7.  In extenuating circumstances, the visit window for Visits 3 to 7 (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.
ADT = antidepressant therapy; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-I = Clinical Global Impression–
Improvement; CGI-S = Clinical Global Impression–Severity; C-SSRS = Columbia–Suicide Severity Rating Scale; ET = early termination; HAM-A = Hamilton 
Anxiety Rating Scale; HAMD-17 = Hamilton Depression Rating Scale–17 items; 
IP = investigational product; IWRS = interactive web-response system; MADRS = Montgomery-Åsberg Depression Rating Scale; PI = Principal Investigator; 
SAS = Simpson-Angus Scale; SF-12 = Short Form-12 v2 Health Survey; WOCBP = women of child-bearing potential; YMRS = Young Mania Rating Scale. .
a
Clinical laboratory assessments, 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.
b
If visit is being performed remotely, this assessment may be omitted. Vital signs should be obtained at the next scheduled in-home or in-person visit. 
c
If visit is being performed remotely, this assessment may be omitted at this timepoint. Patient should have this assessment 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. 
d
If visit is being performed remotely, study staff should verbally administer the Short-Form 12 (SF-12) to the patient and record the patient’s responses in the 
source.  
e
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. 
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
As an alternative to in-person drug dispensing, IP may be dispensed via a secure delivery method (where permissible by local, statutory, federal/country law) 
and after approval by Sponsor.
h
Assessment of compliance should be performed at each visit.  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.
i
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.
j
If visit is being performed remotely or at an alternate laboratory facility, this assessment may be omitted.  In consideration of the processing time required, 
pharmacokinetic samples should not be collected during in-home visits.
k
Pharmacogenetic consent may be obtained at any time between Visit 1(Screening) and Visit 6 (Week 6).  Pharmacogenetic consent may not be obtained 
remotely.


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l
Pharmacogenetic sample (1 per patient for the entire study) may be obtained from randomized patients at any time between Visit 2 (Baseline) and Visit 6 
(Week 6). To be omitted if sampling is not possible due to remote visits being completed.


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12.3
Glossary of Abbreviations
Term/Abbreviation
Definition
ADT
antidepressant therapy
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
ANC
ANCOVA
absolute neutrophil count
analysis of covariance
AST
aspartate aminotransferase
ATRQ
Antidepressant Treatment Response Questionnaire
BARS
Barnes Akathisia Rating Scale
BP
blood pressure
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impressions–Improvement
CGI-S
Clinical Global Impressions–Severity
COVID-19
C-SSRS
Coronavirus disease 2019
Columbia–Suicide Severity Rating Scale
CYP3A4
cytochrome P450 3A4
DB
double-blind
DCAR
desmethyl cariprazine
DDCAR
didesmethyl cariprazine
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EPS
extrapyramidal symptoms
ET
early termination
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
HAM-A
Hamilton Anxiety Rating Scale
HAMD-17
Hamilton Depression Rating Scale–17 items
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
IEC
Independent Ethics Committee
IP
investigational product
IRB
Institutional Review Board
IWRS
interactive web response system
LOCF
last observation carried forward
MADRS
Montgomery-Åsberg Depression Rating Scale
MCS-12
Mental Component Summary-12
MDD
major depressive disorder
MGH CTNI 
Massachusetts General Hospital Clinical Trial Network
MMRM
mixed-effects model for repeated measures


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Term/Abbreviation
Definition
mITT
modified intent-to-treat
PCS
potentially clinically significant
PCS-12
Physical Component Summary-12
PK
pharmacokinetic
QTc 
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)
RNA
Ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Simpson-Angus Scale
SCID-5
Structured Clinical Interview for DSM-5
SF-12
Short Form-12 health survey questionnaire
SFU
TEAE
Safety Follow-up
treatment-emergent adverse event
UDS
urine drug screen
ULN
upper limit of normal
VCT
Verified Clinical Trial
YMRS
Young Mania Rating Scale


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12.4
Protocol Amendment #1 Summary
Title: A Double-Blind, Placebo-Controlled Study of Cariprazine as an Adjunct to 
Antidepressants in the Treatment of Patients With Major Depressive Disorder who Have had 
an Inadequate Response to Antidepressants Alone
Study 3111-302-001 Amendment 1
Date of Amendment: 19 Dec 2018
Amendment Summary
This summary includes changes made to Protocol 3111-302-001 (23 Jul 2018).
Following is a summary of changes that were made to each section of the protocol, and a 
brief rationale for these changes.
Minor editorial and document formatting revisions have not been summarized.
Section 
Revision
Rationale
Title page
Added the EudraCT number.
Number became available.
Protocol Summary,
Study Design and Study 
Population Characteristics
Restructured the description of patients who may 
participate in the study.
For clarity
Protocol Summary,
Study Design: Duration, 
Visit Schedule
Added text to extend the safety follow-up period 
from 1 to 4 weeks: 
Because of the long half-life
of cariprazine and its active 
metabolites, the Sponsor has
extended the safety follow-up
period from 1 week
to 4 weeks.
Figure 1 Study
Schema
Figure 1 was revised to show the extended
4-week safety follow-up period.
Revised to reflect the
longer safety follow-up period.


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Section 
Revision
Rationale
Schedule of Visits and 
Procedures, Table 1
Changed the Safety Follow-up Visit 7 Week 7 to
Visit 7/Week 10, Study Day 50 becomes Study 
Day 71.
New row added for: Blood Alcohol 
Concentration by Breathalyzer performed at 
Screening (Visit 1).
New row added for: Serum pregnancy text (now 
also performed at Safety Follow-up.
Added text to Footnote e: Blood alcohol 
concentration as measured by Breathalyzer will 
be assessed only at Visit 1 (Screening).
Expanded the time-window for collection of the 
pharmacogenetic consent to allow collection 
between Visit 1 (Screening), and Visit 6/ET.
Revised to reflect the
longer safety follow-up period.
Blood alcohol at Visit 1 as 
measured by Breathalyzer was 
added to expedite turnaround 
time for blood alcohol 
concentration results at
Screening. 
Additional serum pregnancy 
test was added for clarity and 
to align with European Union 
contraception requirements.
To make collection of the 
sample more likely.
Section 3 Study Design: 
Study Duration,
Screening/Washout
Period
Study Duration: Added text to extend the safety 
follow-up from 1 to 4 weeks
Added text to the Screening/Washout Period to 
clarify that psychotropic medications, not listed 
as rescue medications, may not be newly initiated 
or reinstated; also that the length and timing of 
the washout of prior psychiatric medications 
during the 14 days allotted for screening is at the 
discretion of the investigator.
Safety follow-up period 
increased from 1 to 4 weeks.
For clarity and internal 
consistency.
Section 4.3 Inclusion 
Criterion 8
Text added to inclusion criterion 8: Patient must 
have an inadequate response (< 50% 
improvement), as measured by the modified 
ATRQ, to 1 to 3 antidepressants administered 
during the current episode at an adequate dose (as 
per package insert) and for at least 6 weeks 
duration, with at least one dose escalation during 
the current depressive episode. Patients with an 
inadequate response to at least 1 ADT in the 
current episode that is above the minimum dose 
(as per package insert) for at least 6 weeks in the 
current episode, can be enrolled.
Clarity.
Section 4.3 Inclusion 
Criterion 13
Duration of use for birth control has been 
extended to 12 weeks. 
13. 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 4.5.1.1
Updated for consistency with 
European Union contraception 
requirements.


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Section 
Revision
Rationale
Section 4.4
Exclusion Criteria 2 and 
11
An additional exclusion criterion has been added: 
2. History of manic or hypomanic episodes
And exclusion criterion 11 has been deleted: 
11.Patient has history of having received an 
anticonvulsant/mood stabilizer within a year prior 
to Visit 1
Exclusion criterion 2 was 
added and exclusion criterion 
#11 was removed to clarify 
that bipolar disorder is 
exclusionary.
Section 4.4
Exclusion Criterion 4
Exclusion for addictive disorders was removed 
and the duration shortened to 3 months:
Patient has a history of meeting DSM-5 diagnosis 
for any substance-related disorders (ie, use 
disorders except caffeine- and tobacco-related) 
and addictive disorders within the 6 3 months 
before Visit 1 (Screening).
For consistency across 
cariprazine programs.
Section 4.4
Exclusion Criterion 5
Two additional drugs (amphetamines and 
barbiturates) were added as exceptions to 
Exclusion Criterion 4: Exception: patients with a 
positive UDS at Visit 1 for opiates, cannabinoids, 
amphetamines, barbiturates, or benzodiazepines 
may be allowed in the study provided…
For clarity and consistency 
with other protocols in the 
program.
Section 4.4 
Exclusion Criterion 13 
and Section 4.5.2 
Prohibited 
Medications/Treatments
Added text to clarify that moderate CYP3A4 
inhibitors (eg, erythromycin or fluconazole) are 
also prohibited.
Added text that rescue meds other than what is 
listed under rescue medications are prohibited.
For clarity and internal 
consistency.
Section 4.4
Exclusion Criteria 29 and 
30
Added exclusion criteria for blood alcohol 
concentration and hemoglobin A1c measured at 
Screening (Visit 1). 
29. Blood alcohol concentration ≥ 0.02 g/dL at 
Visit 1 (Screening) as measured by breathalyzer
30. Hemoglobin A1c >7% at Visit 1 (Screening)
Blood alcohol at Visit 1 as 
measured by Breathalyzer was 
added to expedite turnaround 
time for blood alcohol 
concentration results.
Hemoglobin A1c – eligibility 
criteria added to clarify 
Sponsor’s expectation of 
stable endocrinological 
disease, particularly diabetes. 
Section 4.5.1.1
Permissible 
Medications/Treatments
Changed text to clarify that an additional barrier 
method must be used if hormonal contraception is 
used by a female patient and added text to state 
that contraception must be used for 12 weeks 
after the last dose of study drug.
For clarity and to align with 
European Union contraception 
requirements.


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Section 
Revision
Rationale
Section 5.5 Treatment 
Regiment and Dosing, 
Table 2, footnote
A footnote has been added after Table 2: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.
To clarify how dosing times 
can be switched (ie, must 
allow for 24 hours between 
doses).
Section 6.1.3 The 
Modified Antidepressant 
Treatment Response 
Questionnaire
Added text to clarify that the modified ATRQ 
must be completed by a clinician at the study site 
who has been certified in administration of the 
ATRQ.
For clarity and internal 
consistency.
Section 6.5 
Pharmacogenetic 
Sampling
Expanded the time-window for obtaining consent 
for the pharmacogenetic blood sample to allow 
collection between Visit 1 (Screening), and Visit 
6/ET.
For clarity and internal 
consistency.
Section 6.6.2 Ocular 
Events of Special Interest
Adjusted text to clarify that the Sponsor is 
required to perform expedited reporting to inform 
worldwide regulatory authorities of ocular events 
of special interest.
For clarity.
Section 6.6.3 Clinical 
Laboratory 
Determinations
Text was added to Table 3 Schedule of Clinical 
Laboratory Tests:
Blood alcohol concentration level (parameter 
added): Blood alcohol concentration by 
Breathalyzer
Serum β-hCG (women of
childbearing potential only) (visit added): 1, 
Visit 6/ET, and Visit 7 Safety Follow-up Visit
Blood alcohol at Visit 1 as 
measured by Breathalyzer was 
added to expedite turnaround 
time for blood alcohol 
concentration results.
Additional serum pregnancy 
test was added for safety and 
to align with European Union
contraception requirements.
Section 6.6.6.2 
Columbia–Suicide 
Severity Rating Scale 
Included a 12-month lookback to the C-SSRS 
completed at Visit 1 (Screening). 
Patient Safety
Section 7.3.1 Primary 
Efficacy Analyses
Specified primary estimand; pre-specified a 
sequence of alternative covariance structures in 
the MMRM analysis in case of a convergence 
problem for unstructured covariance matrix.
Added one more sensitivity analysis
Specified primary estimand 
and alternative covariance 
structures according to FDA’s 
comments; added one more 
sensitivity analysis.


Allergan Confidential
Protocol 3111-302-001 Amendment 3
94
Section 
Revision
Rationale
Section 8.2 Washout 
Interval
Added text to clarify that psychotropic 
medications, not listed as rescue medications, 
may not be newly initiated or reinstated; also that 
the length and timing of the washout of prior 
psychiatric medications during the 14 days 
allotted for screening is at the discretion of the 
investigator.
For clarity and internal 
consistency.
Section 8.4.1 Screening 
(Visit 1)
Text added to indicate that the consent for the
pharmacogenetic blood sample may also be 
obtained at Visit 1 (Screening).
Text added to indicate how blood alcohol 
concentration is assessed: Perform blood alcohol 
concentration assessment with Breathalyzer
For clarity and internal 
consistency.
Blood alcohol at Visit 1 as 
measured by Breathalyzer was 
added to expedite turnaround 
time for blood alcohol 
concentration results.
Section 8.4.2 Baseline 
(Visit 2), and Section 
8.4.3 Double-blind 
Treatment Period (Visits 
3 to 6/ET)
Added a reminder that consent for the
pharmacogenetic blood sample may also be 
obtained at Baseline (Visit 2) if not already 
obtained, and that consent can be obtained any 
time between Visit 1 and Visit 6/ET, inclusive.
For clarity and internal 
consistency.
Section 8.4.3 Double-
blind Treatment Period 
(Visits 3 to 6/ET)
Added: Collect blood sample for serum 
pregnancy test for women of childbearing 
potential (Visit 6/ET only).
For clarity and to align with 
contraception guidance.
Section 8.4.4 Safety 
Follow-up (Visit 7)
Text added to make serum pregnancy test 
mandatory at the safety follow-up: Collect blood 
sample for serum pregnancy test
For clarity and to align with 
contraception guidance.
Section 8.5 Instructions 
for Patients
Removed text: On study visit days, patients will 
continue to administer IP and ADT at home 
around the same clock time(s).
For clarity and consistency 
with other protocols in the 
program.
Section 8.9 Withdrawal 
Criteria
Text changed from 48 to 24 hours of awareness: 
The patient has an absolute neutrophil count of < 
1000 per mm3 and, after repeat testing within 48
24 hours of awareness, the values are not 
normalized or are not increasing.
For clarity.
Section 9.4 Reporting of 
Pregnancies Occurring 
During the Study
The reporting period for pregnancies was 
changed from 3 months to 12 weeks.
Updated for consistency with 
approved labeling.
Section 11 References
Additional reference inserted.
To support additional 
sensitivity analyses.

SAP_001.pdf: 
Allergan PLC
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3111-302-001 Statistical Analysis Plan Amendment 2
3111-302-001
A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF CARIPRAZINE AS 
AN ADJUNCT TO ANTIDEPRESSANTS IN THE TREATMENT OF PATIENTS 
WITH MAJOR DEPRESSIVE DISORDER WHO HAVE HAD AN INADEQUATE 
RESPONSE TO ANTIDEPRESSANTS ALONE
STATISTICAL ANALYSIS PLAN
Final: 16 JAN 2019
Amendment 1: 26 Mar 2021
Amendment 2: 28 Jul 2021
Sponsor:
Allergan Sales, LLC
5 Giralda Farms,  Madison, NJ 
07940
Allergan Ltd.
1st Floor, Marlow International,
The Parkway, Marlow 
Buckinghamshire
SL7 1YL United Kingdom
This document is the property of Allergan. 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 Allergan.
• 
-,(i: Allergan. 
NCT03739203


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1.0
TABLE OF CONTENTS
1.0
TABLE OF CONTENTS..................................................................................................................2
2.0
LIST OF ABBREVIATIONS...........................................................................................................4
3.0
INTRODUCTION ............................................................................................................................6
4.0
OBJECTIVES.................................................................................................................................11
5.0
ANALYSIS POPULATIONS.........................................................................................................12
5.1
Screened Population .........................................................................................................12
5.2
Randomized Population....................................................................................................12
5.3
Safety Population..............................................................................................................12
5.4
Modified Intent-To-Treat Population ...............................................................................12
5.5
Study-Specific Data Excluding One Non-Compliant Site................................................12
6.0
PARTICIPANT DISPOSITION .....................................................................................................13
6.1
Protocol Deviations ..........................................................................................................13
7.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................................14
8.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE................................................15
8.1
Extent of Exposure ...........................................................................................................15
8.2
Measurement Of Treatment Compliance..........................................................................15
9.0
EFFICACY ANALYSES ...............................................................................................................16
9.1
Primary Efficacy Parameter..............................................................................................16
9.2
Key secondary efficacy parameter....................................................................................19
9.3
Additional Efficacy parameter(s)......................................................................................20
10.0
SAFETY ANALYSES....................................................................................................................22
10.1
Adverse Events .................................................................................................................22
10.2
Clinical Laboratory Parameters ........................................................................................24
10.3
Vital Signs ........................................................................................................................28
10.4
Electrocardiogram.............................................................................................................29
10.5
Other Safety Parameters ...................................................................................................30
10.5.1
YMRS Scale.......................................................................................................30
10.5.2
EPS Scales..........................................................................................................31
10.5.3
Suicidality Assessment.......................................................................................31
11.0
HEALTH OUTCOMES ANALYSES............................................................................................32
12.0
INTERIM ANALYSIS ...................................................................................................................33
13.0
DETERMINATION OF SAMPLE SIZE .......................................................................................34
14.0
STATISTICAL SOFTWARE.........................................................................................................35
15.0
DATA HANDLING CONVENTIONS ..........................................................................................36


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15.1
Visit Time Windows.........................................................................................................36
15.2
Derived Variables .............................................................................................................37
15.2.1
Scoring Algorithm of SF-12V2 ..........................................................................38
15.3
Repeated or Unscheduled Assessments of Safety Parameters..........................................42
15.4
Missing Date of the Last Dose of STudy Treatment.........................................................42
15.5
Missing Severity Assessment for Adverse Events............................................................42
15.6
Missing Causal Relationship to study drug for Adverse Events.......................................42
15.7
Missing Date Information for Adverse Events .................................................................42
15.8
Missing Date Information for Prior or Concomitant Medications....................................44
15.8.1
Incomplete Start Date.........................................................................................44
15.8.2
Incomplete Stop Date .........................................................................................45
15.9
Character Values of Clinical Laboratory Parameters........................................................46
16.0
COVID-19 RELATED ANALYSES..............................................................................................47
16.1
Efficacy evaluation ...........................................................................................................47
16.2
Safety and other evaluations.............................................................................................48
17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL..........................................................50
18.0
APPENDICES ................................................................................................................................51
Appendix I
Pattern-Mixture Model Details...........................................................................51
Appendix II:
Reporting Selected Laboratory Parameters in Conventional Units ....................56
Appendix III:
Summary of Major Changes for SAP Amendment 2 .........................................57
19.0
REFERENCES ...............................................................................................................................58
LIST OF TABLES
Table 3-1
Treatment Regimen and Dosing ................................................................. 7
Table 3-2
Schedule of Visits and Procedures.............................................................. 8
Table 10-1
Clinical Laboratory PCS Criteria.............................................................. 26
Table 10-2
The Criteria for Treatment-emergent Significant Changes in Lipids and 
Glucose
................................................................................................................... 27
Table 10-3
Criteria for Potentially Clinically Significant Vital Signs........................ 28
Table 10-4
Criteria for Potentially Clinically Significant Electrocardiograms........... 30
Table 15-1
Efficacy and Safety Analysis Visit Definitions ........................................ 36
Table 18-1
List of Selected Parameters to be Reported in Conventional Units.......... 56


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2.0
LIST OF ABBREVIATIONS
ADT
antidepressant therapy
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ANCOVA
analysis of covariance
ATRQ 
Antidepressant Treatment Response Questionnaire 
CGI-I
Clinical Global Impressions–Improvement
CGI-S
Clinical Global Impressions–Severity 
CRF
case report form
DB
Double-blind
ECG
electrocardiogram, electrocardiographic
HAM-A
Hamilton Rating Scale for Anxiety
HAMD-17
Hamilton Depression Rating Scale, 17 items
IP
Investigational Product
ITT
intent-to-treat
LOCF
last observation carried forward
MADRS
Montgomery-Åsberg Depression Rating Scale 
MDD
major depressive disorder
MMRM
mixed-effects model for repeated measures
PCS
potentially clinically significant
PID
participant identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓)


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SAE
serious adverse event
SAP
statistical analysis plan
SI
Le Système International d’Unités (International System of Units)
TEAE
treatment-emergent adverse event


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3.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined and/or specified in the 
final protocol of Study 3111-302-001 (version dated 23 Jul 2018) and the most recent 
amendment (amendment 3, dated 27 Jul, 2020). Specifications of tables, figures, and data 
listings are contained in a separate document. The SAP for pharmacokinetic/
pharmacodynamic will be prepared separately.
Study 3111-302-001 is a Phase 3, global, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group fixed dose study in participants 18 to 65 years of age
comparing cariprazine 1.5 mg/day and cariprazine 3 mg/day with placebo as an 
adjunctive treatment to ongoing ADT in outpatients with a diagnosis of MDD (via the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5]) who have 
an inadequate response, as measured by the modified Antidepressant Treatment Response 
Questionnaire (ATRQ), to 1 to 3 antidepressants administered during the current episode 
at an adequate dose (as defined per package insert) and duration of ≥ 6 weeks, with at 
least one dose escalation during the current depressive episode, and have a total score 
≥22 on the Hamilton Depression Rating Scale-17 items (HAMD-17). Participants, who 
in the current episode, have had an inadequate response to an ADT taken above the 
minimum dose (per package insert), and for at least 6 weeks, can be enrolled. The study 
will consist of up to 14 days of screening and washout of prohibited medications 
followed by 6 weeks of DB treatment followed by a 4-week safety follow-up. Signed
informed consent from the participant or the participant’s legally authorized 
representative will be obtained before any study-related procedures are begun. 
Participants meeting the inclusion criteria will be randomized (1:1:1 ratio) to 1 of 
3 treatment groups (cariprazine 1.5 mg/day +ADT or cariprazine 3 mg/day +ADT or 
placebo + ADT), stratified by ADT failure category (one ADT failure, more than one 
ADT failure) and the country. 
During the DB treatment period (6 weeks), participants will take 1 capsule of IP, orally,
per day in addition to their ongoing ADT as shown in Table 3-1.
The primary analysis will be performed after all participants have completed the 4-week 
safety follow-up or discontinued from the study and the database has been locked and
unblinded.


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Table 3-1
Treatment Regimen and Dosing
Drug/Dose
Investigational Product 
Frequency
Route of Administration
Double-Blind Treatment Period (Visit 2 through Visit 6)
Placebo
Once daily
Oral (capsule)
Cariprazine 1.5 mg
Once daily
Oral (capsule)
Cariprazine 3 mg (1.5 mg/day for 2 weeks, 
starting at Visit 2 [Baseline]; 3 mg/day from 
Visit 4 [Week 2] through Visit 6 [Week 6])
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.
COVID-19 pandemic emerged after March 11, 2020 when WHO declared COVID-19 a 
global pandemic. The Section 16.0 is added to specify analyses for evaluating the impact 
of COVID-19.
The COVID-19 pandemic has potential to impact the conduct of this study, due to 
possible effects on treatment duration and the collection, analysis and the interpretation 
of clinical trial data. Some protocol-specified visits in this study could possibly be 
impacted due to COVID-19 or logistical restrictions during the pandemic. For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic. Impacted visits due to COVID-19 will be 
recorded in the database. The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values. Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at
random (MAR) and the statistical models that require MAR assumption are appropriate. 
The intent is to provide reliable estimates of the treatment effects targeted in the protocol 
under the scenario without the impact of COVID-19 pandemic. In addition to the planned 
sensitivity analyses for the primary and key secondary endpoint, one additional
sensitivity analysis may be performed to assess the impact of missing data due to 
COVID-19 and the robustness of the conclusion. Details are provided in Section 16.1.
The schedule of evaluations for Study 3111-302-001 is presented in Table 3-2.






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d Clinical laboratory tests include hematology, serum chemistry, urinalysis (including urine myoglobin 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), and blood alcohol, as well as 
serum pregnancy test in women of childbearing potential.
e Urine drug screen, blood alcohol concentration, and serum pregnancy test can be repeated at random at request of investigator. 
f Height will be measured only at Visit 1 (Screening). Waist circumference will be measured at Visits 2 and 6/ET.
g SAFER/remote telephone interview will be scheduled and implemented before Visit 2 (Baseline) for patients who meet the screening criteria at 
Visit 1. The patient’s SAFER evaluation score should be reviewed before Visit 2 to confirm eligibility.
h Pharmacogenetic consent may be obtained at any time between Visit 1 (Screening) and Visit 6 (Week 6).
i Pharmacogenetic sampling (1 per patient for the entire study) may be obtained from randomized patients at any time between Visit 2 (Baseline) and 
Visit 6 (Week 6).
j Can be taken at any time during visits 4, 5 and 6/ET. 
k May be up to an additional 7 days (up to 21 days) if needed with Sponsor approval.


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4.0
OBJECTIVES
The objective of this study is to evaluate the efficacy, safety, and tolerability of 
cariprazine 1.5 mg/day and 3 mg/day compared with placebo as an adjunctive treatment
to ADT in patients with MDD who have had an inadequate response to antidepressants 
alone.


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5.0
ANALYSIS POPULATIONS
Four populations will be considered in the statistical analysis of the study.
5.1
SCREENED POPULATION
The screened population will consist of all screened participants who sign informed 
consent.
5.2
RANDOMIZED POPULATION
The randomized population will consist of all participants in the screened population who 
were randomized to a treatment group.
5.3
SAFETY POPULATION
The safety population will consist of all participants in the randomized population who 
took at least 1 dose of double-blind investigational product.
Participants will be included in the treatment group corresponding to the double-blind 
investigational product they actually received in the safety population. 
5.4
MODIFIED INTENT-TO-TREAT POPULATION
The modified intent-to-treat (mITT) population will consist of all randomized participants 
with ≥1 postbaseline assessment of the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score.
Participants will be included in the randomized treatment group for the mITT population.
5.5
STUDY-SPECIFIC DATA EXCLUDING ONE NON-
COMPLIANT SITE
Due to multiple non-compliance issues at one study site (site #130), additional sensitivity 
analyses will be performed by excluding this site from the following:

Demographic characteristics based on the Safety and mITT populations,

Baseline characteristics based on the mITT population,

Primary efficacy analysis (MMRM) based on the mITT population,

Key secondary efficacy analysis (MMRM) based on the mITT population,

Overall summary of safety (TEAEs, TESAEs, Death, TEAEs leading to 
discontinuation from study) based on the Safety population, and

TEAEs by SOC and PT based on the Safety population.


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6.0
PARTICIPANT DISPOSITION
The number and percentage of participants in the Randomized, Safety, and mITT 
Populations will be summarized by treatment group and study center; the number of
participants screened will be summarized overall only by study center. The number and 
percentage of participants in the Randomized, Safety, and mITT Populations will be 
summarized by treatment group and background ADT as well. 
Screen-failure participants (ie, participants screened but not randomized) and the 
associated reasons for failure to randomize will be tabulated overall for the screened 
participants. The number and percentage of participants who prematurely discontinued 
during the double-blind (DB) treatment period, and who entered the safety follow-up
(SFU) period will be presented for each treatment group and pooled across treatment
groups for the safety population. The reasons for premature discontinuation from the 
double-blind treatment period and the safety follow-up period as recorded on the
disposition pages of the electronic case report forms (eCRFs) will be summarized 
(number and percentage) by treatment group and overall for the safety population. All 
participants who prematurely discontinue will be listed by discontinuation reason by 
period (the DB treatment period and the SFU period) for the safety population. The 
participants who were randomized but were not included in the safety population or the 
mITT population will be listed. 
6.1
PROTOCOL DEVIATIONS
The number and percentage of participants with significant protocol deviations will be 
summarized by deviation category and treatment group for the Randomized Population. 
Supportive listings will also be provided. 
These significant protocol deviations will be reviewed and documented before database 
lock and unblinding of treatment codes.


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7.0
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
Demographic parameters (eg, age, race, sex, ethnicity), baseline characteristics (weight, 
height, body mass index, ADT failure category, Country, ADT failure category by 
Country) will be summarized by treatment group for the safety and mITT populations, 
and baseline efficacy variables will be summarized by treatment group for the mITT 
population. Continuous variables will be summarized by number of participants and 
mean, SD, median, minimum, and maximum values. Categorical variables will be 
summarized by number and percentage of participants.
The ADT failure category based on eCRF will be considered primary data on ADT 
failure and will be used in all the statistical models rather than the one based on IWRS.
Abnormalities in participants’ medical and surgical histories will be coded using the 
Medical Dictionary for Regulatory Activities, version 24.0. The number and percentage
of participants with abnormalities in medical and surgical histories in each system organ
class and preferred term will be summarized by treatment group for the Safety 
Population. Psychiatric history, non-drug psychiatric treatment, history of ocular events 
of special interest will be summarized by treatment group for the Safety Population.
Prior medication is defined as any medication taken before the date of the first dose of 
DB IP. Concomitant medication is defined as any medication taken on or after the date of 
the first dose of investigational product, and will be summarized for both double-blind 
treatment period and safety follow-up period.
The March 2017 version of the World Health Organization (WHO) Drug Dictionary 
Enhanced will be used to classify prior and concomitant medications by therapeutic class.
The number and percentage of participants with prior and concomitant drug use will be 
summarized by treatment group and Anatomical Therapeutic Chemical 4 code for the 
safety population.  Multiple drug use by a participant in the same category will be 
counted only once in the summary tables. 
Rescue medications 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
In addition, the number of ADT failures for current episode of depression and the status 
of presently taking ADTs based on ATRQ eCRF will be summarized for the safety
population by treatment group.


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8.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
8.1
EXTENT OF EXPOSURE
Exposure to the DB IP for the Safety Population during the double-blind treatment period 
will be summarized for treatment duration, calculated as the number of days from the 
date of the first dose of DB IP to the date of the last dose of DB IP, inclusive. Descriptive 
statistics (number of participants, mean, SD, median, minimum, and maximum) will be 
presented by treatment group.
Exposure to open-label ADT for the Safety Population during the double-blind treatment 
period will be summarized for treatment duration, calculated as the number of days from 
the date of the first dose taken to the date of the last dose taken, inclusive, during the DB 
treatment period.
Patient-years, defined as exposure to the DB IP in years, will be summarized by 
treatment for the safety population.
8.2
MEASUREMENT OF TREATMENT COMPLIANCE
Dosing compliance for the double-blind investigational product during a specified period 
is defined as the total number of capsules actually taken by a participant during that 
period divided by the number of capsules that were expected to be taken during the same 
period multiplied by 100. The total number of capsules actually taken during a specific
period is calculated as the number of days in that period multiplied by the number of 
capsules taken each day during that period. The number of capsules expected to be taken 
for a specific treatment period will be calculated by multiplying the number of days in 
that period by the number of capsules to be taken per day. Descriptive statistics for 
investigational product compliance will be presented by treatment group for each period 
between 2 consecutive visits, as well as for the period from the first dose of DB IP 
actually taken to the last dose of DB IP actually taken for the Safety Population
Dosing compliance for the background ADT during a specified period is defined as the 
dose actually taken by a participant during that period divided by the dose expected to be
taken during the same period multiplied by 100. Descriptive statistics for ADT 
compliance will be presented for each ADT and overall by the double-blind 
investigational product treatment group for the period from the first dose of DB IP 
actually taken to the last dose of DB IP actually taken for the Safety Population.


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9.0
EFFICACY ANALYSES
All efficacy analyses will be based on the mITT population. Baseline for efficacy is 
defined as the last non-missing efficacy assessment before the date of the first dose of DB
IP. All statistical tests will be conducted at the α=0.05 (2-sided) level for main effects. 
All confidence intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise.
For efficacy analyses in which country is a factor, a small country will be defined as a 
country with fewer than 2 participants in at least one treatment group in the mITT 
Population. Small countries will be pooled to form pseudo-countries so that each 
treatment group includes at least 2 mITT participants within the country. Countries will 
be ranked on number of participants that are part of the mITT Population and lowest 
ranked countries will be pooled (sequentially, i.e., a new ranking is made after each step) 
until the smallest pooled country has reached at least 2 participants in each treatment 
group.
To compare with historic studies, some analyses based on the imputed data using the 
last-observation-carried-forward (LOCF) approach, will be presented for all efficacy 
parameters. Only the postbaseline total score of a parameter will be imputed; individual 
item scores will not be carried forward. The baseline value will be carried forward only 
for the intermittent missing values immediately after baseline. If all the postbaseline 
values are missing, the baseline value will not be carried forward.
9.1
PRIMARY EFFICACY PARAMETER
The primary estimand is provided below through specification of the population, the 
variable, the handling of intercurrent events, and the population-level summary. 
Population
The target population are participants with MDD who have had an inadequate response to 
antidepressant therapy in the current episode and who satisfy the inclusion and exclusion 
criteria as specified in the protocol.
The analysis population is defined to be the mITT population consisting of all 
randomized participants with ≥ 1 postbaseline assessment of the MADRS total score.
Variable
The variable is the primary efficacy endpoint, change from baseline to Week 6 in the 
MADRS total score.
Accounting of Intercurrent Events
Intercurrent events and their handling rules are described as follows:


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
Regardless of whether allowed rescue medications are taken or not, data are 
included in the analysis. Participants are still taking assigned drugs as specified in 
the protocol while taking allowed rescue medications. The clinical objective is to 
assess the efficacy of the treatment regardless of allowed rescue medication use. 

To evaluate the efficacy at Week 6 in the mITT population, participants are 
assumed to adhere to the assigned treatment for the duration of the study. As a 
result, data after the discontinuation from the study treatment due to all reasons 
will not be included in the primary analysis and they will be assumed as missing 
at random. 
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary 
variable means between each cariprazine group and placebo.
To address the primary hypotheses that each dose of cariprazine is superior to placebo in 
the reduction of MADRS total score after 6 weeks of treatment, the change from baseline 
in MADRS total score will be analyzed using a mixed-effects model for repeated 
measures (MMRM) with treatment group, pooled country, ADT failure category (per 
CRF), 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 to model the covariance of within-participant scores. The Kenward-
Roger approximation (Kenward and Roger, 1997) will be used to estimate denominator 
degrees of freedom. In the event of non-convergence of the model using unstructured 
covariance matrix, a structured covariance matrix will be used in combination with 
empirical variance estimate (i.e., sandwich estimator) to address the potential mis-
specified situation. The following sequence of alternative covariance structures (First-
order ante-dependence [ANTE (1)], Toeplitz [TOEP], First-order autoregressive [AR (1)] 
and compound symmetry[CS]) will be considered in the MMRM until convergence.
The analysis will be performed based on all postbaseline scores using only the observed 
cases without imputation of missing values. The treatment difference in the primary 
endpoint at Week 6 for each active treatment group versus placebo in the mITT 
population will be estimated and reported along with the corresponding 95% CI and the 
p-value.
The two-stage mixture parallel gatekeeping procedure (Dmitrienko 2011) (truncated
Hochberg with truncation parameter of 0.9 for the primary endpoint and regular 
Hochberg for the secondary endpoint) will be used to control the overall type I error rate 
at a 0.025 level (1-sided) for multiple comparisons of 2 active doses with placebo for the 
primary endpoint and key secondary endpoint. Details are provided in Section 9.2.
The study will be considered positive if at least 1 dose arm of cariprazine is statistically 
superior to placebo for change from baseline in MADRS total score at Week 6 after
multiplicity adjustment.


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A sensitivity analysis using a pattern-mixture model based on non–future-dependent 
missing value restrictions (Kenward et al, 2003) will be performed to assess the 
robustness of the primary MMRM results to the possible violation of the 
missing-at-random assumption. The details of this sensitivity analyses are as follows:
The pattern for the pattern-mixture model will be defined by the participant’s last visit 
with an observed value. The observed MADRS total score at a visit is assumed to have a 
linear relationship with the participant’s prior measurements. The missing values will be 
imputed under the assumption that the distribution of a missing observation differs from 
the observed only by a shift parameter value Δ. The dataset with missing values imputed 
will be analyzed using an analysis-of-covariance (ANCOVA) model with treatment 
group, pooled country, and ADT failure category (per CRF), as factors and baseline 
MADRS total score as a covariate for between–treatment-group comparison at Week 6. 
The imputation of missing values and the analysis will be performed multiple times, and 
the inference of this sensitivity analysis will be based on the combined estimates using 
the standard multiple imputation technique. The values for Δ will be selected as 0 to 6, 
inclusively. This range is selected because the mean reduction of MADRS score from 
baseline within a treatment group at Week 6 is likely to be within 15 points (Durgam et 
al, 2016; El-Khalili et al, 2010), and a Δ value of 6 accounts for 40% of treatment 
efficacy.
The second sensitivity analysis will consider dropout reasons while imputing missing 
values after the discontinuation. Participants who discontinued due to lack of efficacy in 
the cariprazine arms are assumed to have no treatment effect after the discontinuation. 
These participants are assumed to copy the profile of placebo arm and missing values are 
imputed based on the distribution estimated from the placebo group using copy-reference 
approach (Carpenter et al, 2013). The rest of missing values in the placebo arm and 
cariprazine arms will be imputed using the observed data in their respective group under 
the MAR assumption.
Least squares means and their standard errors for change in MADRS total score based on 
the MMRM analysis will be plotted by treatment group and visit. Mean treatment 
difference (raw mean difference ± standard error) in change in primary endpoint between 
each cariprazine dose and placebo with missing values imputed using the LOCF approach 
will be plotted against country. In addition, summary statistics will be provided by center 
to examine the consistency of treatment effect across the study centers.  The impact of 
dropouts on the efficacy outcomes will be explored graphically by plotting the time 
courses of mean changes by dropout reason. 
To compare with historic studies, the LOCF approach will be used with an ANCOVA 
model that has treatment group, pooled country and ADT failure category (per CRF) as 
factors and the baseline value as the covariate. Results of analyses from MMRM and 
from ANCOVA models will also be reported for each visit between baseline and Week 6. 


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To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a 95% CI) for each cariprazine dose 
versus placebo for the primary efficacy variable will be estimated within each category of 
the following classification variables:

ADT failure category (one ADT failure, more than one ADT failure)

Region (US, Non-US)
The treatment effect within each category of a subgroup factor will be assessed using 
MMRM with terms including treatment group, visit, and treatment group-by-visit 
interaction, the baseline value and baseline-by-visit interaction, in addition to one term 
defined as following: 

Add term ADT failure category while conducting region subgroup analyses

Add term Country while conducting ADT failure category subgroup analyses.
Treatment effects and nominal 95% CI by category for the classification variables listed 
above will be reported. Because the sample size for a specific subgroup category might 
be small, the MMRM might not converge, in which case only summary statistics using 
the LOCF data at Week 6 will be reported.
9.2
KEY SECONDARY EFFICACY PARAMETER
The key secondary endpoint is the change from baseline to Week 6 in the CGI-S score.
To test the secondary hypotheses that each dose of cariprazine is superior to placebo in 
the reduction of CGI-S score after 6 weeks of treatment, the change from baseline in 
CGI-S score will be analyzed using the MMRM approach similar to the one used for the 
primary analysis. A sensitivity analysis will also be performed using ANCOVA (with 
LOCF imputation) as used for the analysis of primary endpoint.
To control the overall familywise type I error rate at the 0.025 level (one-sided), a 
truncated Hochberg will be used for the primary endpoint, and the regular Hochberg 
procedure for the key secondary endpoint. The truncation parameter will be set to γ = 0.9
(Dmitrienko 2011).
The cariprazine dose groups will be labeled as Dose 1 (1.5 mg) and Dose 2 (3.0 mg).
The null hypotheses can be grouped into two families:
(i)
Family 1 includes the null hypotheses 
for the primary endpoint:
denotes the null hypothesis of the difference in mean change from baseline in 
MADRS at Week 6 between cariprazine Dose 1 and placebo is ≥ 0.
denotes the null hypothesis of the difference in mean change from baseline in 
MADRS at Week 6 between cariprazine Dose 2 and placebo is ≥ 0.


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(ii)
Family 2 includes the null hypotheses 
for the key secondary endpoint: 
denotes the null hypotheses of the difference in mean change from baseline in 
CGI-S at Week 6 between cariprazine Dose 1 and placebo is ≥ 0.
denotes the null hypotheses of the difference in mean change from baseline in 
CGI-S at Week 6 between cariprazine Dose 2 and placebo is ≥ 0.
The gatekeeping procedure utilizes the following decision rules:
(i)
Step 1. The null hypotheses in Family 1 are tested using the truncated Hochberg 
procedure at the full α level. Let
<
denote the ordered p-values in Family 
1 and let 
and
denote the associated null hypotheses. The truncated 
Hochberg procedure rejects both
and 
if
or it rejects 
only
if 
and 
.
(ii) 
Step 2. The null hypotheses in Family 2 are tested as follows:
(i)
The null hypotheses are tested using the regular Hochberg procedure at the 
full α level if both
and 
are rejected. Let 
<
denote the 
ordered p-values in Family 2 and let 
and 
denote the associated 
null hypotheses. The Hochberg procedure rejects both 
and 
if 
or it rejects only 
if 
and 
.
(ii)
The null hypothesis logically related to
is tested at 
if 
is rejected and 
is not rejected.
(iii) 
Step 3. If only one null hypothesis is rejected in Family 1 and only one null 
hypothesis is rejected in Family 2, the remaining null hypothesis in Family 1 is re-
tested at the full α level. If this null hypothesis is rejected, the associated null 
hypothesis in Family 2 is tested at the full α level.
9.3
ADDITIONAL EFFICACY PARAMETER(S)
Additional efficacy parameters will include the following at postbaseline visits described 
in Table 3-2:

Change from baseline in MADRS total score at Weeks 1, 2, 4

Change from baseline in the CGI-S score at Weeks 1, 2, 4

CGI-I score at Weeks 1, 2, 4, 6


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
CGI-I response (CGI-I score ≤ 2) at Weeks 1, 2, 4, 6

MADRS response (≥ 50% reduction from baseline in MADRS total score) at Weeks
1, 2, 4, 6

MADRS remission (MADRS total score ≤ 10) at Weeks 1, 2, 4, 6

Change from baseline in the HAMD-17 total score at Week 6

Change from baseline in the HAM-A total score at Week 2, 6

HAM-A response (≥50% reduction from baseline in HAM-A total score) at Weeks 2, 
6

HAM-A remission (HAM-A total score ≤ 7) at Weeks 2, 6

Change from baseline in MADRS individual item scores at Weeks 1, 2, 4, 6

Change from baseline in HAM-A individual item scores at Weeks 2, 6
Additional quantitative efficacy parameters will be analyzed in the following way:
Analysis of CGI-I score, change from baseline in HAM-A total score, change from 
baseline in MADRS and HAM-A individual item scores, and change from baseline in 
CGI-S will be performed using a similar MMRM to that used for the primary analysis. 
Baseline CGI-S score will be used as a covariate for the analysis of CGI-I score. In 
addition, these parameters will be analyzed using ANCOVA (with LOCF imputation) as 
used for the analysis of primary efficacy parameters.
Change from baseline in HAMD-17 total score will be analyzed based on ANCOVA
model using observed cases, with treatment group, pooled country, and ADT failure 
category (per CRF) as factors and baseline HAMD-17 total score as a covariate for 
between–treatment-group comparisons at Week 6.
Additional categorical efficacy parameters will be analyzed in the following way:
Rates for categorical parameters (response and remission) will be reported by treatment 
group and by visit; a logistic regression model (with LOCF imputation) will be used to 
model the probability of a response or the probability of a remission as a function of a 
treatment group, pooled country, ADT failure category (per CRF) and the corresponding 
baseline score (CGI-S for the analysis of the CGI-I response) as explanatory variables.


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10.0
SAFETY ANALYSES
The safety analysis will be performed using the safety population for the double-blind 
treatment period and safety follow-up period. The double-blind treatment period starts
with the first dose of double-blind investigational product and ends with the last 
scheduled assessment at Visit 6 (Week 6) or early termination (before Week 6). The 
safety follow-up period starts the day after the last scheduled assessment at Visit 6 (or
early termination) and ends with the last safety follow-up visit. The safety parameters 
will include adverse events (AEs), clinical laboratory parameters, vital signs, 
electrocardiogram (ECG) parameters, EPS scales, the C-SSRS and the YMRS. For each 
safety parameter, the last assessment made before the first dose of double-blind 
investigational product will be used as the baseline for all analyses of that safety 
parameter. The summarization will be by treatment group for both double-blind and 
safety follow-up periods. Continuous variables will be summarized by number of 
participants and mean, SD, median, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of participants.
10.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 24.0.
An adverse event (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 DB investigational product. Per case report form 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 study intervention.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE 
criterion.
For the DB treatment period, the number and percentage of participants reporting TEAEs 
in each treatment group 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 the IP. If more than 1 AE is coded to the same preferred term for
the same participant, the participant 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 the IP.
The distribution of TEAEs by severity and relationship to the IP will be summarized by 
treatment group.


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The TEAEs during the safety follow-up period will be summarized by body system, 
preferred term, and treatment group for the safety population.
An AE that occurs more than 30 days after the date of the last dose of DB IP or occurs 
after the last safety follow-up 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 participants with common (≥ 2% of participants in any 
treatment group) TEAEs, will be summarized by preferred term and treatment group for 
the double-blind period. 
Summary tables will be provided for participants with TESAEs and participants with
TEAEs leading to discontinuation if these occurred in 5 or more participants. The number 
and percentage of participants with TESAEs will be summarized for both the double-
blind and safety follow-up periods.
Listings will be presented for participants with SAEs, participants with AEs leading to 
discontinuation, and participants who die (if any). All participants with SAEs, including 
SAEs reported during the screening period and the safety follow-up period, and 
participants discontinuing because of AEs occurring before the start of DB IP will be 
included in these listings.
The number and percentage of participants reporting TEAEs of ocular events of special 
interest during the double-blind treatment period will be summarized. A listing of all 
reported ocular events of special interest will be provided.
The number and percentage of participants with EPS TEAEs, EPS treatment-emergent 
SAEs, and the number and percentage of participants with EPS TEAEs leading to 
premature discontinuation during the double-blind treatment period will be summarized 
for the double-blind treatment period.
For EPS AEs, the preferred terms include:
Akathisia, Restlessness, Dystonia cluster (Dystonia, Myoclonus, Oculogyric crisis, 
Oromandibular dystonia, Tongue spasm, Trismus, Torticollis), Parkinsonism cluster
(Akinesia, Bradykinesia, Cogwheel rigidity, Drooling, Dyskinesia, Extrapyramidal 
disorder, Hypokinesia, Reduced facial expression, Muscle rigidity, Muscle tightness, 
Parkinsonism, Salivary hypersecretion, Tremor), Musculoskeletal stiffness, and Tardive 
dyskinesia.
For EPS AEs excluding Akathisia/Restlessness, the preferred terms include all the terms 
listed above except Akathisia and Restlessness.


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Any EPS TEAEs including Akathisia/Restlessness, any EPS TEAEs excluding 
Akathisia/Restlessness, and any TEAEs of Akathisia/Restlessness will also be 
summarized.
10.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point will be presented by treatment group 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)
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
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 II:. A description of reporting the lab values in 
conventional units in participant narratives (along with the standard reporting in SI units) 
is presented at the end of Appendix II:. Only participants with clinical laboratory data at 
baseline and at least one postbaseline visit during the double-blind period will be 
included in the summary.
Laboratory tests values are considered to be potentially clinically significant (PCS) if
they meet either the low or high PCS criteria listed in Table 10-1. The number and 
percentage of participants with PCS postbaseline clinical laboratory values will be 
tabulated by treatment group. The percentages will be calculated relative to the number of 
participants with available non-PCS baseline values and at least 1 postbaseline 
assessment. The numerator will be the total number of participants with available non-
PCS baseline values and at least 1 PCS postbaseline value. A supportive listing of 
participants with PCS postbaseline values will be provided, including the participant
identification number, study center number, and baseline and postbaseline values. A 
listing of all AEs occurring in participants who have PCS laboratory values will also be 
provided.


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The number and percentage of participants with treatment-emergent significant changes 
in lipid parameters (total cholesterol, low-density lipoprotein cholesterol, high-density 
lipoprotein cholesterol, and triglycerides) and glucose will be tabulated by treatment 
group for the DB treatment period. The criteria for treatment-emergent significant 
changes in lipids and glucose is provided in Table 10-2. Percentages will be calculated 
relative to the number of participants with baseline values meeting the specified baseline 
criteria and with at least 1 postbaseline assessment. The change in lipids and glucose 
from baseline to the highest (lowest for high-density lipoprotein cholesterol) postbaseline 
measurement will be summarized. Supportive listings of participants with treatment-
emergent changes in lipids and glucose values will be provided.
The number and percentage of participants meeting potential Hy’s Law criteria (elevation 
of alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥ 3x ULN with 
total bilirubin [TBL] ≥ 2x ULN and alkaline phosphatase [ALP] < 2x ULN in a 24-hour 
period) and Concurrent Elevations criteria in a 24-hour period will be tabulated by DB 
treatment group for the safety population. A supportive listing will be provided. 
Concurrent Elevations in a 24-hour period are defined as:
1. ALT or AST ≥ 3x ULN and TBL≥ 1.5 x ULN
2. ALT or AST ≥ 3x ULN and TBL≥ 2 x ULN


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Table 10-1
Clinical Laboratory PCS Criteria
Laboratory Parameter
SI Unit
PCS Criteria
Low Values
PCS Criteria
High Values
Hematology
Hemoglobin
g/L
< 0.9 × LLN
—
Hematocrit
%
< 0.9 × LLN
—
Eosinophils
%
—
> 10
Neutrophils
%
< 30
> 90
Basophils
%
—
> 6
Monocytes
%
—
> 20
Lymphocytes
%
< 10
> 60
Absolute neutrophils
109/L
< 1.0
—
Platelet count
109/L
≤ 75
≥ 700
White cell count
109/L
≤ 2.5
≥ 15
Chemistry
Albumin
g/L
< 0.9 × LLN
> 1.1 × ULN
Alkaline phosphatase
U/L
—
≥ 3 × ULN
ALT
U/L
—
≥ 3 × ULN
AST
U/L
—
≥ 3 × ULN
GGT
U/L
—
≥ 3 × ULN
LDH
U/L
—
≥ 3 × ULN
Blood urea nitrogen
mmol/L
—
> 1.2 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol
mmol/L
—
> 1.3 × ULN
HDL
mmol/L
< 0.8 × LLN
—
LDL
mmol/L
—
> 1.2 × ULN
CPK
U/L
—
> 1.5 × ULN
Creatinine
μmol/L
—
> 1.3 × ULN
Glucose, fasting
mmol/L
< 0.8 × LLN
> 1.2 × ULN
Magnesium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Total bilirubin
μmol/L
—
> 1.5 × ULN
Total protein
g/L
< 0.9 × LLN
> 1.1 × ULN
Triglycerides, fasting
mmol/L
—
> 1.2 × ULN
Uric acid
μmol /L
—
> 1.1 × ULN
Urinalysis
Protein
—
—
At least 2 +
Glucose
—
—
At least 2 +
Blood
—
—
At least 2 +
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; GGT = gamma
glutamyl transferase; HDL = high-density lipoprotein; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; 
LLN = lower limit of normal laboratory reference range; PCS = potentially clinically significant; SI = Le Système 
International d'Unités (International System of Units); ULN = upper limit of normal laboratory reference range.


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Laboratory Parameter
SI Unit
PCS Criteria
Low Values
PCS Criteria
High Values
Fasting: Includes both, fasting and unspecified fasting status.
Table 10-2
The Criteria for Treatment-emergent Significant Changes in Lipids 
and Glucose 
Laboratory Parameter
Measurement
Category
Criteria
Total cholesterol (Fasting or Non-
fasting)
Actual
Normal
< 200 mg/dL
Borderline
≥ 200 and < 240 mg/dL
Normal/Borderline
< 240 mg/dL
High
≥ 240 mg/dL
Borderline/High
≥ 200 mg/dL
Change from baseline
Increase ≥ 40 mg/dL
Increase ≥ 40 mg/dL
LDL Cholesterol* (Fasting)
Actual
Normal
< 100 mg/dL
Borderline
≥ 100 and < 160 mg/dL
Normal/Borderline
< 160 mg/dL
High
≥ 160 mg/dL
Borderline/High
≥ 100 mg/dL
Change from baseline
Increase ≥ 30 mg/dL
Increase ≥ 30 mg/dL
HDL Cholesterol (Fasting and 
Non-Fasting)
Actual
Normal
≥ 40 mg/dL
Low
< 40 mg/dL
Change from baseline
Decrease ≥ 20 mg/dL
Decrease ≥ 20 mg/dL
Triglycerides (Fasting)
Actual
Normal
< 150 mg/dL
Borderline
≥ 150 and < 200 mg/dL
Normal/ Borderline
< 200 mg/dL
High
≥ 200 mg/dL
Very High
≥ 500 mg/dL
Borderline/High/Very 
High
≥ 150 mg/dL
≥1000 mg/dL
≥ 1000 mg/dL
Change from baseline
Increase ≥ 50 mg/dL
Increase ≥ 50 mg/dL
Triglycerides (Non-Fasting)
Actual
Very High
≥ 500 mg/dL
≥1000 mg/dL
≥1000 mg/dL
Serum Glucose (Fasting)
Actual
Normal
< 100 mg/dL
Impaired
≥ 100 and < 126 mg/dL
Normal/ Impaired
< 126 mg/dL
High
≥ 126 mg/dL
Change from baseline
Increase ≥ 10 mg/dL
Increase ≥ 10 mg/dL
Serum Glucose (Non-Fasting)
Actual
Normal
< 140 mg/dL
Borderline
≥ 140 and < 200 mg/dL
Normal/Borderline
< 200 mg/dL
High
≥ 200 mg/dL
Borderline/High
≥ 140 mg/dL
Change from baseline
Increase ≥ 20 mg/dL
Increase ≥ 20 mg/dL
* LDL direct and LDL calculated are combined.
Fasting: Includes both, fasting and unspecified fasting status.


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10.3
VITAL SIGNS
Descriptive statistics for vital signs (supine radial pulse rate, supine systolic and diastolic
BP, body weight, waist circumference, BMI and temperature) and changes from baseline 
values at each visit and at the end of the double-blind treatment period will be presented 
by treatment group.
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 are provided in
Table 10-3. The percentages will be calculated relative to the number of participants with 
baseline values and at least 1 postbaseline assessment. The numerator will be the total 
number of participants with available baseline values and at least 1 PCS postbaseline
value. A supportive listing of participants with postbaseline PCS values will be provided, 
including the participant identification number, study center number, and baseline and 
postbaseline values. A listing of all AEs occurring in participants who have PCS vital 
sign values will also be provided.
Table 10-3
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteria
Observed Value
Change From Baseline
Supine systolic blood 
pressure, mm Hga
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Supine diastolic blood 
pressure, mm Hga
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Supine pulse rate, 
bpma
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.
The number and percentage of participants with PCS weight increase or decrease will 
also be provided by baseline BMI categories (underweight [< 18.5 kg/m2], normal [≥ 18.5 
and < 25 kg/m2], overweight [≥ 25 and < 30 kg/m2], and obese [≥ 30 kg/m2]) by 
treatment group for the safety population. 


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The number and percentage of participants 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 measured after the participant
stands up after resting in the supine position. Standing measurements should be taken 
after a sufficient amount of time has passed to allow the BP to equilibrate in the standing 
state. A supportive listing will be provided including the participant identification 
number, study center number, and baseline and postbaseline systolic and diastolic BP 
values (supine and standing). A listing of all AEs occurring in participants who have 
orthostatic hypertension will also be provided. 
As specified in the Seventh Report of the Joint National Committee on prevention, 
detection, evaluation and treatment of high blood pressure (NIH Publication No. 04-5230, 
2004), hypertension status is defined as:

Normotensive: supine SBP < 120 mm Hg and DBP < 80 mm Hg. 

Prehypertension: supine SBP 120 to 139 mm Hg or DBP 80 to 89 mm Hg. 

Stage I Hypertension: supine SBP 140 to 159 mm Hg or DBP 90 to 99 mm Hg. 

Stage II Hypertension: supine SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg.
Tabulations showing the number and percentage of participants with hypertension status 
changes from baseline will be provided for:

Shift of hypertension status from baseline to end of the DB treatment period

Shift of hypertension status from baseline to highest category during the DB 
treatment period 
Supportive listings of participants who have a shift in hypertension status from 
normotensive/prehypertension at Baseline to stage I/stage II hypertension will be 
provided.
10.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS 
interval, QT interval, QTcB interval, and QTcF interval) and changes from baseline 
values at each assessment time point to the end of the DB treatment period will be 
presented by treatment group. The QTc will be calculated using both the Bazett and 
Fridericia corrections (if the vendor does not provide).


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Electrocardiographic parameter values are considered PCS if they meet or exceed the 
higher-limit PCS criteria listed in Table 10-4. The number and percentage of participants 
with PCS postbaseline ECG values will be tabulated by treatment group for the double-
blind treatment period. The percentages will be calculated relative to the number of 
participants with available non-PCS baseline values and at least 1 postbaseline
assessment for the double-blind treatment period. The numerator is the total number of 
participants with available non-PCS baseline values and at least 1 PCS postbaseline value
for the double-blind treatment period. A supportive tabular display of participants with 
PCS postbaseline values will be provided, including the participant identification (PID)
number, baseline, all postbaseline (including non-PCS) values, and change from baseline.
In addition, a tabular display showing all AEs that occurred in participants 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 participants with postbaseline clinically significant ECG abnormalities
according to the Investigator’s overall interpretation will be provided.
Table 10-4
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Higher Limit
QRS interval
msec
≥ 150
PR interval
msec
≥ 250
QTc (QTcB or QTcF) interval
msec
>500 
QTc (QTcB or QTcF) interval
msec
Increase of > 60
QTc = QT interval corrected for heart rate.
10.5
OTHER SAFETY PARAMETERS
Other safety parameters include YMRS, EPS scales (AIMS, BARS, and SAS scores) and
C-SSRS.
10.5.1
YMRS Scale
The number and percentage of participants with treatment-emergent mania will be 
presented by treatment group. Treatment-emergent mania will be defined as an YMRS 
total score of 16 or greater at any postbaseline visit. Descriptive statistics for YMRS total 
score and change from baseline values at each assessment time point will be presented by 
treatment group.


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10.5.2
EPS Scales
A participant will be considered to have treatment-emergent parkinsonism if the 
participant’s SAS score was ≤3 at baseline and > 3 at any DB assessment. A participant
will be considered to have treatment-emergent akathisia if the participant’s BARS score 
was ≤ 2 at baseline and > 2 at any DB assessment. The number and percentage of 
participants reporting treatment-emergent parkinsonism or treatment-emergent akathisia 
will be tabulated by treatment group. Listings of participants with treatment-emergent 
parkinsonism and participants with treatment-emergent akathisia will be provided and 
will include the participant identification number, study center number, and baseline and 
postbaseline values. Listings of all AEs occurring in participants who have treatment-
emergent parkinsonism or treatment-emergent akathisia will also be provided.
Descriptive statistics for EPS scale parameters (AIMS, BARS, and SAS) and changes 
from baseline values at each assessment timepoint in this study will be presented.
10.5.3
Suicidality Assessment 
The number and percentage of patients with suicidal ideation or suicidal behavior as 
recorded on the C-SSRS will be summarized by treatment group. The distribution of 
responses for most severe suicidal ideation and most severe suicidal behavior during the 
patient’s lifetime, during the DB treatment period, and during the safety follow-up period 
will also be presented by treatment group for the safety population. Supportive listings 
will be provided and will include the patient identification number, study center number, 
lifetime history, and postbaseline values. Intensity of suicidal ideation, suicidal behavior 
type, and lethality of suicidal behavior will also be included in these listings. A listing of 
all AEs occurring in patients who have suicidal ideation or suicidal behavior will also be 
provided.


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11.0
HEALTH OUTCOMES ANALYSES
The SF-12 will be administered at Visit 2 and Visit 6/ET. 
Analysis of change from baseline in the PCS-12 and MCS-12 score at Week 6 will be 
analyzed using the ANCOVA (based on observed cases) that has treatment group, pooled 
country, ADT failure category (per CRF) as factors and the baseline value as the 
covariate.
The detailed algorithms for derivation of the PCS-12 and MCS-12 score are presented in 
Section 15.2.1.


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12.0
INTERIM ANALYSIS
No interim analysis is planned for this study.


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13.0
DETERMINATION OF SAMPLE SIZE
The study will randomize approximately 750 participants in a 1:1:1 ratio to cariprazine 
1.5mg/day, cariprazine 3mg/day, and placebo groups. A sample size of 250 participants 
per arm will provide approximately 83% statistical power to show statistically 
significantly higher effect in each dose of cariprazine versus placebo based on the mITT
analysis set. The study has approximately 90% statistical power to show that at least 1 of 
the 2 cariprazine doses is statistically significantly more efficacious than placebo in the 
primary endpoint. These calculations assumed an effect size of 0.286. All statistical 
powers presented in this section were calculated adjusting for multiple comparisons
across the two cariprazine doses and the primary and secondary endpoints using the 
Hochberg-based gatekeeping procedure with re-testing with the family-wise type I error 
rate being controlled at a 0.05 level (2-sided). The dropout rate is assumed to be 15% at 
Week 6. Within-person correlation for the primary endpoint is assumed to be 0.58. This 
value is used in the sample size calculation to calculate an inflation factor that accounts 
for information loss due to the missing data at Week 6 for longitudinal data collection.
Assumptions of effect size, intracorrelation and dropout rate are based on cariprazine 
Study RGH-MD-75.


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14.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux
operating system.


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15.0
DATA HANDLING CONVENTIONS
15.1
VISIT TIME WINDOWS
Table 15-1 presents the visits assigned for efficacy and safety analyses and the 
corresponding range of treatment days (window) during which an actual visit may occur.
Table 15-1
Efficacy and Safety Analysis Visit Definitions
Analysis Phase
Derived Visit
Scheduled Visit Day a
Window
Pretreatment
Baseline
Day 1
Days ≤ 1
Double-blind 
Treatment
Week 1
Day 8
Days [2, 11]
Week 2
Day 15
Days [12, 21]
Week 4
Day 29
Days [22, 35]
Week 6
Day 43
Days ≥ 36 and within Double-
blind Treatment Period
End of Double-Blind 
Treatment Period b
Final double-blind 
treatment visit (expected 
Day 43) or ET visit 
during the double-blind 
treatment period
Final non-missing assessment 
during the double-blind 
treatment Period 
Safety Follow-
up
Week 10
Day 71
day of final double-blind or 
ET visit during the double-
blind treatment period 
+1 ≤Days ≤ last visit
a
Relative to the date of the first dose of double-blind investigational product. Day 1 = the date of the first dose of 
double-blind investigational product.
b
Presented in analysis tables for safety parameters, including but not limited to electrocardiograms, clinical 
laboratory values, and vital signs.
ET = early termination.
If the visit date is on or after the date of the first dose of double-blind investigational 
product, the study day is calculated by visit date – date of the first dose of double-blind 
investigational product + 1. If the visit date is before the date of the first dose of 
double-blind investigational product, the study day is calculated by visit date – date of the 
first dose of double-blind investigational product. Therefore, a negative day indicates a 
day before the start of the double-blind investigational product.
If a participant has 2 or more visits within the same window, the last visit with a non-
missing value will be used for analysis.


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15.2
DERIVED VARIABLES
Some efficacy, safety variables and SF-12 health outcome measure are derived as 
follows:

MADRS total score is the sum of the 10 items from the MADRS. If more than 
2 items of MADRS are missing, then the total score will be set to missing

HAMD-17 total score is the sum of the first 17 items from the 24-item Hamilton 
Depression Rating (HAMD) scale. If more than 2 items of the first 17 items of 
HAMD scale are missing, then the score will be set to missing

HAM-A total score is the sum of all the 14 items from the HAM-A. If more than 
2 items of the HAM-A 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. If more than 1 item for 
the AIMS (items 1-7) is missing, then the total score will be set to missing. Items 8 
through 12 will be summarized separately

SAS total score is the sum of the 10 items of the SAS. If more than 1 item for the 
SAS is missing, then the total score will be set to missing

BARS total score is the sum of the first 3 items of the BARS. If any item for the 
BARS (items 1-3) is missing, then the total score will be set to missing. Item 4 will be 
summarized separately

MADRS responders are defined as participants with a ≥50% reduction from baseline 
in MADRS total score. The value is 1 for MADRS responders and 0 otherwise

MADRS remission is defined as a MADRS total score of ≤10. The value is 1 for 
MADRS remission and 0 otherwise

CGI-I responders are defined as participants with a CGI-I score ≤2. The value is 1 
for CGI-I responders and 0 otherwise

PCS-12 and MCS-12 derivation are described in the Section 15.2.1.


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The total score for a specific variable at a particular visit will be calculated using (sum of 
non-missing items) × (total number of items) / (number of non-missing items) only if the 
number of missing items is less than the specified number for this safety variable. 
Otherwise, the total score will be set to missing. For the LOCF analysis, if a participant
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 non-missing 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.
15.2.1
Scoring Algorithm of SF-12V2
SF-12v2 (4-week recall) consists of 12 items. Two composite summary scores, including 
Physical Component Summary (PCS) and Mental Component Summary (MCS), and 8 
scale scores, including Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), 
General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE) and 
Mental Health (MH), will be derived using the following scoring algorithm. Within each 
scale, if there are less than or equal to 50% of the item scores missing, the missing item 
score(s) will be imputed using the mean score of the non-missing items and used to 
calculate the scale score. If more than 50% of the item scores are missing, no imputation 
will be performed and the scale score will be set to missing.
Step 1: Item coding
Code the response to each item as follows such that higher score indicates better health 
state.
Response to Item 1
Response Choices
Precoded Item Value
Final Item Value
Excellent
1
5.0
Very Good
2
4.4
Good
3
3.4
Fair
4
2.0
Poor
5
1.0


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Response to Items 2a and 2b
Respond Choices
Precoded Item Value
Final Item Value
Yes, limited a lot
1
1
Yes, limited a little
2
2
No, not limited at all
3
3
Response to Items 3a, 3b, 4a, 4b and 7
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Response to Item 5
Response Choices
Precoded Item Value
Final Item Value
Not at all
1
5
A little bit
2
4
Moderately
3
3
Quite a bit
4
2
Extremely
5
1
Response to Items 6a, 6b and 6c
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
5
Most of the time
2
4
Some of the time
3
3
A little of the time
4
2
None of the time
5
1


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Step 2: Computing raw scale scores
After item recoding, a raw score is computed for each scale which is the simple algebraic 
sum of the final item values for all items in that scale as shown in the below table. For 
example, the raw score for PF scale is the sum of the final item values of items 2a and 2b.
Scale
Sum Final Item Values
Lowest and 
Highest Possible 
Raw Scores
Possible Raw 
Score Range
PF
Items 2a + 2b
2, 6
4
RP
Items 3a + 3b
2, 10
8
BP
Item 5
1, 5
4
GH
Item 1
1, 5
4
VT
Item 6b
1, 5
4
SF
Item 7
1, 5
4
RE
Items 4a + 4b
2, 10
8
MH
Items 6a + 6c
2,10
8
Step 3: Transforming raw scale scores
Transforming the raw scale score to a 0-100 scale using the formula below. The table 
above include the lowest possible and possible range of raw score for each scale.
For example, the transformed score for PF scale is (Raw PF score – 2) / 4.
Step 4: Standardizing transformed scale scores
Each transformed scale is standardized to a z-score using scale means and standard 
deviations from the 1998 general United States population as shown in the below table.


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Scale
Mean
Standard Deviation
PF
81.18122
29.10558
RP
80.52856
27.13526
BP
81.74015
24.53029
GH
72.19795
23.19041
VT
55.59090
24.84380
SF
83.73973
24.75775
RE
86.41051
22.35543
MH
70.18217
20.50597
The formula for z-score transformation is:
Z-score standardized scale = (Transformed scale score – Mean) / Standard Deviation
For example, the z-score of PF scale = (Transform PF score – 81.18122) / 29.10558. 
Step 5: Aggregating scale scores to compute raw component summary scores
The standardized scales are aggregated using weights (factor score coefficients) from the 
1998 general United States population to derive raw component summary scores (PCS 
and MCS). Formulae for aggregating z-score standardized scales are:
Raw PCS = PF ×.42402 + RP × .35119 + BP × .31754 + GH × .24954 +
                VT × .02877 + SF × -.00753 + RE × -.19206 + MH × .22069
Raw MCS = PF ×-.22999+ RP × -.12329 + BP × -.09731 + GH × -.01571 +
                 VT × .23534 + SF × .26876+ RE × .43407+ MH × .48581
Step 6: Standardizing composite summary scores
The raw PCS and MCS scores are standardized as follows such that the final PCS and 
MCS scores have values with mean 50 and standard deviation 10.
PCS = 50 + Raw PCS ×10
MCS = 50 + Raw MCS ×10


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15.3
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a participant has repeated assessments before the start of the first treatment, the results 
from the final non-missing assessment made prior to the start of the DB investigational 
product will be used as baseline. If end-of-study assessments are repeated or if 
unscheduled visits occur, the last non-missing 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.
15.4
MISSING DATE OF THE LAST DOSE OF STUDY 
TREATMENT
When the date of the last dose of study treatment is missing for a participant in the 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 available dosing record date will be used as the 
last dose date.
15.5
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of study 
treatment, 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 study treatment, 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.
15.6
MISSING CAUSAL RELATIONSHIP TO STUDY DRUG FOR 
ADVERSE EVENTS
If the causal relationship to the study treatment is missing for an AE that started on or 
after the date of the first dose of study treatment, a causality of yes will be assigned. The 
imputed values for causal relationship to study treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings.
15.7
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).


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Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study
treatment, the month and day of the first dose of study treatment will be assigned to
the missing fields

If the year of the incomplete start date is before the year of the first dose of study 
treatment, 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 study 
treatment, 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 study treatment, the day of the first dose of study treatment 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 study treatment 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 study treatment, 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 study treatment 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 study treatment, 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 study treatment, the date of the first 
dose of study treatment will be assigned to the missing start date

If the stop date is before the date of the first dose of study treatment, the stop date will 
be assigned to the missing start date


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15.8
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 participant, the start date will be imputed first.
15.8.1
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 study 
treatment, the month and day of the first dose of study treatment will be assigned to 
the missing fields

If the year of the incomplete start date is before the year of the first dose of study 
treatment, 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 study 
treatment, 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 study treatment, the day of the first dose of study treatment 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 study treatment 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 study treatment, 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 study treatment 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 study treatment, the first 
day of the month will be assigned to the missing day
15.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the date of the last dose of study 
treatment is missing, impute it as descripted in Section 15.4. 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 study 
treatment, the month and day of the last dose of study treatment will be assigned to 
the missing fields

If the year of the incomplete stop date is before the year of the last dose of study 
treatment, 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 study 
treatment, 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 stop date are the same as the month and year 
of the last dose of study treatment, the day of the last dose of study treatment 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 study treatment 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 study treatment, the last 
day of the month will be assigned to the missing day


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
If either the year of the incomplete stop date is after the year of the date of the last 
dose of study treatment 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 study treatment, the first day 
of the month will be assigned to the missing day
15.9
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.


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16.0
COVID-19 RELATED ANALYSES
To eliminate immediate potential hazards to study participants and site staff due to the 
COVID-19 pandemic while ensuring participant safety and maintaining data integrity, the 
Change in Research Memo, followed by COVID-19 global protocol addendum, and
protocol amendment #3 were sent to sites during the pandemic. 
The following protocol modifications (see protocol amendment #3, Section 12.2) can be 
followed for active patients who have completed all assessments through Visit 2 
(inclusive) per Table 3-2, Schedule of Visits and Procedures. The following procedures 
apply in cases where patients are either unable or unwilling to attend study visits as a 
result of the pandemic.
•
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 (preferred method if/when home visits are not 
feasible)
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 (see protocol 
amendment #3, Section 12.2.6.)
This section specifies analyses for evaluating the impact of COVID-19.
16.1
EFFICACY EVALUATION
Efficacy Endpoints
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. 
•
Montgomery-Åsberg Depression Rating Scale (MADRS)
•
Hamilton Anxiety Rating Scale (HAM-A)
•
Clinical Global Impression-Severity scale (CGI-S)
•
Clinical Global Impression-Improvement scale (CGI-I)
•
Hamilton Depression Rating Scale–17 Items (HAMD-17)


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To evaluate the impact of COVID-19, the rate of missing due to COVID-19 and 
assessment done by alternative modalities will be summarized by study visit for each 
assessment. 
For the primary endpoint and key secondary endpoint, one additional sensitivity analysis 
may be conducted to investigate the impact of COVID-19 dropout cases on the 
estimation results by treating the dropout cases due to COVID-19 as MAR. 

Participants who discontinued due to lack of efficacy (but not due to COVID-
19) in the cariprazine arms are assumed to have no treatment effect after the 
discontinuation. These participants are assumed to copy the profile of placebo arm 
and missing values are imputed based on the distribution estimated from the
placebo group under the MAR using copy-reference approach (Carpenter et al, 
2013).

The rest of missing values in the placebo arm and cariprazine arms (including 
dropouts due to COVID-19) will be imputed using the observed data in their 
respective group under the MAR assumption.
In addition, sensitivity analyses for the primary and key secondary endpoints by pre-
COVID and post-COVID randomized participants will be performed: 

pre-COVID randomized participants: date of randomization ≤March 11, 2020

post-COVID randomized participants: date of randomization > March 11, 2020
Lastly, to explore the COVID impact further, the primary analysis for primary and 
secondary endpoints will be repeated on the subset of participants who completed or 
discontinued from the study prior to the COVID cutoff date of March 11, 2020.
16.2
SAFETY AND OTHER EVALUATIONS
This section specifies analyses related to COVID-19 pandemic from the following 
aspects:

COVID-19 Status

Disposition

Demographics and Other Baseline Characteristics

Study visit (missing entire visit due to COVID-19 or missing assessments due to 
COVID-19)

Protocol deviation

Study drug interruption(s) due to COVID-19

TEAEs related to COVID-19 infection


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Safety Population will be used for the planned analyses in this section described above, 
unless stated otherwise.
The number of participants impacted by COVID-19 during the study and COVID-19 
status will be summarized by treatment group. In addition, the number of participants 
impacted by COVID-19 and their corresponding disposition status in the double-blind 
treatment period and the follow-up period will be summarized respectively.
Baseline characteristics (including demographic, baseline disease characteristics, and 
relevant medical history) will be summarized relative to the onset of pandemic (date of 
randomization <= Mar 11, 2020 vs. date of randomization > Mar 11, 2020).
The number of participants who missed at least one entire visit due to COVID-19 will be 
summarized by treatment group. Furthermore, the number of participants who missed at 
least one assessment due to COVID-19 will be summarized by assessment category 
(laboratory, vital signs, ECG, C-SSRS, YMRS, EPS scales) and by visit.
The number of participants with significant protocol deviation due to COVID-19 will be 
provided. The number of participants with any COVID-19 related treatment
interruption(s) will be provided as well. 
The number of participants with TEAEs related to COVID-19 infection will be provided. 
Supporting listings for the above described analyses will be provided. Furthermore, a 
listing of TEAEs leading to study discontinuation related to COVID-19 will be provided.


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17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
In Section 11.0 (Health Outcome Analyses), the term “Study center” in the ANCOVA 
model for analyzing PCS-12 and MCS-12 will be replaced with terms country and 
ADT failure category to align with the analyses for other efficacy endpoints.
In Section 10.1 (Adverse Events), AE summary timeframe was modified to align with 
AE reporting period specified in the protocol amendment 1. The new time frame is 
defined below:
An AE that occurs more than 30 days after the date of the last dose of DB IP or 
occurs after the last safety follow-up 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 summary of SAEs was modified in Section 10.1. The definition of on-therapy 
SAE was updated to TESAE, and summary timeframe will align with general AE 
summary timeframe as specified above.


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18.0
APPENDICES
Appendix I
Pattern-Mixture Model Details
For repeated measures with the monotone missing mechanism, the pattern-mixture model 
with non-future dependent missing assumption, proposed by Kenward et al. (2003), 
provides a feasible solution to accommodate certain missing not at random (MNAR) 
mechanism. The methodology relies on constructing unidentifiable conditional densities 
using identifiable densities and borrows techniques from standard multiple imputation.
1. Non-Future Dependent Missing Assumption
Assume there are T designed visits in a longitudinal study and let 
)
,...,
2,1
(
T
i
yi

represent participant’s measurement at Visit i. When the missing mechanism is 
monotone, the pattern of missing data can be defined by the number of measurements (L) 
actually observed from the participant. Let 
)
|
,...,
(
t
L
y
y
f
j
i

denote the conditional 
density of
yi ,... yj, given that the last observed measurement is at Visit t. Then the overall density 
function for Pattern t can be written as
f (y1,..., yT | L = t) = f (y1,..., yt | L = t) f (yt+1 | y1 ,..., yt, L = t)
(1)
×
T
f (ys | y1 ,..., ys-1, L = t)
Π
s = t+2
Note on the right hand side of (1) the first factor is clearly identifiable from the observed 
data, while the second and the beyond are not, due to lack of available data. The second 
factor 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
t
t


could be identifiable based on an assumed relationship 
between 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
t
t


and f (yt+1 | y1,...yt, L ≥ t + 1). The third and beyond 
factors 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
s
s


(with all s ≥ t + 2) could be identifiable with the help of 
non-future dependent missing assumption.
For longitudinal data with dropouts, non-future dependent missing (NFD) mechanism 
(Kenward et al., 2003) assumes that the unidentifiable conditional distributions of 
sy
(s ≥t + 2), given earlier measurements, in Pattern t, is equal to the corresponding 
distribution in patterns L ≥ s – 1: 
f (ys | y1,..., ys-1, L = t) = f (ys | y1,..., ys-1, L ≥ s – 1)
(2)


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The right hand side of (2) can further be partitioned into
f (ys | y1,..., ys-1, L ≥ s – 1) =
T
ωs-1, j · f (ys | y1,..., ys-1, L = j)
(3)
Σ
j = s-1
Where mixture probabilities ωs-1,j are:
ωs-1,j = 
αj f (y1,...,ys-1 | L = j)
, and αj represents the fraction of 
(4)
T
αt f (y1,...,ys-1 | L = t)
Σ
t = s-1
participants from Pattern j.
Each factor of the unidentifiable conditional distribution of
sy (s ≥ t + 2) on the right side 
of (1) can be expressed using the following:
-
)1
,
,...,
|
(
1
1



s
L
y
y
y
f
s
s
, the unidentifiable conditional distribution of the 
first missing in pattern 
1

s
, 
-
)
,
,...,
|
(
1
1
j
L
y
y
y
f
s
s


, the identifiable conditional distributions of
sy given
1
1,...,

sy
y
of pattern j (j ≥ s), and
- αj, the fraction of participants from pattern j (j ≥ s - 1). 
So under NFD, all the unidentifiable conditional distribution on the right side of (1) can 
be estimated and missing value could be therefore imputed based on the assumption for 
unidentifiable conditional distribution of the first missing.
We re-formulate the partition in (3), for s ≥ t +2, as the following:
f (ys | y1,..., ys-1, L = t) = δs-1 f (ys | y1,..., ys-1, L = s – 1)
(5)
+ (1 – δs-1) f (ys | y1,..., ys-1, L ≥ s)
for s ≥ t +2 with 
1
,1
1



s
s
s
ω
δ
.


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Therefore, under monotone missing and NFD assumption, the unidentifiable conditional 
densities for Visit s in Pattern t (s ≥ t +2) can be expressed as a mixture distribution of 
)1
,
,...,
|
(
1
1



s
L
y
y
y
f
s
s
- the unidentifiable conditional distribution of the first missing 
measurement ys in Pattern
1

s
, and f (ys | y1,...,ys-1, L ≥ s) - the identifiable conditional 
distribution of ys from all the patterns with observed data at Visit s or beyond:
f (ys | y1,..., ys-1, L ≥ s) =
T
λs-1,j f (ys | y1,..., ys-1, L = j)
(6)
Σ
j = s
where the mixture probability λs - 1 = ωs-1,j /(1 – ωs - 1, s - 1) = 
αj f (y1,...,ys-1 | L = j)
for j ≥ s, where αj is the fraction of 
(7)
T
αt f (y1,...,ys-1 | L = t)
Σ
t = s
participants from Pattern j.
The conditional densities for the first missing are selected as:
f (ys | y1,..., ys-1, L = s – 1) = f (ys – Δ | y1,..., ys-1, L ≥ s) for s = 2, ..., T
(8)
Note that the two distributions only differ by a shift (Δ) parameter. When Δ = 0, the 
missing value ys in Pattern s-1 is imputed based on the distribution of all observed data 
up to Visit s, as a result, leading to missing at random (MAR) missingness. When Δ ≠0, 
(8) will introduce a scenario of MNAR. The similar idea was also presented in the recent 
publication “The Prevention and Treatment of Missing Data in Clinical Trials” by the 
National Academies Press. The selection of the plausible values for the shift parameter 
(Δ) is discussed in Section 3.0.
Note that per recommendation in Wang and Daniels (2011), only the observed data 
within pattern is assumed to be multivariate normal. The observed data distribution can 
be expressed in terms of the marginal distribution of baseline measurement and the 
conditional distributions of postbaseline measurements given earlier measurements. 
Assuming that these distributions are normal, the linear regression of each observation on 
prior observations will yield least-squares estimates of model parameters that can be 
utilized for independent posterior draws of model parameters for observed data. Multiple
imputation approach will be used to estimate the overall mean at the final time point.


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2. Imputation Procedure
All the missing data will be imputed to create complete datasets, then statistical analysis 
can be performed using appropriate techniques such as ANCOVA. The imputation can 
accommodate MNAR missing data mechanisms, based on the theory discussed in the 
previous section. 
The model parameters for each dropout pattern, ie, the mean, variance and proportions of 
observations in each pattern, are drawn from their posterior distributions prior to the 
imputation of missing data for a single imputation. 
The details of imputation within a pattern, say Pattern t, are as the following:
Step 1. Impute the first missing value yt+1 for each participant in Pattern t (t = 1,..., T – 1): 
a.
Compute estimates of mixture probabilities λs-1,j in (7) with s = t+1 given the posterior 
draw of proportions of observations in each pattern and the posterior draw of 
regression parameters for the observed data.
b. Draw a random integer from {s,..., T} to index a component distribution on the right 
hand side of (6), using mixture probabilities obtained in a). Draw 
*
1

ty
from the 
identified component normal distribution. Impute the missing yt+1 as 
*
1
1
~


t
t
y
y
+ Δ.
Step 2. Impute the rest of the missing values of yt+2, yt+3,..., yT for participants in Pattern t:
Starting with imputation for yt+2, first, similar to Step 1, draw 
*
2

ty
from the normal 
mixture (6) based on the observed y1,...,yt and the already imputed 
1
~

ty
for the 
participant. Then the missing yt+2 is imputed as 
*
2
2
~


t
t
y
y
+ Δ with probability δt+1 and 
as 
*
2
2
~


t
t
y
y
with probability 1 – δt+1, where the mixture probability δt+1 = ωt+1,t+1 is 
obtained from (4) given the posterior draw of proportions of observations in each pattern 
and the posterior draw of regression parameters for the observed data.
Missing values of yt+3 through yT can be imputed similarly as yt+2. 
To summarize, the imputations of yt+1 through yT is done recursively within each Pattern t 
(for all t = 1,...,T – 1) to create a complete dataset after imputation is done for all patterns 
with missing values. 
The above imputation procedure is applied to all participants in each missing data pattern 
to create a single imputed data set. Repeating the process of drawing parameters from the 
posterior distribution and imputing missing data given the posterior draw m times will 
yield m imputed data sets. The observed or imputed values at the final data point are 
averaged to obtain the overall mean estimate for each imputed data set, and the multiple 
imputation estimate is obtained by averaging the estimates across m imputations. 


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In this sensitivity analysis, m is set to equal to 200. 
3. Determination of the Shift Parameter Values
The common shift parameter Δ is the difference between the mean of yt+1 among those 
who drop out at Visit t and those who remain beyond Visit t (1 ≤ t ≤ T – 1). The exact 
value of Δ is unknown and can’t be estimated from data because of missingness. The 
magnitude of Δ depends on the medical aspects of the trial. Using relevant historical data, 
one may select Δ as a proportion of the sample standard deviation or a proportion of 
observed treatment efficacy. 


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Appendix II:
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 18-1 below.
Table 18-1
List of Selected Parameters to be Reported in 
Conventional Units
Number
Laboratory Parameter
Conventional Unit
Decimal Places
1
Alanine Aminotransferase (SGPT)
U/L
0
2
Albumin
G/dL
1
3
Alkaline Phosphatase
U/L
0
4
Aspartate Aminotransferase (SGOT)
U/L
0
5
Bilirubin, Direct (Conjugated)
mg/dL
1
6
Bilirubin, Indirect (Unconjugated)
mg/dL
1
7
Bilirubin, Total
mg/dL
1
8
Blood Urea Nitrogen
mg/dL
0
9
Calcium
mg/dL
1
10
Cholesterol, HDL
mg/dL
0
11
Cholesterol, LDL
mg/dL
0
12
Cholesterol, LDL direct and calculated 
(combined)
(This lab parameter could be the same 
as #11) 
mg/dL
0
13
Cholesterol, Total
mg/dL
0
14
Creatine Kinase
U/L
0
15
Creatinine
mg/dL
1
16
Glucose
mg/dL
0
17
Insulin
uIU/mL
1
18
Triglycerides
mg/dL
0
19
Uric Acid
mg/dL
1
20
Hemoglobin
G/dL
1
Participant 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 III:
SUMMARY OF MAJOR CHANGES FOR SAP 
AMENDMENT 2
Amendment #2 specifies the following changes to the SAP Amendment #1 for Study 
3111-302-001 dated 26 Mar 2021. The major changes are summarized below:
1. Sections 9.2 and 9.3: updated the key secondary efficacy endpoint (from HAM-A 
to CGI-S at Week 6).
2. Section 16.1: added additional analysis related to COVID-19 impact on primary 
efficacy endpoint for completed or discontinued patients prior to the COVID-19 
pandemic onset, per the FDA feedback.
3. Section 11.0: replaced MMRM by ANCOVA, for consistency with the protocol.
4. Section 7.0: added a clarification that ADT failure based on CRF is primary and 
will be used for all statistical models, rather than per IWRS.
5. Section 9.3: replaced MMRM by ANCOVA for change from baseline in HAMD-
17 total score, per the HAMD-17 data collection at baseline and Week 6.
6. Section 13.0: updated the power that was re-calculated using the mixture parallel
gatekeeping procedure.
7. Section 10.2: added a footnote to Tables 10-1 and 10-2 for the parameters with 
fasting status.
8. Section 10.1: added a paragraph for EPS TEAEs excluding akathisia/restlessness, 
with any Akathisia/Restlessness, including a list of preferred terms.
9. Sections 7.0 and 10.1: updated the Medical Dictionary for Regulatory Activities
version to 24.0.
10. Section 9.1: updated subgroup analyses model, to align with ISE.
11. Section 5.5: added additional selected analyses excluding one non-compliant site.
Amendment #1 specifies the following changes to the final SAP for Study 3111-302-001
dated 16 Jan 2019. The major changes are summarized below:
1. Added “The primary analysis will be performed after all participants have 
completed the 4-week safety follow-up or discontinued from the study and the 
database has been locked and unblinded.” in Section 3.0.
2. Added the key secondary efficacy endpoint in Section 9.2 (HAM-A at Week 6).
3. Added additional efficacy endpoints in Section 9.3: MARDS individual items and 
HAM-A individual items, HAM-A response and HAM-A remission.
4. Added SF-12 analysis in Section 11.0.
5. Added Section 16.0 to specify analyses related to COVID-19 to follow protocol
amendment #3.


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