A Double-Blind, Placebo-Controlled, Randomized Withdrawal, Multicenter Clinical Trial Evaluating the Efficacy, Safety, and Tolerability of Cariprazine in a Dose-Reduction Paradigm in the Prevention of Relapse in Patients With Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: AbbVie

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Protocol RGH-MD-24 Amendment 4
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ALLERGAN – CONFIDENTIAL
The following contains confidential, proprietary information, 
which is the property of Allergan
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED WITHDRAWAL, 
MULTICENTER CLINICAL TRIAL EVALUATING THE EFFICACY, SAFETY, AND 
TOLERABILITY OF CARIPRAZINE IN A DOSE-REDUCTION PARADIGM IN THE 
PREVENTION OF RELAPSE IN PATIENTS WITH SCHIZOPHRENIA
Protocol Number:
RGH-MD-24
Phase:
3B
Name of Investigational 
Product:
Cariprazine
Sponsor:
Allergan Sales, LLC
5 Giralda Farms
Madison, NJ 07940 USA
Allergan Ltd.
1st Floor, Marlow International,
The Parkway, Marlow Buckinghamshire
SL7 1YL United Kingdom
Emergency Telephone 
Number(s):
Refer to the Study Contacts List in the Investigator Site File or 
Trial Master File.
Serious Adverse Event 
Reporting Fax Number/
Back-up Fax Number:
Email:
+1-714-796-9504/ +1-714-246-5295
IR-Clinical-SAE@allergan.com
Medical Safety Physician
Contact Information:
Refer to the Study Contacts List.
Allergan Signatory:
 Clinical Development, CNS
Global Branded Research and Development
Protocol Date:
28 June 2017
NCT03593213

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Protocol Amendment 1 
Date: 
21 December 2017 
Protocol Amendment 2 
Date: 
16 April 2018 
Protocol Amendment 3 
Date: 
28 November 2018 
Protocol Amendment 4 
Date:     
17 December 2019 
The following information can be found on FDA Form 1572 (US) and/or study contacts list 
and/or Trial Master File: Name and contact information of 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. 
 

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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
I agree to: 
x Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
x Maintain all information supplied by Allergan in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Independent Ethics 
Committee (IEC) or another group, it will be submitted with a designation that the 
material is confidential. 
x 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 
 

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Table of Contents 
Title Page ............ ……………………………………………………………………...……...1 
Table of Contents ……………………………………………………………………..………4 
List of Tables ....... ……………………………………………………………………………..9 
List of Figures ..... ……………………………………………………………………………..9 
Protocol Summary .................................................................................................................. 10 
1 Background and Clinical Rationale .................................................................................. 20 
2 Study Objectives and Clinical Hypotheses ....................................................................... 23 
2.1 
Study Objectives ......................................................................................................... 23 
2.2 
Clinical Hypotheses .................................................................................................... 23 
3 Study Design ..................................................................................................................... 23 
3.1 
Screening/Washout Period .......................................................................................... 23 
3.2 
Open-label Treatment Period ...................................................................................... 24 
3.3 
Double-blind Treatment Period................................................................................... 26 
3.4 
Safety Follow-up Period ............................................................................................. 27 
4 Study Population and Entry Criteria ................................................................................. 27 
4.1 
Number of Patients ..................................................................................................... 27 
4.2 
Study Population Characteristics ................................................................................ 27 
4.3 
Inclusion Criteria ........................................................................................................ 28 
4.4 
Exclusion Criteria ....................................................................................................... 29 
4.5 
Response Threshold, Stability, and Maintenance of Stability Criteria During the OL 
Treatment Period ......................................................................................................... 33 
4.6 
Randomization Criteria ............................................................................................... 34 
4.7 
Relapse Criteria During the Double-blind Treatment Period ..................................... 35 
4.8 
Permissible and Prohibited Medications/Treatments .................................................. 36 
4.8.1 
Permissible Medications/Treatments .................................................................... 36 
4.8.2 
Prohibited Medications/Treatments ...................................................................... 37 
4.8.3 
Rescue Medications .............................................................................................. 38 
5 Study Treatments .............................................................................................................. 39 
5.1 
Study Treatments and Formulations ........................................................................... 39 
5.2 
Control Treatment ....................................................................................................... 39 
5.3 
Methods for Masking/Blinding ................................................................................... 39 

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5.4 
Method for Assignment to Treatment Groups/Randomization ................................... 40 
5.5 
Treatment Regimen and Dosing ................................................................................. 40 
5.6 
Treatment Compliance ................................................................................................ 41 
5.7 
Storage of Study Medications/Treatments .................................................................. 41 
6 Response Measures and Summary of Data Collection Methods ...................................... 41 
6.1 
Diagnostic Assessments .............................................................................................. 41 
6.2 
Efficacy Assessments .................................................................................................. 41 
6.2.1 
Primary Efficacy Assessments .............................................................................. 42 
6.2.2 
Additional Efficacy Assessments .......................................................................... 42 
6.3 
Pharmacokinetics Measures ........................................................................................ 43 
6.4 
Pharmacogenetic Sampling ......................................................................................... 43 
6.5 
Safety Measures .......................................................................................................... 44 
6.5.1 
Adverse Events ..................................................................................................... 44 
6.5.2 
Ocular Adverse Events of Special Interest............................................................ 44 
6.5.3 
Clinical Laboratory Determinations ..................................................................... 45 
6.5.4 
Vital Signs ............................................................................................................. 47 
6.5.5 
Electrocardiograms ............................................................................................... 47 
6.5.6 
Physical Examination............................................................................................ 48 
6.5.7 
Ophthalmological Examination ............................................................................ 48 
6.5.8 
Other Safety Assessments ..................................................................................... 48 
6.6 
Summary of Methods of Data Collection ................................................................... 50 
7 Statistical Procedures ........................................................................................................ 50 
7.1 
Analysis Populations ................................................................................................... 50 
7.1.1 
Screened Population.............................................................................................. 50 
7.1.2 
Open-label Safety Population ............................................................................... 50 
7.1.3 
Open-label Intent-to-Treat Population .................................................................. 50 
7.1.4 
Open-label Safety-Follow-up Population ............................................................. 50 
7.1.5 
Randomized Population ........................................................................................ 50 
7.1.6 
Double-blind Safety Population ............................................................................ 51 
7.1.7 
Double-blind Intent-to-Treat Population .............................................................. 51 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ............ 51 
7.2.1 
Primary Efficacy Variable ..................................................................................... 51 
7.2.2 
Secondary Efficacy Variable ................................................................................. 52 
7.2.3 
Other Efficacy Variables ....................................................................................... 52 
7.3 
Hypothesis and Methods of Analysis .......................................................................... 53 

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7.3.1 
Primary Efficacy Analyses .................................................................................... 53 
7.3.2 
Secondary Efficacy Analyses ................................................................................ 54 
7.3.3 
Other Efficacy Analyses ....................................................................................... 54 
7.3.4 
Safety Analyses ..................................................................................................... 55 
7.4 
Subgroup Analyses...................................................................................................... 61 
7.5 
Sample Size Calculation ............................................................................................. 61 
7.6 
Interim Analyses ......................................................................................................... 62 
8 Study Visit Schedule and Procedures................................................................................ 62 
8.1 
Patient Entry Procedures ............................................................................................. 62 
8.1.1 
Overview of Entry Procedures .............................................................................. 62 
8.1.2 
Informed Consent and Subject Privacy................................................................. 62 
8.2 
Washout Intervals/Run-in ........................................................................................... 63 
8.3 
Procedures for Final Study Entry ................................................................................ 63 
8.4 
Visits and Associated Procedures ................................................................................ 63 
8.4.1 
Screening/Visit 1 (Days –7 to –1) ......................................................................... 64 
8.4.2 
Baseline/Visit 2 ..................................................................................................... 65 
8.4.3 
Open-label Treatment Period (Visits 3 to 12) ....................................................... 65 
8.4.4 
End of Open-label Period/Randomization Visit (Visit 13) ................................... 67 
8.4.5 
Double-blind Treatment Period (Visits 14 to 25) .................................................. 68 
8.4.6 
Final or Early Termination Visit (Visit 26) ........................................................... 69 
8.4.7 
Safety Follow-up Visits (Visits 27 and 28) ........................................................... 70 
8.5 
Instructions for Patients .............................................................................................. 70 
8.6 
Unscheduled Visits ...................................................................................................... 71 
8.7 
Compliance with Protocol........................................................................................... 71 
8.8 
Early Discontinuation of Subjects .............................................................................. 71 
8.9 
Withdrawal Criteria ..................................................................................................... 73 
8.10 
Study Termination ....................................................................................................... 74 
9 Adverse Events ................................................................................................................. 74 
9.1 
Definitions................................................................................................................... 75 
9.1.1 
Adverse Event ....................................................................................................... 75 
9.1.2 
Serious Adverse Event .......................................................................................... 75 
9.1.3 
Severity ................................................................................................................. 76 
9.1.4 
Relationship to Study Drug or Study Procedure ................................................... 76 
9.2 
Procedures for Reporting Adverse Events .................................................................. 76 
9.3 
Procedures for Reporting a Serious Adverse Event .................................................... 77 

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9.4 
Reporting of Pregnancies Occurring During the Study .............................................. 77 
9.5 
Potential Hy’s Law Cases ........................................................................................... 78 
9.6 
Procedures for Unmasking of Study Medication ........................................................ 79 
10 Administrative Items ......................................................................................................... 79 
10.1 
Protection of Human Patients ..................................................................................... 79 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations .............................................................................. 79 
10.1.2 
Compliance with IRB or IEC Regulations............................................................ 79 
10.1.3 
Compliance with Electronic Records; Electronic Signatures Regulations (US 21 
CFR Part 11) ......................................................................................................... 80 
10.2 
Changes to the Protocol .............................................................................................. 80 
10.3 
Patient Confidentiality ................................................................................................ 80 
10.3.1 
Patient Privacy ...................................................................................................... 80 
10.4 
Documentation ............................................................................................................ 81 
10.4.1 
Source Documents ................................................................................................ 81 
10.4.2 
Case Report Form Completion ............................................................................. 82 
10.4.3 
Study Summary ..................................................................................................... 82 
10.4.4 
Retention of Documentation ................................................................................. 82 
10.5 
Labeling, Packaging, and Return or Disposal of Study Medications/Treatments ...... 83 
10.5.1 
Labeling/Packaging............................................................................................... 83 
10.5.2 
Clinical Supply Inventory ..................................................................................... 83 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or Supplies ................ 83 
10.6 
Monitoring by the Sponsor ......................................................................................... 83 
10.7 
Handling of Biological Specimens ............................................................................. 84 
10.8 
Publications ................................................................................................................. 84 
10.9 
Coordinating Investigator ........................................................................................... 84 
11 References ......................................................................................................................... 85 
12 Attachments ...................................................................................................................... 87 
12.1 
Elements of Informed Consent ................................................................................... 87 
12.2 
Structured Clinical Interview for the Positive and Negative Syndrome Scale (PANSS)
..................................................................................................................................... 89 
12.3 
Clinical Global Impressions–Severity (CGI-S) .......................................................... 90 
12.4 
Clinical Global Impressions–Improvement (CGI-I) ................................................... 91 
12.5 
Barnes Akathisia Rating Scale .................................................................................... 92 
12.6 
Abnormal Involuntary Movement Scale (AIMS) ....................................................... 94 

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12.7 
Simpson-Angus Scale (SAS) ...................................................................................... 97 
12.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 100 
12.9 
Personal and Social Performance (PSP) Scale .......................................................... 108 
12.10 Ophthalmological Examination .................................................................................110 
12.11 Package Insert ............................................................................................................114 
12.12 Glossary of Abbreviations..........................................................................................115 
12.13 Protocol Amendment 1 Summary ..............................................................................117 
12.14 Protocol Amendment 2 Summary ............................................................................. 120 
12.15 Protocol Amendment #3 Summary ........................................................................... 122 
12.16 Protocol Amendment #4 Summary ........................................................................... 128 

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List of Tables 
Table 1: 
Schedule of Visits and Procedures—Screening/Washout and Open-label 
Treatment Periods ........................................................................................... 15 
Table 2: 
Schedule of Visits and Procedures—Double-blind Treatment Period ............ 18 
Table 3: 
Treatment Regimen and Dosing ..................................................................... 40 
Table 4: 
Schedule of Clinical Laboratory Tests ............................................................ 45 
 
List of Figures 
Figure 1: 
Study Schematic.............................................................................................. 14 
 

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Protocol Summary 
 
Study Compound: Cariprazine 
Phase: 3B 
Study Objectives: 1) To evaluate the efficacy and safety of cariprazine at a target dose of 4.5 mg/d compared 
with placebo in prevention of relapse in patients with schizophrenia; 2) To evaluate the efficacy and safety of 
cariprazine at a target dose of 3.0 mg/d compared with placebo in prevention of relapse in patients with 
schizophrenia who were initially stabilized on a target dose of 4.5 mg/d 
Clinical Hypotheses: 1) In patients with schizophrenia, cariprazine at 4.5 mg/d is safe and effective in 
preventing relapse when compared to placebo; 2) In patients with schizophrenia who were initially stabilized on 
a target dose of 4.5 mg/d, cariprazine at 3.0 mg/d is safe and effective in preventing relapse when compared to 
placebo. 
Study Design 
Structure: This is a multicenter, multinational, double-blind (DB), placebo-controlled, randomized-withdrawal 
study evaluating the safety and efficacy of cariprazine compared with placebo in the prevention of relapse in 
patients with schizophrenia. The study schematic is presented in Figure 1. 
Duration: 
Screening/Washout Period: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) criteria for schizophrenia will undergo a Screening/washout period up to 7 days, during which 
consent, assessment of eligibility, and withdrawal of prior psychiatric and prohibited medications will occur. 
The length and timing of the washout of prior psychiatric medications during the 7 days allotted for the 
Screening period is at the discretion of the investigator. Prior medications should be gradually withdrawn such 
that the washout is completed by Visit 2/Baseline. Please note that during the screening/washout period, 
psychotropic medications, other than those listed as rescue (Section 4.8.3), may not be newly initiated or 
reinstated. In order to ensure the safe transition of patients into the study, based upon the clinical judgment of 
the investigator, patients may be hospitalized during initiation of the study. This hospitalization can be for up to 
14 days during the Screening and Open-label (OL) periods (with the end of hospitalization no later than Visit 3 
[Day 8] of the OL treatment period). This 14-day allowance for hospitalization may include all or part of the 
Screening period. Hospitalization beyond the initial 14 days allowed will require consultation with the medical 
monitor. Following the protocol-allowed 14 days of hospitalization (and any sponsor-allowed extension), 
patients should be treated as outpatients.  
Open-label Treatment Period: Patients who continue to meet eligibility criteria at Visit 2/Baseline will enter 
an OL treatment period for up to 18 weeks. Patients will receive OL cariprazine dosed as 1.5 mg/d beginning at 
Visit 2; titrated to 3.0 mg/d at Visit 3 and then titrated to 4.5 mg/d at Visit 4. Following the dose increase to 4.5 
mg/d, if there are significant tolerability issues, the investigator should utilize rescue medications as clinically 
appropriate. If further tolerability issues arise, a temporary drug holiday up to 3 days, will be allowed. The date 
and reason for any holiday will be recorded on the appropriate page of the electronic case report form. Patients 
who are unable to tolerate the 4.5 mg/d dose will be discontinued. Patients, who are able to tolerate the dose 
will continue on the 4.5 mg/d dose for the remainder of the OL treatment period.  
Beginning at Week 4 (Visit 6), patients will be assessed for response to the initial treatment with cariprazine. 
For the purposes of this protocol, response threshold will be defined as meeting all of the following criteria on 
or after Week 4 (Visit 6):  
x 
Positive and Negative Syndrome Scale (PANSS) total score ≤ 60, and 
x 
 ≥ 20% decrease in PANSS total score from Visit 2/Baseline, and 
x 
Score of ≤ 4 on each of the following 7 PANSS items: P1: delusions; P2: conceptual disorganization; 
P3: hallucinatory behavior; P6: suspiciousness/persecution; P7: hostility; G8: uncooperativeness; 
G14: poor impulse control; and 

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x 
Clinical Global Impression-Severity (CGI-S) ≤ 4, and 
x 
No significant tolerability issues as judged by the investigator 
Once a patient achieves the response threshold criteria, he/she will be evaluated at the subsequent visit to 
determine if the response criteria will be met again. Reconfirmation of response threshold criteria at either the 
visit following first attainment of response threshold or, in the event of an excursion, at the second visit 
following first attainment, will be defined as stability. One clinical excursion outside of the response threshold 
range is allowed between the first attainment of response threshold criteria and the subsequent confirmation of it 
(ie, stability). Following the excursion, patients not meeting response threshold criteria must be discontinued. 
Once stability has been achieved, patients must continue to meet the response threshold criteria for an additional 
8 weeks (ie, maintenance of stability) to qualify for randomization. During the maintenance of stability period, 
one excursion outside the response threshold criteria will be allowed. The excursion may occur at any time 
during the 8-week period with the exception of Visit 13/End of OL, but must be followed by a return to 
response threshold at the next visit. In the event the excursion occurs in a patient’s 8th week of stability, but 
prior to Visit 13/End of OL, the patient should be assessed at the following scheduled visit to confirm whether 
randomization criteria have been met. 
Patients who do not meet the response threshold criteria by Week 8 (Visit 8) or stability criteria by Week 10 
(Visit 9) will be discontinued and undergo early termination (ET) procedures and subsequently complete the 
safety follow-up (SFU) period. Additionally, patients who at any time require either hospitalization (excluding 
protocol-allowed hospitalization during Screening/OL periods for the purpose of washout of prior psychiatric 
medications) or initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 2 mg/d of lorazepam or 
equivalent or for more than 3 consecutive days) to treat worsening symptoms of schizophrenia or any other 
psychiatric disorder as judged by the clinical impression of the investigator will be discontinued. 
During the 8-week maintenance of stability period, patients who meet any of the following will be discontinued 
and will subsequently enter the SFU period:  
x 
PANSS total score increases by ≥ 30% relative to Visit 2/Baseline, or 
x 
Score > 4 on 1 or more of the following 7 PANSS items: P1: delusions; P2: conceptual 
disorganization; P3: hallucinatory behavior; P6: suspiciousness/persecution; P7: hostility; 
G8: uncooperativeness; G14: poor impulse control, or 
x 
Have an increase in CGI-S score by 2 or more points relative to Visit 2/Baseline  
Double-blind Treatment Period: OL patients who are able to maintain the response threshold criteria for  
8 weeks with no more than 1 excursion of response threshold criteria will be randomized 1:1:1 to receive 
cariprazine at the same dose (4.5 mg/d), a reduced dose (3.0 mg/d), or placebo for up to 26 weeks. Patients will 
continue to receive study treatment until a relapse event occurs or until completion of the 26 weeks of 
randomized treatment. 
Relapse is defined as the occurrence of any 1 of the following: 
x 
Increase in PANSS total score by ≥ 30% for patients who had a PANSS total score of ≥ 50 at 
Randomization/Visit 13 or a ≥ 10-point increase in PANSS total score for patients who had a PANSS 
total score < 50 at Randomization/Visit 13  
x 
Increase in CGI-S score by 2 or more points relative to Randomization/Visit 13 
x 
Score of > 4 on 1 or more of the following 7 PANSS items: P1: delusions; P2: conceptual 
disorganization; P3: hallucinatory behavior; P6: suspiciousness/persecution; P7: hostility; 
G8: uncooperativeness; G14: poor impulse control  
x 
Deliberate self-injury or aggressive/violent behavior 
x 
Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 2 mg/d of 
lorazepam or equivalent or for more than 3 consecutive days) to treat worsening symptoms of 
schizophrenia or any other psychiatric disorder as judged by the clinical impression of the investigator 
x 
Psychiatric hospitalization due to worsening of the patient’s underlying condition 

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x 
Exacerbation of psychiatric illness as judged by clinical impression of the investigator (eg, clinically 
significant agitation, suicidal or homicidal ideations) 
Safety Follow-up Period: Patients who complete the study, or who prematurely discontinue from either the OL 
or DB treatment periods will be followed for 4 more weeks and will have 2 evaluations for safety assessments 
at Visits 27 and 28 during the SFU period. During the SFU period, patients will continue as outpatients and will 
receive treatment as usual at the discretion of the investigator or designee. Patients will not receive 
investigational product (IP) during the SFU period. 
Study Treatment Groups: cariprazine 4.5 mg/d and 3.0 mg/d 
Controls: Matching placebo  
Dosage/Dose Regimen: IP in the form of capsules packaged in blister packs will be provided by the sponsor. No 
IP will be administered during the Screening/washout period or the SFU period. During the OL treatment period 
(up to 18 weeks), patients will take 1 capsule daily. Patients will begin with 1.5 mg/d at Visit 2; will be titrated 
to 3.0 mg/d at Visit 3 and then titrated to 4.5 mg/d at Visit 4. For the 26-week DB treatment period, patients will 
be supplied with identically appearing capsules of either cariprazine 4.5 mg/d, cariprazine 3.0 mg/d, or placebo. 
Randomization: After completing the OL treatment period, eligible patients will be randomized in a 1:1:1 ratio 
to cariprazine 4.5 mg/d, cariprazine 3.0 mg/d, or placebo.  
Visit Schedule: There are a total of up to 28 visits that comprise the Screening/washout and the OL treatment 
periods (Table 1) and the DB treatment and the SFU periods (Table 2). 
Patients completing the maintenance of stability period with no more than one excursion outside the remission 
threshold range will be eligible for early randomization beginning at Week 14 (Visit 11) and will move forward 
to the DB treatment period without requiring all visits in the OL treatment period.  
If no tolerability issues arise, all patients will receive at least 8 weeks of OL treatment. Some patients will be 
discontinued after 8 or 10 weeks if response threshold criteria or stability criteria, respectively, have not been 
achieved.  
Study Population Characteristics 
Number of Patients: Approximately 345 patients are planned to be randomized (115 per treatment arm). It is 
anticipated that approximately 1569 patients will be screened and 1035 patients will enter the OL treatment 
period. In the event that screening or randomization failure rates are higher than projected, enrollment will 
continue until approximately 115 patients per treatment arm are randomized.  
Condition/Disease: Patients with schizophrenia 
Key Inclusion Criteria: Male or female 18 to 64 years of age, inclusive; meeting DSM-5 criteria for 
schizophrenia, whose current psychotic episode is < 4 weeks in duration at Visit 1; and having a PANSS total 
score ≥ 70 and ≤ 120 at Visits 1 and 2, and a rating of at least 4 (moderate) on at least 2 of the following 
4 PANSS positive symptoms; P1: delusions; P2: conceptual disorganization; P3: hallucinatory behavior, and 
P6: suspiciousness/persecution at Visits 1 and 2. 
Key Exclusion Criteria: Patients currently meeting DSM-5 criteria for schizoaffective disorder, 
schizophreniform disorder, and other psychotic disorders; bipolar I and II disorder; autism spectrum disorder, 
intellectual development disorder, delirium, major/minor neurocognitive disorder. 
Efficacy Measures 
Primary efficacy parameter: Time to first relapse during the DB treatment period. Time to first relapse is 
defined as number of days from randomization to the first relapse. 
Relapse is defined as the occurrence of any 1 of the following: 
x 
Increase in PANSS total score by ≥ 30% for patients who had a PANSS total score of ≥ 50 at 
Randomization/Visit 13 or a ≥ 10-point increase in PANSS total score for patients who had a PANSS 
total score < 50 at Randomization/Visit 13  
x 
Increase in CGI-S score by 2 or more points relative to Randomization/Visit 13 

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x 
Score of > 4 on 1 or more of the following 7 PANSS items: P1: delusions; P2: conceptual 
disorganization; P3: hallucinatory behavior; P6: suspiciousness/persecution; P7: hostility; 
G8: uncooperativeness; G14: poor impulse control  
x 
Deliberate self-injury or aggressive/violent behavior 
x 
Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than 2 mg/d of 
lorazepam or equivalent or for more than 3 consecutive days) to treat worsening symptoms of 
schizophrenia or any other psychiatric disorder as judged by the clinical impression of the investigator 
x 
Psychiatric hospitalization due to worsening of the patient’s underlying condition 
x 
Exacerbation of psychiatric illness as judged by clinical impression of the investigator (eg, clinically 
significant agitation, suicidal or homicidal ideations) 
Pharmacokinetics: Not Applicable 
Pharmacogenetic Sampling: Blood samples will be collected at any timepoint between Visit 2/ Baseline and 
Visit 8/Week 8 to determine individual genotype status and for pharmacogenetic bio banking. Patient 
participation is optional. 
Safety Assessments: Adverse events recording, clinical laboratory parameters (hematology, chemistry, 
urinalysis, prolactin), vital sign parameters (including orthostatic blood pressure, pulse rate), body mass index, 
weight, waist circumference, physical examinations, electrocardiograms, ophthalmological examinations, 
Columbia–Suicide Severity Rating Scale (C-SSRS), measures of extrapyramidal symptoms (EPS): Barnes 
Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), and Simpson-Angus Scale 
(SAS). 
General Statistical Methods and Types of Analyses: 
The DB safety population will consist of all randomized patients who took at least 1 dose of DB IP. The DB 
intent-to-treat (DB ITT) population will consist of all patients in the DB safety population who had at least 1 post-
randomization assessment of the PANSS or CGI-S scores during the DB treatment period of the study. 
The primary efficacy analysis will compare the time to first relapse between each cariprazine group and the 
placebo group using the log-rank test for the DB ITT population. Estimates of the hazard ratio and 95% CIs will 
be based on the Cox proportional hazards model. The Kaplan-Meier estimates for cumulative distribution function 
of relapse rate for each treatment group will be provided.  
The fixed-sequence testing procedure will be used for multiple comparisons to control the family-wise Type I 
error rate at a 0.05 level. The comparison of cariprazine 4.5 mg/d versus placebo will be tested first at a 0.05 
significance level, only when the testing is significant, the comparison of cariprazine 3.0 mg/d versus placebo 
will be tested.  
All safety parameters will be analyzed descriptively. 
Sample Size Calculation:  
The sample size and power calculations are based on the analysis of time to relapse in the DB treatment period 
to compare each cariprazine dose group versus placebo based on a log-rank test.  
Based on the first 26 weeks’ data from RGH-MD-06, the relapse hazard ratio is assumed to be 0.50, and 
cumulative relapse rate at Week 26 for the placebo group is 46%. In addition, the cumulative dropout rate due 
to reasons other than relapse at 26 weeks is assumed to be 20.0%. A total of approximately 103 in the DB 
treatment period need to be observed in order to have 85% power to detect a statistically significant difference 
between each cariprazine and placebo group, using two-tailed, log-rank tests at a 5% level of significance. The 
study should randomize approximately 345 patients, 115 patients each arm, to provide the required number of 
relapse events. Given the fixed-sequence testing strategy, the higher dose of 4.5 mg/d has 85% statistical power 
to show significance versus placebo, and the 3.0 mg/d dose, would also have an 85% power provided that 
testing for cariprazine 4.5 mg/d group is statistically significant. EAST 6.0 was used for power and sample size 
calculation. 

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Note: Visit 2/Baseline is expected to occur within 7 days of Visit 1; if required, it may be conducted up to 3 days after the scheduled visit. If necessary, Visits 3 
to 13 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 13. 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BACS = Brief Assessment of Cognition in Schizophrenia; BARS = Barnes Akathisia 
Rating Scale; CGI-I = Clinical Global Impression-Improvement scale; CGI-S = Clinical Global Impression-Severity scale; C-SSRS = Columbia-Suicide Severity 
Rating Scale; ECG = electrocardiogram; EPS = extrapyramidal symptoms; IP = investigational product; IWRS = interactive web response system; OL = Open-
label; SCI-PANSS = Structured Clinical Interview for the Positive and Negative Syndrome Scale; PSP = Personal and Social Performance scale; SAE = serious 
adverse event; SAS = Simpson-Angus Scale; SCID-5 = Structured Clinical Interview for DSM-5. 
a 
Verified Clinical Trials database check to be performed where applicable. 
b 
For women of childbearing potential only. 
c 
Blood pressure and pulse rate will be measured both standing and supine.  
d 
The Screening ophthalmological examination must be completed prior to Visit 2/Baseline and the start of OL IP.  
e 
For patients eligible for randomization, every attempt should be made to complete the Visit 13/End of OL ophthalmological examination on the same day as 
all other Visit 13/End of OL procedures. If the examination cannot be accommodated, it must occur within 7 days after randomization.  
f 
Assess response threshold criteria beginning at Visit 6/Week 4 (per Section 4.5). Patients who do not meet response threshold criteria by Visit 8/Week 8 must 
be discontinued and will undergo procedures for Visit 26/early termination (ET) and subsequently complete the Safety follow-up (SFU) period. 
g 
Assess patient for attainment of stability criteria (per Section 4.5). If response threshold criteria are met but are not confirmed at the subsequent visit (ie, 
stability is not attained), reassess patient for attainment of stability (reconfirmation of response threshold criteria) at the next visit. Patients not meeting the 
response threshold criteria following the excursion, must be discontinued. Patients who do not otherwise meet stability of response threshold criteria by 
Visit 9/Week 10 must be discontinued and will undergo procedures for Visit 26/ET and subsequently complete the SFU period.  
h 
Assess PANSS and CGI-S during the 8-week period following achievement of stability to ensure that response threshold criteria continue to be met. During 
the 8 weeks, 1 excursion is allowed (see Section 4.5). 
i 
Patients who have met stability of maintenance criteria (per Section 4.5) should be assessed for fulfillment of randomization criteria (per Section 4.6). 
Patients who meet randomization criteria should undergo Visit 13/End of OL procedures and be randomized to DB treatment. Patients eligible for early 
randomization will skip any remaining visits in the OL treatment period. 
j 
Pharmacogenetic consent may be obtained at any time between Visit 1/Screening and Visit 8/Week 8. 
k 
Pharmacogenetic sampling (one sample) may be obtained at any time between Visit 2/Baseline and Visit 8/Week 8. 
 

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1 
Background and Clinical Rationale 
Schizophrenia is a common and severe, often disabling psychiatric illness of unknown 
etiology that is characterized by extreme disturbances of cognition and thought, affecting 
language, perception and sense of self. It is a chronic disorder typified by a life-long pattern 
of acute psychotic episodes superimposed upon chronically poor psychosocial adjustment 
(Silveira 2012; Owen 2016). 
Symptoms of schizophrenia fall into 3 domains: positive symptoms (auditory hallucinations, 
disorganized or bizarre thoughts, delusions and irrational fears); negative symptoms 
(affective blunting, emotional withdrawal, anhedonia, poverty of speech and apathy); and 
cognitive dysfunction (symptoms ranging from impaired attention to abnormal executive 
function, as well as memory impairment, depression and/or anxiety)  
(Nuechterlein  2012). Positive symptoms appear to reflect an excess or distortion of normal 
functions, while negative symptoms reflect a diminution or loss of normal functions. All 
schizophrenic individuals experience positive symptoms, although not continuously. 
Negative symptoms are present in approximately one-third of all patients, with an especially 
high rate during first-episode psychosis (Miyamoto 2012; Foussias 2014). Cognitive 
dysfunction may present prior to positive and negative symptoms, and can change over time. 
These cardinal symptoms lead to social and occupational dysfunction, which inevitably have 
a profound effect on the family and the place of the affected individual in wider society. 
Symptoms typically emerge in late adolescence or early adulthood and often persist 
throughout the rest of the patient's lifetime, resulting in significant disruption of the patients' 
life, as well as those of family members and friends (Schultz 2007). According to data from 
the World Health Organization’s (WHO) Global Burden of Disease (GBD) study 2010, 
schizophrenia is the fifth most disabling mental/behavioral disorder, accounting for nearly 
15,000 (0.6%) of a total of 2,490 billion disability-adjusted life years worldwide in that year 
(Murray 2013). 
This disorder knows no ethnic, economic or cultural boundaries. According to the National 
Institute of Mental Health in the United States, approximately 1% of Americans have 
schizophrenia (Mental health information: Schizophrenia [National Institute of Mental 
Health 2015]). In the 2015 GBD study, there were approximately 23.4 million prevalent 
cases of schizophrenia worldwide (GBD 2015 Disease and Injury Incidence and Prevalence 
Collaborators 2016). 
In addition to their psychiatric symptoms, patients with schizophrenia are at greater risk for 
medical comorbidities than is the general population. As a result, the mortality rate for 

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schizophrenia patients is 2 to 3 times higher than in the general population (Auquier 2007). 
According to the WHO 2010 GBD study, schizophrenia was the cause of 19,800 (range 
16,600 to 25,000) deaths worldwide in 2010 (Lozano 2012).  
Suicide is a major contributor to morbidity and mortality in patients with schizophrenia. It is 
estimated that approximately 10% to 15% of all schizophrenia patients eventually commit 
suicide, and up to 50% will attempt suicide at some point in their lifetime. In the United 
States, the suicide rate in patients with schizophrenia is about 8 to 13 times greater than that 
of the general population (Meltzer 2002). 
Cariprazine is an orally active and potent dopamine (DA) D3/D2 receptor functional 
antagonist developed by Gedeon Richter Plc., and Allergan Sales, LLC. It is approved in the 
United States for the treatment of schizophrenia and acute treatment of manic or mixed 
episodes associated with bipolar I disorder. For schizophrenia, the starting dose is 1.5 mg/d 
with a recommended dose of 1.5 mg/d to 6 mg/d. 
The chemical name of the hydrochloride salt of cariprazine is trans-N-{4-[2-[4- (2,3-
dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexyl}-N’,N’-dimethylurea hydrochloride. Its 
molecular formula is C21H32Cl2N4O HCl; its molecular weight is 463.87. Desmethyl and 
didesmethyl cariprazine have been identified as circulating plasma metabolites. The  
receptor-binding profile of these 2 metabolites is similar to that of cariprazine. 
Cariprazine also has considerable affinity for, and is a partial agonist and antagonist at, the 
serotonin 5-HT1A and 5-HT2B receptors, respectively. Antidepressant- and/or anxiolytic-like 
effects of cariprazine may also be mediated through these receptors. 
Cariprazine has low potency at other receptor sites, such as the 5-HT2C, histamine H1, and 
adrenergic receptor sites, suggesting a lower potential for side effects such as extrapyramidal 
symptoms (EPS) and body weight gain. Cariprazine displays potent in vivo oral activity in 
various animal models of psychosis and mania and shows antidepressant- and anxiolytic-like 
activity as well as procognitive-like effects. 
Discussion of Study Design, Including the Choice of Control Groups 
In a previously conducted randomized withdrawal trial (RGH-MD-06), cariprazine 3 to 
9 mg/d was shown to reduce time to relapse when compared to placebo. In RGH-MD-06, 
patients were initially treated with cariprazine 3 to 9 mg/d during a 20-week open-label 
period and then randomized to continue cariprazine (3 to 9 mg/d) or placebo, for up to 72 
additional weeks or until relapse. The purpose of this study is to evaluate the efficacy and 

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safety of cariprazine at a target dose of 4.5 mg/d compared with placebo in prevention of 
relapse in patients with schizophrenia. Additionally, the study will evaluate the efficacy and 
safety of cariprazine at a target dose of 3.0 mg/d compared with placebo in prevention of 
relapse in patients with schizophrenia who were initially stabilized on a target dose of 
4.5 mg/d. 
The placebo-controlled, randomized withdrawal design is considered standard to demonstrate 
effectiveness of long-term maintenance treatment. 
Up to 18 weeks of open-label (OL) treatment are included to allow patients to have enough 
time to achieve and maintain stability of symptoms following continuation of treatment at the 
established dose. 
Another feature of this study design is to evaluate if a dose-reduction paradigm can be 
utilized in the maintenance treatment of schizophrenia. The common clinical management of 
schizophrenia is to treat a patient with an established dose until stability of symptoms is 
achieved. Once stability has been achieved, the same dose that was used to achieve stability 
is typically continued during the maintenance treatment of the illness. This study will attempt 
to address the question of whether a dose lower than the one used to achieve stability of 
symptoms can be used to maintain a therapeutic response and prevent relapse.  
The double-blind (DB) design is included to minimize systematic bias resulting from the scale 
raters, patients, or investigator knowing the treatment being administered. Randomization at 
the beginning of the DB treatment period is expected to minimize patient selection bias and 
increase Baseline comparability of the 2 treatment groups. 
The use of placebo control is critical to the study design both to understand the safety 
findings of the drug and to ensure that efficacy results can be interpreted. In this study, the 
placebo control is used during the DB treatment period to demonstrate the reemergence of 
symptoms of schizophrenia upon withdrawal of cariprazine compared with patients who 
continue cariprazine treatment. Patients who continue cariprazine treatment should maintain 
improvement in their schizophrenia symptoms for a longer period of time when compared to 
those switched to placebo. Patients switched to placebo should have an earlier return of 
symptoms of schizophrenia.  
The fixed-dose design during the DB treatment period was selected to maintain patients at 
the cariprazine dose level at which their symptoms of schizophrenia had responded. The dose 
selected, 4.5 mg/d, represents a dose that has been proven to be efficacious in schizophrenia 
while minimizing side effects. The lower dose during the DB treatment period was 

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determined following an FDA request to include doses lower than those used to achieve a 
response in the acute phase, while maintaining a dose within the approved range for that 
indication (1.5 to 6.0 mg/d). If both doses prove to be effective in preventing relapse, an 
evaluation will be made to see if a lower dose also achieves better tolerability during the 
maintenance phase of treatment. 
The duration of the DB treatment period, with a maximum of 26 weeks, was selected to 
provide sufficient time to demonstrate schizophrenia relapse upon withdrawal of cariprazine. 
The 4-week safety follow-up (SFU) period allows continued patient monitoring after 
investigational product (IP) has been discontinued. 
2 
Study Objectives and Clinical Hypotheses 
2.1 
Study Objectives 
1) To evaluate the efficacy and safety of cariprazine at a target dose of 4.5 mg/d compared 
with placebo in prevention of relapse in patients with schizophrenia; 2) To evaluate the 
efficacy and safety of cariprazine at a target dose of 3.0 mg/d compared with placebo in 
prevention of relapse in patients with schizophrenia who were initially stabilized on a target 
dose of 4.5 mg/d.  
2.2 
Clinical Hypotheses 
1) In patients with schizophrenia, cariprazine at 4.5 mg/d is safe and effective in preventing 
relapse when compared to placebo;  
2) In patients with schizophrenia who were initially stabilized on a target dose of 4.5 mg/d, 
cariprazine at 3.0 mg/d is safe and effective in preventing relapse when compared to placebo.  
3 
Study Design 
Structure: This is a multicenter, multinational, DB, placebo-controlled, 
randomized-withdrawal study evaluating the safety and efficacy of cariprazine compared 
with placebo in the prevention of relapse in patients with schizophrenia. The study schematic 
is presented in Figure 1. 
3.1 
Screening/Washout Period 
Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) criteria for schizophrenia will undergo a Screening/washout period of up to 7 days, 

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during which consent, assessment of eligibility, and withdrawal of prior psychiatric and 
prohibited medications will occur. The length and timing of the washout of prior psychiatric 
medications during the 7 days allotted for the Screening period is at the discretion of the 
investigator. Prior medications should be gradually withdrawn such that the washout is 
completed by Visit 2/Baseline. Please note that during the screening/washout period, 
psychotropic medications, other than those listed as rescue (Section 4.8.3), may not be newly 
initiated or reinstated. In order to ensure the safe transition of patients into the study, based 
upon the clinical judgment of the investigator, patients may be hospitalized during initiation 
of the study. This hospitalization can be for up to 14 days during the Screening and OL 
periods (with the end of hospitalization no later than Visit 3 [Day 8] of the OL treatment 
period). This 14-day allowance for hospitalization may include all or part of the Screening 
period. Hospitalization beyond the initial 14 days allowed will require consultation with the 
medical monitor. Following the protocol-allowed 14 days of hospitalization (and any 
sponsor-allowed extension), patients should be treated as outpatients.  
3.2 
Open-label Treatment Period 
Patients who continue to meet eligibility criteria at Visit 2/Baseline will enter an OL 
treatment period for up to 18 weeks. Patients will receive OL cariprazine dosed as 1.5 mg/d 
beginning at Visit 2; titrated to 3.0 mg/d at Visit 3 and then titrated to 4.5 mg/d at Visit 4. 
Following the dose increase to 4.5 mg/d, if there are significant tolerability issues, the 
investigator should utilize rescue medications as clinically appropriate. If further tolerability 
issues arise, a temporary drug holiday up to 3 days, will be allowed. The date and reason for 
any holiday will be recorded on the appropriate page of the electronic case report form 
(eCRF). Patients who are unable to tolerate the 4.5 mg/d dose will be discontinued. Patients, 
who are able to tolerate the dose will continue on the 4.5 mg/d dose for the remainder of the 
OL treatment period.  
Beginning at Week 4 (Visit 6), patients will be assessed for response to the initial treatment 
with cariprazine. For the purposes of this protocol, response threshold will be defined as 
meeting all of the following criteria on or after Week 4 (Visit 6): 
x Positive and Negative Syndrome Scale (PANSS) total score ≤ 60, and 
x ≥ 20% decrease in PANSS total score from Visit 2/Baseline, and 

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x Score of ≤ 4 on each of the following 7 PANSS items:  
o P1: delusions 
o P2: conceptual disorganization 
o P3: hallucinatory behavior 
o P6: suspiciousness/persecution 
o P7: hostility 
o G8: uncooperativeness 
o G14: poor impulse control; and 
x Clinical Global Impression-Severity (CGI-S) ≤ 4, and 
x No significant tolerability issues as judged by the investigator 
Once a patient achieves the response threshold criteria, he/she will be evaluated at the 
subsequent visit to determine if the response criteria will be met again. Reconfirmation of 
response threshold criteria at either the visit following first attainment of response threshold 
or, in the event of an excursion, at the second visit following first attainment, will be defined 
as stability. One clinical excursion outside of the response threshold range is allowed 
between the first attainment of response threshold criteria and the subsequent confirmation of 
it (ie, stability). Following the excursion, patients not meeting response threshold criteria 
must be discontinued. 
Once stability has been achieved, patients must continue to meet the response threshold 
criteria for an additional 8 weeks (ie, maintenance of stability) to qualify for randomization. 
During the maintenance of stability period, one excursion outside the response threshold 
criteria will be allowed. The excursion may occur at any time during the 8-week period with 
the exception of Visit 13/End of OL, but must be followed by a return to response threshold 
at the next visit. In the event the excursion occurs in a patient’s 8th week of stability, but 
prior to Visit 13/End of OL, the patient should be assessed at the following scheduled visit to 
confirm whether randomization criteria have been met. 
Patients who do not meet the response threshold criteria by Week 8 (Visit 8) or stability 
criteria by Week 10 (Visit 9) will be discontinued. Additionally, patients who at any time 
require either hospitalization (excluding protocol-allowed hospitalization during 

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Screening/OL periods for the purpose of washout of prior psychiatric medications) or 
initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, more than  
2 mg/d of lorazepam or equivalent or for more than 3 consecutive days) to treat worsening 
symptoms of schizophrenia or any other psychiatric disorder as judged by the clinical 
impression of the investigator will be discontinued. 
During the 8-week maintenance of stability period, patients who meet any of the following 
will be discontinued and will subsequently enter the SFU period:  
x PANSS total score increases by ≥ 30% relative to Visit 2/Baseline, or 
x Score > 4 on 1 or more of the following 7 PANSS items: P1: delusions; P2: conceptual 
disorganization; P3: hallucinatory behavior; P6: suspiciousness/persecution; 
P7: hostility; G8: uncooperativeness; G14: poor impulse control, or 
x Have an increase in CGI-S score by 2 or more points relative to Visit 2/Baseline  
3.3 
 Double-blind Treatment Period 
Open-label patients who are able to maintain the response threshold criteria for 8 weeks with 
no more than 1 excursion of response threshold criteria will be randomized 1:1:1 to receive 
cariprazine at the same dose (4.5 mg/d), a reduced dose (3.0 mg/d), or placebo for up to  
26 weeks. Patients will continue to receive study treatment until a relapse event occurs or 
until completion of the 26 weeks of randomized treatment. 
Relapse is defined as the occurrence of any 1 of the following: 
x Increase in PANSS total score by ≥ 30% for patients who had a PANSS total score of  
≥ 50 at Randomization/Visit 13 or a ≥ 10-point increase in PANSS total score for 
patients who had a PANSS total score < 50 at Randomization/Visit 13  
x Increase in CGI-S score by 2 or more points relative to Randomization/Visit 13  
x Score of > 4 on 1 or more of the following 7 PANSS items: P1: delusions; 
P2: conceptual disorganization; P3: hallucinatory behavior; 
P6: suspiciousness/persecution; P7: hostility; G8: uncooperativeness;  
G14: poor impulse control  
x Deliberate self-injury or aggressive/violent behavior 

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x Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or 
with a benzodiazepine that exceeds the protocol-specified allowance or duration (ie, 
more than 2 mg/d of lorazepam or equivalent or for more than 3 consecutive days) to 
treat worsening symptoms of schizophrenia or any other psychiatric disorder as judged 
by the clinical impression of the investigator 
x Psychiatric hospitalization due to worsening of the patient’s underlying condition 
x Exacerbation of psychiatric illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations) 
3.4 
Safety Follow-up Period 
Patients who complete the study, or who prematurely discontinue from either the OL or DB 
treatment periods will be followed for 4 more weeks and will have 2 evaluations for safety 
assessments at Visits 27 and 28 during the SFU period. During the SFU period, patients will 
continue as outpatients and will receive treatment as usual at the discretion of the investigator 
or designee. Patients will not receive IP during the SFU period. 
4 
Study Population and Entry Criteria 
4.1 
Number of Patients 
Approximately 345 patients are planned to be randomized (115 per treatment arm). It is 
anticipated that approximately 1569 patients will be screened and 1035 patients will enter the 
OL treatment period. In the event that screening or randomization failure rates are higher 
than projected, enrollment will continue until approximately 115 patients per treatment arm 
are randomized.  
4.2 
Study Population Characteristics 
The study population will include patients with schizophrenia whose diagnosis is based upon 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, 
approached through a structured clinical interview (Structured Clinical Interview for  
DSM-5 [SCID-5] First 2015). 

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4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
1. Written informed consent has been obtained. 
2. Patients are male or female, 18 to 64 years of age, inclusive. 
3. Patient meets DSM-5 criteria for schizophrenia as determined by SCID-5.  
4. Diagnosis of schizophrenia for a minimum of 1 year before Visit 1. 
5. Current psychotic episode < 4 weeks duration at Visit 1. 
6. PANSS total score ≥ 70 and ≤ 120 at Visit 1 and Visit 2. 
7. Rating of at least 4 (moderate) on at least 2 of the following 4 PANSS positive 
symptoms; P1: delusions; P2: conceptual disorganization; P3: hallucinatory behavior; 
P6: suspiciousness/persecution at Visit 1 and Visit 2. 
8. Normal physical examination results, vital signs, clinical laboratory test results, and 
electrocardiogram (ECG) results or abnormal results that are judged not clinically 
significant by the investigator. 
9. 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]). 
10. Ability to follow study instructions, complete study assessment tools with minimal 
assistance and no alteration to the assessment tools, and likely to complete all required 
visits. 
11. Continue to meet all Visit 1 (Screening) inclusion criteria at Visit 2 (Baseline); to be 
assessed at Visit 2. 
12. Each patient must have an identified external contact person or an identified 
responsible person (eg, family member, friend, social worker, case worker, or nurse) 
who is considered reliable by the investigator and who will provide support to the 
patient and act as an external contact in the event the site is having difficulty reaching 
the patient during the trial and to ensure observation of patient’s well-being.  

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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 4.8.1. 
14. Negative qualitative serum β-human chorionic gonadotropin (β-hCG) pregnancy test 
(women of childbearing potential only). 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
Psychiatric Criteria 
1. Currently meeting DSM-5 criteria for any of the following: 
x Schizoaffective disorder, schizophreniform disorder, and other psychotic disorders 
x Bipolar I and II disorder 
x Autism spectrum disorder, intellectual development disorder, delirium, 
major/minor neurocognitive disorder 
2. History of meeting DSM-5 criteria for substance-related disorders (ie, use disorders 
except caffeine- and tobacco-related) within the prior 3 months before Visit 1. 
3. Positive result at Visit 1 from the urine drug screen (UDS). Patients with a positive 
UDS at Visit 1 for opiates, cannabinoids, amphetamines, barbiturates, or 
benzodiazepines may be enrolled if all of the following are satisfied: 
a) The drug was used for a legitimate medical purpose; 
b) The drug can be discontinued prior to participation in the study (except for 
benzodiazepines which may be continued if the patient has been taking a 
stable dose [ie, lorazepam up to 2 mg/d or its benzodiazepine equivalent] for 
at least 1 month prior to Visit 1 or if used as rescue during washout); and  
c) A repeat UDS must be performed prior to Visit 2 and must be negative, except 
benzodiazepine use as described 3(b). 
4. History of intolerance or hypersensitivity to cariprazine or allowed rescue 
medications. 

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5. The patient is at imminent risk of injuring self or others or causing significant damage 
to property, as judged by the investigator. 
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 one year before Visit 1 
b) Significant risk, as judged by the investigator, based on the psychiatric 
interview or information collected in the C-SSRS at Visit 1 (Screening) or 
Visit 2 (Baseline) 
Treatment-Related Criteria: 
7. Patient received treatment with depot antipsychotic within 2 cycles prior to Visit 1. 
8. Patient received treatment with clozapine doses > 50 mg/d in the past 2 years. 
9. Patients requiring concomitant treatment with a moderate or strong cytochrome P450 
(CYP) 3A4 inhibitors or CYP3A4 inducers. If applicable, these drugs must be 
discontinued 7 days prior to Visit 2/Baseline. 
10. Patient requires concomitant treatment with any prohibited medication, supplement, or 
herbal product including any psychotropic drug or any drug with psychotropic activity 
or with a potentially psychotropic component (for exceptions allowed for concomitant 
treatments, refer to Section 4.8). 
11. At Visit 2, patient requires pharmacologic treatment for the control of EPS. 
12. Prior participation in any clinical trials involving experimental or investigational drugs 
within 6 months before Visit 1 or planned during the study. 
Other Medical Criteria: 
13. Female patients who are pregnant, planning to become pregnant during the course of 
the study, or are currently lactating. 

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14. Any concurrent medical condition including psychiatric symptoms possibly secondary 
to any other general medical condition (eg, Vitamin B-12/folate deficiency, Cushing 
syndrome, etc) 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.  
15. Any cardiovascular disease (eg, hypertension) or endocrinological disease (eg, thyroid 
disease/disorders) that is clinically unstable, or decompensated, based on the 
investigator’s judgment. 
16. Gastric bypass or any condition that would be expected to affect drug absorption (lap 
band procedures and gastric sleeve are acceptable if there is no problem with 
absorption). 
17. History of seizure disorder (with the exception of febrile seizure), stroke, significant 
head injury, tumor of the central nervous system, or any other condition that 
predisposes toward a risk of seizure.  
18. Patients who meet any of the following ophthalmological criteria: 
a. A clinically significant finding of lens opacification(s) at the screening 
ophthalmological examination that meets any of the following: 
1. Opacification ≥ AREDS standard photo #2 
OR 
2. Best-corrected visual acuity worse than LogMar 0.1 [20/25 Snellen 
equivalent] 
OR 
3. Cataract surgery is planned or expected at anytime during the trial, 
based upon the ophthalmological examination. 
b. Any clinically significant ocular trauma or complications of ocular trauma, 
or history of retinal detachment, intraocular surgery (with the exception of 
cataract surgery to remove or replace lenses bilaterally) or laser treatment 
c. History or current findings of ocular disease (eg, open- or narrow-angle 
glaucoma, retinopathies, corneal diseases) 
d. History of amiodarone or systemic corticosteroid use for ≥ 3 consecutive 
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e. Intraocular pressure of > 21 mm Hg in either eye 
f. Unable to dilate pupil to at least 5 mm in either eye  
19. Allergies to dilating drops, optic medications, or topical ocular anesthetics that are to 
be used in the ophthalmological examination. 
20. Known human immunodeficiency virus infection. 
21. Positive hepatitis C antibody on screening. 
22. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody 
immunoglobulin M on screening. 
23. Screening liver enzyme test (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT]) results > 2 × the upper limit of normal (ULN) or total 
bilirubin > 1 × ULN. 
24. Absolute neutrophil count < 1000 per mm3 at screening. 
25. Hemoglobin A1c (HbA1c) > 7% at screening. 
26. Blood alcohol concentration ≥ 0.02 g/dL at Visit 1 as measured by breathalyzer. 
27. History of tardive dyskinesia (except for mild cases attributed to use of conventional 
agents), serotonin syndrome, or neuroleptic malignant syndrome. 
Other Criteria: 
28. Employee, or immediate relative of an employee, of the sponsor, any of its affiliates or 
partners, or the study center. 
29. Inability to speak, read, or understand the local language sufficiently to understand the 
nature of the study, to provide signed written informed consent, or to allow the 
completion of all study assessments. 
30. Unable or unlikely to comply with the study protocol or unsuitable for any other 
reason, as judged by the investigator. 

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4.5 
Response Threshold, Stability, and Maintenance of Stability 
Criteria During the OL Treatment Period  
Response threshold is defined as meeting all of the following criteria on or after Week 4 
(Visit 6): 
x PANSS total score ≤ 60, and 
x ≥ 20% decrease in PANSS total score from Visit 2/Baseline, and 
x Score of ≤ 4 on each of the following 7 PANSS items:  
o P1: delusions 
o P2: conceptual disorganization 
o P3: hallucinatory behavior 
o P6: suspiciousness/persecution 
o P7: hostility 
o G8: uncooperativeness 
o G14: poor impulse control; and 
x CGI-S ≤ 4  
x No significant tolerability issues as judged by the investigator 
Note: Patients who do not meet the response threshold criteria by Week 8 (Visit 8) will be 
discontinued and undergo early termination (ET) procedures and subsequently complete the 
SFU period. 
Stability is the reconfirmation of response threshold criteria at either the visit following first 
attainment of response threshold or, in the event of an excursion, at the second visit following 
first attainment. One clinical excursion outside of the response threshold range is allowed 
between the first attainment of response threshold criteria and the subsequent confirmation of 
it (ie, stability). Following the excursion, patients not meeting response threshold criteria 
must be discontinued and undergo ET procedures and subsequently complete the SFU period. 

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Note: Patients who do not meet stability criteria by Week 10 (Visit 9) will be discontinued 
and undergo ET procedures and subsequently complete the SFU period. 
Maintenance of stability criteria: Once stability has been attained, patients must continue to 
meet response threshold criteria for 8 additional weeks. One excursion of response threshold 
is allowed during the 8-week period, provided that it does not occur at Visit 13/End of OL. If 
an excursion occurs, the response threshold criteria must be met at the subsequent visit. 
Patients not meeting response threshold criteria at the visit following an excursion must be 
discontinued and undergo ET procedures and subsequently complete the SFU period. 
Note: If any of the following occurs after stability has been established (ie, during the 8-week 
maintenance of stability period), the patient is to be discontinued: 
x PANSS total score increases by ≥ 30% relative to Visit 2/Baseline; or  
x Score is > 4 on 1 or more of the following 7 PANSS items: P1: delusions; 
P2: conceptual disorganization; P3: hallucinatory behavior; P6: suspiciousness/ 
persecution; P7: hostility; G8: uncooperativeness; G14: poor impulse control; or 
x CGI-S score increases by 2 or more points relative to Baseline/Visit 2; or  
x Hospitalization is required (excluding protocol-allowed hospitalization during 
Screening/OL periods for the purpose of washout of prior psychiatric medications); or  
x Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or 
with a benzodiazepine that exceeds the protocol-specified allowance or duration (ie, 
more than 2 mg/d of lorazepam or equivalent or for more than 3 consecutive days) to 
treat worsening symptoms of schizophrenia or any other psychiatric disorder as judged 
by the clinical impression of the investigator 
4.6 
Randomization Criteria 
Randomization requirements are: 
x Ability to safely tolerate cariprazine 4.5 mg/d 
x Maintenance of response threshold criteria for 8 weeks following attainment of 
stability: 
o PANSS total score ≤ 60; and 
o  ≥ 20% decrease in PANSS total score from Visit 2/Baseline; and 

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o Score of ≤ 4 on each of the following 7 PANSS items:  
 P1: delusions 
 P2: conceptual disorganization 
 P3: hallucinatory behavior 
 P6: suspiciousness/persecution 
 P7: hostility 
 G8: uncooperativeness 
 G14: poor impulse control; and 
o CGI-S ≤ 4 
4.7 
Relapse Criteria During the Double-blind Treatment Period  
After randomization, relapse is defined as the occurrence of any 1 of the following: 
x Increase in PANSS total score by ≥ 30% for patients who had a PANSS total score of  
≥ 50 at Randomization/Visit 13 or a ≥ 10-point increase in PANSS total score for 
patients who had a PANSS total score < 50 at Randomization/Visit 13 
x Increase in CGI-S score by 2 or more points relative to Randomization/Visit 13 
x Score of > 4 on 1 or more of the following 7 PANSS items: P1: delusions; 
P2: conceptual disorganization; P3: hallucinatory behavior; 
P6: suspiciousness/persecution; P7: hostility; G8: uncooperativeness; 
G14: poor impulse control 
x Deliberate self-injury or aggressive/violent behavior 
x Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or 
with a benzodiazepine that exceeds the protocol-specified allowance or duration (ie, 
more than 2 mg/d of lorazepam or equivalent or for more than 3 consecutive days) to 
treat worsening symptoms of schizophrenia or any other psychiatric disorder as judged 
by the clinical impression of the investigator 
x Psychiatric hospitalization due to worsening of the patient’s underlying condition 
x Exacerbation of psychiatric illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations) 

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

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

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4.8.3 
Rescue Medications 
Medically appropriate episodic use (up to 3 consecutive days) of narcotic analgesics for acute 
medical indications (eg, tooth extraction) is allowed during the study. 
4.8.3.1 
Insomnia 
The following will be allowed but should not be prescribed prophylactically: 
x Zolpidem (maximum of 10 mg/d) 
x Zolpidem extended release (maximum of 12.5 mg/d) 
x Zaleplon (maximum of 20 mg/d) 
x Eszopiclone (maximum of 3 mg/d) 
x Zopiclone (maximum of 7.5 mg/d) 
x Chloral hydrate (maximum of 1000 mg/d) may be used acutely with approval from 
the medical monitor 
x Suvorexant (maximum of 20 mg/d) 
These medications must be administered before bedtime as recommended in their prescribing 
information. The medication must be documented on the relevant eCRF. No such medication 
is permitted within 8 hours of psychiatric or neurological assessments. 
4.8.3.2 
Extrapyramidal Symptoms or Akathisia 
The following will be allowed but should not be prescribed prophylactically: 
For EPS or akathisia that emerge or worsen during the study, the rescue medications listed 
below will be allowed. However, each of the 3 EPS scales (Abnormal Involuntary Movement 
Scale [AIMS], Barnes Akathisia Rating Scale [BARS], and Simpson-Angus Scale [SAS]) 
should be administered first to support the decision to dispense these rescue medications. The 
only exception to administering the EPS scales before dispensing rescue medication is 
medical urgency (eg, dystonia, severe akathisia, etc). 
x Benztropine 
x Diphenhydramine 
x Propranolol 
x Biperiden 
x Trihexyphenidyl 

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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. 
4.8.3.3 
Agitation, Restlessness, and Hostility 
Episodic use of lorazepam up to 2 mg/d (or equivalent benzodiazepine) and for up to 
3 consecutive days at a time is allowed for agitation, restlessness, and hostility.  
The medication use and events of 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 (for up-titration only), 3.0 mg of cariprazine, and 
4.5 mg of cariprazine. 
5.2 
Control Treatment 
Matching placebo capsules. 
5.3 
Methods for Masking/Blinding 
There will be no blinding during the OL treatment period of the study.  
During the DB treatment period, all study treatment will be provided in identical blister cards 
to maintain masking of the study. All patients will be instructed to take 1 capsule of IP once 
daily at approximately the same time each day. 

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5.4 
Method for Assignment to Treatment Groups/Randomization 
Prior to initiation of study treatment, each patient who provides informed consent will be 
assigned a patient number that will serve as the patient identification number (PID) on all 
study documents for the duration of the study. 
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 4.5 or 3.0 mg/d, or placebo. 
An automated interactive web response system (IWRS) will be used to manage IP dispensing 
during the OL treatment period of the study. IWRS will also be used for randomization and 
DB treatment assignment. 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 patient in the OL and DB treatment periods. Sites 
will receive the IWRS confirmation notifications for each transaction. All notifications will 
be maintained with the study source documents. 
5.5 
Treatment Regimen and Dosing 
Table 3: 
Treatment Regimen and Dosing 
Drug/Dose 
Investigational Product Frequency 
Route of Administration 
Open-Label Treatment Period: Week 1 (IP dispensed at Visit 2/Baseline) 
Cariprazine 1.5 mg  
Once daily 
Oral (capsule) 
Open-Label Treatment Period: Week 2 (IP dispensed at Visit 3) 
Cariprazine 3.0 mg  
Once daily 
Oral (capsule) 
Open-Label Treatment Period: Weeks 3 through 18 (IP dispensed at Visits 4 through 12)a 
Cariprazine 4.5 mg  
Once daily 
Oral (capsule) 
Double-Blind Treatment Period: Weeks 19 through 44 (IP dispensed at Visits 13 through 25)  
Placebo 
Once daily 
Oral (capsule) 
Cariprazine 3.0 mg 
Once daily 
Oral (capsule) 
Cariprazine 4.5 mg 
Once daily 
Oral (capsule) 
All investigational products will be taken orally as a single daily dose at approximately the same time of day 
(morning or evening). The dosing time can be switched if there are tolerability problems. Any switch must 
allow at least 24 hours between 2 consecutive doses and must be documented in the eCRF. 
eCRF = electronic case report form; IP = investigational product; OL = open-label. 
a 
Patients who meet randomization criteria (Section 4.6) on or after Week 14 are eligible for early 
randomization and will skip any remaining visits in the OL treatment period 
 

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

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6.2.1 
Primary Efficacy Assessments 
Assessment and ratings of efficacy scales will be performed by a trained rater. Every effort 
should be made to have patients assessed by the same rater at each scheduled timepoint. 
6.2.1.1 
Structured Clinical Interview for the Positive and Negative 
Syndrome Scale 
The SCI-PANSS (SCI-PANSS Scoring Sheet in Attachment 12.2) is a 30-item rating scale 
specifically developed to assess both the positive and negative symptom syndromes of 
patients with schizophrenia (Kay 1987). The PANSS total score is rated based on a structured 
clinical interview with the patient and supporting clinical information obtained from family, 
hospital staff, or other reliable informants. This assessment provides scores in 9 clinical 
domains, including a positive syndrome, a negative syndrome, depression, a composite 
index, and general psychopathology. Each item is scored on a 7-point (1 to 7) scale. 
6.2.1.2 
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 of other patients the physician has observed 
(Attachment 12.3). The patient is rated on a scale from 1 to 7 with 1 indicating a “normal 
state” and 7 indicating “among the most extremely ill patients.”  
The CGI-S will be administered by a trained rater with extensive professional training and 
experience in assessing mental illness. 
6.2.2 
Additional Efficacy Assessments 
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 
Clinical Global Impressions–Improvement 
The Clinical Global Impressions–Improvement (CGI-I) scale (Guy 1976) is a clinician-rated 
scale that in this study will be used to rate total improvement or worsening of mental illness 
relative to Visit 2, regardless of whether the investigator considers it to be a result of drug 
treatment or not (Attachment 12.4). The patient will be rated on a scale from 1 to 7, with 1 
indicating that the patient is very much improved and 7 indicating that the patient is very 
much worse.  

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The CGI-I will be administered by a trained rater with extensive professional training and 
experience in assessing mental illness. 
6.2.2.2 
Personal and Social Performance Scale 
The Personal and Social Performance scale (PSP) is a 100-point, single-item, clinician-rated 
scale, which is subdivided into 10 equal intervals (Morosini 2000) (Attachment 12.9). The 
ratings are based mainly on the assessment of functioning in the following 4 domains: (a) 
socially useful activities, including work and study; (b) personal and social relationships; (c) 
self-care; and (d) disturbing and aggressive behaviors. Ratings from 71 to 100 show mild 
difficulties; from 31 to 70 reflect manifest disabilities of various degrees, while ratings from 
1 to 30 reflect functioning so poor that intensive support or supervision is needed. 
The PSP will be administered by a trained rater with extensive professional training and 
experience in assessing mental illness. 
6.2.2.3 
Brief Assessment of Cognition in Schizophrenia 
The Brief Assessment of Cognition in Schizophrenia (BACS) assesses the aspects of 
cognition noted to be most impaired and most strongly correlated with outcome in patients 
with schizophrenia (Keefe 2003). The BACS requires less than 35 minutes to complete in 
patients with schizophrenia. The BACS measures verbal memory, working memory, motor 
speed, verbal fluency, attention and speed of information processing, and executive 
functions.  
6.3 
Pharmacokinetics Measures  
Not applicable. 
6.4 
Pharmacogenetic Sampling 
Pharmacogenetic sampling is to be conducted only at study centers where the institutional 
review board (IRB)/independent ethics committee (IEC) has approved the pharmacogenetic 
portion of the study. Participation in the pharmacogenetic portion of the study is optional and 
will require a separate informed consent form (ICF). The pharmacogenetic ICF must be 
signed before the pharmacogenetic blood sample is taken. Pharmacogenetic consent may be 
obtained at any time between Visit 1/Screening and Week 8 (Visit 8). Pharmacogenetic 
sampling can be conducted at any timepoint between Visit 2/Baseline and Week 8 (Visit 8). 
Following consent, a blood sample will be collected to determine individual genotype status 

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and for pharmacogenetic bio banking. The genetic material from the blood sample will be 
used to study factors which may influence how patients respond to a drug or may explain the 
pathophysiology of the disease. Blood samples will be stored to provide a resource for 
potential future trials conducted by 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. 
6.5 
Safety Measures 
Patients must be evaluated by a physician or an appropriately trained healthcare 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 and Table 2 (Schedules of Visits and 
Procedures). 
6.5.1 
Adverse Events 
Adverse events (AEs) will be collected throughout the study. For all AEs, the investigator 
must provide an assessment of the severity, causal relationship to the IP, start and stop date, 
and seriousness of the event (eg, serious adverse event [SAE]), document all actions taken 
with regard to IP, and detail any other treatment measures taken for the AE. For events noted 
as SAEs, Allergan must be notified immediately to meet their reporting obligations to 
appropriate regulatory authorities (see Section 9.3). 
6.5.2 
Ocular Adverse Events of Special Interest  
The sponsor is required to perform expedited reporting to worldwide regulatory authorities of 
ocular AESIs that meet specific criteria. Therefore, the sponsor must be notified immediately 
regarding any ocular AESIs that occur after informed consent is obtained. 
The following serious and non-serious ocular AESIs require immediate notification: 

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x Cataract*, lens or lenticular abnormality or change, opacity, opacification or 
opalescence 
x Blindness, night blindness, visual acuity or vision decrease, abnormality or change, 
visual acuity test abnormality or change 
x Retinal, macular, or optic nerve degeneration, abnormality or change; retinal pigment 
epithelium detachment, abnormality or change 
x Color vision decrease, abnormality or change 
Within 24 hours of learning of any serious or non-serious AESIs, the study site personnel 
must report the event on the SAE/AESI form for clinical trials. 
*NOTE: When determining whether to report an event as a cataract, please take into 
consideration the AREDS scoring of that lens opacity. Only those changes that have reached 
the threshold of equal to or greater than AREDS standard photo #2 should be reported as a 
cataract. 
In addition to completing the appropriate form, the medical monitor may also be notified by 
telephone. 
All ocular AESIs are to be followed by the study staff until resolution or until the ocular 
AESI is deemed stable. The sponsor may contact the study site to solicit additional 
information or follow-up on the event.  
6.5.3 
Clinical Laboratory Determinations 
Clinical laboratory tests will be performed according to the schedules in Table 1 and Table 2. 
Patients will be asked to fast for at least 10 hours prior to any visits requiring clinical 
laboratory testing. Table 4 presents the schedule of clinical laboratory tests to be performed 
during this study. 
Table 4: 
Schedule of Clinical Laboratory Tests 
Category 
 
Visit Number(s) 
Parameters 
Hepatitis Screening 
1 
Hepatitis C virus antibody, hepatitis B 
surface antigen, and hepatitis B core 
antibody total. Reflex hepatitis B core 
antibody immunoglobulin M will be 
performed for all hepatitis B core antibody 
total positive or reactive results 

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Category 
 
Visit Number(s) 
Parameters 
Hematology 
1, 8, 13, 18, 22, 26/ET 
Absolute and differential white blood cell 
count, erythrocyte count, hemoglobin, 
hematocrit, platelet count, and red blood 
cell indices (mean corpuscular volume, 
mean corpuscular hemoglobin, and mean 
corpuscular hemoglobin concentration) 
Hemoglobin A1c 
1, 8, 13, 18, 22, 26/ET 
-- 
Chemistry 
1, 8, 13, 18, 22, 26/ET 
Sodium, potassium, calcium, chloride, 
bicarbonate, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline 
phosphatase, albumin, total bilirubin, direct 
bilirubin, indirect bilirubin, AST, ALT, Free 
T3, free T4, TSH, lactate dehydrogenase, 
creatine phosphokinase, γ-glutamyl 
transpeptidase, uric acid, phosphate, lipid 
panel (total cholesterol, triglycerides, low 
density lipoproteins, high density 
lipoproteins), prolactin, insulin, and 
magnesium 
Urine myoglobin 
1, 8, 13, 18, 22, 26/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, 8, 13, 18, 22, 26/ET 
Specific gravity, pH, protein, glucose, 
ketones, blood, nitrite, bilirubin, and 
microscopy (red blood cell count [high-
power field], white blood cell count [high-
power field], casts [low-power field], and 
crystals) 
Serum β-hCG (women of 
childbearing potential 
only) 
1, 8, 13, 18, 22, 26/ET, 28 
-- 
Urine drug screen 
1, 13 
Benzoylecgonine (cocaine), barbiturates, 
amphetamines, benzodiazepines, 
cannabinoids, opiates, methadone, 
phencyclidine 
Blood alcohol 
concentration as measured 
by breathalyzer 
1, 13 
-- 
Repeat urine drug screen, 
blood alcohol 
concentration as measured 
by breathalyzer, and serum 
pregnancy test 
At random upon request 
from the investigator 
-- 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = β-human chorionic gonadotropin; 
ET = early termination; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 
 

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6.5.4 
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 take off their jacket 
and shoes. 
Height (without shoes) will be measured at Visit 1 only. 
Waist circumference will be measured at Visits 1, 9, 13/Randomization, 19, 26/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 rate 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. 
6.5.5 
Electrocardiograms 
A 12-lead ECG will be performed at Screening (Visit 1), Visit 13/Randomization, and 
Visit 26/ET using a standard paper speed of 25 mm/sec. ECGs will be electronically 
transmitted for analysis according to the instructions provided by the ECG central reader. 
Measurements (in msec) will be recorded for the following parameters in lead II or lead III 
(other leads may be used only if it is not possible to obtain good-quality tracings from lead II 
or lead III): PR interval, QRS interval, RR interval (preceding the QT), and uncorrected QT 
interval. Copies of the ECG waveforms will also be sent to the central reader, where the ECG 
parameters will be measured and evaluated. The ECG tracing and cardiology report will be 
retained as a source document. 

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6.5.6 
Physical Examination 
A complete physical examination will be done at Screening (Visit 1) and Visit 26/ET, by a 
professionally trained physician or health professional licensed to perform physical 
examinations. 
6.5.7 
Ophthalmological Examination 
All study centers will perform ophthalmological examinations including biomicroscopic 
examinations, lens assessments, best-corrected visual acuity, and color vision testing on all 
patients at Visits 1, 13, 26/ET (and Visit 28 for any patient with a postbaseline finding of 
cataracts). A complete description of the procedure is provided in Attachment 12.10. 
Biomicroscopic examinations will be performed using a slit-lamp. The examinations will 
include evaluation of the condition of the eyelids, conjunctiva, corneas, iris, anterior 
chamber, vitreous, retina, macula, and optic nerve.  
Biomicroscopic findings will be evaluated for the presence and severity of nuclear, cortical, 
and posterior subcapsular lens opacities.  
6.5.8 
Other Safety Assessments 
Assessment and ratings of safety scales will be performed by a trained and experienced rater. 
Every effort should be made to have patients assessed by the same rater at each scheduled 
timepoint. 
6.5.8.1 
Extrapyramidal Symptom Scales 
The following 3 scales will be used to systematically assess EPS side effects at  
Visits 2, 3, 7, 9, 11, 13, 15, 17, 19, 21, 23, 26/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 
(Attachment 12.6). 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.  

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Barnes Akathisia Rating Scale 
The BARS (Barnes 1989) is a 4-item rating scale used to assess drug-induced akathisia 
(Attachment 12.5). The scale comprises items for rating the observable restless movements 
that characterize the condition, the subjective awareness of restlessness, and any distress 
associated with the akathisia (each on a 4-point scale from normal [0] to severe [3]). In 
addition, there is a global severity for akathisia rated on a 6-point scale (absent [0] to severe 
akathisia [5]).  
Simpson-Angus Scale 
The SAS (Simpson 1970) is a 10-item rating scale for assessment of antipsychotic-induced 
parkinsonism in both clinical practice and research settings (Attachment 12.7). 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.  
6.5.8.2 
Columbia-Suicide Severity Rating Scale 
The C-SSRS (Attachment 12.8) 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 (non-specific active suicidal thoughts), 3 (active suicidal ideation with 
any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). The  
C-SSRS also captures information about the intensity of ideation, specifically the frequency, 
duration, controllability, deterrents, and reasons for the most severe types of ideation. 
Suicidal behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts 
or behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). More than 
1 classification can be selected provided they represent separate episodes. For actual attempts 
only, the actual or potential lethality is classified for the initial, most lethal, and most recent 
attempts. The C-SSRS will be completed at all study visits, except Visit 27 and Visit 28. At 
Visit 1 (Screening), the C-SSRS will be completed for the patient’s lifetime history of 
suicidal ideation and behavior. At all other visits the C-SSRS will be completed for ideation 
and behavior since the previous visit. 
The C-SSRS will be completed by a trained rater with extensive professional training. 

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6.6 
Summary of Methods of Data Collection 
An IWRS will be used to dispense IP, randomize patients, and manage IP inventory. All other 
data for this study will be collected using eCRFs via an electronic data capture system, 
except for ECG and laboratory data. 
A qualified central ECG reader will be used for the analysis of all ECGs, and a central 
laboratory for blood and urine samples. ECG and laboratory data will be transferred to 
Allergan or its designee on a periodic basis throughout the study. 
7 
Statistical Procedures 
7.1 
Analysis Populations 
Seven populations will be considered in the statistical analysis of this study. 
7.1.1 
Screened Population 
The screened population will consist of all patients who signed informed consent and 
received a PID number. 
7.1.2 
Open-label Safety Population 
The OL safety population will consist of all patients in the screened population who took at 
least 1 dose of OL cariprazine during the OL treatment period of the study. 
7.1.3 
Open-label Intent-to-Treat Population 
The OL intent-to-treat (ITT) population will consist of all patients in the OL safety 
population who had at least 1 postbaseline assessment of the PANSS or CGI-S scores during 
the OL treatment period of the study. 
7.1.4 
Open-label Safety-Follow-up Population 
The open-label safety-follow-up (OL SFU) population will consist of patients in the OL 
safety population who were not randomized. 
7.1.5 
Randomized Population 
The randomized population will consist of all patients in the OL safety population who were 
randomized to a treatment group in the study. 

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7.1.6 
Double-blind Safety Population 
The DB safety population will consist of all patients in the randomized population who took 
at least 1 dose of DB IP. 
7.1.7 
Double-blind Intent-to-Treat Population 
The double-blind intent-to treat (DB ITT) population will consist of all patients in the DB 
safety population who had at least 1 post-randomization assessment of the PANSS or CGI-S 
scores during the DB treatment period of the study. 
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
7.2.1 
Primary Efficacy Variable  
The primary efficacy parameter is the time to first relapse during the DB treatment period, 
defined as the number of days from the randomization date to the first relapse date.  
Relapse is defined as the occurrence of any 1 of the following: 
x Increase in PANSS total score by ≥ 30% for patients who had a PANSS total score of 
≥ 50 at Randomization/Visit 13 or a ≥ 10-point increase in PANSS total score for 
patients who had a PANSS total score < 50 at Randomization/Visit 13 
x Increase in CGI-S score by 2 or more points relative to Randomization/Visit 13 
x Score of > 4 on 1 or more of the following 7 PANSS items: P1: delusions; 
P2: conceptual disorganization; P3: hallucinatory behavior; 
P6: suspiciousness/persecution; P7: hostility; G8: uncooperativeness; 
G14: poor impulse control  
x Deliberate self-injury or aggressive/violent behavior 
x Initiation of treatment with a mood stabilizer, antidepressant, antipsychotic agent, or 
with a benzodiazepine that exceeds the protocol-specified allowance or duration (ie, 
more than 2 mg/d of lorazepam or equivalent or for more than 3 consecutive days) to 
treat worsening symptoms of schizophrenia or any other psychiatric disorder as judged 
by the clinical impression of the investigator 

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x Psychiatric hospitalization due to worsening of the patient’s underlying condition 
x Exacerbation of psychiatric illness as judged by clinical impression of the investigator 
(eg, clinically significant agitation, suicidal or homicidal ideations) 
7.2.2 
Secondary Efficacy Variable 
Not applicable. 
7.2.3 
Other Efficacy Variables 
The additional efficacy parameters will include the following at scheduled postbaseline 
visits: 
x Change from Baseline in the PANSS total score 
x Change from Baseline in PANSS positive subscale score 
x Change from Baseline in PANSS negative subscale score 
x Change from Baseline in PANSS factor score for positive symptoms 
x Change from Baseline in PANSS factor score for negative symptoms 
x Percentage response (PANSS improvement ≥ 30%) 
x Change from Baseline in the CGI-S score 
x CGI-I score 
x Change from Baseline in the BACS composite score (Z score) and BACS individual 
subtests 
x Change from Baseline in the BACS composite T score  
x Change from Baseline in PSP score and sub-domains 
For the continuous endpoints, the change from Baseline refers to the change from OL 
Baseline during the OL treatment period, and the change from DB Baseline during the DB 
treatment period, unless stated otherwise.  

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7.3 
Hypothesis and Methods of Analysis 
All efficacy analyses for the OL will be performed using the OL ITT population, unless 
stated otherwise. Baselines for efficacy parameters in the OL treatment period will be defined 
as the last non-missing efficacy assessment before the first dose of OL IP. All efficacy 
analyses for the DB treatment period will be performed using the DB ITT population, unless 
stated otherwise. Baselines for the additional efficacy parameters in the DB treatment period 
will be defined as the last non-missing efficacy assessment before the first dose of DB IP. All 
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance and 
all CIs will be 2-sided 95% CIs, unless stated otherwise. 
7.3.1 
Primary Efficacy Analyses 
The primary efficacy parameter is the time to first relapse during the DB treatment period, 
defined as the number of days from the randomization date to the relapse date. 
To test the primary null hypotheses that the distribution of the time to first relapse for each of 
the cariprazine 4.5 mg/d and 3.0 mg/d treatment groups are not different from that for the 
placebo treatment group, the log-rank test is used to compare the time to relapse between 
each cariprazine group and placebo group for the DB ITT population. Estimates of the hazard 
ratio and 95% CIs will be based on the Cox proportional hazards model with treatment group 
as explanatory variable. The Kaplan-Meier estimates for the cumulative distribution of the 
relapse rate for each treatment group will be provided.  
The fixed-sequence testing procedure will be used for multiple comparisons to control the 
family-wise Type I error rate at a 0.05 level. The comparison of cariprazine 4.5 mg/d versus 
placebo for the primary endpoint will be tested first at a 0.05 significance level using the log 
rank test, only when the testing is significant, the comparison of cariprazine 3.0 mg/d versus 
placebo will be tested.  
Two sensitivity analyses will be performed to assess the robustness of the primary analysis 
results to the possible violation of the noninformative censoring assumption. The first 
sensitivity analysis is delta-adjusted imputation method (Zhao 2014). The delta-adjusted 
sensitivity analysis specifies that the hazard of having an event for subjects who discontinued 
before the timepoint is multiplicatively increased relative to the hazard for subjects who 
continued beyond the timepoint for the cariprazine treatment group. The second sensitivity 
analysis is based on the reference-based imputation method (Lu 2015). The reference-based 
sensitivity analyses use a sensitivity parameter to characterize the gradual deviation from the 
noninformative censoring underlying the primary analyses toward the informative censoring, 

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which assumes that the hazard of relapse for cariprazine-treated patients who discontinued is 
the same as the hazard for relapse for placebo-treated patients. A multiple imputation 
approach will be used to implement the sensitivity analyses. 
7.3.2 
Secondary Efficacy Analyses  
None. 
7.3.3 
Other Efficacy Analyses  
To accommodate the flexible duration of the OL treatment period, the derived visits in the 
DB treatment period will be named as Week i post-randomization for a specific Week i after 
the first dose of the DB study medications. The total exposure to IPs for patients in Week i 
post-randomization will vary because of the flexible OL treatment period. The detailed week 
mapping windows will be provided in the statistical analysis plan (SAP). 
Descriptive statistics will be provided by visit for additional quantitative parameters for 
the OL ITT population and the DB ITT population using both last-observation-carried 
forward (LOCF) and observed cases approaches. LOCF approach will be used to impute 
missing postbaseline values. Imputation of missing values will be done for the OL phase and 
the DB phase separately.  
For the DB treatment period, the continuous variables (change from DB Baseline) will be 
analyzed by using a mixed-effects model for repeated measures with treatment group, 
country, visit, and treatment group-by-visit interaction as fixed effects and the Baseline value 
and Baseline-by-visit interaction as the covariates. An unstructured covariance matrix will be 
used. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The analysis will be performed based on post-DB Baseline scores using only the 
observed cases without imputation of missing values. Least squares means and their standard 
errors based on the model for repeated measures analysis will be plotted by treatment group 
and visit.  
Additional categorical efficacy parameters will be analyzed in the following way: 
Rates for categorical parameters (response) will be reported by treatment group and by visit 
for both the OL treatment period and the DB treatment period (with LOCF imputation). For 
the DB treatment period, logistic regression model (with LOCF imputation) will be used to 
model the probability of a response or the probability of a response as a function of a 
treatment group and the corresponding Baseline score as explanatory variables. 

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7.3.4 
Safety Analyses 
The safety analyses will be performed for the OL safety, OL SFU, and DB safety 
populations. The summarization will be overall for the OL treatment period in the OL safety 
population and for the OL SFU period in the OL SFU population. The summarization will be 
by treatment group for the DB treatment period and DB SFU period in the DB safety 
population. The summarization for the OL treatment period will use the OL safety population 
as the denominator. The summarization for the DB treatment period will use the DB safety 
population as the denominator. The summarization for the OL SFU period and DB SFU 
period will use the OL SFU population and the DB safety population as the denominator, 
respectively.  
Safety parameters will include AEs, clinical laboratory parameters, vital signs, ECG 
parameters, ophthalmological parameters, C-SSRS, and EPS scales (AIMS, BARS, and 
SAS).  
For each safety parameter, the last assessment made before the first dose of OL IP will be 
used as the Baseline for all analyses of that safety parameter, unless stated otherwise. 
The derived visits in the DB treatment period will use the same strategy as described for the 
additional efficacy endpoints. The detailed week mapping windows will be provided in the 
SAP.  
7.3.4.1 
Adverse Events 
AEs will be coded by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 21.0 or newer. 
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the first dose of OL IP.  
The number and percentage of patients reporting TEAEs during the OL treatment period will 
be tabulated by system organ class and preferred term, by system organ class, preferred term, 
and severity, and by system organ class, preferred term, and relationship to IP.  
The number and percentage of patients reporting TEAEs during the DB treatment will be 
tabulated for each treatment group by system organ class and preferred term, by system organ 
class, preferred term, and severity, and by system organ class, preferred term, and 
relationship to IP. 

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

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SAEs, and the number and percentage of patients with EPS AEs leading to premature 
discontinuation of IP will also be summarized. 
The number and percentage of patients reporting TEAEs of ocular AESIs will be summarized 
overall for the OL treatment period in the OL safety population and the OL SFU period in the 
OL SFU population, and by treatment for the DB treatment period and the DB SFU period in 
the DB safety population. The listing of all reported ocular AESIs will be provided. 
7.3.4.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from Baseline values at each 
assessment timepoint will be presented for each clinical laboratory parameter in SI units, and 
for selected clinical laboratory parameters in conventional units. 
The number and percentage of patients with potentially clinically significant (PCS) clinical 
laboratory values will be presented. The criteria for PCS laboratory values will be detailed in 
the 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 postbaseline 
PCS value. A supportive listing of patients with postbaseline PCS value will be provided, 
including the PID number, study center number, and Baseline and postbaseline values. A 
listing of all AEs for patients with PCS laboratory values will also be provided.  
The number and percentage of patients with treatment-emergent significant changes in lipids 
parameters (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) and 
glucose will be tabulated by treatment group for the OL treatment period and 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 one 
postbaseline assessment during the specific period. The change in lipids and glucose from 
Baseline to the highest (lowest for HDL cholesterol) postbaseline measurement during the 
specific period will be summarized. Supportive listings of patients with treatment-emergent 
changes in lipids and glucose values will be provided. 
7.3.4.3 
Vital Signs 
Descriptive statistics for vital signs and changes from Baseline values at each visit and at end 
of study will be presented overall for the OL treatment period and OL SFU period, and by 
treatment group for the DB treatment period and DB SFU period. 

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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 PID number, 
Baseline and postbaseline values. A listing of all AEs occurring in patients who have PCS 
vital sign values will also be provided.  
The number and percentage of patients with orthostatic hypotension will be provided by 
treatment group. Orthostatic hypotension is defined as a reduction of ≥ 20 mm Hg in systolic 
BP or a reduction of ≥ 10 mm Hg in diastolic BP when the patient changes from the supine 
position to the standing position. A supportive listing will be provided including the PID 
number, study center number, and Baseline and postbaseline systolic and diastolic BP values 
(supine and standing). 
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: 
x Shift of hypertension status from Baseline to end of the OL treatment period 
x Shift of hypertension status from Baseline to highest category during the OL 
treatment period 
x Shift of hypertension status from Baseline to end of the DB treatment period 
x Shift of hypertension status from Baseline to highest category during the DB 
treatment period 
Supportive listings of patients with shift in hypertension status from 
normotensive/prehypertension at Baseline to Stage I /Stage II will be provided. 
7.3.4.4 
Electrocardiogram 
Descriptive statistics for ECG parameters (ie, heart rate, PR interval, QRS interval, RR 
interval, QT interval, QTcB, and QTcF) and changes from Baseline values at each assessment 
timepoint in this study will be presented. 

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The number and percentage of patients with postbaseline PCS ECG values will be tabulated 
by treatment group for the DB treatment period. The criteria for PCS ECG values will be 
detailed in the SAP. The percentages will be calculated relative to the number of patients with 
available non-PCS Baseline values and at least 1 postbaseline assessment for the DB 
treatment period. The numerator will be the total number of patients with available non-PCS 
Baseline values and at least 1 postbaseline PCS value for the DB treatment period. A 
supportive tabular display of patients with postbaseline PCS values will be provided, 
including the PID number, Baseline, all postbaseline (including non-PCS) values, and change 
from Baseline. In addition, a tabular display showing all AEs that occurred in patients who 
had postbaseline PCS ECG values will be provided. 
A shift table from Baseline to the end of study in the investigator’s overall interpretation of 
the ECG will be presented by treatment group for the following categories: normal; 
abnormal, not clinically significant; abnormal, clinically significant. A tabular display 
showing patients with postbaseline clinically significant ECG abnormalities according to the 
investigator’s overall interpretation will be provided. 
The number and percentage of patients with a change from Baseline QTc > 30 msec but not 
exceeding 60 msec and of patients with an increase > 60 msec will be tabulated by treatment 
group. A supportive listing that includes PID number, study center number, all QTc values 
(including change from Baseline values), and all AEs will be provided for all patients with 
postbaseline QTc changes > 30 msec. 
7.3.4.5 
Other Safety Parameters 
Other safety parameters include EPS scales (AIMS, BARS, and SAS scores), C-SSRS, and 
ophthalmological parameters. 
7.3.4.5.1 
Extrapyramidal Symptom Scales 
A patient will be considered to have treatment-emergent parkinsonism if the patient’s SAS 
score was ≤ 3 at Baseline and > 3 at any postbaseline assessment. A patient will be 
considered to have treatment-emergent akathisia if the patient’s BARS score was ≤ 2 at 
Baseline and > 2 at any postbaseline assessment. The number and percentage of patients with 
treatment-emergent parkinsonism or akathisia will be tabulated. Listings of patients with 
treatment-emergent parkinsonism or akathisia will be provided, including the PID number, 
Baseline and postbaseline values. Listings of all AEs for patients with treatment-emergent 
parkinsonism or akathisia will also be provided. 

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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. 
7.3.4.5.2 
Columbia-Suicide Severity Rating Scale 
For the C-SSRS, the number and percentage of patients with suicidal ideation or suicidal 
behavior, as recorded on the C-SSRS scale, will be presented. The distribution of response 
for most severe suicidal ideation and suicidal behavior during the lifetime history, the OL and 
the DB treatment periods will be presented. Supportive listings will be provided, including 
the PID number, treatment group, visit number, lifetime history, and postbaseline values for 
each patient. Intensity of ideation, suicidal behavior type, and lethality of suicidal behavior 
will also be included in these listings. 
7.3.4.5.3 
 Ophthalmological Parameters 
Ophthalmological parameters include best-corrected visual acuity (BCVA); intraocular 
pressure (IOP); lens opacity; color discrimination; and slit-lamp biomicroscopy examination 
results. 
Descriptive statistics for each numeric ophthalmological parameter (eg, visual acuity, IOP) 
and changes from Baseline at each assessment timepoint will be presented. 
The number and percentage of patients with a change from Baseline in visual acuity ≥ +0.3 
in each eye and in either eye will be summarized overall for the OL treatment period, and by 
treatment group for the DB treatment period. 
The number and percentage of patients with postbaseline IOP > 21 mm Hg will be presented. 
A supportive listing will be provided, including PID number, Baseline and postbaseline IOP 
values. 
The number of patients with phakic, pseudophakic, and aphakic lens status will be 
summarized for both the OL and DB treatment periods. For patients with phakic eyes, the 
number and percentage of patients with cataract will be assessed by presence and severity of 
nuclear, cortical, and posterior subcapsular cataract lens opacities using a 3point scale 
(0: absent, 1: < standard photo #2, and 2: ≥ standard photo #2). Patients with nuclear, 
cortical, or posterior subcapsular cataract lens opacities will be summarized for each eye (left 
and right) and for either eye using the higher scale of the 2 eyes by treatment group for each 
period (OL, DB, and SFU periods). A patient will be counted once in the highest lens opacity 

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severity in the specific period. A supportive listing will be provided, including PID number, 
Baseline and postbaseline assessment values. 
In addition, a shift table from normal Baseline to abnormal postbaseline in color 
discrimination, slit-lamp biomicroscopy examination results will be provided. 
7.4 
Subgroup Analyses 
The analysis for the primary efficacy parameter will be performed within each category of 
the following: 
x Age group (< 55 years, ≥ 55 years) 
x Sex (male, female) 
x Race (white, all other races) 
x Region (US, Non-US) 
7.5 
Sample Size Calculation 
The sample size and power calculations are based on the analysis of time to relapse in the DB 
treatment period to compare each cariprazine dose group versus placebo based on a log-rank 
test. The trial will be a fixed follow-up design. Patients are followed from randomization 
until dropout, relapse or a fixed duration of 26 weeks. 
Based on the first 26 weeks’ data from RGH-MD-06, the relapse hazard ratio is assumed to 
be 0.50, and cumulative relapse rate at Week 26 for the placebo group is 46%  
(Study RGH-MD-06, 2015). In addition, the cumulative dropout rate due to reasons other 
than relapse at 26 weeks is assumed to be 20.0%. 
Using these assumptions, a total of approximately 103 in the DB phase need to be observed 
in order to have 85% power to detect a statistically significant difference between each 
cariprazine and placebo group, using 2-tailed, log-rank tests at an overall 5% level of 
significance. The trial should randomize approximately 345 patients, 115 patients each arm, 
to provide the required number of relapse events. EAST 6.0 was used to for sample size and 
power calculation.  
A fixed-sequence procedure will be used for multiple comparisons to control the family-wise 
Type I error rate at a 0.05 level. First, the cariprazine 4.5 mg/d group will be compared with 

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the placebo group in the primary endpoint; if the testing is significant at the 0.05 level, then 
cariprazine 3.0 mg/d arm will be compared with the placebo group. 
Assume the screening failure rate is 34%, and approximately 33.3% of patients enrolled into 
the OL treatment period will be randomized into the DB treatment period. Then, 
approximately 1035 patients will be expected to be enrolled into the OL treatment period, 
and approximately 1569 patients are expected to be screened.  
7.6 
Interim Analyses 
No formal interim analysis is planned. 
8 
Study Visit Schedule and Procedures 
Table 1 and Table 2 present the study visits and procedures for OL and DB periods in the 
study.  
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 Subject Privacy 
The study will be discussed with the patient and/or the patient's legally authorized 
representative, and a patient wishing to participate must give informed consent prior to any 
study-related procedures or change in treatment. The patient must also give authorization 
(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 checked in the Verified 

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Clinical Trials database, indicated in the Schedule of Visits and Procedures (Table 1). Partial 
patient identifiers will be utilized but will not be accessible to the sponsor. Patients who are 
identified as verification failures by VCT should not continue in trial without documented 
approval from the sponsor. 
8.2 
Washout Intervals/Run-in  
Patients will undergo a Screening/washout period of up to 7 days. The length and timing of 
the washout of prior psychiatric medications during the 7 days allotted for the Screening 
period is at the discretion of the investigator. Prior medications should be gradually 
withdrawn such that the washout is completed by Visit 2/Baseline. Please note that during the 
screening/washout period, psychotropic medications, other than those listed as rescue 
(Section 4.8.3), may not be newly initiated or reinstated. In order to ensure the safe transition 
of patients into the study, based upon the clinical judgment of the investigator, patients may 
be hospitalized during initiation of the study. This hospitalization can be for up to 14 days 
during the screening and OL periods (with the end of hospitalization no later than Visit 3 
[Day 8] of the OL treatment period). This 14-day allowance for hospitalization may include 
all or part of the Screening period. Hospitalization beyond the initial 14 days allowed will 
require consultation with the medical monitor. Following the protocol-allowed 14 days of 
hospitalization (and any sponsor-allowed extension), patients should be treated as 
outpatients.  
No run-in period will be used in this study. 
8.3 
Procedures for Final Study Entry 
Patients meeting all eligibility criteria to continue into the OL treatment period at Visit 2 
(Baseline) must meet the stability criteria specified in Section 4.5 and randomization criteria 
specified in Section 4.6 to be eligible for randomization (Visit 13). Rescreening of screen 
failures is permitted in certain situations after consultation with the Allergan medical monitor. 
Also, all females of childbearing potential must have negative qualitative results on the 
serum pregnancy test at the Screening Visit (Visit 1). 
See Section 5.4 for the method for assignment to treatment groups/randomization. 
8.4 
Visits and Associated Procedures 
All assessments will be conducted at the appropriate visits as outlined in Table 1 and Table 2 
and the timing of the visits should occur as close as possible to the specified day. 

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Visit 2/Baseline is expected to occur within 7 days of Visit 1; however, if required it may be 
conducted up to 3 days after the scheduled visit.  
If necessary, Visits 3 to 28 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 13, 
relative to Visit 13 for Visits 14 through 26/ET, and relative to Visit 26/ET for Visits 27 and 
28.  
The schedule of study procedures and assessments is displayed by visit in Table 1 and 
Table 2. The descriptions of the procedures to be performed at each visit are provided below. 
8.4.1 
Screening/Visit 1 (Days –7 to –1) 
The following procedures will be performed at Screening (Visit 1): 
x Obtain informed consent and patient privacy; consent for pharmacogenetic sampling 
may also be obtained 
x Verified Clinical Trials database check to be performed where applicable 
x Access IWRS to register the patient and assign a PID number 
x Assess inclusion/exclusion criteria 
x Collect and assess medical and psychiatric history 
x Administer and assess SCID-5 
x Collect blood sample for hepatitis screening 
x Collect samples for UDS; assess blood alcohol concentration via breathalyzer 
x Collect blood samples for clinical laboratory determinations  
x Collect blood samples for serum pregnancy test (women of childbearing potential 
only) 
x Collect blood sample for hemoglobin A1c 
x Review prior and concomitant medications 

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x Administer SCI-PANSS, CGI-S, and C-SSRS 
x Collect vital signs measurements, including weight, waist circumference, and height 
x Perform physical examination 
x Perform ECG 
x Review and assess AEs and SAEs 
x Perform ophthalmological examination (Note: The screening ophthalmological 
examination must be completed prior to Visit 2/Baseline and the start of OL IP.) 
8.4.2 
Baseline/Visit 2  
The following procedures will be performed at Baseline /Visit 2: 
x Review and assess AEs and SAEs 
x Review concomitant medications 
x Assess inclusion/exclusion criteria 
x Administer SCI-PANSS, BACS, CGI-S, PSP, and C-SSRS 
x Evaluate EPS symptoms (AIMS/BARS/SAS) 
x Collect vital signs measurements (including weight) 
x Obtain consent for and/or collect blood for pharmacogenetic sampling (consent for 
pharmacogenetic sampling may be obtained any time between Visit 1 and Visit 8, 
inclusive. For patients providing consent, the sample for pharmacogenetic testing must 
be obtained between Visit 2 and Visit 8, inclusive) 
x Access IWRS to dispense IP 
8.4.3 
Open-label Treatment Period (Visits 3 to 12) 
The following procedures will be performed during the OL treatment period at every visit 
except where noted: 
x Review concomitant medications 

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x Collect vital signs measurements (including weight) 
x Collect waist circumference measurement (only Visit 9) 
x Administer SCI-PANSS, CGI-S, CGI-I, and C-SSRS 
x Assess PSP (only Visit 8)  
x Evaluate patients for attainment of response threshold criteria (Section 4.5). Continue 
to assess between Visits 6 to 8 until criteria have been met. Patients not meeting 
response threshold criteria by Visit 8 should be discontinued and undergo procedures 
as for Visit 26/ET and subsequently complete the SFU period 
x At Visits 7 through 9, evaluate patients for attainment of response threshold criteria 
(Section 4.5) if response threshold criteria were met at the preceding visit. 
o 
Patients who have not met stability of response threshold criteria by Week 10 
(Visit 9) should be discontinued and undergo procedures as for Visit 26/ET 
and subsequently complete the SFU period 
o 
Patients who have met stability of response threshold criteria (Section 4.5) 
must maintain stability threshold for 8 consecutive weeks in order to be 
randomized, with allowance for 1 excursion 
o 
For patients who have met stability of response threshold criteria, evaluate 
randomization criteria (Section 4.6) 8 weeks after stability of response 
threshold criteria are met (may be as early as Visit 11). Patients who meet 
randomization criteria (Section 4.6) prior to Visit 13 are to undergo 
procedures specified for Visit 13/End of OL treatment period (Section 8.4.4; 
any remaining visits in the OL treatment period will be skipped). 
o 
Patients who have attained stability of response threshold criteria and who 
meet any of the following criteria will be discontinued and should undergo 
Visit 26/ET procedures and subsequently complete the SFU period:  
 PANSS total score increases by ≥ 30% relative to Visit 2/Baseline, or 
 Score > 4 on 1 or more of 7 PANSS items P1: delusions; P2: conceptual 
disorganization; P3: hallucinatory behavior; 
P6: suspiciousness/persecution; P7: hostility; G8: uncooperativeness; or 
G14: poor impulse control, or  

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 Patients who have an increase in CGI-S score by 2 or more points 
relative to Visit 2/Baseline 
x Evaluate EPS symptoms (AIMS/BARS/SAS) (Visits 3, 7, 9, and 11) 
x Collect blood samples for serum pregnancy test (women of childbearing potential 
only) (Visit 8) 
x Collect blood samples for clinical laboratory determinations and for hemoglobin A1c 
(Visit 8) 
x Collect IP blister card(s) and perform IP compliance and accountability 
x Obtain consent for and collect blood for pharmacogenetic sampling (consent for 
pharmacogenetic sampling may be obtained any time between Visit 1 and Visit 8, 
inclusive. For patients providing consent, the sample for pharmacogenetic testing must 
be obtained between Visit 2 and Visit 8, inclusive  
x Review and assess AEs and SAEs 
x Access IWRS to dispense IP 
8.4.4 
End of Open-label Period/Randomization Visit (Visit 13) 
The following procedures will be performed at Visit 13: 
x Review concomitant medications 
x Collect vital signs measurements, including weight 
x Measure waist circumference  
x Administer SCI-PANSS and CGI-S to determine whether randomization criteria  
(Section 4.6) have been met 
o 
Eligible patients: Access IWRS to randomize patient and dispense DB IP 
o 
Patients who do not meet randomization criteria are to undergo procedures as for 
Visit 26/ET and scheduled to return for the SFU Visits (Visit 27 and Visit 28)  
x Assess C-SSRS, BACS, CGI-I, and PSP 

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x Evaluate EPS symptoms (AIMS/BARS/SAS) 
x Perform ECG 
x Perform ophthalmological examination. NOTE: For patients eligible for 
randomization, every attempt should be made to complete the Visit 13 
ophthalmological examination on the same day as all other Visit 13 procedures. If the 
examination cannot be accommodated, it must occur within 7 days after 
randomization.  
x Collect samples for UDS; assess blood alcohol concentration via breathalyzer 
x Collect blood samples for clinical laboratory determinations 
x Collect blood samples for serum pregnancy test (women of childbearing potential 
only) 
x Collect blood sample for hemoglobin A1c 
x Review and assess AEs and SAEs 
x Collect IP blister cards and perform IP compliance and accountability 
x Access IWRS to dispense IP 
8.4.5 
Double-blind Treatment Period (Visits 14 to 25) 
The following procedures will be performed during the DB treatment period at every visit 
except as noted: 
x Review concomitant medications 
x Collect vital signs measurements (including weight) 
x Collect waist circumference measurement (Visit 19) 
x Administer SCI-PANSS and CGI-S and assess patient for relapse (per Section 4.7) 
x Assess CGI-I and C-SSRS 
x Assess PSP (Visits 16 and 20) 

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x Assess BACS (Visit 16) 
x Evaluate EPS symptoms (AIMS/BARS/SAS) (Visits 15, 17, 19, 21, and 23) 
x Assess patient for relapse (Section 4.7) 
x Collect blood samples for clinical laboratory determinations (Visits 18 and 22)  
x Collect samples for serum pregnancy test (women of childbearing potential only) 
(Visits 18 and 22) 
x Review and assess AEs and SAEs 
x Collect IP blister cards and perform IP compliance and accountability 
x Access IWRS to dispense IP 
8.4.6 
Final or Early Termination Visit (Visit 26) 
The following procedures will be performed at the final visit at the end of the DB treatment 
period (Visit 26) or at ET: 
x Review concomitant medications 
x Collect vital signs measurements, including weight and waist circumference 
x Administer SCI-PANSS, BACS, CGI-S, CGI-I, PSP, and C-SSRS 
x Evaluate EPS (AIMS/BARS/SAS) 
x Assess patient for relapse (Section 4.7) 
x Perform physical examination 
x Perform ECG 
x Perform ophthalmological examination.  
NOTE: every attempt should be made to complete the Visit 26/ET ophthalmological 
examination on the same day as all other Visit 26/ET procedures.  
x Collect blood samples for clinical laboratory determinations 

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x Collect sample for hemoglobin A1c 
x Collect sample for serum pregnancy test (women of childbearing potential only) 
x Review and assess AEs and SAEs 
x Collect IP blister card(s) and perform IP compliance and accountability 
8.4.7 
Safety Follow-up Visits (Visits 27 and 28) 
Patients who complete the study, and those who prematurely discontinue from either the OL 
or DB treatment periods, will complete a 4-week SFU period (2 visits: one at the end of 
every 2 weeks). During the SFU period, patients will be stabilized on appropriate 
medications, and additional evaluations (laboratory studies, ECG, UDS, etc) may be 
performed as deemed necessary by the investigator. This period may also be used for follow-
up and management of all abnormal findings and AEs observed during OL or DB treatment 
periods. No IP will be administered during the SFU period.  
The following procedures will be carried out at the SFU Weeks 46 and 48 (Visits 27 and 28): 
x Collect blood sample for serum pregnancy test (women of child-bearing potential only 
[Visit 28 only]) 
x Review concomitant medications 
x Collect vital signs measurements (including weight)  
x Perform a follow-up ophthalmological examination only for patients with a 
postbaseline finding of cataracts (Visit 28 only) 
Note: Every attempt should be made to complete the Visit 28 ophthalmological 
examination on the same day as all other Visit 28 procedures. If the examination 
cannot be accommodated, it must occur within 7 days of Visit 28.  
x Review and assess AEs and SAEs 
8.5 
Instructions for Patients 
Patients are to be instructed to take their study medication daily around the same clock time; 
study medication should not be taken with grapefruit juice. Patients are to be reminded to 
return used/partially used blister cards at every study visit. The investigator (or designee) is 
to ensure that concomitant medications are reviewed against the prohibited and allowed 

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rescue medications detailed in Section 4.8; patients are to be advised accordingly. If the 
permissibility of a specific medication/treatment is in question, the investigator should 
consult the medical monitor. 
Patients are to be asked to abstain from drinking alcohol during the study. 
Patients are to be asked to fast for at least 10 hours before blood and urine samples are 
collected at Screening (Visit 1), Visits 8, 13 (End of OL/Randomization), 18, 22, and 26/ET. 
8.6 
Unscheduled Visits 
Additional examinations and laboratory assessments may be performed as necessary to 
ensure the safety and well-being of the patients during the study period. Unscheduled visit 
eCRF pages will be completed for each unscheduled visit. For all parameters not measured, 
indicate “not done.”  
8.7 
Compliance with Protocol 
All assessments will be conducted at the appropriate visits as outlined in Table 1 and Table 2 
and the timing of the visits should occur as close as possible to the specified day. 
Visit 2/Baseline is expected to occur within 7 days of Visit 1. If required, Visit 2/Baseline 
assessments may be conducted up to 3 days after the scheduled visit. If necessary, Visits 3 to 
28 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 13, relative to Visit 13 for 
Visits 14 through 26/ET, and relative to 26/ET for Visits 27 and 28. Every attempt should be 
made to complete the postbaseline ophthalmological examinations (Visits 13 and Visits 
26/ET, and Visit 28 if required) on the same date as all other study procedures for that visit. 
At each visit, the patient will be asked if the patient changed the dose/regimen of any existing 
concomitant medications or initiated the use of any new concomitant medications since the 
last visit to ensure compliance with the protocol. 
8.8 
Early Discontinuation of Subjects 
Patients may discontinue from the study at any time for any reason. Discontinuation is 
permanent; once a patient is discontinued, he/she shall not be allowed to enroll again.  
Patients can be prematurely discontinued for one of the following reasons: 
x AE 

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x Noncompliance with protocol  
x Noncompliance with IP dosing regimen 
x Withdrawal of consent (a clear reason must be documented when possible) 
x Lost to follow-up (every effort must be made to contact the patient; a 
certified/traceable letter must be sent) 
x Study terminated by sponsor 
x Site terminated by sponsor 
x Pregnancy 
x 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 (OL treatment period or the DB treatment period) and who prematurely discontinue 
from the study, regardless of cause, should be seen for a final assessment. A final assessment 
will be defined as completion of the evaluations scheduled for Visit 26/ET. If the patient 
discontinues after IP is taken, the patient is also expected to return for the SFU Visits 
(Visit 27 and Visit 28) 2 weeks and 4 weeks after completion of the ET visit. 
At a minimum, collect the following information when a patient discontinues: 
1. The reason the patient discontinued; 
2. The date of the last dose of IP from the trial; 
3. The date of the last assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate; 
4. (S)AEs; 
5. Compliance with the 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 26/ET and 
subsequently Visit 27 and Visit 28 (SFU Visits) are performed (Table 2, Schedule of 
Visits and Procedures). 

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7. Retrieve IP from the patient. 
For all patients who discontinue as a result of being lost to follow-up, a determination must 
be noted in the eCRF as to whether the loss is related to an acute exacerbation of 
schizophrenia. 
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 for any of the following reasons:  
1. 
The patient is unable to tolerate the 4.5 mg/d dose. 
2. 
The patient fails to attain response threshold by Week 8 (Visit 8) or stability of 
response threshold criteria by Week 10 (Visit 9) (see Section 4.5); 
3. 
After stability has been attained, except for the single allowed excursion above 
the response threshold prior to Visit 13/End of OL, there is a lack of ongoing 
stability as evidenced by PANSS total score increases by ≥ 30% relative to 
Visit 2/Baseline; or PANSS item score is > 4 on one or more of PANSS items P1: 
delusions; P2: conceptual disorganization; P3: hallucinatory behavior; 
P6: suspiciousness/persecution; P7: hostility; G8: uncooperativeness; 
G14: poor impulse control; or CGI-S score increases by 2 or more points relative 
to Baseline/Visit 2;  
4. 
The patient required or initiated hospitalization for his/her psychiatric symptoms 
(excluding the discretionary hospitalization stay, which is to end no later than 
Visit 3 [Day 8] of the OL treatment period, or extension of the initial 
hospitalization described in this protocol); 
5. 
The patient took or required prohibited medication, including initiation of 
treatment with a mood stabilizer, antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-specified allowance or duration (ie, 
more than 2 mg/d of lorazepam or equivalent or for more than 3 consecutive days) 
to treat worsening symptoms of schizophrenia or any other psychiatric disorder as 
judged by the clinical impression of the investigator; 

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6. 
At the end of the OL treatment period, the patient does not meet all criteria to 
enter the DB treatment period (Section 4.6); 
7. 
Positive UDS after enrollment, confirmed by retest at next scheduled visit; for 
exceptions see Exclusion Criterion 3 and Section 4.8.3; 
8. 
The patient meets the criteria for relapse during the DB treatment period; 
9. 
The patient experiences 1 of the following elevated liver enzyme conditions, 
which is confirmed by repeat testing within 48 to 72 hours of awareness: 
x ALT or AST > 3× ULN and total bilirubin > 2 × ULN, 
x ALT or AST > 8 × ULN, 
x ALT or AST > 5 × ULN for more than 2 weeks, 
x 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. 
10. 
The patient has an absolute neutrophil count of < 1000 per mm3 and, after repeat 
testing within 24 hours of awareness, the values are not normalized or are not 
increasing; 
11. 
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. Allergan may 
stop the study (and/or the study site) for any reason with appropriate notification. A study 
may also be stopped by a regulatory authority. 
9 
Adverse Events 
AEs occurring during the study will be recorded on an adverse event eCRF. If AEs occur, the 
first concern will be the safety of the study participants. 

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9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject 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 subject has been administered study drug. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
AEs unless the disease progression is greater than anticipated in the natural course of the 
disease. 
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 subject 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 case report form. 
9.1.2 
Serious Adverse Event 
A SAE is any AE occurring at any dose that results in any of the following outcomes: death, 
a life-threatening AE, 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 or subject 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 an 
SAE.) 
Allergan considers all cancer AEs to be SAEs. Elective abortions and abnormal pregnancy 
outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 

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pregnancy) or genetic abnormalities (whether leading to an elective abortion or not) are 
considered SAEs. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
subject requires hospitalization is not reportable as an SAE. 
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the subject’s entry into the 
study. If it has not been documented at the time of the subject’s entry into the study, 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 severity assessment for a 
clinical AE must be completed using the following definitions as guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an AE may be an ‘all or nothing’ finding which cannot 
be graded. 
9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an AE and the IP 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 IP-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 exit visit must be followed up as appropriate. 

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9.3 
Procedures for Reporting a Serious Adverse Event 
Any SAE occurring during the study period (beginning with informed consent) and for at 
least 30 days after the last dose of study drug must be immediately reported but no later than 
24 hours after learning of an SAE. SAEs must be reported to Allergan (or agent of Allergan 
eg, Contract Research Organization) as listed on the Allergan study contacts list and recorded 
on the SAE/AESI form. All patients with an SAE must be followed up and the outcomes 
reported. The investigator must supply the sponsor and the IRB/IEC with any additional 
requested information (eg, autopsy reports and discharge summaries). 
In the event of 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 protocol and study contacts list. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide 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 IP. 
4. Promptly inform the governing IRB/IEC of the SAE as required by the IRB/IEC, 
local regulations, and the governing health authorities. 
9.4 
Reporting of Pregnancies Occurring During the Study 
Study site personnel must report every pregnancy from the time the patient signs the ICF 
until 12 weeks following the last dose of IP. Within 24 hours of learning of the pregnancy, the 
study site personnel must report the event to the sponsor’s Global Patient Safety department 
on the clinical trial pregnancy form and fax/email it to the following SAE/pregnancy fax 
number/email address, even if no AE has occurred: 
Fax number: +1-714-796-9504 (back-up fax number: +1-714-246-5295) 

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Email: IR-Clinical-SAE@allergan.com 
Pregnancies in female partners of male patients occurring during the time frame described 
above must also be reported. 
The pregnancy must be followed to term and the outcome reported by completing a  
follow-up clinical trial pregnancy form. If the pregnancy is associated with an SAE (eg, if the 
mother is hospitalized for hemorrhage), a separate SAE/AESI form for clinical trials must be 
filed with the appropriate serious criterion (eg, hospitalization) indicated in addition to the 
pregnancy form. 
9.5 
Potential Hy’s Law Cases 
Criteria for potential Hy’s Law cases are as follows: 
x ALT or AST ≥ 3 × ULN AND 
x Total bilirubin ≥ 2 × ULN AND 
x Alkaline phosphatase < 2 × ULN 
Study site personnel must report every patient who meets these 3 criteria. Typically, all  
3 analytes will be obtained from the same sample, but they may come from multiple samples 
taken within a 24-hour period. This requirement applies from the time the patient signs the 
ICF for the trial until 30 days after the final protocol-defined study visit or the last known 
dose of IP (if the final visit does not occur). 
A laboratory alert for potential Hy’s Law cases will be in place, and will notify investigators 
and the sponsor immediately when the above criteria have been met. A potential Hy’s Law 
case must be faxed/emailed to the sponsor on the SAE/AESI form as soon as possible (within 
24 hours of learning of the potential Hy’s Law) to the following SAE/pregnancy fax 
number/email address, even if no AE has occurred: 
Fax number: +1-714-796-9504 (back-up fax number: +1-714-246-5295) 
Email: IR-Clinical-SAE@allergan.com 
The eCRF pages for potential Hy’s Law cases must be completed within 7 calendar days. 
Every effort to determine the cause of the liver enzyme abnormalities must be made, and 
close monitoring must be initiated in conjunction with the study physician and in accordance 

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with the FDA “Guidance for Industry: Drug-Induced Liver Injury-Pre-Marketing Clinical 
Evaluation” Jul 2009. 
9.6 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care. When possible, the sponsor (medical monitor) 
should be notified prior to unmasking study medication. The investigator should inform the 
sponsor (medical monitor) of the unmasking if there is no notification prior to the 
unmasking. 
The treatment assignment for the patient can be determined by designated site personnel 
logging into the IWRS system via password protected access. The reason for breaking the 
code must be recorded in the patient’s source documents. 
10 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Council on Harmonization (ICH) 
Guideline on GCP. 
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, and/or from the patient's legally authorized 
representative. 
10.1.2 
Compliance with IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations. The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually. 
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. 

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10.1.3 
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 
Any amendment to this protocol will be provided to the investigator in writing by the 
sponsor. No protocol amendment may be implemented (with the exceptions noted below) 
before it has been approved by the IRB/IEC and the signature page, signed by the 
investigator, has been received by the sponsor. If the protocol is amended to eliminate or 
reduce the risk to patients, the amendment may be implemented before IRB/IEC review and 
approval. However, the IRB/IEC must be informed in writing of such an amendment, and 
approval must be obtained within reasonable time limits. Deviating from the protocol is 
permitted only if absolutely necessary for the safety or clinical management of the patients 
and must immediately be reported to the sponsor. 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents. The subject'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 subject prior to enrollment into the study, 
and/or from the subject's legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”), European Union Data 
Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study. 

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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: 
x Patient’s name. 
x Patient’s contact information. 
x The date that the patient entered the study, patient number, and patient randomization 
[or medication kit] number. 
x The study title and/or the protocol number of the study and the name of Allergan. 
x A statement that informed consent was obtained (including the date). A statement that 
written authorization (US sites only), data protection consent (EU sites only), or other 
country and local patient privacy required documentation for this study has been 
obtained (including the date). 
x Dates of all patient visits. 
x All concurrent medications (list all prescription and non-prescription medications 
being taken at the time of enrollment. At each subsequent visit, changes to the list of 
medications should be recorded.). 
x Occurrence and status of any AEs. 
x The date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation. 
x Key study variables. 
Source documentation practices must follow ALCOA-C principles (ie, records must be 
Attributable, Legible, Contemporaneous, Original, Accurate, and Complete). 

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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. 
10.4.4 
Retention of Documentation 
All study-related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all IPs, and copies of case report forms 
should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the sponsor-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirement(s) or if needed 
by the sponsor. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
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 
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10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
Investigational product will be supplied in blister cards and will be labeled with the protocol 
number, storage information, warning language, and instructions to take the capsules as 
directed. The card will also include the medication number. Immediately before dispensing 
the blister card, the investigator or designee will write the study center number, patient’s 
initials (if applicable), patient number, visit number, and dispensing date on the blister card. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed or administered to the patients, the number of units 
returned to the investigator by the patient (if applicable), and the number of units returned to 
Allergan during and at the completion of the study. A detailed inventory must be completed 
for all IP. Investigational product must be dispensed or administered only by an appropriately 
qualified person to patients in the study. The medication is to be used in accordance with the 
protocol. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All IP and/or supplies will be returned to Allergan or Allergan designee for destruction. 
10.6 
Monitoring by the Sponsor 
A representative of the sponsor will monitor the study on a periodic basis. The determination 
of the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. 
Authorized representatives of 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 
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10.7 
Handling of Biological Specimens 
Blood and urine samples for evaluation of hematology, chemistries, and urinalysis will be 
analyzed at a central clinical laboratory with certification from a recognized accreditation 
agency (eg, College of American Pathology or Clinical Laboratory Improvement 
Amendments certification). 
Patients consenting to participate in pharmacogenetic sampling will have a single blood 
sample collected to determine individual genotype status and for pharmacogenetic bio 
banking. The genetic material from the blood sample will be used to study factors which may 
influence how patients respond to a drug or may explain the pathophysiology of the disease. 
Blood samples will be stored to provide a resource for potential future trials conducted by 
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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11 
References 
Auquier P, Lançon C, Rouillon F, Lader M, Holmes C. Mortality in schizophrenia. 
Pharmacoepidemiol Drug Saf. 2007;16(12):1308. 
Barnes T. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
First M, Williams J, Karg R, Spitzer R. Structured Clinical Interview for DSM-5 Disorders, 
Clinical Trials Version (SCID-5-CT). Arlington, VA, American Psychiatric Association; 
2015.  
Foussias G, Agid O, Fervaha G, Remington G. Negative symptoms of schizophrenia: Clinical 
features, relevance to real world functioning and specificity versus other CNS disorders. Eur. 
Neuropsych. 2014,24(5):693. 
Global Burden of Disease Study —Disease and injury incidence and prevalence collaborators 
global, regional, and national incidence, prevalence, and years lived with disability for 310 
diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease 
Study 2015. Lancet. 2016;388:1545–1602. 
Guy W. ECDEU assessment manual for psychopharmacology. Revised. DHEW publication 
no. (ADM) 76-338. Rockville, MD: U.S. Department of Health, Education, and Welfare, 
Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National 
Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural 
Research Programs; 1976:534-537. 
Kay SR, Stanley R, Fiszbein A, Opfer L. The positive and negative syndrome scale (PANSS) 
for schizophrenia. Schizo. Bull. 1987;13:261-276. 
Keefe RSE, Goldberg TE, Harvey PD, Gold JM, Poe M, Coughenour L. The Brief 
Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a 
standard neurocognitive battery. Schizo. Res. 2004;68(2–3):283–297. 
Lozano R, Naghavi M, Foreman, et al. Global and regional mortality from 235 causes of 
death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of 
Disease Study 2010. Lancet. 2012;380:2095-2128. 
Lu K, Li D, Koch GG. Comparison between two controlled multiple imputation methods for 
sensitivity analyses of time-to-event data with possibly informative censoring. American 
Statistical Association—Statistics in Biopharmaceutical Research. 2015;7(3):199-213.  

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Meltzer, HY. Suicidality in schizophrenia: A review of the evidence for risk factors and 
treatment options. Cur Psychiatry Rep. 2002;4(4):279. 
Miyamoto S, Miyake N, Jarskoq LF, et al. Pharmacological treatment of schizophrenia: A 
critical review of the pharmacology and clinical effects of current and future therapeutic 
agents. Mol Psychiatry. 2012;17(12):1206–1227. 
Morosini P, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
acceptability of a new version of the DSM-IV Social and Occupational Functioning 
Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 
2000;101:323-329. 
Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman A, Michaud C, et al. Disability-adjusted 
life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: A systematic 
analysis for the global burden of disease study 2010. Lancet. 2013;380(9859): 2197. 
National Institute of Mental Health. 2015. 
https://www.nimh.nih.gov/health/statistics/prevalence/schizophrenia.shtml  
Accessed 21 March 2017. 
Nuechterlein KH, Subotnik K, Ventura J, Green M. The puzzle of schizophrenia: Tracking 
the core role of cognitive deficits. Dev Psychopathol. 2012;24(2): 529.  
Owen MJ, et al. Schizophrenia. Lancet. 2016;388(10039):86. 
Schultz SH, et al. Schizophrenia: A review. Am Fam Physician (1970). 2007;75(12):1821. 
Silveira C, et al. More than one century of schizophrenia: An evolving perspective. J Nerv 
Ment Dis. 2012;200(12):1054. 
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr 
Scand Suppl. 1970;212:11-19.  
Zhao Y, Herring AH, Zhou H, et al. A multiple imputation method for sensitivity analyses of 
time-to-event data with possibly informative censoring. Journal of Biopharmaceutical 
Statistics. 2014;24(2):229-253. 

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Attachments 
12.1 
Elements of Informed Consent 
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study or from the patient’s 
legally authorized representative. This consent must include the following items: 
x A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation 
x A description of any reasonably foreseeable risks or discomforts to the patient 
x A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence) 
x A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient 
x A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA; the 
sponsor; the IRB; or an authorized contract research organization may inspect the 
records 
x For research involving more than minimal risk, an explanation of whether any medical 
treatment is available if injury occurs and, if so, what it consists of or where further 
information may be obtained 
x An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In some 
cases, it may be necessary to identify a person other than the investigator as the 
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x A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled 
x A statement that the particular treatment or procedures may involve risks to the patient 
(or to the embryo or fetus if the patient is, or may become, pregnant) that are at present 
unforeseeable 
x The expected circumstances for which the patient’s participation may be terminated by 
the investigator without regard to the patient’s consent 
x Any additional costs to the patient that may result from participation in the research 
x The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation 
x A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided to 
the patient 
x The approximate number of patients involved in the study 
x A statement of consent (eg, “I agree to participate . . .”) 
x A place for the patient’s signature and date of signing 
x A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov. 
A copy of the signed consent form must be given to the patient. 

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12.2 
Structured Clinical Interview for the Positive and Negative 
Syndrome Scale (PANSS) 
SCI-PANSS Scoring Sheet 
 

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12.3 
Clinical Global Impressions–Severity (CGI-S) 
SEVERITY OF ILLNESS 
Considering your total clinical experience with this population, how mentally ill is the patient 
at this time? 
Check one: 
1 = Normal, not at all ill 
2 = Borderline ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill patients 

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

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12.5 
Barnes Akathisia Rating Scale 
Rating scale for drug-induced akathisia (BARS) 
Patient name: 
Patient research no.: 
Hospital No.: 
Ward: 
Rater: 
Instructions 
Patient should be observed while they are seated, and then standing while engaged in neutral 
conversation (for a minimum of 2 minutes in each position). Symptoms observed in other 
situations, for example while engaged in activity on the ward, may also be rated. 
Subsequently, the subjective phenomena should be elicited by direct questioning. 
Objective 
0 
Normal, occasional fidgety movements of the limbs 
1 
Presence of characteristic restless movements: shuffling or tramping movements of 
the legs/feet, or swinging of one leg while sitting, and/or rocking from foot to foot or 
“walking on the spot” when standing, but movements present for less than half the 
time observed 
2 
Observed phenomena, as described in (1) above, which are present for at least half the 
observation period 
3 
Patient is constantly engaged in characteristic restless movements, and/or has the 
inability to remain seated or standing without walking or pacing, during the time 
observed 
Subjective 
Awareness of restlessness 
0 
Absence of inner restlessness 
1 
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2 
The patient is aware of an inability to keep the legs still, or a desire to move the legs, 
and/or complains of inner restlessness aggravated specifically by being required to 
stand still 
3 
Awareness of intense compulsion to move most of the time and/or reports strong 
desire to walk or pace most of the time 
Distress related to restlessness 
0 
No distress 
1 
Mild 
2 
Moderate 
3 
Severe 
Global clinical assessment of akathisia 
0 
Absent. No evidence of awareness of restlessness. Observation of characteristic 
movements of akathisia in the absence of a subjective report of inner restlessness or 
compulsive desire to move the legs should be classified as pseudoakathisia 
1 
Questionable. Non-specific inner tension and fidgety movements 
2 
Mild akathisia. Awareness of restlessness in the legs and/or inner restlessness worse 
when required to stand still. Fidgety movements present, but characteristic restless 
movements of akathisia not necessarily observed. Condition causes little or no 
distress 
3 
Moderate akathisia. Awareness of restlessness as described for mild akathisia above, 
combined with characteristic restless movements such as rocking from foot to foot 
when standing. Patient finds the condition distressing 
4 
Marked akathisia. Subjective experience of restlessness includes a compulsive desire 
to walk or pace. However, the patient is able to remain seated for at least 5 minutes. 
The condition is obviously distressing 
5 
Severe akathisia. The patient reports a strong compulsion to pace up and down most 
of the time. Unable to sit or lie down for more than a few minutes. Constant 
restlessness which is associated with intense distress and insomnia 
Reproduced from: A rating scale for drug-induced akathisia. T.R.E. Barnes, British Journal of 
Psychiatry (1989), 154, 672-676. 
© 1989 The Royal College of Psychiatrists. 
 

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12.6 
Abnormal Involuntary Movement Scale (AIMS) 
EXAMINATION PROCEDURE 
Either before or after completing the Examination Procedure, observe the patient 
unobtrusively, at rest (eg, in waiting room). The chair to be used in this examination should 
be hard, firm without arms. 
1. 
Ask patient whether there is anything in his/her mouth (ie, gum, candy, etc.) and if there 
is, to remove it. 
2. 
Ask patient about the current condition of his/her teeth. Ask patient if he/she wears 
dentures. Do teeth or dentures bother patient now? 
3. 
Ask patient whether he/she notices any movements in mouth, face, hands or feet. If yes, 
ask to describe and to what extent they currently bother patient or interfere with their 
activities. 
4. 
Have patient sit in chair with hands on knees, leg slightly apart, and feet flat on floor. 
(Look at entire body for movements while in this position.) 
5. 
Ask patient to sit with hands hanging unsupported. If male, between legs, if female and 
wearing a dress, hanging over knees. (Observe hands and other body areas.) 
6. 
Ask patient to open mouth. (Observe tongue at rest within mouth.) Do this twice. 
7. 
Ask patient to protrude tongue. (Observe abnormalities of tongue movement.) Do this 
twice. 
8. 
Ask patient to tap thumb, with each finger, as rapidly as possible for 10 to 15 seconds; 
separately with right hand. (Observe facial and leg movements.)* 
9. 
Flex and extend patient’s left and right arms (one at a time). 
10. Ask patient to stand up. (Observe profile. Observe all body areas again, hips included.) 
11. Ask patient to extend both arms outstretched in front with palms down. (Observe trunk, 
legs and mouth.) * 
12. Have patient walk a few paces, turn, and walk back to chair. (Observe hands and gait.) 
Do this twice. * 
* Activated movements 

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12.7 
Simpson-Angus Scale (SAS) 
 

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12.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, 
P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the  
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination 
of the presence of suicidality depends on clinical judgment. 
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia-Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, 
Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 
103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements 
contact posnerk@childpsych.columbia.edu 

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

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Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the 
pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you 
were feeling) or was it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others. (4) Mostly to end or stop the pain (you               
(2) Mostly to get attention, revenge or a reaction from others.         couldn’t go on living with the pain or
                                                                                                                how you were feeling).
(3) Equally to get attention, revenge or a reaction from others        (5) Completely to end or stop the pain      and to 
end/stop the pain.                                                                    (you couldn’t go on living with the          
(0) Does not apply                                                                                   pain or how you were feeling).
____
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought 
of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, 
then it can be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for 
injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an 
attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (eg, gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they 
thought that what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, 
feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes No
□ □
Total # of
Attempts
______
Yes No
□ □ 
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for 
that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt 
rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or 
is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. 
Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but 
has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something 
stopped you before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of 
interrupted
______ 
Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have 
engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops 
him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself 
before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of
aborted

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

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

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

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

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

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Occasional is defined as occurring 3 or more times in the reference period or occurring even less than 3 times 
but in circumstances and/or with such a previous history to convince the rater that there is a risk of recurrence in 
the near future. If the aggressive behavior has been present occasionally, the rating may be decreased by one 
degree, eg, from severe to marked. 
* Main areas: a=socially useful activities, including work and study; b=personal and social relationships;  
c=self-care; d=disturbing and aggressive behaviors. 
Guidelines for PSP Total Score 
x Ratings from 71-100 reflect only mild difficulties. 
x Ratings from 31-70 reflect manifest disabilities of various degrees. 
x Ratings from 1-30 reflect functioning so poor that intensive support or supervision is 
needed. 
The levels of functioning in other areas should be taken into account to adjust the rating 
inside the decimal level (for instance, from 31 to 40). Suicidal risk is not included in the 
scale. 
10-point 
Intervals  
PSP Descriptions 
100 – 91 
Excellent function in all 4 main areas*. He/she is held in high consideration for his/her 
qualities, copes adequately with life problems, is involved in a wide range of interests and 
activities 
90 – 81 
Good functioning in all 4 main areas, presence of only common problems or difficulties 
80 - 71  
Mild difficulties in 1 or more areas of a-c 
70 – 61 
Manifest, but not marked difficulties in 1 or more areas of a-c or mild difficulties in d 
60 - 51 
Marked difficulties in 1 of areas a-c, or manifest difficulties in d 
50 – 41 
Marked difficulties in 2 or more, or severe difficulties in 1 of areas a-c, with or without 
manifest difficulties in d 
40 - 31 
Severe difficulties in 1 and marked difficulties in at least 1 of areas a-c, or marked difficulties in 
d 
30 - 21 
Severe difficulties in 2 of areas a-c, or severe difficulties in d, with or without impairment in 
areas a-c 
20 - 11 
Severe difficulties in all areas a-d or very severe in d with or without impairment in general 
areas a-c. If the person reacts to external prompts the suggested score are 20-16, if not, the 
suggested scores are 15-11 
10 - 1 
Lack of autonomy in basic functioning with extreme behaviours but without survival risk 
(ratings 6-10) or with survival risk, eg, death risk due to malnutrition, dehydration, infections, 
inability to recognize situations of manifest dander (ratings 5-1) 

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12.10 
Ophthalmological Examination 
The ophthalmological examinations will consist of measurement of: 
1. Best-corrected visual acuity (BCVA) 
2. Color vision testing 
3. Slit-lamp assessment of the lids, conjunctivae, corneas, iris and anterior chamber 
4. Lens status and opacification: modified Age-Related Eye Disease Study (AREDS) 
severity scale 
5. Slit-lamp assessment of the vitreous, retina, macula, and optic nerve 
Best-corrected visual acuity (BCVA): BCVA will be documented at all scheduled 
ophthalmological visits. For the purpose of this study, every effort should be made that the 
same chart in the same examination room with the same lighting conditions that provide 
standardized chart illumination should be used for testing all study subjects at each visit 
where refraction and vision testing are required. Each eye will be assessed using the Early 
Treatment Diabetic Retinopathy Study (ETDRS) wall charts at a standard distance. The same 
distance should be used for all subsequent visits where vision testing is required. Floor 
markers should be used to ensure that the correct distance is measured at each examination. 
As far as possible the same examiner should do the testing for all visits where vision testing 
is required.  
The appropriate lens correction will be used for each test to ensure that the test will be done 
with the actual best correction. The smallest line on which the majority of letters are read by 
each eye will be recorded (5 letters on each line, thus a maximum of 2 errors per line will be 
acceptable). The test will continue until a complete line is missed, ie, less than 3 characters in 
a line are identified.  
Changes from the pre-treatment values (Screening, Visit 1) will be determined for each eye 
and classified as deterioration, improvement, or no change in visual acuity at each post-dose 
assessment. Clinically significant improvement or deterioration will be defined as a change 
of at least 2 standard lines (0.2 logMAR) on the ETDRS chart (Birch et al, 2002). The 
appropriate lens correction will be assessed before each test by a trained vision examiner 
using the ETDRS chart (R chart) to ensure that the test will be done with the actual best 
correction. As to the ETDRS charts, each eye will be tested using a different chart. The right 
eye will always be tested with Chart 1, and the left eye with Chart 2. 

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Scoring for ETDRS Chart: ETDRS is scored by the total number of letters correct. For 
example, reading the top line at 4 meters is a score of 35, each letter adds one to the score. In 
logMAR, each letter is 0.02, so a line adds 0.1 logMAR. Using this system, a correct reading 
of line 11 yields a score of 85 that is equivalent to 20/20 in the Snellen notation. 
Color Vision Testing: Color vision testing will be performed to include both Blue-Yellow 
confusion and Red-Green confusion tests. For newly screened patients, testing to be 
completed using Hardy Rand Rittler (HRR) pseudoisochromatic color plates. 
Slit-lamp assessment of the lids, conjunctivae, corneas iris and anterior chamber: Slit-
lamp assessment of the lids, conjunctivae, corneas iris and anterior chamber will be 
conducted to evaluate the presence of disease and to assess anterior chamber depth and 
chamber angles to ascertain if chambers are too shallow to allow safe pupillary dilatation. 
Patients whose anterior chamber angles are too shallow for safe dilatation will be excluded 
from the study. Those whose angles are sufficiently deep to allow safe pupillary dilatation 
may have their pupils maximally dilated with appropriate mydriatics. 
Intraocular pressure should be determined after completion of the biomicroscopic 
examination, before dilating the pupil. If necessary, IOP measurement may be repeated to 
obtain a reliable pressure. The most accurate measurement (as determined by the 
ophthalmologist) should be entered into the eCRF. 
Lens Status and Opacification: 
At screening and protocol-specified intervals, lens status will be assessed as phakic, 
pseudophakic, or aphakic.  
For phakic eyes, the presence and severity of nuclear, cortical, and posterior subcapsular 
cataract lens opacities will be evaluated according to the modified AgeǦRelated Eye Disease 
Study (AREDS) Clinical Lens Grading Protocol. Biomicroscopic findings will be compared 
with standard photographs from the AREDS Clinical Lens Standards grading guide. Allergan 
will supply the site with a copy of the guide.  
Pupils should be dilated to at least 5 mm. The slit-lamp should be used at 10x magnification.  
Grading will be performed as described below. 
Cortical Opacities 
x 
Use retroillumination. 

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x 
Include both anterior and posterior cortical opacities that are visible with 
retroillumination. 
x 
Combine all opacities and compare total area with Cortical Standard Photograph #2 
(about 25% of the visible lens). 
x 
Standard photographs. Only Cortical Standard Photograph #2 is used in grading. 
Standard #2 with lines at the borders of the opacities is provided for reference. 
x 
Grading scale 
o Opacity is absent. 
o Opacity is present, but less than Cortical Standard Photograph #2. 
o Opacity is present and is as severe as or is worse than Cortical Standard 
Photograph #2. 
Nuclear Opacities 
x 
Adjust the slit beam to a width of 0.3 mm and a height of 8.0 mm when using a 
Topcon SL-6E slit-lamp. When other slit lamps are used, set the slit beam width at 
0.3 mm and height of 9.0 mm. If the Haag-Streit BX 900 Slit-lamp is used, please 
note that the width control knob does not indicate units in millimeters. A slit beam 
width of 0.3 mm may be set by turning the knob counter-clockwise to the second 
tick on the slit width control knob. Each tick opens the slit beam ~0.15 mm. 
x 
Orient the slit beam at 45º to the viewing axis. 
x 
Compare the slit-lamp appearance with Nuclear Standard Photograph #2. The 
primary considerations are: the opalescence (reflectance) of the nucleus and the 
blurring of the normal landmarks, ie, the dark interval at the center of the nucleus 
(the “sulcus”) and the short, bright bands adjacent to it anteriorly and posteriorly (the 
“lentils,” so named for their somewhat bean-like shape). 
x 
Standard photographs. Only Nuclear Standard Photograph #2 is used in grading. 
Standard Photographs #1 and #3 are provided as examples of lenses that have less 
and more nuclear sclerosis, respectively, than Standard Photograph #2. 
x 
Grading scale 

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o Opacity is absent. 
o Opacity is present, but less than Nuclear Standard Photograph #2. 
o Opacity is present and is as severe as or is worse than Nuclear Standard 
Photograph #2. 
Posterior Subcapsular (PSC) Opacities 
x 
Use retroillumination and include PSC opacities visible with it. 
x 
Standard photographs. Only PSC Standard Photograph #2 is used for grading. PSC 
Standard Photograph #2 with lines at the borders of the opacity is provided for 
reference. 
x 
Grading scale 
o Opacity is absent. 
o Opacity is present, but less than PSC Standard Photograph #2. 
o Opacity is present and is as severe as or is worse than PSC Standard 
Photograph #2. 
Every attempt should be made to have the same ophthalmologist perform both Baseline and 
follow-up examinations. 
Slit-lamp assessment of the vitreous, retina, macula, and optic nerve: When the lens 
examination is completed, the ophthalmologist will perform an examination of the vitreous, 
retina, macula, and optic nerve. Findings from these examinations will be recorded as normal 
or abnormal; abnormal findings will be specified with descriptive text.  

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12.11 
Package Insert 
The appropriate package insert will be supplied to investigators in countries where the 
product is marketed. 
 

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12.12 
Glossary of Abbreviations 
Term/Abbreviat
ion 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
β-hCG 
β-human chorionic gonadotropin 
BCVA 
best-corrected visual acuity 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impressions-Improvement  
CGI-S 
Clinical Global Impressions-Severity 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DB 
double-blind 
DB ITT 
double-blind intent-to-treat 
DSM-5 
Diagnostic & Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
Early Termination 
EU 
European Union 
GBD 
Global Burden of Disease 
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
HRR 
Hardy Rand Rittler 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
Institutional Review Board 

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ITT 
Intent-to-treat 
IWRS 
interactive web response system 
LOCF 
last-observation-carried forward 
NEAE 
newly emergent adverse event 
OL 
open-label 
OL SFU 
open-label safety follow-up 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
potentially clinically significant 
PID 
patient identification number 
PSP 
Personal and Social Performance Scale 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using the Bazett formula  
QTcF 
QT interval corrected for heart rate using the Fridericia formula  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Scale 
SCID-5 
Structured Clinical Interview for DSM-5 
SCI-PANSS 
Structured Clinical Interview for the Positive and Negative 
Syndrome Scale 
SFU 
safety follow-up 
TEAE 
treatment-emergent adverse event 
UDS 
urine drug screen 
US 
United States 
ULN 
upper limit of normal 
WHO 
World Health Organization 

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12.13 
Protocol Amendment 1 Summary 
Title: A Double-Blind, Placebo-Controlled, Randomized Withdrawal, Multicenter Clinical 
Trial Evaluating the Efficacy, Safety, and Tolerability of Cariprazine in a Dose-Reduction 
Paradigm in the Prevention of Relapse in Patients With Schizophrenia 
Protocol RGH-MD-24 Amendment 1 
Date of amendment: 21 December 2017 
The protocol was revised to clarify relapse and discontinuation criteria, clarify plans for 
summarization of ophthalmological data, clarify plans for summarization of safety data 
collected during the SFU period, and to remove an erroneous statement in Section 12.10 
(Ophthalmological Examination). Following is a summary of content-oriented changes that 
were made to the protocol. Minor editorial and document formatting revisions have not been 
summarized. 
Section 
Revision 
Rationale 
Title page 
Updated sponsor address to: 
5 Giralda Farms 
Madison, NJ 07940 USA 
Update to current address 
Protocol Summary; 
Section 3.2 
Open-label 
Treatment Period; 
Section 4.6 
Randomization 
Criteria;  
Section 8.9 
Withdrawal Criteria 
The discontinuation criteria associated with the 
requirement for either hospitalization or the initiation of 
treatment with a mood stabilizer, antidepressant, 
antipsychotic agent, or benzodiazepine were clarified to 
read as follows (new text in bold font): 
Additionally, patients who require either hospitalization 
(excluding protocol-allowed hospitalization during 
Screening/OL periods for the purpose of washout of prior 
psychiatric medications) or initiation of treatment with a 
mood stabilizer, antidepressant, antipsychotic agent, or 
with a benzodiazepine that exceeds the protocol-
specified allowance or duration (ie, more than 2 mg/d of 
lorazepam or equivalent or for more than 3 consecutive 
days) to treat worsening symptoms of schizophrenia or 
any other psychiatric disorder as judged by the clinical 
impression of the investigator will be discontinued. 
Clarification 
Protocol Summary;  
Section 3.3 
Double-blind 
Treatment Period;  
Section 4.7 Relapse 
Criteria During the 
Double-blind 
Treatment Period;  
Section 7.2.1 
Primary Efficacy 
Variable 
The first of the 7 defined relapse criteria was revised to 
read (new text in bold font): 
x 
Increase in PANSS total score by ≥ 30% for 
patients who had a PANSS total score of ≥ 50 at 
Randomization/Visit 13 or a ≥ 10-point increase 
in PANSS total score for patients who had a 
PANSS total score < 50 at Randomization/Visit 
13 
Clarification 

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Section 
Revision 
Rationale 
Protocol Summary;  
Section 3.3 
Double-blind 
Treatment Period;  
Section 4.7 Relapse 
Criteria During the 
Double-blind 
Treatment Period;  
Section 7.2.1 
Primary Efficacy 
Variable 
The fifth of the 7 defined relapse criteria was revised to 
read (new text in bold font): 
x 
Initiation of treatment with a mood stabilizer, 
antidepressant, antipsychotic agent, or with a 
benzodiazepine that exceeds the protocol-
specified allowance or duration (ie, more than 2 
mg/d of lorazepam or equivalent or for more 
than 3 consecutive days) to treat worsening 
symptoms of schizophrenia or any other 
psychiatric disorder as judged by the clinical 
impression of the investigator 
Clarification 
Section 6.4 
Pharmacogenetic 
Sampling 
The following sentence was added: 
Pharmacogenetic consent may be obtained at any time 
between Visit 1/Screening and Week 8 (Visit 8). 
Clarification 
Section 6.5.7 
6.5.7Ophthalmologi
cal Examination 
The following sentence was added: 
Patients with a finding of cataracts at any time during the 
study must be discontinued. 
Clarification and 
consistency with patient 
safety considerations. 
Section 6.5.8.2 
Columbia-Suicide 
Severity Rating 
Scale 
The following sentence was revised to read as follows 
(new text in bold font): 
The C-SSRS will be completed at all study visits, except 
Visit 27 and Visit 28. 
Clarification 
Section 7.1.4 
Open-label 
Safety-Follow-up 
Population 
A new analysis population was added, defined as follows: 
The open-label safety-follow-up (OL SFU) population will 
consist of patients in the OL safety population who were 
not randomized. 
Clarification 
Section 7.3.4 Safety 
Analyses  
The planned summarization of the safety data collected 
during the SFU period was clarified to read (new text in 
bold font): 
The safety analyses will be performed for the OL safety, 
OL SFU, and DB safety populations. The summarization 
will be overall for the OL treatment period in the OL 
safety population and for the OL SFU period in the OL 
SFU population. The summarization will be by 
treatment group for the DB treatment period and DB SFU 
period in the DB safety population. The summarization 
for the OL treatment period will use the OL safety 
population as the denominator. The summarization for the 
DB treatment period will use the DB safety population as 
the denominator. The summarization for the OL SFU 
period and DB SFU period will use the OL SFU 
population and the DB safety population as the 
denominator, respectively. 
Clarification 
Section 7.3.4.3  
Vital Signs 
The definition of different hypertension status will be 
detailed in the SAP. 
Clarification 

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Section 
Revision 
Rationale 
Section 7.3.4.1 
Adverse Events 
New text added for summarization of ocular events of 
special interest, as follows: 
The number and percentage of patients reporting TEAEs of 
ocular events of special interest will be summarized overall 
for the OL treatment period in the open-label safety 
population and the OL SFU period in the OL SFU 
population, and by treatment for the DB treatment period 
and the DB SFU period in the double-blind safety 
population. The listing of all reported ocular events of 
special interest will be provided. 
For clarification and 
consistency with other 
cariprazine studies. 
Section 7.3.4.5.3 
Ophthalmological 
Parameters 
Description of summarization of BCVA outliers revised as 
follows (new text in bold font):  
The number and percentage of patients with a change 
from Baseline in visual acuity ≥ +0.3 in each eye and in 
either eye will be summarized overall for the OL treatment 
period, and by treatment group for the DB treatment 
period. 
The threshold for tabulation of postbaseline IOP values 
was revised from 25 mm Hg to 21 mm Hg; revised 
sentence reads (new text in bold font): 
The number and percentage of patients with postbaseline 
IOP > 21 mm Hg will be presented. 
For clarification and 
consistency with other 
cariprazine studies. 
Section 8.4.5 
Double-blind 
Treatment Period 
(Visits 14 to 25); 
Section 8.4.6 Final 
or Early 
Termination Visit 
(Visit 26) 
The following bullet point was added: 
• Assess patient for relapse (per Section 4.7) 
Clarification 
Section 12.10 
Ophthalmological 
Examination 
Deleted the following statement: 
At Screening, the presence of pseudophakic or aphakic 
eyes will lead to a screen failure.  
To harmonize the 
ophthalmologic 
examination instructions 
with eligibility criteria. 

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12.14 
Protocol Amendment 2 Summary 
Title: A Double-Blind, Placebo-Controlled, Randomized Withdrawal, Multicenter Clinical 
Trial Evaluating the Efficacy, Safety, and Tolerability of Cariprazine in a Dose-Reduction 
Paradigm in the Prevention of Relapse in Patients With Schizophrenia 
Protocol RGH-MD-24 Amendment 2 
Date of Amendment 2: 16 April 2018 
Amendment Summary 
This summary includes changes made to Protocol RGH-MD-24 Amendment 1 
(21 December 2017).  
Minor editorial and document formatting revisions have not been summarized. The following 
is a summary of the major changes that were made to each section of the protocol, and a brief 
rationale for these changes.  
Section 
Revision 
Rationale 
Global 
x 
Updated PANSS to SCI-PANSS where 
applicable  
x 
Changed “Threshold Symptoms” to 
“response criteria” where applicable 
For clarity 
Protocol Summary 
Section 3.2 Open-label 
Treatment Period 
x 
Revision: included provision for a drug 
holiday in the event of tolerability issues 
on the 4.5 mg/d dose during the OLP 
Added to adjust for 
tolerability issues arising 
from dose escalation 
Table 1 schedule of visits 
and procedures 
Section 4.2 Study 
Population Characteristics 
Section 4.3 Inclusion 
Criteria #3 
Section 6.1 Diagnostic 
Assessments 
Section 8.4.1 
Screening/Visit 1 (Days -
7 to -1) 
x 
Replaced the scale used to make the 
diagnostic assessment from MINI to 
SCID-5 
x 
Removed EPS assessment from Visit 1 
Operational change 
Section 3 Study Design 
Text regarding OL period was clarified globally  
For clarity 
Section 4.4 Exclusion 
Criteria 
Exclusion around urine drug screen has been 
clarified 
For clarity 

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Section 
Revision 
Rationale 
Protocol Summary  
Section 4.1 Number of 
Patients 
Section 7.5 Sample Size 
Calculation 
Sample size was changed 
Assumptions for sample 
size calculation were 
updated to reflect 
modified relapse data 
based on feedback from 
FDA during the review of 
the schizophrenia 
maintenance sNDA.  
Section 4.5 Response 
Threshold, Stability, and 
Maintenance of Stability 
Criteria During the OL 
Treatment Period 
Text was clarified to defined stability and 
maintenance 
For clarity 
Section 6.5.7 
Ophthalmological 
Examination 
Appendix 12.10 
Added: anterior chamber and iris to slit-lamp 
examination  
 
These are standard 
components of a slit-lamp 
examination. 
 
Section 9.4 Reporting of 
Pregnancies Occurring 
During the Study 
Changed period for reporting of pregnancies 
during the study from 30 days after last dose to 3 
months following last dose. 
The reporting period for 
pregnancies is being 
extended in order to 
harmonize pregnancy 
reporting globally. 
Section 12.2 Structured 
Clinical Interview for the 
Positive and Negative 
Syndrome Scale (PANSS) 
SCI-PANSS Scoring 
Sheet 
Replaced SCI-PANSS Scoring Sheet 
Updated for clarity 
Section 12.9 PSP Scale  
Updated with full copy of scale 
For clarity 
Appendix 12.10 
Deleted “At the end of the retinal evaluation the 
IOP will be measured again to ensure that there 
has not been a large rise in IOP postmydriasis. “ 
Requirement is being 
removed as this is not 
typically done during an 
ophthalmic exam 
In Schedule of Visits and 
Procedures and globally 
throughout protocol: 
Deleted any statement requiring patients with a 
postbaseline finding of cataracts to be 
discontinued (eg, “Patients with a finding of 
cataracts at any time during the study must be 
discontinued.) (This deletion does not impact 
exclusion criteria) 
 
This requirement is being 
removed to align with US 
Package Insert. If a 
cataract does occur, the 
patient will have a 
reassessment by an 
ophthalmologist at end of 
SFU (ie, following drug 
discontinuation)   

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12.15 
Protocol Amendment #3 Summary 
Title: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Clinical 
Trial Evaluating the Efficacy, Safety, and Tolerability of Cariprazine in a Dose-Reduction 
Paradigm in the Prevention of Relapse in Patients With Schizophrenia 
Study RGH-MD-24 Amendment 3 
Date of Amendment 3: 28 November 2018 
Amendment Summary 
This summary includes changes made to Protocol RGH-MD-24 Amendment 2 
(16 April 2018). 
Minor editorial and document formatting revisions have not been summarized. The following 
is a summary of the major changes that were made to each section of the protocol, and a brief 
rationale for these changes. 

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Section 
Major Revision 
Rationale 
Global 
Corrected Serious Adverse Event Reporting 
Fax Number 
To correct an error 
Global 
Changed Forest Laboratories to Allergan 
Sales 
For clarity 
Title Page 
Added text to clarify the location of the 
Emergency Telephone Numbers 
For clarity 
Protocol Summary, 
Screening/Washout period 
Added text to clarify that psychotropic 
medications, not listed as rescue medications, 
may not be newly initiated or reinstated 
For clarity 
Protocol Summary, 
Screening/Washout period 
Added text to clarify that Day 8 is Visit 3 
For clarity 
Protocol Summary, Table 1 
Added visit windows of + 3 days for Visit 
2/Baseline and ± 3 days for Visit 3 through 
13 
For clarity 
Protocol Summary, Table 1 
Added “concentration by Breathalyzer” to 
Urine Drug Screen/Blood Alcohol 
To expedite turnaround time 
for blood alcohol 
concentration results 
Protocol Summary, Table 2 
Added visit windows of + 3 days for Visit 
2/Baseline and ± 3 days for Visit 14 through 
28 
For clarity 
Protocol Summary, Table 2 
Added serum pregnancy test at Visit 28 
For clarity and for 
consistency with approved 
labeling 
Protocol Summary, Table 2 
Added text to clarify the timing of visits 
For clarity 
Section 3.1 
Screening/Washout Period 
Added text to clarify that psychotropic 
medications, not listed as rescue medications, 
may not be newly initiated or reinstated 
For clarity and internal 
consistency 
Section 3.1 
Screening/Washout Period 
Added text to clarity that Day 8 is Visit 3 
For clarity and internal 
consistency 
Section 4.3 Inclusion 
Criteria, criterion 13 
Added text to clarify the need to use birth 
control for 12 weeks after the last dose of 
investigational product 
For clarity and for 
consistency with approved 
labeling 
Section 4.3 Inclusion 
Criteria, criterion 14 
Added text to clarify that the serum 
pregnancy test is qualitative 
For clarity 
Section 4.4 Exclusion 
Criteria, criterion 2 
Added text to clarify use disorders 
For clarity and consistency 
across cariprazine programs 
Section 4.4 Exclusion 
Criteria, criterion 3b 
Added text to clarify that a positive UDS is 
not exclusionary if the drug was used as 
rescue medication during washout 
For clarity 
Section 4.4 Exclusion 
Criteria, criterion 9 
Added text to exclude moderate CYP3A4 
inhibitors 
For clarity and for 
consistency with approved 
labeling 
Section 4.4 Exclusion 
Criteria, criterion 15 
Change example of endocrinological disease 
For clarity 
Section 4.4 Exclusion 
Criteria, criteria 18a and 18f 
Added text to clarify cataracts as “lens 
opacifications” and changed 6 mm to 5 mm 
For clarity and to align 
protocol with AREDS 
requirements 

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Section 
Major Revision 
Rationale 
Section 4.4 Exclusion 
Criteria, criteria 24, 25, and 
26 
Added: 
24. Absolute neutrophil count < 1000 per 
mm3 at screening 
25. Hemeglobin A1c (HbA1c) > 7% at 
screening 
26. Blood alcohol concentration > 0.02 g/dL 
at Visit 1 as measured by breathalyzer 
Criterion 24 has been added 
to align with withdrawal 
criteria. Criterion 25 has 
been added to clarify 
definition of stable 
endocrinological disease, 
and criterion 26 has been 
added to clarify expectation 
around alcohol use 

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Section 
Major Revision 
Rationale 
Section 4.8.1 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 for 
consistency with approved 
labeling 
Section 4.8.2 Prohibited 
Medications/Treatments 
Added text to clarify that moderate CYP3A4 
inhibitors are also prohibited, psychotropic 
drugs not listed under rescue medications are 
prohibited, and phenazepam is prohibited 
For clarity and internal 
consistency 
Section 4.8.3.1 Insomnia 
Added Suvorexant (maximum of 20 mg/d) to 
the list of allowed medications for insomnia 
The list of allowable 
medications has been 
augmented to included 
additional rescue medication 
options 
Section 4.8.3.2 
Extrapyramidal Symptoms 
or Akathisia 
Added Biperiden to permissible rescue 
medications for EPS or akathisia and 
removed dosing guidance 
For clarity and to align with 
other protocols across the 
program 
Section 5.5 Treatment 
Regimen and Dosing, Table 
3 footnote 
Added: 
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 that dosing times 
can be switched but must 
allow for 24 hours between 
doses 
Section 5.6 Treatment 
Compliance 
Added text to state that any patient who 
misses ≥ 4 consecutive doses of IP must be 
discontinued from the study 
To clarify the definition of 
non-compliance 
Section 6.2.1.2 Clinical 
Global Impressions-Severity 
Changed text to state that the rating scale 
must be performed by a trained rater 
For clarity 
Section 6.2.2.1 Clinical 
Global Impressions-
Improvement 
Changed text to state that the rating scale 
must be performed by a trained rater 
For clarity 
Section 6.2.2.2 Personal and 
Social Performance Scale 
Changed text to state that the rating scale 
must be performed by a trained rater 
For clarity 
Section 6.5.2 Ocular Events 
of Special Interest 
Changed text to clarify that serious ocular 
events must be reported and how serious or 
non-serious events are to be reported 
For clarity 
Section 6.5.3 Clinical 
Laboratory Determinations, 
Table 4 
Added text to include a serum pregnancy test 
at Visit 8 and 28 
For internal consistency with 
changes to Tables 1 and 2 

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Section 
Major Revision 
Rationale 
Section 6.5.3 Clinical 
Laboratory Determinations, 
Table 4 
Added “concentration as measured by 
breathalyzer” to Blood alcohol 
To expedite turnaround time 
for blood alcohol 
concentration results 
Section 6.5.8.2 
Columbia-Suicide Severity 
Rating Scale 
Added text to state that the rating scale must 
be performed by a trained rater 
For clarity 
Section 7.3.4.1 Adverse 
Events 
Replaced all text to define how AEs and 
TEAEs will be coded and summarized 
To reflect current sponsor 
standards 
Section 8.2 Washout 
Intervals/Run-in 
Added text to clarify that psychotropic 
medications, not listed as rescue medications, 
may not be newly initiated or reinstated 
For clarity and internal 
consistency 
Section 8.2 Washout 
Intervals/Run-in 
Added text to clarify that Day 8 is Visit 3 
For clarity and internal 
consistency 
Section 8.3 Procedures for 
Final Study Entry 
Added text to allow rescreening under certain 
situations after consultation with the Allergan 
medical monitor 
To allow additional 
flexibility in allowing 
potentially eligible patients 
to be reconsidered for the 
study 
Section 8.3 Procedures for 
Final Study Entry 
Added text to clarify that the serum 
pregnancy test is qualitative 
For clarity 
Section 8.4 Visits and 
Associated Procedures 
Added text to clarify the timing of visits 
For clarity 
Section 8.4.1 
Screening/Visit 1 (Days -7 
to -1) 
Changed text to clarify how blood alcohol 
concentration is assessed 
For clarity 
Section 8.4.3 Open-label 
Treatment Period (Visits 3 
to 12) 
Added serum pregnancy at Visit 8 
For clarity and to align with 
contraception guidance 
Section 8.4.4 End of OL 
Period/Randomization Visit 
(Visit 13) 
Changed text to clarify how blood alcohol 
concentration is assessed 
For clarity 
Section 8.4.7 Safety 
Follow-up Visits (Visits 27 
and 28) 
Edited text to make serum pregnancy test 
mandatory at Visit 28 
For clarity and to align with 
contraception guidance 
8.7 Compliance with 
Protocol 
Added text to clarify the timing of visits 
For clarity 
Section 8.9 Withdrawal 
Criteria, number 4 
Added text to clarify that Day 8 is Visit 3 
For clarity and internal 
consistency 
Section 8.9 Withdrawal 
Criteria, number 7 
Added text to number 7 to clarify that a 
patient with a positive UDS after enrollment 
should only be withdrawn if the positive test 
is confirmed at the next scheduled visit and to 
cross reference to Section 4.8.3 
For clarity 
Section 8.9 Withdrawal 
Criteria, number 10 
Added text to number 10 to clarify the timing 
of repeat testing and that the patient should be 
discontinued if his or her neutrophil values 
are not normalized or are not increasing 
For clarity 

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Section 
Major Revision 
Rationale 
Section 9.4 Reporting of 
Pregnancies Occurring 
During the Study 
Changed 3 months to 12 weeks 
To align with contraception 
language 
Section 10.4.1 Source 
Documents 
Added text to clarify that source documents 
must follow ALCOA-C 
For clarity 
Section 12.9 Personal and 
Social Performance Scale, 
Guidelines for PSP Total 
Score 
Changed interval 40-31 to Severe difficulties 
in 1 and marked difficulties in at least 1 of 
areas a-c, or marked difficulties in d 
To correct the scoring 
guidelines 
Section 12.10 
Ophthalmological 
Examination 
Deleted text listing wall chart standard 
distances 
For flexibility and clarity 

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12.16 
Protocol Amendment #4 Summary 
Title: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Clinical 
Trial Evaluating the Efficacy, Safety, and Tolerability of Cariprazine in a Dose-Reduction 
Paradigm in the Prevention of Relapse in Patients With Schizophrenia 
Study RGH-MD-24 Amendment 4 
Date of Amendment 4: 17 December 2019 
Amendment Summary 
This summary includes changes made to Protocol RGH-MD-24 Amendment 3 
(28 November 2018). 
Minor editorial and document formatting revisions have not been summarized. The following 
is a summary of the major changes that were made to each section of the protocol, and a brief 
rationale for these changes. 
Section 
Major Revision 
Rationale 
Global 
Phrase ocular events of special interest changed 
to ocular AESIs. 
For clarity. 
Global 
There is no longer a distinct SAE reporting form 
and AESI reporting form. It is a combined 
SAE/AESI form. 
To reflect an administrative 
change in forms. 
4.4 Exclusion Criteria 
Exclusion Criterion #18a revised. 
In light of ophthalmology 
consultation and FDA 
feedback, criterion revised 
to allow for inclusion of 
patients with non-clinically 
significant opacifications in 
order to facilitate 
recruitment. 
6.5.2 Ocular Adverse Events 
of Special Interest 
Addition of a text note with associated asterisk 
to clarify reporting requirements specifically 
around cataracts. 
Text amended to provide 
direction regarding cataract 
reporting when using the 
AREDS grading system, 
consistent with regulatory 
feedback. 
9.1.2 Serious Adverse Event 
Text revised to clarify which pregnancy 
outcomes or genetic abnormalities are 
considered SAEs. 
For clarity. 
12.10 Ophthalmological 
Examination 
Protocol was updated to specify that color vision 
testing is to be completed using HRR color 
plates for newly screened patients. 
To standardize data 
collection.