Clinical trial NCT02431702
Conditions: Schizophrenia Psychotic Disorders
Keywords: Paliperidone Palmitate Oral Antipsychotics Schizophrenia Psychotic Disorders Cognition in Schizophrenia Brain intracortical myelin volume Personal and Social Performance Disease Modification
Sponsor: Janssen Scientific Affairs, LLC
Start date: 2015-07-08; Completion date: 2019-11-12
Enrollment: 337 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to compare effectiveness of paliperidone palmitate (PP: paliperidone palmitate once-monthly and 3-month injections) versus oral antipsychotic (OAP \[that is oral paliperidone extended release {ER}, oral risperidone, or another OAP\]) in delaying time to treatment failure. The study will also evaluate changes in cognition, functioning, brain intracortical myelin (ICM) volume following treatment with PP compared with OAP in participants with recent-onset schizophrenia or schizophreniform disorder.

Detailed description:
A Prospective, matched-control, Randomized (assignment of study drug by chance), open-label, flexible-dose, study in participants with recent-onset schizophrenia or schizophreniform disorder to compare disease progression and disease modification following treatment with PP long-acting injection (once-monthly followed by 3-month injections) or OAP (Any of the following 7 OAPs are permitted: aripiprazole, haloperidol, olanzapine, paliperidone ER, perphenazine, quetiapine, and risperidone). The study consists of 3 parts. Part-1 (Oral Run-In Phase), Part-2 (Disease Progression) and Part-3 (Extended Disease Progression and Disease Modification) with unique endpoints. Screening period will be up to 4 Weeks. Duration of Parts will be as: 2 months for Part-1, 9 months for Part-2 and Part-3. All participants will initially receive oral paliperidone ER or oral risperidone in Part-1. After paliperidone/risperidone treatment in Part-1, participants will be randomized into 1:2 ratio to receive PP or OAP in Part-2. Participants who complete Part-2 will enter into Part-3 wherein OAP group participants of Part-2 will be re-randomized into 1:1 ratio to OAP-OAP group and OAP-PP group, and PP group will continue without further randomization. Treatment failures will be evaluated in Part-2 and Part-3 of the study. Also changes in cognition, functioning, brain intracortical myelin (ICM) volume will be evaluated in the study. Participants' safety will be monitored throughout. Healthy controls (comparable in age, sex, race, and highest parental education to the treated participants) were recruited at each of the 3 MRI centers as controls for the MRI machine calibration for the duration of the study. These healthy controls were to undergo MRI assessments, but were not otherwise involved with the study and did not receive study medication. No safety or efficacy data were collected for these healthy controls.

Arms: arm 1: All Participants will receive Paliperidone Extended Release (ER) 1.5 to 12 milligram (mg) or risperidone 1 to 6 mg once daily orally for 2 months. Subjects who tolerate paliperidone ER/risperidone but find it inadequately efficacious after treatment for an adequate duration at an adequate dosage (per clinical judgment), may be switched to another protocol-specified OAP at the discretion of the investigator. arm 2: Participants who will complete Part-1 will be randomized to receive oral Paliperidone Palmitate (PP) treatment. Participants will receive 5 doses of PP1M (paliperidone palmitate once-monthly injection). First dose at a starting dose of 234 mg on Day 1 and thereafter second dose in second week and then, every month up to Day 92. Participants will be subsequently switched to PP3M (paliperidone palmitate three-monthly injection) following a minimum of 5 injections of PP1M. Participants receiving PP3M may go back to treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the duration of the study with the approval of the medical monitor. arm 3: Participants who will complete Part-1 will be randomized to receive Oral Antipsychotics for 9 months. arm 4: Participants who will complete Part-2 (with PP treatment) will continue to receive Paliperidone Palmitate for 9 months. arm 5: Participants who will complete Part-2 (with OAP treatment) will be randomized to receive PP treatment for 9 months. PP treatment includes PP1M and PP3M. Participants will be subsequently switched to PP3M following a minimum of 5 injections of PP1M. Participants receiving PP3M may go back to treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the duration of the study with the approval of the medical monitor. arm 6: Participants who will complete Part-2 (with OAP treatment) will be randomized to receive OAP treatment for additional 9 months.
Interventions: intervention 1: Aripiprazole intervention 2: Haloperidol intervention 3: Olanzapine intervention 4: Oral Paliperidone ER intervention 5: Perphenazine intervention 6: Quetiapine intervention 7: Oral Risperidone intervention 8: Paliperidone Palmitate Injection (PP1M) intervention 9: Paliperidone Palmitate Injection (PP3M)
Intervention descriptions: intervention 1: Aripiprazole will be administered in accordance with the label or Investigator's discretion intervention 2: Haloperidol will be administered in accordance with the label or Investigator's discretion intervention 3: Olanzapine will be administered in accordance with the label or Investigator's discretion intervention 4: Paliperidone Extended Release (ER) tablets 1.5 to 12 milligram (mg) per day will be administered orally. intervention 5: Perphenazine will be administered in accordance with the label or Investigator's discretion intervention 6: Quetiapine will be administered in accordance with the label or Investigator's discretion intervention 7: Risperidone tablets 1-6 mg per day will be administered orally. intervention 8: Participants will receive 5 doses of PP1M. First dose at a starting dose of 234 mg on Day 1 and a second dose of 156 mg on Day 8 and then 78 to 234 mg (in 3 flexible doses), every month up to Day 92. intervention 9: Paliperidone Palmitate injection (PP3M) will be administered once every 12 weeks intramuscularly. The initial dose will be calculated as 3.5 fold multiple of the final PP1M dose administered on Day 92 (or Day 176). Dose will be increased based on Investigator's discretion.

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 2 November 2017
Janssen Scientific Affairs, LLC*
Clinical Protocol
A Prospective, Matched-Control, Randomized, Open-Label, Flexible-Dose, Study in 
Subjects with Recent-Onset Schizophrenia or Schizophreniform Disorder to Compare 
Disease Progression and Disease Modification Following Treatment with Paliperidone 
Palmitate Long-Acting Injection or Oral Antipsychotics
Disease Recovery Evaluation and Modification (DREaM) Study
Protocol R092670SCH3013; Phase 3b
AMENDMENT 2
R092670 (paliperidone palmitate)
*Janssen Scientific Affairs is a global organization that operates through different legal entities in various 
countries. Therefore, the legal entity acting as the sponsor for Janssen Scientific Affairs studies may vary, 
such as, but not limited to Janssen Scientific Affairs, LLC or Janssen-Cilag International NV. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is 
identified on the Contact Information page that accompanies the protocol.  
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved
Date:
2 November 2017
Prepared by:
Janssen Scientific Affairs, LLC
EDMS no:
EDMS-ERI-89097435, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
LIST OF ATTACHMENTS ............................................................................................................................4
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................5
PROTOCOL AMENDMENTS .......................................................................................................................6
SYNOPSIS ....................................................................................................................................................9
TIME AND EVENTS SCHEDULE: SCREENING .......................................................................................21
TIME AND EVENTS SCHEDULE: PART I, PART II, AND PART III .........................................................22
ABBREVIATIONS.......................................................................................................................................25
DEFINITIONS OF TERMS ..........................................................................................................................26
1.
INTRODUCTION................................................................................................................................27
1.1.
Background ....................................................................................................................................28
1.1.1.
Nonclinical Studies......................................................................................................................28
1.1.2.
Clinical Studies............................................................................................................................29
1.1.2.1.
Human Pharmacokinetics........................................................................................................29
1.1.2.2.
Efficacy/Safety Studies ............................................................................................................31
1.2.
Comparator Drugs..........................................................................................................................35
1.3.
Overall Rationale for the Study ......................................................................................................36
2.
OBJECTIVES AND HYPOTHESES ..................................................................................................37
2.1.
Part II Objectives: Disease Progression.........................................................................................37
2.2.
Part III Objectives: Extended Disease Progression and Disease Modification..............................38
2.3.
Hypothesis......................................................................................................................................40
3.
STUDY DESIGN AND RATIONALE .................................................................................................40
3.1.
Overview of Study Design ..............................................................................................................40
3.2.
Study Design Rationale..................................................................................................................43
3.2.1.
Overall Design Concept ..............................................................................................................43
3.2.2.
General Design Elements ...........................................................................................................46
3.2.2.1.
Subject Selection Criteria.........................................................................................................46
3.2.2.2.
Selection of Efficacy and Safety Evaluations...........................................................................47
3.2.2.3.
Treatment and Dose Selection Rationale................................................................................51
3.2.3.
Phase-Specific Design Considerations.......................................................................................54
4.
SUBJECT POPULATION..................................................................................................................55
4.1.
Selection Criteria for Subjects with Schizophrenia or Schizophreniform Disorder ........................55
4.1.1.
Inclusion Criteria .........................................................................................................................55
4.1.2.
Exclusion Criteria ........................................................................................................................57
4.2.
Selection Criteria for Healthy Controls ...........................................................................................58
4.3.
Prohibitions and Restrictions..........................................................................................................59
4.3.1.
Prohibited Medications................................................................................................................59
4.3.2.
Restrictions Related to Study Eligibility.......................................................................................59
5.
TREATMENT ALLOCATION AND BLINDING .................................................................................60
6.
DOSAGE AND ADMINISTRATION...................................................................................................61
6.1.
Part I: Oral Run-In ..........................................................................................................................61
6.2.
Part II: Disease Progression...........................................................................................................62
6.2.1.
Paliperidone Palmitate Treatment Group ...................................................................................62
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6.2.1.1.
Supplemental Oral Antipsychotic Medication During Paliperidone Palmitate 
Treatment.................................................................................................................................64
6.2.1.2.
Missed Doses of Paliperidone Palmitate .................................................................................64
6.2.2.
Oral Antipsychotic Treatment Group...........................................................................................66
6.3.
Part III: Extended Disease Progression and Disease Modification................................................66
7.
TREATMENT COMPLIANCE............................................................................................................67
8.
PRESTUDY AND CONCOMITANT THERAPY.................................................................................67
9.
STUDY EVALUATIONS ....................................................................................................................68
9.1.
Study Procedures...........................................................................................................................68
9.1.1.
Overview .....................................................................................................................................68
9.1.2.
Screening ....................................................................................................................................69
9.1.3.
Part I: Oral Run-In.......................................................................................................................69
9.1.4.
Part II: Disease Progression .......................................................................................................70
9.1.5.
Part III: Extended Disease Progression and Disease Modification ............................................71
9.1.6.
Unscheduled Visits......................................................................................................................71
9.1.7.
Re-Entry Following Missed Injections or Visits ...........................................................................72
9.1.8.
End-of-Study or Early Termination Visit......................................................................................72
9.2.
Efficacy...........................................................................................................................................72
9.2.1.
Efficacy Raters............................................................................................................................72
9.2.2.
Efficacy Evaluations....................................................................................................................73
9.2.2.1.
Treatment Failure.....................................................................................................................73
9.2.2.2.
MATRICS Consensus Cognitive Battery .................................................................................74
9.2.2.3.
Personal and Social Performance Scale .................................................................................75
9.2.2.4.
Clinical Global Impression of Severity Scale ...........................................................................75
9.2.2.5.
Clinician-Rated Dimensions of Psychosis Symptom Severity.................................................75
9.2.2.6.
Medication Satisfaction Questionnaire ....................................................................................76
9.3.
MRI Brain Imaging Assessments ...................................................................................................76
9.4.
Exploratory Assessments...............................................................................................................77
9.4.1.
Resource Utilization Questionnaire.............................................................................................77
9.4.2.
Goal Setting and Daily Activity Evaluations ................................................................................77
9.5.
Pharmacogenomic (DNA) Evaluations...........................................................................................78
9.6.
Safety Evaluations..........................................................................................................................78
10.
SUBJECT COMPLETION/WITHDRAWAL .......................................................................................81
10.1.
Completion .....................................................................................................................................81
10.2.
Withdrawal From the Study............................................................................................................81
11.
STATISTICAL METHODS.................................................................................................................83
11.1.
Hypotheses.....................................................................................................................................85
11.1.1.
Part II: Disease Progression .......................................................................................................85
11.1.2.
Part III: Extended Disease Progression and Disease Modification ............................................85
11.1.2.1.
Extended Disease Progression ...............................................................................................85
11.1.2.2.
Disease Modification................................................................................................................86
11.2.
Sample Size Determination............................................................................................................87
11.3.
Analysis Populations ......................................................................................................................88
11.4.
Subject Characteristics, Disposition, Study Medication .................................................................89
11.5.
Efficacy Analyses ...........................................................................................................................90
11.5.1.
Part II: Disease Progression .......................................................................................................90
11.5.2.
Part III: Extended Disease Progression and Disease Modification ............................................92
11.5.2.1.
Extended Disease Progression ...............................................................................................92
11.5.2.2.
Disease Modification................................................................................................................93
11.6.
Safety Analyses..............................................................................................................................95
12.
ADVERSE EVENT REPORTING.......................................................................................................97
12.1.
Definitions.......................................................................................................................................97
12.1.1.
Adverse Event Definitions and Classifications............................................................................97
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12.1.2.
Attribution Definitions ..................................................................................................................98
12.1.3.
Severity Criteria...........................................................................................................................99
12.2.
Special Reporting Situations ..........................................................................................................99
12.3.
Procedures .....................................................................................................................................99
12.3.1.
All Adverse Events......................................................................................................................99
12.3.2.
Serious Adverse Events............................................................................................................100
12.3.3.
Pregnancy.................................................................................................................................101
12.4.
Contacting Sponsor Regarding Safety.........................................................................................102
13.
PRODUCT QUALITY COMPLAINT HANDLING ............................................................................102
13.1.
Procedures ...................................................................................................................................102
13.2.
Contacting Sponsor Regarding Product Quality ..........................................................................102
14.
STUDY DRUG INFORMATION .......................................................................................................102
14.1.
Physical Description of Study Drug(s)..........................................................................................102
14.2.
Packaging.....................................................................................................................................103
14.3.
Labeling ........................................................................................................................................103
14.4.
Preparation, Handling, and Storage.............................................................................................103
14.5.
Drug Accountability.......................................................................................................................103
15.
STUDY-SPECIFIC MATERIALS .....................................................................................................104
16.
ETHICAL ASPECTS........................................................................................................................105
16.1.
Study-Specific Design Considerations .........................................................................................105
16.2.
Regulatory Ethics Compliance .....................................................................................................107
16.2.1.
Investigator Responsibilities .....................................................................................................107
16.2.2.
Independent Ethics Committee or Institutional Review Board..................................................107
16.2.3.
Informed Consent......................................................................................................................109
16.2.4.
Privacy of Personal Data ..........................................................................................................109
16.2.5.
Long-Term Retention of Samples for Additional Future Research...........................................110
16.2.6.
Country Selection......................................................................................................................110
17.
ADMINISTRATIVE REQUIREMENTS.............................................................................................110
17.1.
Protocol Amendments ..................................................................................................................110
17.2.
Regulatory Documentation...........................................................................................................111
17.2.1.
Regulatory Approval/Notification...............................................................................................111
17.2.2.
Required Prestudy Documentation...........................................................................................111
17.3.
Subject Identification, Enrollment, and Screening Logs...............................................................112
17.4.
Source Documentation.................................................................................................................112
17.5.
Case Report Form Completion.....................................................................................................113
17.6.
Data Quality Assurance/Quality Control.......................................................................................113
17.7.
Record Retention..........................................................................................................................114
17.8.
Monitoring.....................................................................................................................................114
17.9.
Study Completion/Termination.....................................................................................................115
17.9.1.
Study Completion......................................................................................................................115
17.9.2.
Study Termination.....................................................................................................................115
17.10.
On-Site Audits ..............................................................................................................................115
17.11.
Use of Information and Publication ..............................................................................................116
REFERENCES..........................................................................................................................................118
INVESTIGATOR AGREEMENT ...............................................................................................................127
LIST OF ATTACHMENTS
Attachment 1:
Injection Site Guidelines ...........................................................................................125
Attachment 2:
Anticipated Events ....................................................................................................126
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Doses of Oral Paliperidone ER and PP1M Needed to Attain Similar Steady-State 
Paliperidone Exposure During Maintenance Treatment ...........................................................52
Table 2:
Doses of Oral Risperidone and PP1M Needed to Attain Similar Steady-State 
Paliperidone Exposure During Maintenance Treatment ...........................................................53
Table 3:
Conversion Between PP1M Dose and PP3M Doses Using a 1:3.5 Fixed Ratio......................63
Table 4:
Paliperidone Palmitate Dosing Administration Schedule..........................................................63
Table 5:
Management of a Missed Second Initiation Dose of PP1M......................................................64
Table 6:
Management of a Missed Maintenance Dose of PP1M............................................................65
Table 7:
Re-Initiation Regimen after Missing >4 Months up to 9 Months of PP3M ................................65
Table 8:
MCCB Tests..............................................................................................................................74
Table 9:
Treatment-Emergent Abnormality Categories for Vital Signs ...................................................96
FIGURES
Figure 1:
Overview of the Study Design...................................................................................................41
Figure 2:
Hypothesized Disease Progression and Disease Modification Effect  (Based on 
Change in MCCB Composite Score Over Time [for Illustration Purposes Only]).....................46
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
28 January 2015
Amendment 1
7 June 2017
Amendment 2
02 November 2017
Amendments are listed beginning with the most recent amendment.
Amendment 2 (2 November 2017)
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
The overall reason for the amendment is to allow for additional dose titration using PP1M in subjects who are not 
responding adequately to the PP3M dose administered.
Applicable Section(s)
Description of Change(s)
Rationale: Allow for additional dose titration using PP1M in subjects who are not responding adequately to the 
PP3M dose administered.
Synopsis, Time and 
Event Schedule and
footnotes, Section 3.1, 
3.2.2, 16.1; Figure 1 
footnote.
Added text: “For optimal management of symptoms/tolerability, subjects receiving PP3M
(during either Part II or Part III) may go back to treatment with PP1M (monthly injections 
of 78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the duration 
of the trial with the approval of the medical monitor.”
(to improve achieving an appropriate paliperidone palmitate dose)
Rationale: Clarification of protocol conduct (nonsubstantial)
Throughout the 
protocol
Minor grammatical, formatting, spelling changes, etc
Amendment 1 (7 June 2017)
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
The overall reason for the amendment is to make the possible treatments during the run-in phase consistent with 
labeling instructions for paliperidone palmitate and to improve the overall design and conduct of the study. When 
example text is shown below, new text is shown in italics and text that is removed is shown in strike out. Individual 
rationale for each change is added in parentheses. 
Applicable Section(s)
Description of Change(s)
Rationale: Oral risperidone has been added as an optional treatment to oral paliperidone extended release (ER)
during the run-in period (Part I) and adjustment of dose range for the run-in treatments.
Synopsis, Time and 
Event Schedule 
footnotes, Section 
1.1.2, 2.1, 3.1, 
3.2.2.3, 3.2.3, 4.1.2, 
6.1, 6.2.1, 6.2.2, 8, 
9.1.2, 9.1.3, 9.2.2, 
Inclusion of an optional use of oral risperidone (1-6 mg) during the run-in period (Part I)
instead of oral paliperidone ER. 
(To be consistent with labeling instructions for treatment preceding paliperidone 
palmitate)
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10.2, 11.2, 14.1, 15, 
16.1, Figure 2
Synopsis, Time and 
Event Schedule 
footnotes, Section
3.1, 6.1, 6.2.1.1
The lower limit of the dose range for oral paliperidone ER was changed from 3 mg/day to 
1.5 mg/day
(To account for subjects who are naive to oral paliperidone ER treatment)
Synopsis, Section 1.2, 
3.1, 3.2.3
Subjects should be able to tolerate a minimum dose of oral paliperidone ER (3 mg) or oral 
risperidone (2 mg) for at least 2 weeks before entering Part II. 
(To be aligned with the lowest available dose of PP1M to be administered in Part II)
Section 6.1
Addition of instructions for dosing with oral risperidone
(To adjust dosing with risperidone during the run-in phase)
Synopsis, Time and 
Event Schedule 
footnotes, Section 
3.1, 6.2.1
Addition of the following text to Part II for the PP treatment group who will receive a 
minimum of 5 doses of PP1M followed by PP3M once every 12 weeks:
“At the Day 120 visit (±7 days), subjects will start PP3M treatment if in the investigator’s 
judgment, the subject is receiving an optimal maintenance dose of PP1M.”
“In some cases, if on Day 120 the investigator feels they have not identified the 
appropriate maintenance dose of PP1M, with approval of the medical monitor and 
sponsor, the subject may continue to receive flexible doses of PP1M injections on Day 
120, 148, and 176, and on Day 204 receive an injection of PP3M (using a 3.5-fold multiple 
of the PP1M dose received on Day 176) either in the deltoid or gluteal muscle.   If 
required, supplemental oral paliperidone ER (up to at a dosage of 1.5-6 mg/day or oral 
risperidone (up to 3 mg/day may be given. It should be noted that adding oral 
paliperidone/oral risperidone will not be considered a treatment failure unless 
supplemental oral paliperidone ER/oral risperidone is given for a combined total of more 
than 84 days or if oral paliperidone ER doses exceed 6 mg/day or oral risperidone doses 
exceed 3 mg/day.”
(to be consistent with the labeling statement of a minimum of 4 months of PP1M 
necessary to transition to PP3M treatment to ensure that the correct maintenance dose is 
identified, to provide sufficient time for dose finding, and to expand the dose ranges to be 
consistent with the expansion in the oral run-in phase)
Rationale: Changes to clarify study conduct
Section 3.2.2.3, Table 
1 and Table 2
Starting dose of PP1M to be administered is based on the final oral paliperidone ER or oral 
risperidone dose received during the run-in phase and is specified in 2 added tables
(clarification)
Synopsis, Section 3.1
“Approximately half of the enrolled subjects will also undergo brain magnetic resonancy 
imaging (MRI) scans for assessment of ICM volume and other exploratory MRI 
endpoints. In addition, approximately 20 healthy control subjects (comparable in age, sex, 
race, and highest parental education to the subjects with schizophrenia/schizophreniform 
disorder undergoing MRI scans) will be identified at each MRI center and followed as 
controls for the MRI machine calibration for the duration of the study without treatment.”
(clarification) 
Rationale: Improvements in the conduct of the protocol (nonsubstantial)
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Throughout the 
protocol
Changes for consistency between sections and for clarification of text were made that had 
no impact on safety
Minor updates to content resulting from completion of previously ongoing study
(R092670-PSY-3011) and approval of PP3M 
Throughout the 
protocol
Minor grammatical, formatting, spelling changes, etc
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SYNOPSIS
A Prospective, Matched-Control, Randomized, Open-Label, Flexible-Dose, Study in Subjects with 
Recent-Onset Schizophrenia or Schizophreniform Disorder to Compare Disease Progression and 
Disease Modification Following Treatment with Paliperidone Palmitate Long-Acting Injection or 
Oral Antipsychotics
Paliperidone is a monoaminergic antagonist that exhibits the characteristic dopamine type 2 (D2) 
combined with predominant serotonin (5-hydroxytryptamine type 2A [5HT2A]) antagonism of the newer, 
or second-generation, antipsychotic drugs. Paliperidone palmitate is the ester prodrug of paliperidone 
and is formulated as an aqueous suspension for intramuscular (IM) injection. Two formulations of 
paliperidone palmitate have been developed: the first formulation has a 1-month injection interval 
(PP1M; INVEGA SUSTENNA® or XEPLION®) and the second formulation has a 3-month injection 
interval (PP3M; INVEGA TRINZA® or TREVICTA®). Both formulations are approved in the United 
States (US) and numerous other countries for the treatment of schizophrenia in adults. 
The current study will compare paliperidone palmitate versus oral antipsychotic (OAP) treatment in 
subjects with recent-onset schizophrenia or schizophreniform disorder. Subjects randomized to 
paliperidone palmitate will receive PP1M for a minimum of 4 months prior to transitioning to PP3M; 
this treatment sequence starting with stabilization on PP1M followed by PP3M treatment will hereafter 
be referred to as ‘PP’.
OBJECTIVES AND HYPOTHESES
The study includes 3 treatment phases: a 2-month, open-label, flexible-dose, oral run-in phase (Part I), 
and 2 sequential, 9-month, matched-control, randomized, open-label, active-controlled, flexible-dose
treatment phases (Part II, referred to as the ‘Disease Progression Phase’ and Part III, referred to as the 
‘Extended Disease Progression and Disease Modification Phase’). Part II and Part III each have their 
own objectives. 
An overview of the study design is provided below:
   
      = PP1M injection 
         = PP3M injection
a
All subjects will be started on oral paliperidone ER or oral risperidone. Subjects who find oral paliperidone ER/oral 
risperidone intolerable will be withdrawn from the study; subjects who tolerate oral paliperidone ER/oral risperidone but 
find it inadequately efficacious may be switched to another protocol-specified OAP at the discretion of the investigator. 
b
Subjects randomized to the OAP treatment group will continue their OAP treatment (ie, oral paliperidone ER, or other 
OAP) from Part I. 
Note: For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part II or Part III) may go back 
to treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the 
duration of the trial with the approval of the medical monitor.  
OAP=oral antipsychotic; Pali ER=paliperidone extended-release; Ris=oral risperidone; PP=paliperidone palmitate;
PP1M=paliperidone palmitate 1-month injection; PP3M=paliperidone palmitate 3-month injection; SCZ=schizophrenia or 
schizophreniform disorder.
    PP
  OAP
(Pali ER or 
Risa )
Subjects 
with
Recent-
Onset
SCZ
Randomize 
     (1:2)
Randomize 
      (1:1)
    PP (Delayed Start)
        PP
     OAP 
      OAPb
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Part II Objectives: Disease Progression
Subjects who complete the Part I oral run-in phase will enter Part II and will be randomized in a 1:2 ratio 
to either start PP treatment (ie, PP1M followed by PP3M) or to continue their OAP treatment from Part 
I. It is expected that most subjects will be receiving either oral paliperidone ER or oral risperidone at the 
start of Part II, but some subjects may be on an alternative OAP. The Part II treatment duration is 
9 months.
Primary Objective

To compare the effectiveness of PP versus OAP treatment (ie, oral paliperidone ER, oral 
risperidone. or other OAP) in delaying time to first treatment failure over 9 months’ treatment in 
subjects with recent-onset schizophrenia or schizophreniform disorder (Refer to EFFICACY 
EVALUATIONS section below for a definition of treatment failure).
Key Secondary Objectives:

To evaluate changes in cognition as measured by the Measurement and Treatment Research to 
Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite 
score following 9 months’ treatment with PP compared to 9 months’ treatment with OAP.

To evaluate changes in functioning as measured by the Personal and Social Performance scale 
(PSP) following 9 months’ treatment with PP compared to 9 months’ treatment with OAP.

To evaluate changes in brain intracortical myelin (ICM) volume as measured by inversion recovery 
(IR) and spin echo (SE) magnetic resonance imaging (MRI) in the frontal lobe following 9 months’ 
treatment with PP compared to 9 months’ treatment with OAP.
Secondary Objectives:

To evaluate changes in cognition as measured by the individual domains of the MCCB (ie, working 
memory, verbal learning, speed of processing, attention/vigilance, visual learning, reasoning and 
problem solving, and social cognition) following 9 months’ treatment with PP compared to 
9 months’ treatment with OAP.

To evaluate changes in illness severity as measured by the Clinical Global Impression-Severity 
scale (CGI-S) following 9 months’ treatment with PP compared to 9 months’ treatment with OAP.

To evaluate changes in severity of psychotic symptoms, as measured by the 8 items of the 
Clinician-Rated Dimensions of Psychosis Symptom Severity scale (CRDPSS) (ie, delusions, 
hallucinations, disorganized speech, abnormal psychomotor behavior, negative symptoms 
[restricted emotional expression or avolition], impaired cognition, depression, and mania) following 
9 months’ treatment with PP compared to 9 months’ treatment with OAP.

To evaluate changes in medication satisfaction as measured by the Medication Satisfaction 
Questionnaire (MSQ) [patient-reported outcome] following 9 months’ treatment with PP compared 
to 9 months’ treatment with OAP.

To assess overall safety of PP.
Exploratory Objectives:

To assess changes in resting state functioning MRI (fMRI), and changes in cortical thickness, gray 
matter volume, white matter volume, ventricular volume, intrasulcal cerebrospinal fluid (CSF)
volume, and subcortical myelin integrity, as measured by MRI following 9 months’ treatment with 
PP compared to 9 months’ treatment with OAP.
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
To explore the overall healthcare resource utilization use as measured by the Resource Utilization 
Questionnaire (RUQ) following 9 months’ treatment with PP compared to 9 months’ treatment with
OAP.

To explore differences in satisfaction with goal setting following 9 months’ treatment with PP
compared to 9 months’ treatment with OAP.

To explore quantitative assessments of daily activities following 9 months’ treatment with PP
compared to 9 months’ treatment with OAP.
Part III Objectives: Extended Disease Progression and Disease Modification 
Subjects who complete Part II will be eligible to enter Part III. At the start of Part III, subjects treated 
with OAP during Part II will be re-randomized in a 1:1 ratio to either continue treatment with OAP 
(OAP-OAP group) or to switch to PP (OAP-PP group). Subjects treated with PP during Part II will 
continue the same treatment (PP-PP group). The Part III treatment duration is 9 months.
The Extended Disease Progression objectives will focus on comparisons between the OAP-OAP and 
PP-PP groups; the Disease Modification objectives will focus on comparisons between the PP-PP and 
OAP-PP groups (ie, subjects who started treatment with PP early vs. subjects who started PP treatment 
9 months later).
Extended Disease Progression Objectives
Primary Objective

To evaluate changes in cognition as measured by the MCCB composite score following 18 months’ 
treatment with PP compared to 18 months’ treatment with OAP in subjects with recent-onset 
schizophrenia or schizophreniform disorder.
Key Secondary Objectives:

To evaluate changes in functioning as measured by the PSP following 18 months’ treatment with 
PP compared to 18 months’ treatment with OAP.

To evaluate changes in brain ICM volume in the frontal lobe following 18 months’ treatment with 
PP compared to 18 months' treatment with OAP.
Secondary Objectives:

To evaluate changes in cognition as measured by the individual domains of the MCCB following 
18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To evaluate changes CGI-S following 18 months’ treatment with PP compared to 18 months’ 
treatment with OAP.

To evaluate changes in severity of psychotic symptoms, as measured by the 8 items of the CRDPSS 
following 18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To evaluate changes in medication satisfaction as measured by the MSQ (patient-reported outcome) 
following 18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To evaluate differences in time to first treatment failure and subsequent treatment failures over 
18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To assess overall safety of PP. 
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Exploratory Objectives:

To assess changes in resting state fMRI, and changes in cortical thickness, gray matter volume, 
white matter volume, ventricular volume, intrasulcal CSF volume, and subcortical myelin integrity, 
as measured by MRI following 18 months’ treatment with PP compared to 18 months’ treatment 
with OAP.

To explore the overall healthcare resource utilization use as measured by the RUQ following 
18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To explore differences in satisfaction with goal setting following 18 months’ treatment with PP 
compared to 18 months’ treatment with OAP.

To explore quantitative assessments of daily activities following 18 months’ treatment with PP 
compared to 18 months’ treatment with OAP.
Disease Modification Objectives:
Primary Objective

Using a delayed-start approach, to compare changes in cognition as measured by the MCCB 
composite score following 9 months’ additional PP treatment in subjects originally randomized to 
PP (PP-PP group) compared to 9 months’ delayed-start PP treatment in subjects originally 
randomized to OAP treatment (OAP-PP group).
Key Secondary Objectives:

Using a delayed-start approach, to compare changes in functioning as measured by the PSP 
following 9 months’ additional PP treatment in subjects originally randomized to PP (PP-PP group) 
compared to 9 months’ delayed-start PP treatment in subjects originally randomized to OAP 
treatment (OAP-PP group).

Using a delayed-start approach, to compare changes in brain ICM volume in the frontal lobe 
following 9 months’ additional PP treatment in subjects originally randomized to PP (PP-PP group) 
compared to 9 months’ delayed-start PP treatment in subjects originally randomized to OAP 
treatment (OAP-PP group).
Hypothesis
The overall primary hypothesis to be tested in this study is that 9 months’ treatment with PP is superior 
to 9 months’ treatment with OAP in delaying time to first treatment failure in subjects with 
recent-onset schizophrenia or schizophreniform disorder. The primary efficacy null hypothesis is that 
there is no difference in the distribution of time to first treatment failure in Part II between the PP and 
OAP treatment groups.
OVERVIEW OF STUDY DESIGN
This is a prospective, matched-control, randomized, open-label, active-controlled, flexible-dose, 
multicenter study designed to compare the effectiveness of PP versus OAP in delaying time to first 
treatment failure in subjects with recent-onset schizophrenia or schizophreniform disorder. The study 
will also evaluate whether long-acting injectable (LAI) treatment with PP can slow disease progression 
and possibly modify disease course compared to OAP medications, by tracking changes in cognition, 
functioning, and frontal lobe ICM volume. Other efficacy, safety, and exploratory endpoints will also be 
assessed. 
Approximately 275 men and women between the age of 18 and 35 years, who have a Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of schizophrenia or 
schizophreniform disorder who experienced their first psychotic episode within 2 years of study entry 
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will be enrolled. The total study duration for each subject will be approximately 86 weeks, including a 
screening phase (up to 4 weeks), a 2-month oral run-in phase (Part I), and two 9-month treatment phases 
(Part II and Part III). The study periods are briefly described below:

Screening (up to 4 weeks; Day -28 to -1): Subjects who provide written informed consent will 
undergo the screening procedures, including a review of the study entry criteria. Any prestudy OAP
other than oral risperidone or oral paliperidone ER will be tapered off and must be discontinued by 
Week 5 of Part I.  Subjects already being treated with oral risperidone or oral paliperidone ER
should be continued at the dose deemed to be most appropriate by the investigator). Tapering of the 
previous OAP can start at the beginning of the screening period. Tapering and discontinuation 
should be managed by the investigator, as clinically appropriate.

Part I, Oral Run-In Phase (2 months): After completing the screening period, subjects meeting 
the inclusion and exclusion criteria will be entered into Part I, a 2-month oral run-in phase. All 
subjects will initially receive flexible dosing with oral paliperidone ER (1.5-12 mg/day) OR oral 
risperidone (1-6 mg). Treatment with oral paliperidone ER or oral risperidone will enable 
investigators to establish tolerability prior to randomization to the LAI formulation in Part II. 
Subjects who find either oral paliperidone ER or oral risperidone intolerable will be withdrawn 
from the study. To be eligible for randomization in Part II, subjects must be able to tolerate a 
minimum dose of 3 mg of oral paliperidone or 2 mg of oral risperidone for at least 2 weeks prior to 
entry to Part II. Subjects who tolerate oral paliperidone ER or oral risperidone but find it 
inadequately efficacious after treatment for an adequate duration at an adequate dosage (per clinical 
judgment), may be switched to another protocol-specified OAP at the discretion of the investigator. 
Any of the following 7 OAPs are permitted: aripiprazole, haloperidol, olanzapine, oral paliperidone 
ER, perphenazine, quetiapine, and risperidone. The following demographic and baseline 
characteristics and clinical data will be collected during Part I to be used for matching during 
randomization into Part II and Part III: age, gender, race, prior antipsychotic exposure, substance 
use history, MCCB composite score, and PSP total score.  

Part II, Disease Progression Phase (9 months): Subjects who complete Part I with appropriate 
tolerability of oral paliperidone or oral risperidone (as described above) will be eligible to enter Part 
II. On Day 1 of Part II (Day 57 of Part I), subjects will be randomized in a 1:2 ratio to open-label 
treatment with either PP or to continued OAP treatment for 9 months. Dynamic central 
randomization will be performed, based on matching criteria determined in Part I. It is estimated 
that approximately 225 subjects will be randomized in Part II, ie, approximately 75 subjects will be 
randomized to the PP treatment group and 150 subjects to the OAP treatment group.

Subjects randomly assigned to the OAP treatment group will continue their OAP treatment 
from Part I. It is expected that most subjects will be receiving oral paliperidone ER or oral 
risperidone, but some subjects may be receiving an alternative OAP. Investigators are 
encouraged to continue the OAP prescribed at the Part II baseline) as monotherapy throughout 
the remainder of the study but, if clinically indicated, a switch to an alternative OAP or add-on 
of an additional OAP is permitted after the first randomization visit. Switching or add-on of 
another OAP due to inadequate efficacy, tolerability, or safety will be assessed as a treatment 
failure (see definition of treatment failure in EFFICACY EVALUATIONS). Subjects with 
treatment failure will continue participation in the study. Multiple switches (ie, treatment 
failures) are permitted during the study. The same 7 OAPs identified in Part I are allowed (ie, 
aripiprazole, haloperidol, olanzapine, oral paliperidone ER, perphenazine, quetiapine, and 
risperidone). 

Subjects randomly assigned to the PP treatment group will receive a minimum of 5 doses of 
PP1M followed by PP3M once every 12 weeks. PP1M initiation dosing (first injection 234 mg 
[150 mg eq.] on Day 1 of Part II and second injection 156 mg [100 mg eq.] on Day 8, both in 
the deltoid muscle) followed by 3 injections of flexible doses of PP1M (78-234 mg [50-150mg 
eq.]) on Days 36, 64, and 92, either in the deltoid or gluteal muscle. On Day 120, subjects will 
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receive an injection of PP3M (using a 3.5-fold multiple of the PP1M dose received on Day 92) 
either in the deltoid or gluteal muscle. On Day 204, subjects will receive a flexible dose of 
PP3M (273-819 mg [175-525 mg eq.]) either in the deltoid or gluteal muscle. In some cases, if 
on Day 120 the investigator feels they have not identified the appropriate maintenance dose of 
PP1M, with approval of the medical monitor and sponsor the subject may continue to receive 
flexible doses of PP1M injections on Day 120, 148, and 176, and on Day 204 receive an 
injection of PP3M (using a 3.5-fold multiple of the PP1M dose received on Day 176) either in 
the deltoid or gluteal muscle.  Investigators are encouraged to use PP1M and PP3M as 
antipsychotic monotherapy and to adjust the injection dose for management of 
symptoms/tolerability. If required, supplemental oral paliperidone ER (up to 6 mg/day) or oral 
risperidone (up to 3 mg/day) may be given during PP1M or PP3M treatment. It should be 
noted that adding oral paliperidone/oral risperidone will not be considered a treatment failure 
unless supplemental oral paliperidone ER/oral risperidone is given for a combined total of 
more than 84 days or if oral paliperidone ER doses exceed 6 mg/day or oral risperidone doses 
exceed 3 mg/day (see further details in the DOSAGE AND ADMINISTRATION 
SECTION). Adding any other antipsychotic will also be considered a treatment failure. 
Subjects with treatment failures will continue the study unless the PP injection is discontinued 
permanently.

Part III, Extended Disease Progression and Disease Modification Phase (9 months): Subjects 
who complete Part II will be entered into Part III. On Day 1 of Part III (Day 260 of Part II), subjects 
in the OAP treatment arm will be re-randomized in 1:1 ratio to continued treatment with their OAP 
(OAP-OAP group) or to PP (OAP-PP or ‘Delayed-start PP’ arm). The Delayed-start PP arm will 
receive PP1M and PP3M treatment as described in Part II (ie, a minimum of 5 doses of PP1M 
followed by PP3M once every 12 weeks). Subjects previously assigned to treatment with PP in Part 
II will continue in that treatment group with paliperidone palmitate treatment (PP-PP group). 
Randomization will be based on matched criteria identified in Part I. Subjects will be followed for 
an additional 9 months.  
For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part II or Part 
III) may go back to treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) 
for further dose adjustment or for the duration of the trial with the approval of the medical monitor.  
Subjects will be assessed for treatment failure at all visits during Part II and Part III. Other efficacy 
assessments (MCCB, PSP, CGI-S, CRDPSS, and MSQ) will be performed as specified in the Time and 
Events Schedule. Safety will be monitored through evaluation of AEs, clinical laboratory parameters, 
vital signs, electrocardiograms (ECGs), body weight, ESRS, ISST-Plus, and physical examination 
findings. Resource use (measured using the RUQ), goal setting experience, and quantitative assessment 
of daily activities will be assessed as exploratory endpoints. A pharmacogenomic blood sample will be 
collected from subjects who consent separately to this component of the study (where local regulations 
permit). Subject participation in pharmacogenomic research is optional.
Approximately half of the enrolled subjects will also undergo brain MRI scans for assessment of ICM 
volume and other exploratory MRI endpoints. In addition, approximately 20 healthy control subjects 
(comparable 
in 
age, 
sex, 
race, 
and 
highest 
parental 
education
to 
the 
subjects 
with 
schizophrenia/schizophreniform disorder undergoing MRI scans) will be identified at each MRI center 
and followed as controls for the MRI machine calibration for the duration of the study without treatment. 
Note that subjects who experience a treatment failure and do not withdraw consent or meet the criteria 
for withdrawal from the study will continue in the study and be followed through to the end of the study.
Subjects, who miss scheduled injections or visits, are allowed to re-enter the same assigned treatment 
group of the study as long as their re-entry is within the same part of the study (ie, Part I, Part II or Part 
III) based on their original visit schedule. In all cases of re-entry, the site should contact the medical 
monitor to determine the best way to re-enter the subject and re-initiate treatment.
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SUBJECT POPULATION
Subjects with schizophrenia or schizophreniform disorder: Approximately 275 subjects who meet all 
inclusion and none of the exclusion criteria will be enrolled in the study. Refer to the main text for a 
complete list of inclusion and exclusion criteria. 
The key inclusion criteria include the following: men and women aged 18 to 35 years, inclusive, current 
diagnosis of schizophrenia (295.90) or schizophreniform disorder (295.40) as defined by DSM-5 and 
confirmed by the Structured Clinical Interview for DSM-5 Disorders (SCID) with a first psychotic 
episode within the 24 months prior to the Screening visit, and requiring treatment with an antipsychotic 
medication or a change in antipsychotic medication due to lack of efficacy, tolerability, safety issues, or 
investigator/subject preference. 
The key exclusion criteria include: positive urine drug screen test for cocaine, amphetamines, opiates, or 
phencyclidine (PCP) at screening; current DSM-5 diagnosis of dissociative disorder, bipolar disorder, 
major depressive disorder, schizoaffective disorder, autistic disorder, or intellectual disabilities; and 
meets the DSM-5 definition of moderate or severe substance use disorder (except for nicotine) within 
2 months prior to screening.
Healthy Control Subjects: Each MRI site will identify and enroll approximately 20 healthy control 
subjects who will undergo MRI assessments only. These healthy control subjects should be comparable 
in age, sex, race, and highest parental education to the subjects with schizophrenia/schizophrenia 
disorder undergoing MRI scans. Refer to the main text for a complete list of inclusion and exclusion 
criteria.
Key exclusion criteria are: evidence of a known psychiatric disorder, neurological disorder (eg, epilepsy) 
or significant head injury; first degree relative who has schizophrenia, schizophreniform, schizoaffective, 
or bipolar disorder; or meets the DSM-5 definition of moderate or severe substance use disorder (except 
for nicotine) within 2 months prior to screening. Subjects who are unable to undergo MRI scan for any 
reason, including because of body size (unable or difficult to fit in MRI instrument) or MRI 
contraindicated due to presence of metallic objects (pacemaker, etc.) will also be excluded.
DOSAGE AND ADMINISTRATION
Part I, Oral Run-In Phase
During Part I, all subjects will initially be treated with either oral paliperidone ER (1.5 to 12 mg/day) or 
oral risperidone (1-6 mg/day). Any prestudy OAP other than risperidone or oral paliperidone ER will be 
tapered off and must be discontinued by Week 5 of Part I.  Subjects already being treated with oral 
risperidone or oral paliperidone ER should be continued at the dose deemed to be most appropriate by 
the investigator). Adjustment of the dosage will be done at the investigator’s discretion, based on the 
individual subject’s clinical response to and tolerability of the study drug. To be eligible for 
randomization in Part II, subjects must be able to tolerate a minimum dose of 3 mg of oral paliperidone 
or 2 mg of oral risperidone for at least 2 weeks prior to entry to Part II.  Subjects who find either oral 
paliperidone ER or oral risperidone intolerable will be withdrawn from the study. Subjects who tolerate 
oral paliperidone ER/oral risperidone but find it inadequately efficacious after treatment for an adequate 
duration at an adequate dosage (per clinical judgment), may be switched to another protocol-specified 
OAP at the discretion of the investigator. The following 7 OAPs are permitted: aripiprazole, haloperidol, 
olanzapine, oral paliperidone ER, perphenazine, quetiapine, and risperidone. 
Part II and Part III, Active-Controlled Treatment Phases
Paliperidone Palmitate (PP1M/PP3M) 
All drug injections must be administered by an individual who has received appropriate medical training 
to administer an IM injection. 
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Subjects who are randomly assigned to the PP treatment group at the start of Part II will discontinue their 
OAP treatment from Part I and will be started on PP1M. Subjects will be subsequently switched to 
PP3M following a minimum of 5 injections of PP1M. A transition period of a maximum of 5 weeks will 
be allowed for the previous OAP.  
PP1M will be administered IM once-monthly, after the first 2 injections that are given one week apart 
(Day 1 and Day 8). The first two doses will be administered through a deltoid injection on alternating 
arms. The subsequent injections can be given either in the deltoid or the gluteal muscle. The first dose of 
PP1M will be 234 mg given in the deltoid muscle at Day 1 of the treatment phase. The second dose of 
PP1M will be 156 mg given in the deltoid muscle at Day 8 of the treatment phase. Subsequent doses of 
PP1M will be given every 28 (±7) days in either the deltoid or gluteal muscle. The investigator may 
select from 78, 117, 156, or 234 mg, according to the subjects’ clinical needs. Subjects will continue to 
return to the study site every 4 weeks for injections and for study evaluations. 
At the Day 120 visit (±7 days), subjects will start PP3M treatment if in the investigator’s judgment, the 
subject is receiving an optimal maintenance dose of PP1M. If on Day 120 the investigator feels they
have not identified the appropriate maintenance dose of PP1M, with approval of the medical monitor and 
sponsor the subject may continue to receive flexible doses of PP1M injections on Day 120, 148, and 176, 
and on Day 204 start PP3M treatment. The initial PP3M dose will be calculated as 3.5-fold multiple of 
the final PP1M dose administered on Day 92 (or Day 176). Subjects will receive PP3M injections once 
every 12 weeks (±14 days). Investigators will be permitted to flexibly adjust the dose of PP3M as 
clinically necessary with the dose options for PP3M being 273, 410, 546, or 819 mg. Injections of PP3M 
may be administered in either the deltoid muscle or the upper outer portion of the gluteal muscle. The 
side of each injection (left or right) should be alternated and recorded. For optimal management of 
symptoms/tolerability, subjects receiving PP3M (during either Part II or Part III) may go back to 
treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) for further dose 
adjustment or for the duration of the trial with the approval of the medical monitor.  
Supplemental OAP Use in the PP Treatment Group: Investigators are strongly encouraged to use PP1M 
and PP3M as antipsychotic monotherapy and to adjust the injection dose for management of 
symptoms/tolerability. Subjects in the PP treatment group who are tolerating the medication but 
experience symptom exacerbation during the study will be allowed to have supplemental antipsychotic 
medication, ie, oral paliperidone ER (up to 6 mg/day or oral risperidone (up to 3 mg/day, for no longer 
than a total of 84 days during the total PP treatment period. If the supplemental treatment with oral 
paliperidone ER/oral risperidone is longer than 84 days or if oral paliperidone ER doses exceed 6 
mg/day or oral risperidone doses exceed 3 mg/day, the subject will be considered a treatment failure. 
Adding any other antipsychotic will also be considered a treatment failure. 
A switch to an alternative antipsychotic is not permitted in the PP treatment group. If it is deemed 
clinically necessary to stop paliperidone palmitate in a subject assigned to PP treatment, the subject will 
be withdrawn from the study and discontinuation of PP will be recorded as a treatment failure.  
Oral Antipsychotic Treatment 
Subjects randomly assigned to the OAP treatment group at the start of Part II will continue their OAP 
treatment from Part I. It is expected that most subjects will be receiving oral paliperidone ER or oral 
risperidone, but some subjects may be receiving an alternative OAP at entry into Part II. 
Investigators are encouraged to continue the OAP prescribed at Part II baseline as monotherapy 
throughout the remainder of the study, and to adjust the OAP dose for management of 
symptoms/tolerability at any time. After the initial randomization visit, a switch to a different OAP or 
the addition of another OAP is allowed in the OAP treatment arm if clinically indicated; however, 
switching or add-on of another OAP due to inadequate efficacy, tolerability, or safety will be assessed as 
a treatment failure (see definition of treatment failure in EFFICACY EVALUATIONS). The same 7 
OAPs specified for Part I (aripiprazole, haloperidol, olanzapine, oral paliperidone ER, perphenazine, 
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quetiapine, and risperidone) will be permitted. Multiple switches to other protocol-specified OAPs will 
be allowed during the study. Any change in antipsychotic medication (switching, discontinuation, or 
add-on) must be evaluated against the treatment failure criteria.
Administration of PP or an alternative LAI antipsychotic is prohibited in subjects assigned to OAP 
treatment. If an LAI agent is deemed clinically necessary for subjects assigned to the OAP group, their 
data will be censored as a treatment failure and they will be discontinued from the study.
Subjects should generally be treated within the approved label for all OAPs. Any exceptions should first 
be discussed with the medical monitor.
EFFICACY EVALUATIONS
Subjects will be assessed at each visit during Part II and Part III for the occurrence of treatment failure. 
Treatment failure is defined as any of the following: 1) Psychiatric hospitalization due to worsening 
symptoms (including Emergency Room visits ≥23 hours, and not including hospitalization due to social 
reasons); 2) Any deliberate self-injury, suicidal ideation or behavior, homicidal ideation or violent 
behavior that is clinically significant and needs immediate intervention as determined by the study 
physician; 3) New arrest or incarceration (not related to probation or existing warrant); 4) 
Discontinuation of antipsychotic treatment due to inadequate efficacy as determined by the study 
physician; 
5) Discontinuation of antipsychotic treatment due to safety or tolerability as determined by the study 
physician; 6) Treatment supplementation with another antipsychotic due to inadequate efficacy as 
determined by the study physician (note: use of oral paliperidone ER in the PP treatment group will not 
be considered a treatment failure unless supplemental treatment with oral paliperidone ER or oral 
risperidone is longer than 84 days or if oral paliperidone ER doses exceed 6 mg/day or oral risperidone
doses exceed 3 mg/day); 7) Increase in the level of psychiatric services (such as from office visit to day 
hospitalization) in order to prevent imminent psychiatric hospitalization as determined by the study 
physician.  
Any changes in antipsychotic medications (switching, discontinuation, or add-on) must be evaluated 
against the treatment failure criteria. If any of these changes do not meet the treatment failure criteria, 
these must be documented and recorded in the eDC.
Other efficacy assessments include measures of cognition (MCCB), patient functioning (PSP), disease 
severity (CGI-S), schizophrenia symptoms (CRDPSS), and a patient-reported outcome of medication 
satisfaction (MSQ).
MRI BRAIN IMAGING 
Selected sites will perform MRI brain imaging. All images will be sent to a central site for analysis. The 
imaging raters at the central site will not be otherwise involved with the conduct of the study, and will be 
blind to clinical characteristics, treatment assignment, and demographic characteristics of subjects. 
A separate manual will be provided to the relevant sites with detailed information regarding MRI 
procedures. In brief, brain ICM volume will be measured by IR and SE MRI sequences focused on the 
frontal lobe. The cortical thickness, gray matter and white matter volumes will be measured by 3D 
MPRAGE MRI. The ventricular volume and intrasulcal CSF will be measured by SE MRI sequences. 
The subcortical myelin will be measured by MRI sequences optimized for diffusion tensor imaging 
(DTI). Resting state fMRI will also be measured.
EXPLORATORY ASSESSMENTS
Exploratory evaluations include assessment of medical resource use (based on the RUQ), goal setting
experiences, and quantitative assessment of daily activities. 
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PHARMACOGENOMIC (DNA) EVALUATIONS
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research, as 
necessary (where local regulations permit). Subject participation in the pharmacogenomic research is 
optional.
SAFETY EVALUATIONS
Safety evaluations include the monitoring of adverse events, clinical laboratory tests, ECGs, vital sign 
measurements (temperature, pulse, and blood pressure), body weight, and the monitoring of 
extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A). 
Suicidality will be assessed using the InterSePT Scale for Suicidal Thinking-Plus (ISST-Plus).
STATISTICAL METHODS
A brief description of the statistical methods is provided in the protocol. Additional details of the 
statistical analysis will be described in the statistical analysis plan (SAP). 
Sample Size Determination
The primary efficacy null hypothesis is that there is no difference in the distribution of time to treatment 
failure between the PP and OAP in the treatment of recent-onset schizophrenia or schizophreniform 
subjects in Part II. Treatment differences will be compared using a log-rank test. It is assumed that 
treatment failure rate in Part II is approximately 40% for the OAP group and 20% for the PP group at 
Month 9 with a corresponding hazard ratio of 0.44. It is also assumed that the hazard rates of treatment 
failure for the two groups are proportional. Additional assumptions made to calculate the expected 
number of subjects that need to be randomized to obtain the required number of treatment failures are: 

In both treatment groups, 10% of the randomized subjects will be lost-to-follow-up.

Uniform accrual rate during the 15-month accrual period. 
With these assumptions, it is planned to randomize at least 225 (75 in PP and 150 in OAP group) 
subjects in a 1:2 ratio to receive either PP or OAP to obtain at least 62 treatment failures to show that PP 
is significantly different from OAP at the 2-sided significance level of 0.05, with 80% power to detect a 
hazard ratio of 0.44 using a log rank test. 
Blinded surveillance of the total number of events in Part II will be performed during the study to assess 
the appropriateness of the assumptions. The number of subjects enrolled and the number of subjects who 
discontinue before entering the Part II will be closely monitored.
Assuming 20% attrition rate during the 2-month Run-in period (Part I), the total number of subjects to be 
enrolled in Part I will be approximately 275.
Efficacy Analyses
Part II: Disease Progression
At the completion of Part II, the database will be locked and data analyzed.
Primary endpoint: The primary endpoint in Part II is time to treatment failure. Treatment differences 
will be compared using a log-rank test. The cumulative distribution function of the time to treatment 
failure will be estimated by the Kaplan-Meier method. The 95% confidence intervals (CIs) for the 
median treatment failure rates, as well as the failure rates at 3 months, 6 months, and at 9 months will be 
provided. In addition, the estimate of the hazard ratio and its 95% CI will be provided by treatment 
group based on the Cox proportional hazards model. The reasons for treatment failure will be 
summarized.
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Key secondary endpoints: The change from baseline in MCCB composite score will be analyzed using a 
mixed model repeated measures (MMRM) analysis of covariance (ANCOVA) model. The analysis will 
be based on observed data, ie, data collected at each time point without carrying forward previous 
values. Changes in ICM volume and PSP total score will be analyzed using the same method as the 
MCCB analysis. At each PSP assessment point, frequency counts, percentages, and cumulative 
percentages of subjects reporting each PSP level will also be summarized by treatment group for the 
observed cases and last observation carried forward (LOCF) data. Time to 7-point worsening in PSP will 
be analyzed using the similar methodology for the primary endpoint.
Part III: Extended Disease Progression and Disease Modification
At the conclusion of Part III, the database will be locked again and data analyzed to assess superiority of 
PP versus OAP on Disease Progression and Disease Modification.
Three effects (outcomes) will be analyzed: δ31, δ32, and δ33. These are illustrated in the figure below, 
based on the hypothesized change in MCCB composite score over time. These effects will be assessed 
for the MCCB composite score (primary endpoint), and for PSP total score and ICM volume (key 
secondary endpoints).
Hypothesized Disease Progression and Disease Modification Effect at Completion of Part III 
(Based on Change in MCCB Composite Score Over Time [for Illustration Purposes Only])
ER= extended-release; MCCB= MATRICS Consensus Cognitive Battery; OAP=other antipsychotic; PP=paliperidone palmitate 
δ21:Treatment effect on disease progression; δ31: Lead treatment effect; δ32: Delayed-start treatment effect on disease 
progression; 
δ33: Overall effect of treatment.
The quantity δ31 represents the lead treatment effect after an early start with 18 months of PP treatment 
and shows the lead effect remaining in the early start group over the delayed-start effect after a 9-month 
treatment duration. The quantity δ32 represents the delayed-start effect on disease progression for PP 
compared to continuing OAP after 9 months of additional treatment. The quantity δ33 represents the 
NCT02431702


R092670 (paliperidone palmitate)
Amendment 2 Clinical Protocol R092670SCH3013
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Approved, Date: 2 November 2017
cumulative effect on extended disease progression at the end of Part III following early start for PP 
compared to continuing OAP after a total of 18 months of treatment.
Extended Disease Progression Analyses:
The objective of these analyses is to examine the quantity δ33. The change from baseline in MCCB 
composite score at the end of Part III will be analyzed using a MMRM ANCOVA model. Changes in 
ICM volume and PSP total score will be analyzed using the same method as the MCCB analysis. 
Treatment differences for time to 7-point worsening in PSP score will be compared using a log-rank test 
and Cox’s proportional hazards model. 
Disease Modification Analyses:
The quantity δ31 (lead treatment effect) will be examined as a function of δ21 (treatment effect on disease 
progression) at the end of Part III using Part III baseline scores. The observed score differences in 
MCCB composite score will be analyzed using a MMRM ANCOVA model. Changes in ICM volume 
and PSP total score will be analyzed using the same method as the MCCB analysis as a function of 
corresponding δ21 value. 
The quantity δ32 (the delayed-start effect on disease progression) will be examined using change scores 
from Part III baseline to Part III endpoint. The differences in scale scores will be analyzed using MMRM 
ANCOVA models.
Positive results (δ33 is significant [a differential treatment effect is still evident] and δ31 is significant [the 
lead effect remains significant after 9 months]) will be used to support a conclusion of disease 
modification using MCCB composite score. Similar observations for changes in PSP and ICM will be 
assessed. The quantity δ31 (lead treatment effect) will also be examined using Bayesian repeated 
measures analysis for each endpoint. Bayesian approach based on Markov Chain Monte Carlo will be 
employed to make an inference on significance of δ31 as a function of δ21. This analysis will also use all 
observed scores including assessments from the unscheduled visits.
Safety Analyses
For each study phase and each treatment group, adverse events, clinical laboratory results, vital signs, 
and ECGs will be summarized using descriptive statistics and listed for each subject at each 
measurement time point. The results of the ESRS-A will be summarized using descriptive statistics and 
frequency counts on changes from Part II or Part III baseline values. Suicidality data collected using 
ISST-Plus will be summarized descriptively.
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TIME AND EVENTS SCHEDULE: SCREENING
Treatment Phase
Screening
Visit:
1
Day (Part I)
-28 to -1
Screening/Administrative
Informed consent
X
Informed consent for optional genetic research samples
X
Inclusion/exclusion criteria
X
Medical and psychiatric history
X
SCID
X
Pre-morbid IQ estimate (WTAR)a
X
Urine Drug Screen
X
Informed consent for the subject's designated individual
X
Efficacy Assessments
MCCB
X
PSP
X
CRDPSS (DSM-5)
X
CGI-S
X
MSQ
X
Safety Assessments
Physical examination
X
ECG
X
Clinical laboratory tests
X
Urine Pregnancy test
X
ESRS-A
X
ISST-Plus Short formb
X
Vital signs (blood pressure, pulse rate) and weight
X
Adverse Events
X
Concomitant medication
X
a
An alternative test will be defined by the sponsor if the study is conducted in countries 
other than the United States.
b
If suicidality is identified (ie, ‘yes’ is answered to questions 1.0, 2.2, 2.3, or 2.4 of the 
ISST-Plus Short Form) the full ISST-Plus must be administered in its entirety.
KEY: CGI-S=Clinical Global Impression-Severity scale; CRDPSS=Clinician-Rated 
Dimensions of Psychosis Symptom Severity; DSM-5=Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition; ECG=electrocardiogram; ESRS-A=Extrapyramidal Symptom
Rating Scale-Abbreviated; IQ=intelligence quotient; ISST-Plus=InterSePT Scale for Suicidal 
Thinking-Plus; MCCB=MATRICS Consensus Cognitive Battery; MSQ=Medication 
Satisfaction Questionnaire; PSP=Personal and Social Performance scale; SCID=Structured 
Clinical Interview for DSM-5 Disorders; UV=unscheduled visit; WTAR=Wechsler Test of 
Adult Reading
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R092670 (paliperidone palmitate)
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TIME AND EVENTS SCHEDULE: PART I, PART II, AND PART III
Treatment Phase:
Part Ia 
(Oral Run-in)
Part II
(Disease Progression)
Part III 
(Extended Disease Progression and Disease Modification)
Visit: 2
3
4
5
6
7p
8
9
10
11
12
13s
14
15
16s
17p
18
19o
20
21
22
23s
24
25
26s
27/EOSp UVm
Day (Part I) 1
8
15 29 43
57
Day (Part II)
1
8
36
64
92
120
148 176
204
232
260
Day (Part III)
1
8
36
64
92
120
148 176
204
232
260
Visit window
±4 ±4 ±4 ±4
±7
±4
±7
±7
±7
±7
±7
±7
±7n
±7
±7
±4
±7n
±7
±7
±7n
±7
±7
±7n
±7
Administrative
Inclusion/exclusion criteria
X
Urine Drug Screen
X
X
X
Randomization
Xb
Xc
Contact designated individuald
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample collection for DNAr
X
Study Drug Administration/Prescriptione
Administer study drug (PP)f
or provide prescription (O)g
O
O
O
O
O
1M 1M
1M
1M
1M
3Mu
-
-
3Mv
-
-
-s
3Mv
-
-
3Mv
-
-
3Mv
-
-
O
Os
O
O
O
O
O
O
O
O
1M
1M
1M
1M
1M
3Mu
-
-
3Mv
-
-
O
Os
O
O
O
O
O
O
O
O
-
Efficacy Assessmentsh
Assessment for treatment failure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
MCCBi
X
X
X
X
X
X
X
X
Xh
PSP
X
X
X
X
X
X
X
X
Xh
CRDPSS (DSM-5)
X
X
X
X
X
X
X
X
X
Xh
CGI-S
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
MSQ
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Imagingh,t
MRI
X
X
X
X
X
Xh
Exploratory Assessments
Goal setting and reviewj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of daily activities
X
X
X
X
X
X
X
X
RUQ
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
ECG
X
X
X
Clinical laboratory tests
X
X
X
Urine Pregnancy test
X
X
X
ESRS-A
X
X
X
X
X
X
X
ISST-Plus Short formk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsl and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NCT02431702


R092670 (paliperidone palmitate)
Amendment 2 Clinical Protocol R092670SCH3013
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Approved, Date: 2 November 2017
a
During Part I, all subjects will initially receive flexible doses of oral paliperidone ER (1.5-12 mg/day) or 1-6 mg/day of oral risperidone. Subjects who find oral paliperidone ER or oral 
risperidone intolerable will be withdrawn from the study. Subjects who tolerate oral paliperidone ER or oral risperidone but find it inadequately efficacious may be switched to another 
protocol-specified OAP. Any of the following 7 OAPs will be permitted during Part I: aripiprazole, haloperidol, olanzapine, oral paliperidone ER, perphenazine, quetiapine, and risperidone.  
b
At the start of Part II, subjects will be randomized in a 1:2 ratio to start PP injections or to continue OAP treatment from Part I. 
c
At the start of Part III, subjects who were randomized to OAP in Part II will be re-randomized in a 1:1 ratio to continue OAP from Part II (OAP-OAP group) or switch to PP injections 
(OAP-PP group). Subjects randomized to PP in Part II will continue the same treatment (PP-PP group). 
d
The subject’s designated individual should be contacted to check on the subject’s well-being, such as subject’s general health, common daily activities and progress in personal or health 
goals. Contact may be by telephone if the designated individual does not accompany the subject at the scheduled visit.
e
All procedures should be performed prior to study drug administration/prescription, except for MRI, which does not need be performed on the day of a scheduled visit, but should be 
completed within ±7 days.
f
Subjects who are randomly assigned to start PP treatment will receive PP1M injections on Day 1, Day 8 (±4 days), Day 36 (±7 days), Day 64 (±7 days), and Day 92 (±7 days). The first dose 
of PP3M will be given on Day 120 (±7 days) if in the investigator’s judgment the subject is receiving an optimal maintenance dose of PP1M, and then every 12 weeks (±14 days) thereafter. 
If these windows are exceeded, contact the medical monitor. Refer to Section 6.2.1 for details on PP dosing as well as re-initiation of PP in cases of missed doses. 
g
Subjects who are randomly assigned to the OAP treatment group will continue their OAP treatment from Part I. Subjects will be provided a voucher to present at a local pharmacy to receive 
their assigned study drug. Following the initial randomization visit, a switch to a different OAP or the addition of another OAP is allowed in the OAP treatment group if clinically indicated; 
however, switching or add-on of another OAP due to inadequate efficacy, safety, or tolerability will be assessed as a treatment failure. Refer to Section 9.2.2.1 for definition of treatment 
failure. Any of the following 7 agents will be permitted during Part II and Part III: aripiprazole, haloperidol, olanzapine, oral paliperidone ER, perphenazine, quetiapine, and risperidone. 
Multiple switches to alternative OAPs (ie, multiple treatment failures) are allowed during the study. 
h
All efficacy assessments and MRI scans (in the subgroup of subjects undergoing MRI assessment) must be completed at the first occurrence of treatment failure, or as soon as possible, even 
they are not scheduled to be done for the visit or for the unscheduled visit. At subsequent treatment failures, PSP, CGI-S, CRDPSS, and MSQ assessments should be performed.
i
For every individual subject, MCCB should be administered at the same time of day (+1 hour from the first assessment) for subsequent evaluations.
j
Patient Happiness Assessment and Goal Setting Preparation will be performed at Day 1 Part I only; Patient Goal Setting Documentation will be completed on Day 1 of Part I, II, and III; 
Assessment of Patient Goal Attainment will be assessed by the subject every month.
k 
If suicidality is identified (ie, ‘yes’ is answered to questions 1.0, 2.2, 2.3, or 2.4 of the ISST-Plus Short Form) the full ISST-Plus must be administered in its entirety.
l
Blood pressure and pulse rate.
m
Unscheduled visits should be performed, as necessary for the following reasons:

Unscheduled visits that are clinically indicated: Unscheduled visits should be performed as necessary in the judgment of the physician for appropriate clinical care, including reasons 
of safety or tolerability.

Unscheduled visits for investigational purposes: Any subject who experiences a protocol-defined treatment failure event after randomization to Part II (Visit 7) should undergo an 
unscheduled visit. This applies to every treatment failure episode; not just the initial one. If an unscheduled visit can’t be performed before the next scheduled protocol visit, applicable 
unscheduled visit procedures should be performed during the scheduled visit even when they are not normally part of the scheduled visit. Note that subjects who experience a 
treatment failure event should continue in the study, unless they meet study withdrawal criteria.
n
At these visits (Visit 15, 19, 22, and 25), the treatment window for PP3M dosing will be ±14 days, except for the first PP3M injection, which will be ±7 days.
o
In order to synchronize visit dates for all 3 treatment arms, Visit 19 occurs 92 days (instead of 84 days, ie, 12 weeks) after the previous PP3M injection. However, it is still within the ±14-
day window.
p
Note that completion and discontinuation will be recorded in the CRF for each treatment phase. 
r
The pharmacogenomic (DNA) sample should be collected at the specified time point, however if necessary it may be collected at a later time point without constituting a protocol deviation.
s
These visits can be conducted by telephone.
t
Approximately half the subjects will undergo MRI scans at selected study sites. MRI assessments are optional to subjects. MRI scans will also be performed in the healthy control group; the 
schedule for MRI assessments in healthy control subjects will be provided in a separate MRI manual.
u
At the Day 120 visit (±7 days), subjects will start PP3M treatment if in the investigator’s judgment the subject is receiving an optimal maintenance dose of PP1M. If on 
Day 120 the investigator feels they have not identified the appropriate maintenance dose of PP1M, with approval of the medical monitor and sponsor the subject may 
continue to receive flexible doses of PP1M injections on Day 120, 148, and 176, and on Day 204 will start PP3M treatment.
NCT02431702


R092670 (paliperidone palmitate)
Amendment 2 Clinical Protocol R092670SCH3013
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Approved, Date: 2 November 2017
v      For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part II or Part III) may go back to treatment with PP1M (monthly injections of 
78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the duration of the trial with the approval of the medical monitor. 
KEY: CGI-S=Clinical Global Impression-Severity scale; CRDPSS=Clinician-Rate Dimensions of Psychosis Symptom Severity; CRF=case report form; ECG=electrocardiogram; EOS=end of 
study; ESRS-A=Extrapyramidal Symptom Rating Scale-Abbreviated; ISST-Plus= InterSePT Scale for Suicidal Thinking-Plus; MCCB=MATRICS Consensus Cognitive Battery; 
MRI=magnetic resonance imaging; MSQ=Medication Satisfaction Questionnaire; O=oral antipsychotic; 1M=paliperidone palmitate 1-month formulation; 3M=paliperidone palmitate 3-month 
formulation; PP=paliperidone palmitate; PSP=Personal and Social Performance scale; RUQ=Resource Use Questionnaire; UV=unscheduled visit 
NCT02431702


R092670 (paliperidone palmitate)
Amendment 2 Clinical Protocol R092670SCH3013
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Approved, Date: 2 November 2017
ABBREVIATIONS
5HT2A
5-hydroxytryptamine type 2A
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APA
American Psychiatric Association
AUC
area under the concentration-time curve
BACS
Brief Assessment of Cognition in Schizophrenia
BMI
body mass index
CATIE
Clinical Antipsychotic Trials of Intervention Effectiveness e
CDM
Clinical Data Manager
CGI-S
Clinical Global Impression-Severity scale
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
Cmax
maximum plasma concentration
CRDPSS
Clinician-Rated Dimensions of Psychosis Symptom Severity scale (DSM-5)
CRF
case report form (paper or electronic as appropriate for this study)
CSF
cerebrospinal fluid
D2
dopamine type 2
dv50
volume based median diameter, ie, the median or the 50th percentile of the
particle size distribution as measured by volume
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders (4th edition)
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
DTI
diffusion tensor imaging
ECG
Electrocardiogram
eDC
electronic Data Capture
eITT
explanatory intent-to-treat
EOS
end-of-study
ER
extended release
ESRS-A
Extrapyramidal Symptom Rating Scale-Abbreviated
EU
European Union
EUFEST
European First Episode Schizophrenia Trial
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEE
Generalized Estimation Equations
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Conference on Harmonisation
ICM
intracortical myelin
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IM
Intramuscular
IR
inversion recovery
IRB
Institutional Review Board
ISST-Plus
InterSePT Scale for Suicidal Thinking-Plus
ITT
intent-to-treat
IVRS
interactive voice response system
IWRS
interactive web response system
LAI
long-acting injectable
LOCF
last-observation-carried-forward
LS
least squares 
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia 
MCCB
MATRICS Consensus Cognitive Battery
MedDRA
Medical Dictionary for Regulatory Activities
mg eq
milligrams equivalent of paliperidone
MMRM
mixed model repeated measures
MRI
magnetic resonance imaging
MSQ
Medication Satisfaction Questionnaire
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R092670 (paliperidone palmitate)
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Approved, Date: 2 November 2017
NDA
New Drug Application
NIMH
National Institute of Mental Health
OAP
oral antipsychotic 
PANSS
Positive and Negative Syndrome Scale
PCP
Phencyclidine
PD
proton density
PI
package insert
PK
Pharmacokinetic
PP
paliperidone palmitate treatment sequence (PP1M followed by PP3M)
PP1M
paliperidone palmitate 1-month injection
PP3M
paliperidone palmitate 3-month injection
PQC
product quality complaint
PSP
Personal and Social Performance scale
Ris
Risperidone
RUQ
Resource Use Questionnaire
SAP
statistical analysis plan
SCID
Structured Clinical Interview for DSM-5 Disorders
SE
spin echo
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
US
United States
UV
unscheduled visit
VAS
visual analog scale
DEFINITIONS OF TERMS
OAP-OAP
Subject group treated with OAP in Part II and Part III
OAP-PP
Subject group treated with OAP in Part II and PP in Part III (Delayed-Start PP)
PP-PP
Subject group treated with PP in Part II and Part III
δ21
Treatment effect on disease progression at end of Part II
δ31
Lead treatment effect at end of Part III
δ32
Delayed-start treatment effect on disease progression at end of Part III
δ33
Overall effect of treatment at end of Part III
NCT02431702


R092670 (paliperidone palmitate)
Amendment 2 Clinical Protocol R092670SCH3013
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Approved, Date: 2 November 2017
1.
INTRODUCTION
Paliperidone (9-hydroxy-risperidone) is a monoaminergic antagonist that exhibits the 
characteristic dopamine type 2 (D2) and serotonin (5-hydroxytryptamine type 2A [5HT2A]) 
antagonism of the newer, or second-generation, antipsychotic drugs. Three formulations of 
paliperidone have been developed: an oral extended-release (ER) osmotic pump technology 
(OROS®) tablet formulation (oral paliperidone ER tablets, INVEGA®) and 2 long-acting 
injectable (LAI) formulations: paliperidone palmitate 1-month injection (PP1M; INVEGA 
SUSTENNA® or XEPLION®) and paliperidone palmitate 3-month injection (PP3M; INVEGA 
TRINZA® or TREVICTA®). 
Paliperidone palmitate is an aqueous suspension for intramuscular (IM) injection. Based on its 
extremely low water solubility, paliperidone palmitate dissolves slowly after injection before 
being hydrolyzed to paliperidone, which then enters the systemic circulation. By slowly releasing 
paliperidone from the injection site, the paliperidone palmitate formulation enables a dosing 
interval that achieves potentially therapeutic plasma concentrations of paliperidone for 1 month 
(PP1M) or 3 months (PP3M), depending on the particle size and dose.
The oral formulation of paliperidone (INVEGA) has been approved for the treatment of 
schizophrenia and schizoaffective disorder in the United States (US) and numerous other 
countries. The PP1M formulation (INVEGA SUSTENNA) is also approved in the US and 
numerous countries for the treatment of schizophrenia and for the treatment of schizoaffective 
disorder in US.
The PP3M formulation has been approved in the US and other countries for the treatment of 
schizophrenia in adults. This formulation has been developed building upon the extensive 
knowledge collected during the development of the PP1M formulation. This formulation
contains the same drug substance and similar excipients as the PP1M formulation and is 
manufactured using the same equipment and process.22 The main differences between PP3M and 
PP1M are the suspension strength, particle size (dv50 7 µm vs. 1 µm), and the fill volume for 
injection. These formulation changes enable a longer dosing interval and allow maintenance of 
therapeutic paliperidone plasma concentrations during a 3-month dosing interval. The indication 
for PP3M is for the treatment of adults with schizophrenia who have been adequately treated 
with PP1M for a minimum of 4 months.22 Due to the slow release characteristics of PP3M, the 
product is not intended to be used for initiation of treatment in acutely symptomatic patients or in 
patients who are immediately transitioning from oral to LAI antipsychotic therapy. Rather, 
PP3M is intended to be used in patients who have already demonstrated therapeutic effect and 
tolerability with PP1M during treatment over a period of at least 4 months at the time of 
initiation of PP3M. With this approach, treatment with PP3M can be initiated with a dose 
equivalent to the dose of PP1M achieved at the end of the period of prior treatment, without the 
need for concurrent use of PP3M with oral paliperidone ER or PP1M. This also ensures that 
adequate paliperidone plasma concentrations can be maintained or attained without delay after 
initiation of treatment with PP3M.
NCT02431702


R092670 (paliperidone palmitate)
Amendment 2 Clinical Protocol R092670SCH3013
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Approved, Date: 2 November 2017
The efficacy, safety, tolerability, and pharmacokinetics (PK) of PP3M are supported by the 
results of 2 completed studies: a single-dose, Phase 1 safety/PK study (R092670-PSY-1005) and 
a Phase 3, double-blind, placebo-controlled, relapse prevention study in subjects with 
schizophrenia (R092670-PSY-3012). A Phase 3, randomized, double-blind, noninferiority study 
found PP3M to be non-inferior to PP1M (R092670-PSY-3011).
The current study is a multi-phase, matched-control, randomized, open-label, active-controlled, 
flexible-dose study designed to compare the effectiveness of PP (ie, PP1M followed by PP3M) 
versus oral antipsychotic (OAP) treatment in delaying time to first treatment failure in subjects
with recent-onset schizophrenia or schizophreniform disorder. Using a novel, multi-phase, study 
design, the study will also examine the possibility that LAI treatment with PP can slow down 
disease progression and possibly modify disease course in recent-onset subjects compared to 
OAP medications, by tracking changes in cognition, functioning, and brain imaging assessments.
For the most comprehensive nonclinical and clinical information regarding oral paliperidone ER,
risperidone, PP1M, and PP3M, refer to the latest version of the Investigator's Brochures,102 or the 
current local prescribing information for paliperidone ER, PP1M, PP3M or risperidone. The term 
"sponsor" used throughout this document refers to the entities listed in the Contact Information 
page(s), which will be provided as a separate document.
In this document, all paliperidone palmitate quantities (PP1M and PP3M) are expressed in 
milligrams (mg); the correspondence between mg of paliperidone palmitate and milligram 
equivalents (mg eq.) of paliperidone are provided in Table 3.
1.1.
Background
Background regarding nonclinical and clinical experience with paliperidone palmitate, including 
the PP1M and PP3M formulations, is provided below. 
1.1.1.
Nonclinical Studies
Paliperidone is a monoaminergic antagonist with high affinity for 5HT2A and D2 receptors. 
Paliperidone also binds to 1-adrenergic receptors and, with lower affinity, to H1-histaminergic 
and 2-adrenergic receptors. It has no affinity for cholinergic receptors. It has been proposed that 
the drug’s therapeutic activity in schizophrenia is mediated through a combination of D2 and 
5HT2 receptor antagonism. Antagonism at receptors other than D2 and 5HT2A may explain some 
of its other effects.102
The nonclinical profile of paliperidone has been extensively evaluated during the development of 
the approved oral and PP1M formulations. Paliperidone is neither mutagenic nor teratogenic and 
is associated with toxicologic effects typical of D2 receptor antagonists.102 The PP1M and PP3M 
formulations showed comparable local tolerability in 2 minipig studies90,91 when tested up to the 
maximum dose level used in humans (234 mg for PP1M and 819 mg for PP3M).
Paliperidone undergoes little or no metabolism following incubation with human liver 
microsomes, and does not affect cytochrome P450 activity at clinically relevant in vitro 
concentrations. Paliperidone is mainly metabolized by alicyclic hydroxylation, oxidative 
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N dealkylation, and benzisoxazole scission; alcohol dehydrogenation is an additional pathway in 
humans and dogs. The major route of excretion in humans (79.63%) and dogs (59.8%) was via 
the urine.102   
1.1.2.
Clinical Studies
1.1.2.1.
Human Pharmacokinetics
Due to the very low solubility of the drug substance, paliperidone palmitate particles dissolve 
very slowly in the muscle and allow the release of the active substance over an extended period 
after injection. During development of PP1M, particle size and injected dose (injection volume 
and suspension strength) were shown to be key determinants of the release rate of paliperidone 
from the palmitate formulation. The PP3M formulation differs from the PP1M formulation in its 
suspension strength (200 mg eq./mL vs. 100 mg eq./mL), particle size (~7 µm vs. ~1 µm), and 
higher fill volume in order to ensure a physically and chemically stable 3-month formulation that 
is easily resuspendable and minimizes injection force.22,102
Paliperidone Palmitate 1-Month Injection (PP1M)
The PP1M formulation produces a slowly increasing plasma concentration of paliperidone that 
peaks at about 2 to 3 weeks after dosing. Potentially therapeutic plasma concentrations can be 
reached as early as Day 8 after administration of the recommended initiation regimen (ie, an 
initial IM injection of PP1M 234 mg on Day 1 and a second injection of 156 mg on Day 8, both 
in the deltoid muscle). Plasma concentrations decline with an average t½ of 20 to 50 days. The 
total exposure (AUC) of paliperidone increased dose proportionally over the dose range studied 
(39 to 234 mg) in both deltoid and gluteal muscles. The Cmax for the dose range of 39 to 234 mg 
increased less than dose proportionally. The Cmax is approximately 45% higher following deltoid 
injections compared with gluteal injections; AUCis similar for these injection sites.102
Administration of PP1M at once-monthly intervals
leads to steady-state paliperidone 
concentrations after the fourth to fifth injection and a peak-to-trough variation of 1.7 to 2.1. The 
time-to-peak after repeated injections was shorter (tmax 3 to 5.5 days) than after single injections. 
For the different doses, the accumulation ratio (based on AUC) was 1.7 to 3.6.102
Paliperidone Palmitate 3-Month Injection (PP3M)
Following a single IM dose of 117 to 819 mg PP3M in the gluteal or deltoid muscle, 
paliperidone was slowly absorbed, reflected by a median tmax of approximately 23 to 34 days and 
an apparent half-life (t½) of approximately 2 to 4 months (Study PSY-1005). These results were 
in general agreement with those from the population-PK model in which tmax was achieved 
within 30 to 33 days after a single injection of PP3M (273 to 819 mg), and the apparent half-life 
was in the range of 84 to 95 days following a deltoid injection and 118 to 139 days following a 
gluteal injection. The apparent half-life estimates for paliperidone after administration of PP3M 
from Study PSY-1005 and from the population-PK model support a once every 3 months 
injection cycle for PP3M.
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The multiple-dose PK profile of PP3M was characterized in Study PSY-3012. Overall, 
steady-state conditions were maintained after switching from the PP1M formulation to the PP3M 
formulation. Median paliperidone predose plasma concentrations after administration of 117, 
156, and 234 mg PP1M in the Transition Phase were comparable to paliperidone predose plasma 
concentrations after administration of the corresponding 3.5-fold higher PP3M doses (410, 546, 
and 819 mg, respectively) in the maintenance and double-blind phases, providing further support 
for the once every 3 months injection cycle for PP3M. When steady state was achieved with 
PP3M, the median peak-to-trough ratio (based on the population PK model) was 1.6 to 1.7 
following gluteal and deltoid administrations, which is similar to the median peak-to-trough 
concentration ratios following deltoid PP1M injections.
Based on the population PK models developed for paliperidone when administered as PP3M, 
PP1M, and oral paliperidone ER, between subject variability after multiple injections of PP3M 
over a 3-month period was similar to the variability seen with once daily oral paliperidone ER.
Dose-proportionality of paliperidone PK was evaluated in subjects with schizophrenia and 
schizoaffective disorder after single-dose injection of 117 to 819 mg PP3M into both the deltoid 
and gluteal muscle (Study PSY-1005). Total paliperidone exposure (area under concentration 
time curve (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose 
after a single-dose injection of PP3M in either injection site. Results of the population PK 
analysis that included data from Study PSY-1005 and PSY-3012 also found that the PK of PP3M
was dose proportional for paliperidone overall exposure and approximately dose-proportional for 
Cmax over a dose range of 273 to 819 mg.
Pharmacokinetics During Conversion from PP1M to PP3M
Paliperidone plasma concentration-time profiles after at least 4 months of treatment with PP1M, 
followed by a transition to PP3M, were simulated for the various PP3M dose levels (273, 410, 
546, and 819 mg) and compared with simulated paliperidone plasma concentration-time profiles 
during continuous treatment with PP1M or with the oral paliperidone ER formulation.22
Based on the simulations, was concluded that:22

PP3M (273 to 819 mg injected once every 3 months), when administered at doses that are 
3.5-fold higher than those of PP1M, appears to result in paliperidone exposure similar to the 
exposures obtained with doses of PP1M (78 to 234 mg once every 4 weeks) and oral 
paliperidone ER (4 to 12 mg once daily. The exposure range for PP3M was encompassed 
within the exposure range for the approved dose strengths of oral paliperidone ER.

Based on the visual inspection of the simulation results, the between-subject variability after 
multiple injections of PP3M was higher over a 3-month timeperiod than the variability 
observed for PP1M over a 1-month time period and similar to the variability for once daily 
oral paliperidone ER.

Paliperidone plasma concentrations are stable after injection of the fourth PP3M dose.
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1.1.2.2.
Efficacy/Safety Studies
Paliperidone Palmitate 1-Month Injection (PP1M)
Efficacy: Paliperidone palmitate 1-month injection (INVEGA SUSTENNA [or XEPLION in the 
European Union]) is approved in the US and numerous other countries for the treatment of 
schizophrenia. INVEGA SUSTENNA is also approved for the treatment of schizoaffective 
disorder in the US. Pivotal clinical studies supporting the safety and efficacy of PP1M in the 
treatment of schizophrenia include 4 short-term double-blind, randomized, placebo-controlled, 
fixed-dose Phase 2/3 studies in acutely relapsed subjects (R092670-SCH-201,36 -PSY-3003, 28
-PSY-3004,29 –PSY-300732) and one long-term double-blind, placebo-controlled Phase 3 relapse 
prevention study (R092670-PSY-300125). Additional supportive studies include a long-term 
Phase 1 safety study (R092670-PSY-100824), three Phase 3 noninferiority studies comparing 
PP1M and risperidone LAI (R092670-PSY-3006,31 -PSY-3008,33 and -PSY-300226,27), and an 
injection site [deltoid-gluteal] cross-over trial
(R092670-PSY-300530). These studies 
demonstrated the efficacy of PP1M (39 to 234 mg) in the treatment of the acute symptoms of 
schizophrenia as well as for the prevention of relapse during maintenance treatment. Long-term 
safety and efficacy of PP1M in schizoaffective disorder was demonstrated in one 15-month 
double-blind, placebo-controlled Phase 3B relapse prevention study (R092670-SCA-3004).35
The efficacy of PP1M compared with OAP treatment in subjects with schizophrenia has been 
assessed in 2 Phase 3B studies: Study R092670SCH3006 and R092670SCH3005. These studies 
are discussed in more detail below:

Study R092670SCH300638 (also known as the PRIDE study): This was a Phase 3B, 
15-month, 
randomized, 
prospective, 
open-label, 
active-controlled, 
parallel-group, 
multicenter study comparing treatment with PP1M versus OAP in prevention of treatment 
failure in subjects with schizophrenia. For eligibility, subjects had to have been placed into 
custody (ie, documented involuntary detainment by an officer of the law) at least twice, with 
at least one of them leading to incarceration within the 24 months before study start, and 
were released from the most recent custody within 90 days before the start of the screening 
period. The study consisted of a screening period (up to 14 days) and a 15-month open-label 
treatment period. 
Results from the primary efficacy analysis demonstrated that treatment with PP1M 
(50-150 mg eq.) was superior to treatment with an OAP in delaying time to first treatment 
failure (p = 0.011), with a hazard ratio of 1.43 (95% CI: 1.09, 1.88). A total of 90 (39.8%) 
subjects in the PP1M group and 117 (53.7%) subjects in the OAP group had a treatment 
failure event. The estimated median time (95% CI) to first treatment failure was 416 days 
(285, not estimable [could not be reliably estimated due to study duration]) for subjects 
treated with PP1M, compared with 226 days (147, 304) for subjects treated with OAP. The 
overall findings from this study demonstrated the efficacy and safety of PP1M in adults with 
schizophrenia who had been incarcerated and supported previous findings regarding the 
long-term efficacy and safety of PP1M in schizophrenia.

Study R092670SCH3005 (PROSIPAL)37: This was a Phase 3B, randomized, open-label, 
rater-blinded study to compare treatment with PP1M versus treatment as usual with 
frequently prescribed OAPs in subjects with recently diagnosed schizophrenia who were 
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experiencing an acute schizophrenic episode. For eligibility, subjects needed to have been 
diagnosed with schizophrenia within the 1 to 5-year period before screening, with a history 
of treatment with antipsychotics, 2 or more relapses requiring psychiatric hospitalization in 
the preceding 24 months, and predicted (by the treating physician) to benefit from a switch 
of antipsychotic medication to either PP1M or one of the pre-specified OAPs. The study 
consisted of an initial acute oral treatment phase (2 weeks) and a core treatment phase (until 
relapse or maximally 24 months).
The primary endpoint was the time to relapse during the 24-month core treatment phase, 
with relapse defined according to the criteria of Csernansky et al.40
Based on the pre-specified relapse criteria, treatment with PP1M significantly delayed the 
time to relapse compared with treatment as usual with OAP during the 24-month core 
treatment period in subjects with recently diagnosed schizophrenia in this study (p=0.0191). 
A total of 52 (14.8%) subjects in the PP1M group and 76 (20.9%) subjects in the OAP group 
had a relapse event during the 24-month core treatment phase (p=0.0323), reflecting a 
29.4% relative risk reduction for PP1M treatment versus OAPs. There was also a 
significantly greater improvement in psychotic symptoms at Day 8 and a trend for better 
symptom control at endpoint in favor of PP1M.
Overall, findings from this study provide support that long-acting treatment with PP1M is 
efficacious and well tolerated and may provide favorable relapse prevention compared to 
treatment as usual with OAP in subjects with recently diagnosed schizophrenia.
Safety: The safety profile of PP1M is well established based on the clinical trial data and the 
postmarketing evidence. Up to the most recent clinical cutoff date of 31 December 2013, a total 
of 6,160 adult subjects with schizophrenia or schizoaffective disorder have been exposed to at 
least one dose of PP1M in completed clinical studies (5,008 in Phase 2/3 studies and 1,152 in 
Phase 1 studies). Based on the 4,535,916 syringes of PP1M distributed worldwide, the estimated 
exposure of PP1M from launch to 31 December 2013 is 467,637 person-years.102
The most common treatment-emergent adverse events reported during the development program 
of PP1M (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site 
reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.68 With respect 
to findings possibly associated with antipsychotic use in schizophrenia or predicted by 
paliperidone pharmacology, unwanted cardiovascular and central nervous system effects were 
not common.102 As with other drugs that antagonize D2 receptors, paliperidone administration is 
associated with increases in prolactin levels, but prolactin-related adverse events were rarely 
reported. Metabolic issues (glucose dysregulation, obesity, and hyperlipidemia) were seldom 
reported, but body weight and body mass index (BMI) increased after administration of PP1M, 
generally in a dose-related manner, and decreased after placebo administration. Injections of
PP1M were generally characterized by good local injection site tolerability; there is no evidence 
for a clinically notable safety risk with regard to potential systemic post-injection side effects.102
Refer to the Investigator’s Brochure for paliperidone102 or the current local health authority 
approved prescribing information for PP1M for more complete information.
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Paliperidone Palmitate 3-Month Injection (PP3M)
Paliperidone palmitate 3-month injection is approved in the US and numerous other countries. 
The efficacy and safety of PP3M in the treatment of schizophrenia is supported by the results of 
a Phase 3 relapse prevention study (R092670-PSY-3012).34 Additional safety data are available 
from a completed, single-dose, Phase 1 safety/PK study (R092670-PSY-1005),23 and from a 
completed Phase 3 noninferiority study comparing PP3M with the PP1M formulation 
(R092670-PSY-3011).22,100
Overall, the number of adult subjects with schizophrenia who have received at least 1 dose of 
PP3M across the 3 completed clinical studies is 1,191. This includes 379 who received exposure 
to PP3M in Study PSY-3012 (at least 1 dose in Maintenance Phase), 308 who received a single 
dose of PP3M in Study PSY-1005, and 504 who received treatment with PP3M during the 
double-blind phase of Study PSY-3011.22
Administration of all formulations of paliperidone (oral paliperidone ER, PP1M, and PP3M) 
results in exposure to the same pharmacologically-active moiety, paliperidone (9-hydroxy-
risperidone). Therefore, the safety of PP3M is further supported by the extensive clinical and 
postmarketing experience with the oral and PP1M formulations. Refer to the Investigator’s 
Brochure102 for the most complete information regarding paliperidone. Results of the pivotal 
Phase 3 study (R092670-PSY-3012) are discussed further below.
Phase 3 Study with PP3M (R092670-PSY-3012)
Study R092670-PSY-3012 was a Phase 3, randomized, multicenter, double-blind, relapse 
prevention study designed to evaluate the efficacy of PP3M compared with placebo in delaying 
the time to first occurrence of relapse in subjects with schizophrenia. This study consisted of 
4 phases: a Screening Phase (up to 3 weeks); a 17-week open-label Transition Phase; a 12-week 
open-label Maintenance Phase; and a randomized, double-blind, fixed-dose, placebo-controlled 
relapse prevention phase (referred to as the Double-blind Phase) of variable duration. Men or 
women between 18 and 70 years of age (inclusive) who met the Diagnostic and Statistical 
Manual of Mental Disorders 4th Edition (DSM-IV-TR) criteria of schizophrenia for at least 
1 year before screening and had a Positive and Negative Syndrome Scale (PANSS) total score of 
<120 at screening and baseline (Day 1) were eligible for enrollment. A total of 506 subjects 
entered the study and received at least 1 dose of study drug during the Transition Phase; 
379 subjects received at least 1 dose during the Maintenance Phase, and 305 received at least 
1 dose during the Double-blind Phase.
During the Transition Phase, subjects were treated with PP1M (78-234 mg) for 17 weeks. 
Subjects completing the Transition Phase, and with a PANSS total score <70 at Week 17, were 
entered into the open-label Maintenance Phase where they received a single dose of PP3M. The 
dose of PP3M administered in the Maintenance Phase was 273, 410, 546, or 819 mg, calculated 
using a 3.5 multiple of the final PP1M dose administered during the Transition Phase (see 
Table 3). Subjects who met pre-defined stability criteria during the 12-week Maintenance Phase 
were eligible to enter the Double-blind Phase. At entry into the Double-blind Phase, subjects 
were randomized in a 1:1 ratio to receive PP3M (n=160) or Placebo (n=145) and monitored for 
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relapse. The dose of PP3M remained fixed throughout the Double-blind Phase, using the same 
dose level administered in the Maintenance Phase (ie, 273, 410, 546, or 819 mg), administered in 
the deltoid or gluteus.
Efficacy: The primary efficacy variable was time to relapse during the Double-blind phase.
These relapse criteria were identical to those used in the PP1M relapse prevention study 
(R092670-PSY-3001).25
A group sequential design was utilized with one interim analysis for efficacy. Based on the 
preplanned interim analysis conducted by the Independent Data Monitoring Committee (IDMC)
after 42 relapse events had occurred, 31 (23.0%) of 135 subjects randomly switched from 
open-label PP3M to double-blind placebo experienced a relapse event compared with 11 (7.4%) 
of 148 subjects randomized to remain on PP3M. Subjects who continued treatment on PP3M 
during the double-blind phase experienced relapse significantly later than those who were 
switched to placebo (p<0.001, based on log rank test). The median time to first relapse, based on 
Kaplan-Meier estimation, was 274 days in the placebo group and was not estimable in the PP3M 
group. Based on these positive findings, Study PSY-3012 was terminated as per the 
recommendations of the IDMC. 
The final analysis of the relapse data confirmed the findings of the interim analysis. There was a 
statistically significant difference between the 2 treatment groups in the time to relapse with a 
longer time to relapse in subjects assigned to PP3M (p<0.001). Three times as many subjects in 
the Placebo group (29.0%) as in the PP3M group (8.8%) experienced a relapse event. The 
median estimated time to relapse was 395 days for subjects in Placebo group and not estimable 
for PP3M group. The 25% quantile of time to relapse was 141 days in the Placebo group and not 
estimable in the PP3M group, based on the Kaplan-Meier estimates. The instantaneous risk 
(Hazard Ratio) for relapse of schizophrenia symptoms was 3.81 (95% CI: 2.08, 6.99) ie, a 
subject switching to placebo was 3.81 times more likely to experience a relapse than a subject 
continuing to receive PP3M in the final analysis. The most common reasons for relapse were 
increase in PANSS total score and psychiatric hospitalization.
Safety: The PP3M formulation was generally safe and well tolerated in the R092670-PSY-301234
study, with a safety profile broadly consistent with that of PP1M. Across the 379 subjects who 
received at least 1 dose of PP3M in Study PSY-3012, the combined exposure to PP3M was 
160.18 patient-years, and 28 subjects received at least 48 weeks of exposure to PP3M.22
During the Open-label Phase (ie, Transition Phase and Maintenance Phase combined; N=506), 
TEAEs were reported in 65.2% of subjects. The most common TEAEs (>5% of the subjects) in 
the Open-label Phase were weight increased (10.1%), insomnia (9.9%), anxiety and injection site 
pain (each 8.7%), and headache (6.5%). When TEAEs were assessed for the Maintenance Phase
only (N=379), 42.7% subjects experienced at least 1 TEAE and the most common TEAEs were 
anxiety (5.8%), insomnia (4.7%), weight increased (4.5%), and headache (2.9%). 
During the Double-blind Phase, 61.9% of subjects in the PP3M group and 57.9% of subjects in 
the Placebo group experienced at least 1 TEAE that was new in onset or worsened in severity 
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after the first dose of double-blind treatment. The TEAEs that were reported more frequently in 
the Placebo group than in the PP3M group (≥3% difference between groups) were insomnia 
(11.7% vs. 6.9%), schizophrenia (10.3% vs. 1.3%), and weight decreased (7.6% vs. 1.3%). The 
TEAEs that occurred more frequently in the PP3M group than in the Placebo group were weight 
increased (8.8% vs. 3.4%), headache (8.8% vs. 4.1%), nasopharyngitis (5.6% vs. 1.4%), and 
akathisia (4.4% vs. 0.7%).
The mean increases in body weight from open-label baseline to double-blind end point were 0.55 
kg and 2.38 kg for Placebo and PP3M groups, respectively. None of the weight abnormalities 
were reported as SAEs or resulted in study drug discontinuation. Twenty-five subjects (18%) in 
the Placebo group and 38 subjects (24%) in the PP3M group experienced an abnormal increase 
in body weight (≥7%) from open-label baseline to double-blind end point.
PP3M injections in both deltoid and gluteal muscles were safe and well tolerated. Six PP3M and 
no placebo subjects reported injection site-related TEAEs during the Double-blind Phase. 
Investigator evaluations of swelling, redness and induration were similar across treatment 
groups, as were subject evaluations of injection pain as measured by a visual analog scale 
(VAS). No apparent dose-related effects were observed. While all injection site adverse events 
with objective findings and a severity assessment of “moderate” or “severe” were to be 
photographed, no such photographs or biopsies were taken by the investigators, indicating the 
well tolerated nature of observed events and supporting the overall benign tolerability profile of 
PP3M injectable formulation.
Overall, safety findings from study PSY-3012 were generally similar to those observed in 
previous studies with PP1M. Specifically, the types and incidences of AEs and ADRs, including 
AEs of special interest for class of atypical antipsychotics and injection site reactions, were 
generally consistent with those previously observed for subjects with schizophrenia treated with 
a once-monthly injection of PP1M. No new safety signals were detected.22,34
1.2.
Comparator Drugs
All subjects will initially be treated with oral paliperidone ER or oral risperidone during the Part 
I oral run-in phase. Subjects who find either oral paliperidone ER or oral risperidone intolerable 
will be withdrawn from the study. Subjects who tolerate oral paliperidone ER or oral risperidone 
but find it inadequately efficacious after treatment for an adequate duration at an adequate 
dosage, per clinical judgment, may be switched to another protocol-specified OAP during Part I
at the discretion of the investigator. To be eligible for randomization in Part II, subjects must be 
able to tolerate a minimum dose of 3 mg of oral paliperidone or 2 mg of oral risperidone for at 
least 2 weeks prior to entry to Part II.  Subjects who enter Part II and are randomly assigned to 
the OAP treatment group will continue their OAP treatment from Part I. Subjects are encouraged 
to continue their original OAP throughout the remainder of the study, but a switch to another 
protocol-specified OAP is permitted if clinically indicated.
The following commercially available OAPs will be permitted: aripiprazole, haloperidol, 
olanzapine, oral paliperidone ER, perphenazine, quetiapine, and risperidone.
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All OAPs have indications for schizophrenia. For the most up-to-date safety and efficacy 
information regarding these comparator drugs, please refer to the relevant local health authority 
approved prescribing information. 
1.3.
Overall Rationale for the Study
Schizophrenia is a chronic disease characterized by an early deterioration in functioning,
recurrent psychotic exacerbations, and persistent deficits in cognition.5,78 Antipsychotic 
medications are the cornerstone of treatment for schizophrenia, and effective management of 
schizophrenia requires long-term treatment to maintain symptom control and prevent relapse.5
Discontinuation and/or intermittent use of currently available OAP drugs, however, is 
widespread, particularly during the early stages of the disorder.13,115 In one study analyzing data 
from 2,588 patients recovering from a first psychotic episode, only 58% collected their 
prescription during the first 30 days of hospital discharge, and only 46% continued their initial 
treatment for 30 days or longer.109 Other studies show more than 30% to 40% of patients with 
first-episode schizophrenia are nonadherent and discontinue medication during the first 9 months 
of treatment,85,86 at which point the chances of relapse increase dramatically.55,103,108 A recent 
review of clinical trials investigating relapse of symptoms following effective treatment of 
first-episode psychosis estimated the risk of relapse within the first year following medication 
discontinuation to be approximately 77% compared to a 1-year risk of relapse of 3% with 
continued antipsychotic therapy.118 With each relapse, recovery is slower and less complete, the 
level of functioning declines, and disabling treatment-resistant symptoms may develop.47,50,116
Antipsychotic treatment lowers the risk of relapse and reduces the psychotic symptoms of 
schizophrenia5; however, currently available OAP medications have not received recognition to 
have significant benefit in terms of improving other aspects of the disorder, such as cognitive 
impairment. Establishing treatments for cognitive impairment is particularly important as it is 
highly correlated with functional ability and long-term outcome60,66; the search for pro-cognitive 
treatments that also improve functional outcomes has therefore become an important, but as yet 
unrealized, goal in the treatment of schizophrenia.  
Recurrent relapses and persisting cognitive deficits are thought to contribute to clinical and 
functional deterioration in patients with recent-onset schizophrenia.50,80 Although the course of
deterioration varies, most of it occurs within the first 5 years following the onset of symptoms, 
and this period is considered to represent a critical period in the pathophysiology of the 
disease.15,80 Imaging data also suggest that there are structural brain changes that occur early in 
the course of the disorder that may be exacerbated by relapses.2,3 Furthermore, longitudinal 
studies show that brain tissue loss continues to progress over time, and is related to declines in 
cognition,, functioning, illness course and treatment outcome.3,65,95 In addition, recent MRI 
studies show that deficits in some brain areas (eg, frontal lobe intracortical myelin [ICM]) can be 
slowed or even improved with use of antipsychotic medications.9,10,11 These findings provide 
evidence that the pathophysiology of schizophrenia is progressive after the onset of illness,45
highlighting the importance of early intervention in schizophrenia to improve adherence, reduce
relapse, and prevent further disease progression. 
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Long-acting injectable antipsychotic formulations may offer particular advantages over OAP 
agents in the treatment of recent-onset schizophrenia. Clinical studies examining effectiveness of 
LAI antipsychotic drugs in the early stages of schizophrenia are limited, but reports in the 
literature suggest that atypical LAI antipsychotics are associated with good adherence and 
clinical outcomes in subjects with first-episode or recent-onset schizophrenia,6,51,109,113,114 and 
may reduce discontinuation, relapse, and rehospitalization rates in these subjects compared with 
OAP agents.52,77,107,109 Recent work by Nuechterlein, Bartzokis and Subotnik also suggest that 
LAI agents may be associated with greater improvements in cognition and functioning compared 
with OAPs in subjects with first-episode schizophrenia, and may be more effective at preserving 
ICM volume in the brain.9,10,94 These results suggest that the use of an LAI antipsychotic early in 
the course of schizophrenia may slow disease progression and possibly modify the trajectory of 
the disorder, potentially leading to improved long-term outcomes.
The current study has been designed to build upon previous work by Nuechterlein, Bartzokis and 
Subotnik.9,10,94 This study will compare the effectiveness of PP versus OAP treatment on 
delaying time to treatment failure in subjects
with recent-onset schizophrenia or 
schizophreniform disorder. Using a novel, multi-phase study design, the study will also evaluate 
whether LAI treatment with PP can slow down disease progression and possibly modify disease 
course compared to OAP medications by tracking changes in cognition, functioning, and brain 
ICM volume.
2.
OBJECTIVES AND HYPOTHESES
The study includes 3 treatment phases: a 2-month, open-label, flexible-dose, oral run-in phase 
(Part I), and 2 sequential 9-month, matched-control, randomized, open-label, active-controlled, 
flexible-dose treatment phases (Part II, referred to as the ‘Disease Progression Phase’ and 
Part III, referred to as the ‘Extended Disease Progression and Disease Modification Phase’) [see 
Figure 1]. Part II and Part III each have their own objectives.
2.1.
Part II Objectives: Disease Progression
Subjects who complete the Part I oral run-in phase will enter Part II and will be randomized in a 
1:2 ratio to either start PP treatment (ie, PP1M followed by PP3M) or to continue OAP treatment
from Part I. It is expected that most subjects will be receiving oral paliperidone ER or oral 
risperidone at the start of Part II, but some subjects may be on an alternative OAP. The Part II 
treatment duration is 9 months.
Primary Objective

To compare the effectiveness of PP versus OAP treatment (ie, oral paliperidone ER, oral 
risperidone, or another OAP) in delaying time to first treatment failure over 9 months’ 
treatment in subjects with recent-onset of schizophrenia or schizophreniform disorder (see 
definition of treatment failure in Section 9.2.2.1, Treatment Failure).
Key Secondary Objectives:

To evaluate changes in cognition as measured by the Measurement and Treatment Research 
to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) 
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composite score following 9 months’ treatment with PP compared to 9 months’ treatment 
with OAP.

To evaluate changes in functioning as measured by the Personal and Social Performance 
scale (PSP) following 9 months’ treatment with PP compared to 9 months’ treatment with 
OAP.

To evaluate changes in brain ICM volume as measured by inversion recovery (IR) and spin 
echo (SE) magnetic resonance imaging (MRI) in the frontal lobe following 9 months' 
treatment with PP compared to 9 months' treatment with OAP.
Secondary Objectives:

To evaluate changes in cognition as measured by the individual domains of the MCCB (ie, 
working memory, verbal learning, speed of processing, attention/vigilance, visual learning, 
reasoning and problem solving, and social cognition) following 9 months’ treatment with PP
compared to 9 months’ treatment with OAP.

To evaluate changes in illness severity as measured by the Clinical Global Impression-
Severity scale (CGI-S) following 9 months’ treatment with PP compared to 9 months’ 
treatment with OAP.

To evaluate changes in severity of psychotic symptoms, as measured by the 8 items of the 
Clinician-Rated Dimensions of Psychosis Symptom Severity scale (CRDPSS) (ie, delusions, 
hallucinations, disorganized speech, abnormal psychomotor behavior, negative symptoms 
[restricted emotional expression or avolition], impaired cognition, depression, and mania).

To evaluate changes in medication satisfaction as measured by the Medication Satisfaction 
Questionnaire (MSQ) [patient-reported outcome] following 9 months’ treatment with PP
compared to 9 months’ treatment with OAP. 

To assess overall safety of PP. 
Exploratory Objectives:

To assess changes in resting state functioning MRI (fMRI), and changes in cortical 
thickness, gray matter volume, white matter volume, ventricular volume, intrasulcal CSF
volume, and subcortical myelin integrity, as measured by MRI, following 9 months’
treatment with PP compared to 9 months’ treatment with OAP.

To explore the overall healthcare resource utilization use as measured by the Resource 
Utilization Questionnaire (RUQ) following 9 months’ treatment with PP compared to 
9 months’ treatment with OAP.

To explore differences in satisfaction with goal setting following 9 months’ treatment with 
PP compared to 9 months’ treatment with OAP.

To explore quantitative assessments of daily activities following 9 months’ treatment with 
PP compared to 9 months’ treatment with OAP.
2.2.
Part III Objectives: Extended Disease Progression and Disease 
Modification
Subjects who complete Part II will be eligible to enter Part III. At the start of Part III, subjects
treated with OAP during Part II will be re-randomized in a 1:1 ratio to either continue treatment 
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with OAP (OAP-OAP group) or to switch to PP (OAP-PP group). Subjects treated with PP
during Part II will continue the same treatment (PP-PP group). The Part III treatment duration is 
9 months.
The Extended Disease Progression objectives will focus on comparisons between the OAP-OAP 
and PP-PP groups; the Disease Modification objectives will focus on comparisons between the 
PP-PP and OAP-PP groups (ie, subjects who started treatment with PP early vs. subjects who 
started PP treatment 9 months later).
Extended Disease Progression Objectives
Primary Objective:

To evaluate changes in cognition as measured by the MCCB composite score following 
18 months’ treatment with PP compared to 18 months’ treatment with OAP in subjects with 
recent-onset schizophrenia or schizophreniform disorder.
Key Secondary Objectives:

To evaluate changes in functioning as measured by the PSP following 18 months’ treatment 
with PP compared to 18 months’ treatment with OAP.

To evaluate changes in brain ICM volume in the frontal lobe following 18 months’ 
treatment with PP compared to 18 months’ treatment with OAP.
Secondary Objectives:

To evaluate changes in cognition as measured by the individual domains of the MCCB 
following 18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To evaluate changes CGI-S following 18 months’ treatment with PP compared to 
18 months’ treatment with OAP.

To evaluate changes in severity of psychotic symptoms, as measured by the 8 items of the 
CRDPSS following 18 months’ treatment with PP compared to 18 months’ treatment with 
OAP.

To evaluate changes in medication satisfaction as measured by the MSQ (patient-reported 
outcome) following 18 months’ treatment with PP compared to 18 months’ treatment with 
OAP.

To evaluate differences in time to first treatment failure and subsequent treatment failures 
over 18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To assess overall safety of PP. 
Exploratory Objectives:

To assess changes in resting state fMRI, and changes in cortical thickness, gray matter 
volume, white matter volume, ventricular volume, intrasulcal CSF volume, and subcortical 
myelin integrity, as measured by MRI following 18 months’ treatment with PP compared to 
18 months’ treatment with OAP.

To explore the overall healthcare resource utilization use as measured by the RUQ following 
18 months’ treatment with PP compared to 18 months’ treatment with OAP.
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
To explore differences in satisfaction with goal setting following 18 months’ treatment with 
PP compared to 18 months’ treatment with OAP.

To explore quantitative assessments of daily activities following 18 months’ treatment with 
PP compared to 18 months’ treatment with OAP.
Disease Modification Objectives:
Primary Objective

Using a delayed-start approach, to compare changes in cognition as measured by the MCCB 
composite score following 9 months’ additional PP treatment in subjects originally 
randomized to PP (PP-PP group) compared to 9 months’ delayed-start PP treatment in 
subjects originally randomized to OAP treatment (OAP-PP group).
Key Secondary Objectives:

Using a delayed-start approach, to compare changes in functioning as measured by the PSP 
following 9 months’ additional PP treatment in subjects originally randomized to PP (PP-PP 
group) compared to 9 months’ delayed-start PP treatment in subjects originally randomized 
to OAP treatment (OAP-PP group).

Using a delayed-start approach, to compare changes in brain ICM volume in the frontal lobe 
following 9 months’ additional PP treatment in subjects originally randomized to PP (PP-PP 
group) compared to 9 months’ delayed-start PP treatment in subjects originally randomized 
to OAP treatment (OAP-PP group).
2.3.
Hypothesis
The overall primary hypothesis to be tested in this study is that 9 months’ treatment with PP is 
superior to 9 months’ treatment with OAP in delaying time to first treatment failure in subjects 
with recent-onset schizophrenia or schizophreniform disorder. The primary efficacy null 
hypothesis is that there is no difference in the distribution of time to first treatment failure in 
Part II between the PP and OAP treatment groups.
See Section 11.1, Hypotheses, for details regarding additional hypotheses to be evaluated in this 
study.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a prospective, matched-control, randomized, open-label, active-controlled, flexible-dose, 
multicenter study to assess time to treatment failure and to measure changes in cognition, 
functioning, and ICM volume in subjects with recent-onset schizophrenia or schizophreniform 
disorder treated with PP versus OAPs. Other efficacy, safety, and exploratory endpoints will also 
be assessed. An overview of the study design is provided in Figure 1.
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Figure 1:
Overview of the Study Design
   
      = PP1M injection 
        = PP3M injection
a
All subjects will be started on oral paliperidone ER or oral risperidone. Subjects who find oral paliperidone ER/oral 
risperidone intolerable will be withdrawn from the study; subjects who tolerate oral paliperidone ER/oral risperidone but find 
it inadequately efficacious may be switched to another protocol-specified OAP at the discretion of the investigator.
b
Subjects randomized to the OAP treatment group will continue their OAP treatment (ie, oral paliperidone ER, or other OAP) 
from Part I. 
Note: For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part II or Part III) may go back 
to treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the 
duration of the trial with the approval of the medical monitor.  
OAP=oral antipsychotic; Pali ER=paliperidone extended-release; Ris= oral risperidone; PP=paliperidone palmitate; 
PP1M=paliperidone palmitate 1-month injection; PP3M=paliperidone palmitate 3-month injection; SCZ=schizophrenia or 
schizophreniform disorder.
Approximately 275 men and women between the age of 18 and 35 years with a Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of schizophrenia or 
schizophreniform disorder who experienced their first psychotic episode within 2 years of study 
entry will be enrolled in this study. Refer to Section 4.1 for further details regarding 
inclusion/exclusion criteria. The total study duration for each subject will be approximately
86 weeks, including a screening phase (up to 4 weeks), a 2-month oral run-in phase (Part I), and 
two 9-month treatment periods (Part II and Part III). The study periods are briefly described 
below:

Screening phase (up to 4 weeks; Day -28 to -1): Subjects who provide written informed 
consent will undergo the screening procedures, including a review of the study entry criteria. 
Any prestudy OAP other than oral risperidone or oral paliperidone ER will be tapered off 
and must be discontinued by Week 5 of Part I. Subjects already treated with oral risperidone
or oral paliperidone ER should be continued at the dose deemed to be most appropriate by 
the investigator).  Tapering of the previous OAP can start at the beginning of the screening 
period. Tapering and discontinuation should be managed by the investigator, as clinically 
appropriate.

Part I: Oral Run-In Phase (2 months): After completing the screening period, subjects 
meeting the inclusion and exclusion criteria will be entered into Part I, a 2-month oral run-in 
phase. All subjects will initially receive flexible dosing with oral paliperidone ER
(1.5-12 mg/day) or with oral risperidone (1-6 mg/day). Treatment with oral paliperidone ER
or oral risperidone will enable investigators to establish tolerability of paliperidone prior to 
randomization to the LAI formulation in Part II. Subjects who find either oral paliperidone 
ER OR oral risperidone intolerable will be withdrawn from the study. Subjects who tolerate 
oral paliperidone ER/oral risperidone but find it inadequately efficacious after treatment for 
an adequate duration at an adequate dosage (per clinical judgment) may be switched to 
another protocol-specified OAP. Any of the following 7 OAPs are permitted: aripiprazole, 
haloperidol, olanzapine, paliperidone ER, perphenazine, quetiapine, and risperidone. The 
    PP
  OAP
(Pali ER or 
Risa )
Subjects 
with
Recent-
Onset
SCZ
Randomize 
     (1:2)
Randomize 
      (1:1)
    PP (Delayed Start)
        PP
     OAP 
      OAPb
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following demographic, baseline characteristic, and clinical data will be determined during 
Part I to be used for matching during randomization into Part II and Part III: age, gender, 
race, prior antipsychotic exposure, substance use history, MCCB composite score, and PSP 
total score (see Section 5, Treatment Allocation and Blinding). To be eligible for 
randomization in Part II, subjects must be receiving a minimum dose of 3 mg of oral 
paliperidone ER or of 2 mg of oral risperidone for at least 2 weeks prior to entry to Part II.

Part II: Disease Progression Phase (9 months): Subjects who complete Part I with 
acceptable run-in dosages will be eligible to enter Part II. On Day 1 of Part II (Day 57 of 
Part I), subjects will be randomized in a 1:2 ratio to open-label treatment with either PP or 
continued OAP treatment for 9 months. Dynamic central randomization will be performed 
based on matching criteria determined in Part I. It is estimated that approximately 225 
subjects will be randomized in Part II; therefore approximately 75 subjects will be 
randomized to the PP treatment group and 150 subjects to the OAP group. 

Subjects randomly assigned to the OAP treatment group will continue their OAP 
treatment from Part I. It is expected that most subjects will be receiving oral 
paliperidone ER or oral risperidone, but some subjects may be receiving an alternative 
OAP. Investigators are encouraged to continue the original OAP (ie, the OAP 
prescribed at Part II baseline) as monotherapy throughout the remainder of the study 
but, if clinically indicated, a switch to an alternative OAP or add-on of an additional 
OAP is permitted after the first randomization visit. Switching or add-on of another 
OAP due to inadequate efficacy, tolerability, or safety will be assessed as a treatment 
failure (see definition of treatment failure, Section 9.2.2.1, Treatment Failures). Subjects 
with treatment failure will continue participation in the study. The same 7 OAPs
indicated for Part I are allowed (ie, aripiprazole, haloperidol, olanzapine, paliperidone 
ER, perphenazine, quetiapine, and risperidone).

Subjects randomly assigned to the PP treatment group will receive a minimum of 5 
doses of PP1M followed by PP3M once every 12 weeks. PP1M initiation dosing (first 
injection 234 mg on Day 1 of Part II and second injection 156 mg on Day 8, both in the 
deltoid muscle) followed by 3 injections of flexible doses (78, 117, 156, or 234 mg) of 
PP1M on Days 36, 64, and 92, either in the deltoid or gluteal muscle. On Day 120, 
subjects will receive an injection of PP3M (using a 3.5-fold multiple of the PP1M dose 
received on Day 92) either in the deltoid or gluteal muscle, if in the investigator’s 
judgment, the subject is receiving an optimal maintenance dose of PP1M. On Day 204, 
subjects will receive injections of flexible doses (273, 410, 546, or 819 mg) of PP3M 
either in the deltoid or gluteal muscle. In some cases, if on Day 120 the investigator 
feels they have not identified the appropriate maintenance dose of PP1M, with approval 
of the medical monitor and sponsor the subject may continue to receive flexible doses 
of PP1M injections on Day 120, 148, and 176, and on Day 204 receive an injection of
PP3M (using a 3.5-fold multiple of the PP1M dose received on Day 176) either in the 
deltoid or gluteal muscle. Investigators are encouraged to use PP1M and PP3M as 
antipsychotic monotherapy and to adjust the injection dose for management of 
symptoms/tolerability. If required, supplemental oral paliperidone ER (up to 6 mg/day)
or oral risperidone (up to 3 mg/day) may be given between injections. It should be noted 
that adding oral paliperidone or oral risperidone will not be considered a treatment 
failure unless supplemental oral paliperidone ER or oral risperidone is given for a 
combined total of more than 84 days or if oral paliperidone ER doses exceed 6 mg/day 
or oral risperidone doses exceed 3 mg/day (see Section 0 for further details on allowed 
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OAP usage in the PP treatment group). Adding any other antipsychotic will also be
considered a treatment failure. Subjects with treatment failures will continue the study 
unless the PP injection is discontinued permanently.

Part III: Extended Disease Progression and Disease Modification (9 months):
Subjects who complete Part II will be entered into Part III. On Day 1 of Part III (Day 
260 of Part II), subjects in the OAP treatment group will be re-randomized in 1:1 ratio 
to continued treatment with their OAP (OAP-OAP group) or to PP (OAP-PP or 
‘Delayed-start PP’ group). The Delayed-start PP group will receive PP1M and PP3M 
treatment as described in Part II (ie, a minimum of 5 doses of PP1M followed by PP3M 
once every 12 weeks). Subjects previously assigned to treatment with PP in Part II will 
continue in that treatment group with PP3M injections every 12 weeks for a total of 3 
injections (PP-PP group). Randomization will be based on matched criteria identified in 
Part I. Subjects will be followed for an additional 9 months.

Subjects will be assessed for treatment failure at all visits during Part II and Part III.
Efficacy assessments (MCCB, PSP, CGI-S, CRDPSS, and MSQ) will be performed as 
specified in the Time and Events Schedule. Safety will be monitored through evaluation 
of AEs, clinical laboratory parameters, vital signs, ECGs, body weight, ESRS, ISST-
Plus, and physical examination findings. Resource use (measured using the RUQ), goal 
setting experience, and quantitative assessment of daily activities will be assessed as 
exploratory endpoints. A pharmacogenomic blood sample will be collected from 
subjects who consent separately to this component of the study (where local regulations 
permit). Subject participation in pharmacogenomic research is optional.

For optimal management of symptoms/tolerability, subjects receiving PP3M (during 
either Part II or Part III) may go back to treatment with PP1M (monthly injections of 
78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the duration 
of the trial with the approval of the medical monitor.
Approximately half of the enrolled subjects will also undergo brain MRI scans for assessment of 
ICM volume and other exploratory MRI endpoint at selected study sites. In addition, 
approximately 20 healthy control subjects (comparable in age, sex, race, and highest parental 
education to the subjects with schizophrenia/schizophreniform disorder undergoing MRI scans) 
will be identified at each MRI center and followed as controls for the MRI machine calibration 
for the duration of the study without treatment.
Note that subjects who experience a treatment failure and do not withdraw consent or meet the 
criteria for withdrawal (see Section 10.2, Withdrawal from the Study) will continue in the study 
and be followed through to the end of the study.
Subjects who miss scheduled injections or visits are allowed to re-enter the same assigned 
treatment group of the study (see Section 9.1.7, Re-Entry Following Missed Injections).
3.2.
Study Design Rationale
3.2.1.
Overall Design Concept
The primary objective of Part II is to compare effectiveness of PP versus OAP on delaying time 
to treatment failure in subjects with recent-onset schizophrenia. Treatment failure was selected as 
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the primary outcome because stopping or changing medication is a frequent occurrence in 
patients with recent-onset schizophrenia, and discontinuation or inconsistent use of antipsychotic 
medication can have a significant impact on symptom control and disease course.50 This measure 
integrates assessments of efficacy, safety, and tolerability and also captures potential outcomes 
of treatment failure (eg, hospitalization, arrest) to provide a global effectiveness measure that 
reflects ‘real-world’ treatment scenarios.
The study will also measure changes in cognition (MCCB), functioning (PSP), brain imaging 
assessments (ICM volume), and overall treatment response in order to examine whether LAI 
treatment with PP can slow disease progression and possibly modify disease course compared to 
OAP medications in subjects with recent-onset schizophrenia or schizophreniform disorder. The 
underlying premise is that changes in these measures represent a way to track disease 
progression (ie, disease worsening) in patients with schizophrenia/schizophreniform disorder.
Changes in frontal lobe ICM will be measured to extend earlier work by Nuechterlein, Bartzokis, 
and Subotnik9,10,94 suggesting that these neuroanatomical changes track with changes in 
cognition and functioning. Other efficacy, safety, and exploratory assessments will also be 
measured; see Section 9 for full details.
Disease modification is defined as a modification of the underlying pathophysiology of the 
disease that results in a beneficial outcome on the overall course of the disorder. In order to 
evaluate disease modification, the sponsor has developed a unique clinical trial design which 
builds upon the randomized delayed-start design proposed by Dr. Paul Leber in 1996.79 In the 
traditional delayed-start design,79 subjects are initially randomized to an active intervention arm 
or to placebo. After an interval of time sufficient to demonstrate a difference in an efficacy 
measure between the two groups, the placebo group switches to the active drug. If subjects who 
begin active drug late ‘catch up’ with those who begin the active drug earlier, the treatment 
response is assumed to be symptomatic; if on the other hand, the delayed treatment arm fails to 
improve to the degree demonstrated by the active treatment arm, then disease ‘modification’ is 
supported. In this design, the underlying interpretive principle is that early treatment with a 
disease modifying drug should continue to provide a benefit compared to later initiation of 
treatment; that is, early (longer) treatment provides a persistent benefit that cannot be achieved if 
treatment is delayed, presumably due to an effect on the underlying pathology that cannot be 
“re-captured”. 
There are several challenges associated with the traditional delayed-start design.41,42 In this 
setting, it is uncertain how long subjects might require treatment before a therapeutic response 
could be demonstrated. In addition, the 2 arms of the trial are starting at different levels of 
disease severity, and it is not clear how this might affect the calculation of therapeutic response.  
Interpretation of results is also hampered by the need for long follow-up periods and the effect of 
dropouts, particularly if this is different in the two periods. Although here has been regulatory 
support for this study design,49,53,81 there have been few applications and, to date, this approach 
has not been successfully used in a clinical trial to establish a disease modifying effect. 
In order to address some of the limitations of traditional delayed-start designs, the sponsor has 
built in some modifications into the current study; these modifications include a hybrid of 
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randomized and epidemiologic design approaches that introduces a run-in period (Part I) and 
implements a second randomization at the start of the delayed-start treatment phase (Part III). 
The run-in period will be used to collect demographic and baseline characteristic data (including 
age, gender, race, prior antipsychotic exposure, MCCB composite score, PSP score, and 
substance use history) which will be used as the basis for a matched-control analysis for 
evaluating disease modification in Part III. This treatment phase will also help to identify 
subjects who have a propensity to discontinue the study, and so will help reduce dropouts during 
the Part II/Part III treatment phases.
Strong efforts will be made to retain subjects in the study by allowing flexibility in treatment and 
‘real-world’ visit structure. Nevertheless, it is inevitable that some subjects will drop out early 
which could result in a discontinuation bias. Management of this potential bias will be addressed 
by re-randomizing subjects at the onset of Part III of this trial using a matched pairing approach 
and analyzing results according to the intent-to-treat (ITT) principle. 
The hypothesized effect of PP versus OAP on Disease Progression and Disease Modification is 
summarized in Figure 2, based on the predicted change from baseline in the MCCB composite 
score over time. 
At the end of Part II, the database will be locked and data analyzed to determine if there is an 
early treatment effect (δ21= treatment effect on disease progression) demonstrating superiority of 
PP relative to oral control. Differences between the 2 treatment groups will be assessed for 
cognition (MCCB), functioning (PSP), and ICM volume. 
At the onset of Part III subjects in the OAP arm will be re-randomized to continued treatment 
with their prior OAP or to PP. Subjects will be followed for an additional 9 months. Three 
effects (outcomes) will be assessed for a given endpoint: δ31, δ32, and δ33.  The quantity δ31
represents the lead treatment effect after an early start with 18 months of PP treatment and shows 
the lead effect remaining in the early start group over the delayed-start effect after a 9-month 
treatment duration. The quantity δ32 represents the delayed-start effect on disease progression for 
PP compared to continuing OAP after 9 months of additional treatment. The quantity δ33
represents the cumulative effect on extended disease progression at the end of Part III following 
early start for PP compared to continuing OAP after a total of 18 months of treatment. 
At the end of Part III, the database will again be locked and data analyzed to assess response in 
variables δ31, δ32, and δ33. Positive results (δ33 is significant [a differential treatment effect is still 
evident] and δ31 is significant [the lead effect remains significant after 9 months]) will be used to 
support a conclusion of disease modification using MCCB composite score. Similar observations 
for changes in PSP and ICM will be assessed. 
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Figure 2:
Hypothesized Disease Progression and Disease Modification Effect 
(Based on Change in MCCB Composite Score Over Time [for Illustration Purposes Only])
ER= extended-release; MCCB= MATRICS Consensus Cognitive Battery; OAP=other antipsychotic; PP=paliperidone palmitate 
δ21:Treatment effect on disease progression; δ31:Lead treatment effect; δ32:Delayed-start treatment effect on disease progression; 
δ33:Overall effect of treatment.
3.2.2.
General Design Elements 
3.2.2.1.
Subject Selection Criteria
Subjects with Schizophrenia or Schizophreniform Disorder
The study will enroll men and women between the age of 18 and 35 years with a DSM-5 
diagnosis of schizophrenia or schizophreniform disorder who experienced their first psychotic 
episode within 24 months prior to the screening visit.
Evidence suggests that schizophrenia is particularly progressive during the first years after initial 
manifestation of symptoms,
and that this period represents a critical period in the 
pathophysiology of the disease.15,80 Recurrent relapses (often due to nonadherence to 
antipsychotic medications) and persisting cognitive deficits are thought to play a role in the 
clinical and functional deterioration in patients with recent-onset schizophrenia.50,80 Although the 
extent
of deterioration can vary across individual patients, the deterioration process 
predominantly occurs in the early phases of the illness—in the prepsychotic prodromal period 
and during the first 5 to10 years after the initial episode.80 Brain imaging studies also show there 
are volumetric changes in the brain that are rapidly progressing during the early stages of the 
disease,3,65,95 which may be exacerbated by relapse.2,110 These results highlight the importance of 
early intervention in patients with recent-onset schizophrenia to prevent further relapses, reduce 
clinical deterioration and to improve long-term outcomes.
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It is hypothesized that the improved adherence and consistent antipsychotic coverage that can be 
achieved with an LAI formulation may offer particular advantages over OAP agents in the 
treatment of recent-onset schizophrenia or schizophreniform disorder. Studies comparing LAI 
agents versus OAP agents in the treatment of recent-onset schizophrenia are limited, but 
available data suggest LAI agents may improve adherence, reduce relapse,77,107 improve 
cognitive and functional outcomes,94 and preserve ICM volume in the brain9,10 more effectively 
than oral agents. This study seeks to extend these findings using the LAI formulation of 
paliperidone.
Subjects within a limited age range (18 to 35 years) will be enrolled; this age range is inclusive 
of the age of onset for the large majority of patients who are able to give informed consent to 
participate in such a study. Expanding the age group beyond 35 may result in inclusion of 
persons who have had an undiagnosed but active disease which is already considerably 
progressed and may be less impacted by this treatment approach.
Inclusion of a Healthy Control Group
A separate cohort of healthy subjects who are comparable in age, sex, and race to the subjects 
with schizophrenia/schizophreniform disorder undergoing MRI scans will be identified at each 
MRI center and followed as controls for the MRI machine calibration for the duration of the 
study without treatment. These individuals will receive MRI scans but will not undergo any other 
study assessments. The purpose of inclusion of a healthy control group that undergoes MRI 
scans over a similar time period is to standardize the change in ICM for the patient group relative 
to normal controls, and to detect and correct magnetic drift of the MRI machine during the study.
3.2.2.2.
Selection of Efficacy and Safety Evaluations
Efficacy Evaluations
Treatment Failure
Discontinuation and frequent switching of antipsychotic medication are common in the treatment 
of patients with recent-onset schizophrenia. The main reasons for discontinuing or changing
antipsychotic medications can include lack of efficacy, tolerability issues, poor adherence, 
patient lack of insight, or patient preference.64 Ideally the clinician is involved in patient 
decisions regarding medication changes, but this is not always the case. In these situations, the 
first indication that a subject has discontinued treatment may be when symptom recurrence leads 
to hospitalization, arrest, or even suicide. Multiple relapses are associated with clinical and 
functional deterioration, and relapse may also have a negative impact on the neuroanatomy of the 
brain in patients with schizophrenia.2,5,50 Therefore, maintaining patients on consistent 
antipsychotic therapy is an important aim, particularly during the early stages of the disorder.
The primary endpoint of Part II is time to treatment failure. Treatment failure is a robust and 
well-characterized endpoint including a composite of various measures (see definition in 
Section 9.2.2.1, Treatment Failure). This endpoint integrates measures of efficacy, safety, and 
tolerability to provide a global measure of effectiveness which reflects real-world treatment 
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scenarios. Its clear definition allows investigators to apply it consistently under most 
circumstances, making it well suited to pragmatic study designs.
Cognition (MCCB) 
Neurocognitive impairment is a core and enduring component of schizophrenia. Measures of 
certain crucial functions, such as attention, memory, executive functions, and motor speed, in 
patients have been reported to reach 2 standard deviations below the mean for healthy 
comparison subjects.63,73 Neurocognitive impairment is usually already present at the first 
episode of psychosis, and patients with a first episode of psychosis may be as severely impaired 
in many cognitive domains as patients with chronic schizophrenia.14,67,83,92,105
Neurocognitive impairment is associated with key features of schizophrenia, such as outcome 
and adaptive dysfunction, including the inability to acquire skills, poor social problem solving, 
and poor community functioning.58,60,62,66 Indeed, there is increasing evidence that cognitive 
impairment may be a stronger correlate of poor outcome than other symptom domains.60,66 The 
severity of cognitive impairment also predicts poorer treatment adherence and increased relapse 
risk in first-episode patients.19,20,101 Due to the clinical relevance of neurocognitive impairment in 
schizophrenia and in particular its relationship to poor functional outcomes, development of new 
approaches to enhance cognition in schizophrenia remains one of the most pressing challenges in 
psychopharmacology. 
Overall, first-generation (typical) antipsychotics have had little benefit in treating the cognitive 
disturbances of patients with schizophrenia. Oral atypical antipsychotics (clozapine, risperidone, 
olanzapine, and quetiapine) have been reported to result in some improvement in cognitive 
performance.74,75,117
However, data from the National Institute of Mental Health 
(NIMH)-sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the 
European First Episode Schizophrenia Trial (EUFEST) trials have failed to confirm the 
superiority of atypical agents vs. typical agents on cognitive function,43,71 and patients treated 
with atypical antipsychotics continue to show marked deficits in cognition. Furthermore, some 
studies suggest that the improvements in neurocognition observed with atypical antipsychotics 
may be no greater than placebo or practice effects.56
In response to the lack of effective cognitive treatments, the NIMH sponsored the MATRICS 
initiative in order to bring together academic, industrial, and governmental bodies to address this 
unmet therapeutic need.59,73 This initiative facilitated the development of guidelines for the 
design of clinical trials of drugs for neurocognitive impairment in schizophrenia,16,17 and 
created the MCCB72,76,93 for measuring cognitive treatment outcomes in schizophrenia. The 
MCCB has been endorsed by the FDA as the gold standard for use in trials of pharmacological 
agents targeting cognition in schizophrenia,17 and will be the primary cognitive endpoint in this 
study.
Functioning (Personal and Social Performance Scale)
Improving patient functioning and preventing further deterioration of functioning is an important 
goal in the treatment of schizophrenia.16 Several instruments have been proposed over the years 
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to measure functioning in schizophrenia. Of these, the PSP captures information about several 
functional domains as well as providing an overall score, and has been shown to be useful across 
cultures. It has been proposed as being well suited for measurement of functioning in 
schizophrenia,18,88,97 and will be used in this study. The validity and reliability of the PSP in 
patients with schizophrenia have been previously reported.69,88,89,98
Other Efficacy Assessments
Schizophrenia symptoms will be assessed throughout the study using the CGI-S61 and the 
DSM-5 CRDPSS.4 The CGI-S provides a global assessment of disease severity and is a 
well-accepted tool that has been widely used in clinical trials and is easy to administer in general 
practice. The CRDPSS is one of the ‘emerging measures’ developed by the American Psychiatric 
Association (APA) to monitor treatment progress in patients with schizophrenia.4 This measure 
assesses the severity of mental health symptoms that are important across psychotic disorders, 
including delusions, hallucinations, disorganized speech, abnormal psychomotor behavior, 
negative symptoms (restricted emotional expression or avolition), impaired cognition, 
depression, and mania. The severity of these symptoms can predict important aspects of the 
illness, such as the degree of cognitive and/or neurobiological deficits. 
The MSQ, a patient-reported outcome, will be used to assess subjects’ general medication 
satisfaction. Previous research in patients with schizophrenia has demonstrated that positive 
symptom improvement is associated with increased medication satisfaction measured by 
MSQ.54,112
Brain Imaging Assessments
Structural and functional brain abnormalities have been extensively and consistently described in 
patients with schizophrenia. High-resolution MRI studies evaluating brain volume measurements 
in patients with schizophrenia at the time of illness onset have indicated that patients have 
smaller mean volumes in many regions, particularly the frontal lobes, when compared with 
healthy volunteers. Furthermore, longitudinal studies have shown that the mean differences in 
brain volumes continue to progress over time, and are related to illness course and treatment 
outcome.3,65,95
These findings suggest that although schizophrenia may arise from a 
neurodevelopmental diathesis, its pathophysiology may be progressive after the onset of 
illness.45
Results of a recent longitudinal MRI study in patients with first-episode schizophrenia suggest 
that progressive brain changes are most pronounced during the early years after onset of 
schizophrenia,3 and that the magnitude of these changes may be related to relapse duration.2
Results of this study showed significant decreases in both white matter and gray matter regions 
and an increase in CSF over time in patients with schizophrenia compared with healthy controls.3
One possible explanation for a decline in white matter after the clinical onset of schizophrenia is 
that normal processes are diminished, eg, normal white matter expansion8 is reduced, because of 
an impairment in myelination and factors that affect it.12
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The importance of myelin pathology in schizophrenia is widely recognized.7,12,44,48 Imaging and 
post-mortem studies provide converging evidence that patients with schizophrenia have a 
dysregulated frontal lobe myelination.12 A dysregulation in this myelination process is 
hypothesized to result in an insufficient capacity to maintain temporal synchrony of the brain’s 
widely distributed functional neural networks and thus manifest in the heterogeneity of 
symptoms and cognitive impairments that characterize disorders such as schizophrenia.7,12,48
A method has recently been developed using IR MRI images that measures myelinated white 
matter and ICM volumes.11 Initial studies using this method indicate that atypical antipsychotics 
may increase ICM volume in patients with schizophrenia, and that this effect is most pronounced 
with LAI antipsychotic formulations.9,10,11 In a recent randomized study, patients with first-
episode schizophrenia treated with the LAI formulation of risperidone for 6 months showed a 
significant increase in ICM volume when compared with healthy control subjects, whereas 
patients receiving oral risperidone for 6 months showed no change in ICM volume versus 
healthy subjects. Increased myelin volume was also found to be significantly associated with 
improved cognitive function, with faster reaction times observed on 2 higher-order executive 
tasks involving working memory and mental flexibility.9 Results of this prospective study 
suggest that, early in the course of illness, antipsychotic medications may act, at least in part, by 
increasing ICM in patients with schizophrenia. In addition, the data suggest that medication 
delivery mode (LAI vs. oral) may have a significant differential effect on ICM volume.9,10
Therefore, ICM volume is selected as a pathophysiology biomarker for evaluating disease 
progression and disease modification in this study.
Exploratory Assessments
The RUQ will be administered to capture information related to socio-demographics (eg, 
education level, employment status), daily living (eg, accommodation status, financial 
management), hospitalizations, emergency room visits, partial hospitalizations, outpatient and 
additional services.
Subjects will set up to 3 personal goals and up to 3 health goals at the start of each treatment 
phase. The patient goals are not binding but progress towards attaining these goals will be 
followed throughout the study. Learning to set and work towards personal goals is an important 
aspect of recovery in those with serious mental illness. Self-determination and self-direction are 
the foundations for recovery as individuals define their own life goals and design their unique 
path(s) towards those goals. Individuals optimize their autonomy and independence to the 
greatest extent possible by leading, controlling, and exercising choice over the services and 
supports that assist their recovery and resilience. In doing so, they are empowered and provided 
the resources to make informed decisions, initiate recovery, build on their strengths, and gain or 
regain control over their lives.104
The Quantitative Assessment of Daily Activities is a patient-reported outcome which will be 
used to document the time a subject spends in a broad array of common daily 
activities. Categories include sleep and rest, self-care, work, recreation and social activities.
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DNA Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect DNA to allow 
the identification of genetic factors that may influence the pharmacodynamics, efficacy, safety, 
or tolerability of paliperidone palmitate compared with oral antipsychotics, and to identify 
genetic factors associated with schizophrenia or schizophreniform disorder.
Safety Evaluations
Safety evaluations for this study will include the monitoring of adverse events, clinical 
laboratory tests, ECGs, vital sign measurements (temperature, pulse, and blood pressure), 
weight, and the monitoring of extrapyramidal symptoms using the Extrapyramidal Symptom 
Rating Scale-Abbreviated (ESRS-A). The risk of suicide is elevated in patients with 
schizophrenia compared with the general population,96 particularly in recent-onset patients.99
Suicidality will be assessed by the InterSePT Scale for Suicidal Thinking (ISST-Plus).
3.2.2.3.
Treatment and Dose Selection Rationale
Oral Antipsychotic Treatment Group
This study is designed to compare the effectiveness of PP to OAP treatment in subjects with 
recent-onset schizophrenia. Oral antipsychotics were selected as the active comparator because 
this is the standard therapy for the large majority of recent-onset patients (nearly 100%) yet it is 
associated with very high long-term non-adherence.39,70,84 According to the literature, at least
30% to 40% of patients will discontinue treatment within the first 9 months, 85,86 with 
these proportions increasing to 50% within 1 year and 75% within 2 years of beginning 
treatment.57,115
In this study, all subjects will initially receive treatment with oral paliperidone ER or oral 
risperidone during the Part I oral run-in phase. Subjects who find oral paliperidone ER or oral 
risperidone inadequately efficacious after treatment for an adequate duration at an adequate 
dosage per clinical judgment, may be switched to another protocol-specified OAP during Part I
at the discretion of the investigator. Subjects who find either oral paliperidone ER or oral 
risperidone intolerable will be withdrawn from the study prior to randomization. It is expected 
that most subjects will be on oral paliperidone ER or oral risperidone treatment at the end of Part 
I. To be eligible for randomization in Part II, subjects must be able to tolerate a minimum dose of 
3 mg of oral paliperidone or 2 mg of oral risperidone for a minimum of 2 weeks prior to entry to 
Part II.  
At Day 1 of Part II, subjects will be randomized in a 1:2 ratio to either start PP or to continue 
their OAP treatment from Part I. Before randomization, subjects must be evaluated by the 
investigator to assess their suitability to enter Part II. If for any reason the investigator considers 
it clinically inappropriate for a given subject to be randomized to PP, the subject should be 
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withdrawn from the study prior to randomization. After the initial randomization visit, subjects
in the OAP group will have the flexibility to switch to another OAP or add another OAP if 
clinically indicated. This flexibility has been incorporated to address the unique risk:benefit 
profile of each individual patient, to improve subject retention, and to mimic real-world practice 
as much as possible. While such medication changes are permitted in the OAP group, 
investigators are encouraged to continue the original OAP (ie, the OAP prescribed at Part II 
baseline) as monotherapy throughout the study, and to only make switches or use add-on OAP
treatment if clinically required. Any switch to an alternative OAP or add-on of another OAP due 
to inadequate efficacy, tolerability, or safety will be considered a treatment failure (see
Section 9.2.2.1, Treatment Failure).
Subjects who complete Part II will be eligible to enter Part III. The second randomization will be 
performed on Day 1 of Part III for the subjects who are randomized to OAP treatment during 
Part II. These subjects will be randomized in a 1:1 ratio to either start PP or to continue their 
OAP treatment from Part II. Before randomization, subjects must be evaluated by the 
investigator to assess their suitability to enter Part III. If for any reason the investigator considers 
it clinically inappropriate for a given subject to be randomized to PP, the subject should be 
withdrawn from the study prior to randomization. Similarly, as in Part II, subjects in the OAP 
group will have the flexibility to switch to another OAP or add another OAP if clinically 
indicated during Part III. Any switch to an alternative OAP or add-on of another OAP due to 
inadequate efficacy, tolerability, or safety will be considered a treatment failure.
Seven OAP agents will be permitted in the OAP treatment group: aripiprazole, haloperidol, 
olanzapine, paliperidone ER, perphenazine, quetiapine, and risperidone. These agents were 
selected as they have all demonstrated efficacy in the treatment of schizophrenia, and represent 
the most commonly used antipsychotics in US. All OAPs should be administered in accordance 
with the label.
Paliperidone Palmitate (PP1M/PP3M)
Subjects randomized to the PP treatment group will be initiated on PP1M and then transitioned 
to PP3M. Subjects previously stabilized on a range of doses of oral paliperidone ER or oral 
risperidone can attain similar paliperidone steady-state exposure during maintenance treatment 
with PP1Mmonthly dosing (following standard initiation dosing; see Section 6.2.1). Table 1 and 
Table 2 provide suggestions for maintenance doses of PP1M based on the selected treatment 
dose of oral paliperidone ER or oral risperidone, respectively.
Table 1:
Doses of Oral Paliperidone ER and PP1M Needed to Attain Similar Steady-State Paliperidone 
Exposure During Maintenance Treatment
Formulation
Oral Paliperidone ER
PP1M
Dosing Frequency
Once Daily
Once Every 4 Weeks (deltoid or gluteal)
Dose
3 mg 
78 mg 
6 mg
117 mg
9 mg
156 mg
12 mg
234 mg
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Table 2:
Doses of Oral Risperidone and PP1M Needed to Attain Similar Steady-State Paliperidone 
Exposure During Maintenance Treatment
Formulation
Oral Risperidone a
PP1M Monthly Maintenance Injection
Dosing Frequency
Daily
Once Every 4 Weeks (deltoid or gluteal)
Dose
2 mg
78 mg
3 mg
117 mg
4 mg
156 mg
6 mg
234 mg
a   Conversion factor: 1 mg oral RIS = 39 mg PP1M. Note: The conversion does not take into account the potential 
effects of CYP2D6 inhibitors (i.e. paroxetine, sertraline or fluoxetine) or inducers (i.e. carbamazepine) on active 
moiety concentrations.
The indication for PP3M is for the treatment of schizophrenia in adults who have been 
adequately treated with PP1M for at least 4 months. As PP3M has a very long elimination 
half-life and requires extended time to reach steady state plasma concentrations, subjects need to 
be stabilized on PP1M before transitioning to the longer-acting injectable PP3M. A 4-month 
treatment period with PP1M allows for four complete 4-week intervals between administrations 
of PP1M after the initial 1-week PP1M initiation regimen. Four months is considered sufficiently 
long for subjects with schizophrenia to successfully switch to a new treatment. A flexible-dose 
regimen with PP1M will allow clinicians to establish an efficacious and tolerable dose for each 
subject, and to allow transition to PP3M to occur within a limited period of time. PP1M will be 
administered in line with the label, with the exception that 39 mg will not be included in this 
study.68
The selection of the PP3M dose is based on a fixed ratio (1:3.5) relative to the dose of PP1M that 
affords an acceptable benefit:risk during initiation of treatment. The PP3M doses evaluated in 
this study will be 273, 410, 546, or 819 mg, which correspond to a 3.5-fold multiple of marketed 
PP1M doses of 78, 117, 156, or 234 mg, respectively (see Table 3). This is consistent with the 
PP3M/PP1M dose range that was evaluated in the pivotal Phase 3 PP3M relapse prevention 
study (R092670-PSY-3012). PP1M is also available commercially at a lower, 39 mg dose level. 
This dose level represents less than 1% of the PP1M syringes distributed in the US and 
worldwide as of 31 December 2013, and for this reason, the sponsor has no plans to develop a 
PP3M dose corresponding to the 39-mg dose of PP1M. Therefore, the lower 39 mg dose of 
PP1M will not be evaluated in this study. 
For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part 
II or Part III) may go back to treatment with PP1M (monthly injections of 78, 117, 156 or 234 
mg, flexibly dosed) for further dose adjustment or for the duration of the trial with the approval 
of the medical monitor.
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Supplementation with OAP medications is not required with PP1M or PP3M. However, due to 
the long-acting nature of these formulations, it can take time for dosage adjustments to take 
effect. Therefore, oral supplementation with paliperidone ER or oral risperidone will be allowed 
in the PP treatment group if required (eg, during periods of acute symptom exacerbation, or to 
provide additional antipsychotic coverage in subjects requiring a dose increase), and such use 
will not be considered a treatment failure unless the use of oral paliperidone ER or oral 
risperidone exceeds the dose levels or treatment durations specified in Section 0. Supplemental 
use of any other OAP in the PP treatment group will be considered a treatment failure.
Unlike the OAP treatment group, subjects receiving PP will not have the option to change 
medications. If it is deemed clinically necessary to stop PP1M/PP3M in a subject assigned to PP
treatment, the subject will be withdrawn from the study and discontinuation of PP will be 
recorded as a treatment failure.
3.2.3.
Phase-Specific Design Considerations
Screening
A screening phase of up to 4 weeks was chosen to allow adequate time for completion of all 
screening procedures with results available to the investigator before enrolling a subject into the 
study. 
Part I, Oral Run-In Phase 
All subjects will initially be treated with oral paliperidone ER or oral risperidone during the Part 
I oral run-in phase. Use of oral paliperidone ER or oral risperidone will allow the investigator to 
evaluate the efficacy and tolerability of paliperidone or oral risperidone prior to randomization to 
the LAI formulation of paliperidone. 
Those subjects who find oral paliperidone ER or oral risperidone inadequately efficacious after 
treatment for an adequate duration at an adequate dosage per clinical judgment will have the 
option to switch to another protocol-specified OAP at the discretion of the investigator. 
However, subjects who find either oral paliperidone ER or oral risperidone intolerable will be 
withdrawn from the study.
The objective of this phase is to transition subjects to treatment with oral paliperidone ER or oral 
risperidone and to collect demographic and baseline characteristic data (including age, gender, 
race, prior antipsychotic exposure, substance use history, PSP, and MCCB composite score) for 
matching during randomization of subjects into Parts II and III of this study. This phase will also 
help identify those subjects who have a higher propensity to discontinue the study and therefore 
potentially help to reduce dropouts during Part II/Part III.
All subjects who complete Part I and have tolerated a minimum of 3 mg oral paliperidone ER or 
2 mg oral risperidone for a minimum of 2 weeks will be eligible to enter Part II.
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Part II and Part III, Randomized, Active-Controlled Treatment Phases 
Treatment during Part II and Part III will be open-label and the treating clinician will have the 
flexibility to adjust PP1M/PP3M and OAP doses according to patient’s individual needs. Rater 
blinding will be used to minimize bias in the evaluation of brain imaging endpoints, but other 
assessments will be performed in an open-label fashion, consistent with real-world clinical 
practice.
The Part II treatment duration is 9 months. There are limited data available in the literature 
comparing oral and LAI antipsychotic agents in recent-onset schizophrenia, but based on prior 
work by Nuechterlein, Bartzokis and Subotnik,9,10,94,107 9 months is estimated to be a sufficient 
period to detect a difference between an oral versus LAI formulation on time to treatment failure, 
ICM, and cognitive and functional endpoints.94
Efforts consistent with ethical good clinical practice will be made to retain subjects in this study. 
Subjects in the oral arm will be allowed multiple switches to alternative oral medications. 
However, in order to answer the primary questions associated with this study, if it is deemed 
clinically necessary to stop PP1M/PP3M in a subject assigned to PP treatment, the subject will 
be withdrawn from the study. 
4.
SUBJECT POPULATION
Approximately 275 subjects with a recent-onset DSM-5 diagnosis of schizophrenia or 
schizophreniform disorder will be enrolled in this study. The inclusion and exclusion criteria for 
enrolling these subjects are described in Section 4.1. Screening for eligible subjects will be 
performed within 28 days before administration of the study drug.
In addition, approximately 20 healthy volunteers will be enrolled at each MRI center; the 
inclusion and exclusion criteria for enrolling the healthy control subjects are described in 
Section 4.2. Screening for healthy controls will occur when each MRI center has enrolled the 
first patient.
If there is a question about the inclusion or exclusion criteria below, the investigator should 
consult with the medical monitor before enrolling a subject in the study. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Selection Criteria for Subjects with Schizophrenia or Schizophreniform 
Disorder
4.1.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be a man or woman 18 to 35 years of age, inclusive.
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2.
Subject must have a current diagnosis of schizophrenia (295.90) or schizophreniform 
disorder (295.40) as defined by DSM-5 and confirmed by the Structured Clinical 
Interview for DSM-5 Disorders (SCID) with a first psychotic episode within the last 
24 months prior to the screening visit.
3.
Subject requires treatment with an antipsychotic medication or a change in antipsychotic 
medication due to lack of efficacy, tolerability, safety issues, or investigator/subject 
preference.
4.
Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and are willing to 
participate in the study.
5.
Subject must have available a designated individual (eg, family member, significant 
other, friend) who has knowledge of the subject and is generally aware of the subject's 
daily activities, and who agrees to let the study site personnel know of changes in the 
subject's circumstances when the subject is not able to provide this information. The 
designated individual must sign an ICF.
6.
Subject is anticipated to have a stable place of residence for the duration of the trial.
7.
Subject must be physically healthy and medically stable on the basis of physical 
examination, medical history, vital signs, clinical laboratory tests, and ECG performed 
at screening.
8.
A woman who is heterosexually active must:

Be surgically sterile (eg, tubal occlusion, hysterectomy, bilateral salpingectomy); or 
otherwise be incapable of pregnancy, or

Agree to abstinence or practice a highly effective method of birth control, including 
hormonal prescription oral contraceptives, contraceptive injections, contraceptive 
patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or 
cervical cap, with spermicidal foam, cream, or gel), or male partner sterilization, 
consistent with local regulations regarding use of birth control methods for subjects 
participating in clinical studies.

Agree to continue using these methods of contraception throughout the study and 
for at least 6 months after receiving the last dose of PP1M/PP3M.

Have a negative urine pregnancy test at screening.
Note: If the childbearing potential changes after start of the study (eg, woman who is 
not heterosexually active becomes active) a woman must begin a highly effective 
method of birth control, as described above.  
9.
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm 
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or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men 
must also not donate sperm during the study and for 6 months after receiving the last 
dose of PP1M/PP3M.
10.
Each subject must sign a separate ICF if he or she agrees to provide an optional DNA 
sample for research (where local regulations permit).  Refusal to give consent for the 
optional DNA research sample does not exclude a subject from participation in the 
study.
4.1.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Subject has a positive urine drug screen test for cocaine, amphetamines, opiates, or 
phencyclidine (PCP) at screening, unless they have a valid prescription. (Note: subjects
excluded on this basis may return and enroll if they can achieve a clean urine screen
within 7 days).
2.
Subject has a current DSM-5 diagnosis of dissociative disorder, bipolar disorder, major 
depressive disorder, schizoaffective disorder, autistic disorder, or intellectual 
disabilities.
3.
Subject meets the DSM-5 definition of moderate or severe substance use disorder 
(except for nicotine) within 2 months prior to screening.
4.
Subject has evidence of clinically significant, unstable cardiovascular, renal, hepatic, 
gastrointestinal, neurological, immunological, endocrine, metabolic or pulmonary 
disease that may indicate increased risk associated with taking study medication or 
would interfere with study participation or make safety/efficacy results difficult to 
interpret.
5.
Subject has a history of neuroleptic malignant syndrome.
6.
Subject has known allergies, hypersensitivity, or intolerance to paliperidone or
risperidone or to the excipients of the oral paliperidone ER/oral risperidone or 
PP1M/PP3M formulations (refer to the Investigator’s Brochure).
7.
Subject has a prior history of lack of response to oral or LAI risperidone or 
paliperidone. Lack of response is defined by failure to respond to 2 adequate trials of a 
minimum of 4 weeks at the subject’s maximum tolerated dose.
8.
Subject is at imminent risk of suicide according to the investigator’s clinical judgment.
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9.
Subject has mental retardation, defined as pre-morbid IQ as measured by Wechsler Test 
of Adult Reading at screening <70. [An alternative test will be defined by the sponsor if 
the study is conducted in countries other than the US].
10.
Subject has received LAI medication within 2 injection cycles prior to the screening 
visit. 
11.
Subject has received an investigational drug or used an investigational medical device 
within 1 month of the screening visit, or is currently enrolled in an investigational study.
12.
Subject is a woman who is pregnant or breast-feeding, or planning to become pregnant
while enrolled in this study or within 6 months after the last dose of PP1M/PP3M.
13.
Subject has evidence of a known neurological disorder (eg, epilepsy) or significant head 
injury.
14.
Subject has any condition for which, in the opinion of the investigator, participation will 
not be in the best interest of the subject (eg, compromise the well-being) or that can 
prevent, limit, or confound the protocol-specified assessments.
15.
Subject previously enrolled in this study.
16.
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as 
well as family members of the sponsor, the investigator or the clinical staff and the 
investigating site.
4.2.
Selection Criteria for Healthy Controls
Approximately 20 healthy subjects at each MRI center will be included as controls for the MRI 
machine calibration. These subjects will undergo MRI assessments, but will not otherwise be 
involved with the study and will not receive study medication. These subjects will be comparable 
in age, gender, race, and highest parental education to the schizophrenia/schizophreniform 
disorder subjects undergoing MRI assessments.
Inclusion Criteria
Each potential healthy control subject must satisfy all of the following criteria to be enrolled in 
the study. 
1.
Subject must be a man or woman 18 to 35 years of age, inclusive.
2.
Subject must sign an informed consent document indicating that they understand the 
purpose of and procedures required for the study and are willing to participate in the 
study.
Exclusion Criteria
Any potential healthy control subject who meets any of the following criteria will be excluded 
from participating in the study:
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1.
Subject has evidence of a known psychiatric disorder, neurological disorder (eg, 
epilepsy) or significant head injury.
2.
Subject has a first-degree relative who has schizophrenia, schizophreniform, 
schizoaffective, or bipolar disorder.
3.
Subject meets the DSM-5 definition of moderate or severe substance use disorder 
(except for nicotine) within 2 months prior to screening.
4.
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as 
well as family members of the employees or the investigator.
5.
Subject is unable to undergo MRI scan for any reason, including because of body size 
(unable or difficult to fit in MRI instrument) or MRI contraindicated due to presence of 
metallic objects (pacemaker, etc.). Note: if the initial MRI is clinically abnormal and 
shows presence of a severe brain abnormality that would preclude analyses (eg, large 
hemangioma) the subject will be withdrawn from the study (see Section 10.2, 
Withdrawal From the Study).
6.
Subject is a woman who is pregnant or plans to become pregnant during the course of 
the study.
4.3.
Prohibitions and Restrictions 
Note that the following prohibitions and restrictions only apply to subjects with schizophrenia or 
schizophreniform disorder, not to healthy controls.
4.3.1.
Prohibited Medications

Only those OAPs listed in Section 6.2.2, Oral Antipsychotic Treatment, are permitted in the 
OAP treatment group.

Administration of PP1M/PP3M or an alternative LAI antipsychotic is prohibited in subjects 
assigned to OAP treatment. If an LAI agent is deemed clinically necessary for subjects 
assigned to the OAP group, their data will be censored as a treatment failure and they will be 
discontinued from the study. 
4.3.2.
Restrictions Related to Study Eligibility
Subjects must be willing and able to adhere to the following prohibitions and restrictions during 
the course of the study to be eligible for participation:

Female subjects of childbearing potential who are heterosexually active must remain on a 
highly effective method of birth control (see Inclusion criterion 8).

Male subjects who are sexually active with a female partner of childbearing potential must 
use a double-barrier method of birth control (see Inclusion criterion 9). Male subjects must 
agree to not donate sperm during the study and for an additional 6 months after receiving the 
last dose of study drug.
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5.
TREATMENT ALLOCATION AND BLINDING
Procedures for Randomization and Stratification
There will be 2 randomizations in this study, once at the start of Part II and once at the start of 
Part III. Randomization will be used to minimize bias in the assignment of subjects to treatment 
groups, to increase the likelihood that known and unknown subject attributes (eg, demographic 
and baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups.
Matching will be performed using dynamic central randomization. In Part II, subjects will be 
assigned to receive either PP or OAP in a 1:2 ratio based on an algorithm implemented in the 
interactive voice response system (IVRS) or interactive web response system (IWRS) before the 
study. It is estimated that approximately 225 subjects will be randomized in Part II; therefore 
approximately 75 subjects will be randomized to the PP treatment group and 150 subjects to the 
OAP treatment group. Dynamic central randomization minimizes the imbalance in the 
distribution of the number of subjects across treatment groups within the levels of each 
individual stratification factor: age, race, gender, duration of previous antipsychotic usage prior 
to screening, baseline MCCB composite score, baseline PSP score, substance use history, MRI 
participation, and site. Based on the algorithm, the IVRS/IWRS will assign a unique treatment 
code, which will dictate the treatment assignment. The requestor must use his or her own user 
identification and personal identification number when contacting the IVRS/IWRS, and will then 
give the relevant subject details to uniquely identify the subject. To eliminate the predictability 
of randomization for the next subject, treatment assignment probabilities will also be utilized. 
Subjects who complete Part II will be entered into Part III. On Day 1 of Part III (Day 260 of 
Part II), subjects in the OAP treatment arm will be re-randomized in a 1:1 ratio to continued 
treatment with their oral treatment or to PP (Delayed-start PP arm). The Delayed-start PP arm 
will receive PP1M and PP3M treatment as described in Part II. Subjects previously assigned to 
treatment with PP in Part II will continue with PP treatment in Part III). Randomization will be 
based on matched criteria identified in Part I. Similar to the Part II randomization, dynamic 
central randomization will be implemented for Part III. Stratification factors will include age, 
race, gender, duration of previous antipsychotic usage prior to screening, baseline PSP score at 
Part I, baseline MCCB score at Part I, substance abuse history, and site. 
Subjects who re-enter the study after missing scheduled injections or visits must stay in the same 
assigned treatment group.
Blinding
No blinding of investigators or subjects will be used in this study.
Centralized blinded evaluations will be utilized for the assessment of imaging endpoints (eg, 
ICM volume) to reduce potential bias during data collection and evaluation. For the imaging 
endpoints, the assessment of the MRI images will be performed by a rater who is blinded to 
drug-treatment information and to clinical and demographic characteristics of the subjects. 
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MCCB assessments will be performed by raters at each study site and there is no blinding for the 
local MCCB raters. All MCCB data collected at each study site will be sent to central raters for 
review. Assessments will each be scored by central raters who are blinded to treatment 
information. Central raters will also review the neurocognitive data quality and correct any 
errors. The central raters will enter the final scores into the MCCB Scoring program to derive 
T-scores and composites scores and enter the raw and derived MCCB scores to the eDC.
6.
DOSAGE AND ADMINISTRATION
6.1.
Part I: Oral Run-In
During the Part I oral run-in phase (Day 1-56), all subjects will initially be treated with oral 
paliperidone ER or oral risperidone. Any prestudy OAP will be tapered off and must be 
discontinued by Week 5 of Part I.
The recommended dose of oral paliperidone ER is 6 mg administered once daily, although some 
subjects may benefit from higher or lower doses within a dose range of 1.5 to 12 mg/day. Initial 
dose titration is not required. Although it has not been systematically established that doses 
above 6 mg have additional benefit, there was a general trend for greater effects with higher 
doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some 
subjects may benefit from higher doses, up to 12 mg/day, and for some subjects, a lower dose of 
3 mg/day may be sufficient. 
Adjustment of the dosage will be done at the investigator’s discretion, based on the individual 
subject’s clinical response to and tolerability of the study drug. Dose increases above 6 mg/day 
should be made only after clinical reassessment and generally should occur at intervals of more 
than 5 days. When dose increases are indicated, increments of 3 mg/day are recommended. The 
maximum dose allowed in this study is 12 mg/day. Oral paliperidone ER can be taken with or 
without food.
Subjects should be instructed to swallow oral paliperidone ER whole with the aid of liquids 
(each tablet swallowed individually). They must also be instructed not to chew, divide, or crush 
oral paliperidone ER tablets. The active substance is contained within a non-absorbable shell 
designed to release the active substance at a controlled rate. The tablet shell, along with insoluble 
core components, is eliminated from the body. Subjects should not be concerned if they 
occasionally notice in their stool something that looks like a tablet.
The recommended maintenance dose of oral risperidone is 4 mg, although some although some 
subjects may benefit from higher or lower doses within a dose range of 1 to 6 mg/day. Initial 
dose titration is suggested, with a starting dose of 2 mg (or 1 mg based on clinical judgment) and 
titration increments of 1-2 mg. Although it has not been systematically established that doses 
above 6 mg have additional benefit, there was a general trend for greater effects with higher 
doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some 
subjects may benefit from higher doses, up to 6 mg/day, and for some subjects, a lower dose of 2 
mg/day may be sufficient.
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Subjects who find either oral paliperidone ER or oral risperidone intolerable will be withdrawn 
from the study (see Section 10.2, Withdrawal from the Study). Subjects who find oral 
paliperidone ER or oral risperidone inadequately efficacious after treatment for an adequate 
duration with an adequate dosage per clinical judgment may be switched to another protocol-
specified OAP during Part I at the discretion of the investigator. Any of the following 7 OAPs 
will be permitted: aripiprazole, haloperidol, olanzapine, paliperidone ER, perphenazine, 
quetiapine, and risperidone.
Oral antipsychotics used during Part I will not be directly provided by the sponsor. The 
investigator will determine the appropriate dose for each subject and provide the subject with a 
voucher and prescription for the OAP that the subject can take to a local pharmacy to collect his 
or her medication. For countries where voucher is not applicable, the OAP will be dispensed by 
the study site or by a local pharmacy directly to the subject.
Subjects should generally be treated within the approved label for all antipsychotics. Any 
exceptions should first be discussed with the medical monitor. 
Subjects should use antipsychotic monotherapy during Part I. 
6.2.
Part II: Disease Progression
Subjects completing Part I with specified dosing requirements will be eligible to enter Part II. At 
entry into Part II, subjects will be randomized in a 1:2 ratio to either PP or OAP.
6.2.1.
Paliperidone Palmitate Treatment Group
Subjects who are randomly assigned to the PP treatment group will discontinue OAP treatment 
and will be started on PP1M. A transition period of a maximum of 5 weeks will be allowed for 
the previous OAP. Subjects will be subsequently switched to PP3M following a minimum of 
5 injections of PP1M.
PP1M and PP3M are intended for IM use only and should be injected slowly, deep into the 
deltoid or gluteal muscle (please refer to the Instructions for Use). Care should be taken to avoid 
inadvertent injection into a blood vessel. Each injection should be administered by a health care 
professional. Administration should be in a single injection. Do not administer the dose in 
divided injections. Do not administer intravascularly or subcutaneously. 
Injection site guidelines are provided in Attachment 1. Prior to administration, it is critical to 
shake the PP1M and PP3M containing syringes vigorously for at least 10 and 15 seconds, 
respectively. Gluteal injections should be made into the upper outer quadrant of the gluteal area 
and alternated between the left and right gluteal muscles. Deltoid injections should also be 
alternated between the left and right deltoid muscles. Refer to Attachment 1 for details on 
selection of needle sizes for PP1M/PP3M.
PP1M will be administered IM once-monthly, after the first 2 injections that are given one week 
apart (Day 1 and Day 8). The first 2 doses will be administered through a deltoid injection on 
alternating arms. The subsequent injections can be given either in the deltoid or the gluteal 
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muscle. The first dose of PP1M will be 234 mg given in the deltoid muscle at Day 1 of the 
treatment phase. The second dose of PP1M will be 156 mg given in the deltoid muscle at Day 8 
(±4 days). Subsequent doses of PP1M will be given every 28 (±7) days on Days 36, 64, and 92 in 
either the deltoid or gluteal muscle. The investigator may select from 78, 117, 156, or 234 mg, 
according to the subjects’ clinical needs. Subjects will continue to return to the study site every 
4 weeks for injections and for study evaluations.
The location site and side of each injection should be noted in the case repor form (CRF) for 
reference at the subsequent visit.
At the Day 120 visit (±7 days), subjects will start PP3M treatment if in the investigator’s 
judgment, the subject is receiving an optimal maintenance dose of PP1M. If on Day 120 the 
investigator feels they have not identified the appropriate maintenance dose of PP1M, with 
approval of the medical monitor and sponsor the subject may continue to receive flexible doses 
of PP1M injections on Day 120, 148, and 176, and start PP3M treatment on Day 204.  The initial 
PP3M dose will be calculated as 3.5-fold multiple of the final PP1M dose administered on Day 
92 (or Day 176) (see Table 3 for conversion between PP1M and PP3M doses). Subjects will 
receive PP3M injections once every 12 weeks with a ±14 day window as described in Time and 
Events Schedule. Investigators will be permitted to flexibly adjust the dose of PP3M as clinically 
necessary with the dose options for PP3M being 273, 410, 546, or 819 mg. Injections of PP3M 
may be administered in either the deltoid muscle or the upper outer portion of the gluteal muscle. 
The side of each injection (left or right) should be alternated and recorded in the CRF.
Table 3:
Conversion Between PP1M Dose and PP3M Doses Using a 1:3.5 Fixed Ratio
                                PP1M Dose                              
                Corresponding_PP3M Dose                    
(mg paliperidone palmitate)
(mg eq. paliperidone) (mg paliperidone palmitate) (mg eq. paliperidone)
78 mg
50 mg eq.
273 mg
175 mg eq.
117 mg
75 mg eq.
410 mg
263 mg eq.
156 mg
100 mg eq.
546 mg
350 mg eq.
234 mg
150 mg eq.
819 mg
525 mg eq.
mg eq.=milligram equivalents of paliperidone.
PP1M = paliperidone palmitate 1-month injection; PP3M = paliperidone palmitate 3-month injection.
An overview of the PP dosing schedule is summarized in Table 4. If subject misses a dose or 
receives a dose outside of these dosing windows, please contact the sponsor’s medical monitor.
Further details regarding handling of missed doses are provided in Section 6.2.1.2.
A switch to an alternative antipsychotic is not permitted in the PP treatment group. If it is 
deemed clinically necessary to stop PP1M/PP3M in a given subject, the subject’s data will be 
censored as a treatment failure and the subject will be withdrawn from the study. 
Table 4:
Paliperidone Palmitate Dosing Administration Schedule
Day 1
Day 8
(±4 days)
Day 36
(±7 days)
Day 64
(±7 days)
Day 92
(±7 days)
Day 120
(±7 days)
Every 12 wks
(±14 days)
(starting Day 204)
Agent
PP1M
PP1M
PP1M
PP1M
PP1M
PP3M
PP3M
Dose (mg)
234
156
78-234
78-234
78-234
273-819
273-819
Muscle 
D
D
D or G
D or G
D or G
D or G
D or G
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Flexible or Fixed
Fixed
Fixed
Flexible
Flexible
Flexible
Fixeda
Flexible
D=deltoid muscle; G=gluteal muscle; PP1M=paliperidone palmitate 1 month formulation; PP3M=paliperidone 
palmitate 3-month formulation.
a The dose of PP3M given will be a 3.5-fold multiple of the PP1M dose given on Day 92 (see Table 3).
For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part 
II or Part III) may go back to treatment with PP1M (monthly injections of 78, 117, 156 or 234 
mg, flexibly dosed) for further dose adjustment or for the duration of the trial with the approval 
of the medical monitor.   
6.2.1.1.
Supplemental Oral Antipsychotic Medication During Paliperidone 
Palmitate Treatment
Investigators are strongly encouraged to use PP1M/PP3M as antipsychotic monotherapy and to 
adjust the injection dose for management of symptoms/tolerability. Subjects in the PP treatment 
group who are tolerating the medication but experience symptom exacerbation during the study 
will be allowed to have supplemental antipsychotic medication, ie, oral paliperidone ER (up 
to 6 mg/day or oral risperidone (up to 3 mg/day) may be given between injections for no longer 
than a total of 84 days during the total PP treatment period. If the supplemental treatment with 
oral paliperidone ER or oral risperidone is longer than 84 days or if oral paliperidone ER doses 
exceed 6 mg/day or oral risperidone doses exceed 3 mg/day, the subject will be considered a 
treatment failure. Adding any other OAP will also be considered a treatment failure (see 
Section 9.2.2.1, Treatment Failure).
6.2.1.2.
Missed Doses of Paliperidone Palmitate
Please contact the sponsor immediately when subject misses an injection within the visit 
windows described in the Time and Events schedule. Below is the general guideline regarding
management of missed doses.
Management of a Missed Second Initiation Dose of PP1M (Day 8 of Part II)  
If the target date for the second PP1M injection (Day 8 ± 4 days in Part II) is missed, the
recommended re-initiation depends on the length of time that has elapsed since the subject’s first 
injection. In case of a missed second initiation dose, follow the dosing instructions provided in 
Table 5.
Table 5:
Management of a Missed Second Initiation Dose of PP1M 
Timing of Missed Second 
Initiation Dose
Dosing
Less than 4 weeks since first 
injection
Administer the second initiation dose of 156 mg in the deltoid muscle as 
soon as possible.
1. It is recommended to administer a third injection of 117 mg 5 weeks after 
the first injection (regardless of the timing of the second injection).
2. Thereafter, resume regular monthly dosing in either the deltoid or gluteal 
muscle.
4 to 7 weeks since first injection
Resume dosing with two injections of 156 mg in the following manner:
1. Administer a deltoid injection as soon as possible.
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2. Administer a second deltoid injection 1 week later.
3. Thereafter, resume regular monthly dosing in either the deltoid or gluteal 
muscle.
More than 7 weeks since 
first injection
Restart dosing with recommended initiation:
1. Administer a 234 mg deltoid injection.
2. Administer a 156 mg deltoid injection 1 week later.
3. Thereafter, resume regular monthly dosing in either the deltoid or gluteal 
muscle.
Management of a Missed PP1M Maintenance Dose (Days 36, 64, or 92 of Part II)
In case of a missed maintenance dose of PP1M, follow the dosing instructions provided in 
Table 6.
Table 6:
Management of a Missed Maintenance Dose of PP1M
Timing of Missed 
Maintenance Dose
Dosing
4 to 6 weeks since last injection
Resume regular monthly dosing as soon as possible and followed by 
injections at monthly intervals.
More than 6 weeks to 6 months 
since last injection
Resume the same dose the subject was previously stabilized on (unless the 
subject was stabilized on a dose of 234 mg, then the first 2 injections should 
each be 156 mg) in the following manner:
1. Administer a deltoid injection as soon as possible.
2. Administer a second deltoid injection 1 week later at the same dose.
3. Thereafter, resume administering the previously stabilized dose in the 
deltoid or gluteal muscle 1 month after the second injection.
More than 6 months since 
last injection
Restart dosing with recommended initiation:
1. Administer a 234 mg deltoid injection.
2. Administer a 156 mg deltoid injection 1 week later.
3. Thereafter, resume administering the previously stabilized dose in the 
deltoid or gluteal muscle 1 month after the second injection.
Management of a Missed PP3M Dose
Missed Dose > 3½ Months up to 4 Months
If more than 3½ months (up to 4 months) have elapsed since the last injection of PP3M, the 
previously administered PP3M dose should be administered as soon as possible, then continue 
with the 3-month injections following this dose.
Missed Dose > 4 Months up to 9 Months
If more than 4 months (up to 9 months) have elapsed since the last injection of PP3M, do NOT 
administer the next dose of PP3M. Instead, use the re-initiation regimen shown in Table 7.
Table 7:
Re-Initiation Regimen after Missing >4 Months up to 9 Months of PP3M
Last PP3M Dose
Administer PP1M,
two doses one week apart
(into deltoid muscle)
Then administer
PP3M Dose
(into deltoida or
gluteal muscle)
Day 1    
Day 8  
1 month after Day 8
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273 mg       
78 mg  
78 mg  
273 mg
410 mg
117 mg  
117 mg  
410 mg
546 mg
156 mg  
156 mg  
546 mg
819 mg
156 mg  
156 mg  
819 mg
a See Attachment 1 for deltoid injection needle selection based on body weight.
6.2.2.
Oral Antipsychotic Treatment Group
Subjects randomly assigned to the OAP treatment group will continue their OAP treatment from 
Part I. It is expected that most subjects will be on oral paliperidone ER or oral risperidone at 
entry into Part II, but some subjects may have been switched to an alternative OAP during the 
oral run-in phase (Part I).
Investigators are encouraged to continue the same OAP (ie, the OAP prescribed Part II baseline) 
as monotherapy for the remainder of the study, and to adjust the OAP dose for management of 
symptoms/tolerability at any time. However, after the initial randomization visit, subjects may be 
switched to an alternative protocol-specified OAP if clinically indicated. The same 7 agents 
specified for Part I are permitted: aripiprazole, haloperidol, olanzapine, paliperidone ER, 
perphenazine, quetiapine, and risperidone. Multiple switches to alternative OAPs are permitted. 
Add-on of other OAPs is also allowed. However, switching to another OAP or add-on of another 
OAP due to inadequate efficacy, safety, or tolerability will be assessed as treatment failures (see 
Section 9.2.2.1, Treatment Failure). Any change in antipsychotic medication (switching, 
discontinuation, or add-on) must be evaluated against the treatment failure criteria.
Oral antipsychotics will not be directly provided by the sponsor. The investigator will select the 
OAP treatment and the dose appropriate for the subject and provide a prescription and voucher 
for the assigned medication which the subject can present at a local pharmacy. For countries 
where voucher is not applicable, the OAP will be dispensed by the study site or by a local 
pharmacy directly to the subject.
Subjects should generally be treated within the approved label for all antipsychotics. Any 
exceptions should first be discussed with the medical monitor.
A switch to PP1M/PP3M or an alternative long-acting injectable (LAI) antipsychotic is not 
permitted. If a LAI agent is deemed clinically necessary for subjects assigned to the OAP group, 
their data will be censored as a treatment failure and they will be discontinued from the study. 
Supplemental OAPs should not be used as a sleeping aid or for sedation.
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated in the local health authority approved package insert.
6.3.
Part III: Extended Disease Progression and Disease Modification
All subjects completing Part II will be eligible to enter Part III. At entry into Part III, subjects in 
the OAP treatment group will be re-randomized in a 1:1 ratio to either continue OAP treatment 
or switch to PP. Subjects assigned to PP in Part II will continue the same treatment.
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There will therefore be 3 treatment groups in Part III, which will be referred to as follows:

OAP-OAP: This group will receive OAP in Part II and will be randomized to continue OAP 
treatment in Part III. OAP dosing in Part III will be the same as that specified for Part II (see 
Section 6.2.2, Oral Antipsychotic Treatment).

PP-PP: This group will receive PP treatment in Part II and will continue PP treatment in 
Part III. The first dose of PP during Part III will be administered at Visit 19 (Day 36 of Part 
III; or Day 296 of Part II) in order to synchronize visit date for all 3 treatment arms. This 
visit occurs 92 days [instead of 84 days, ie, 12 weeks] after the previous PP injection). 
However, it is still within the ±14-day window. 

OAP-PP (or ‘Delayed-Start PP’): This group will receive OAP in Part II and will be 
randomized to PP in Part III. At entry into Part III, subjects will receive PP according to the 
same schedule as that described for Part II (see Section 6.2.1, Paliperidone Palmitate 
Treatment, and Table 4). The first dose of PP1M will be given on Day 1 of Part III. A 
transition period of a maximum of 5 weeks will be allowed for the previous OAP. 
7.
TREATMENT COMPLIANCE
Paliperidone Palmitate
During Part II and Part III of the study, injections of PP1M and PP3M will be administered by 
qualified staff at the study site and the details of each administration will be recorded in the CRF. 
The investigator or designated study personnel will maintain a log of all PP1M/PP3M received 
and injected. 
Oral Antipsychotics
Oral antipsychotics will not be directly provided by the sponsor. The investigator will determine 
the appropriate dose for each subject and provide the subject with a voucher and prescription for 
the OAP that the subject can take to a local pharmacy to collect his or her medication. For 
countries where voucher is not applicable, the OAP will be dispensed by the study site or by a 
local pharmacy directly to the subject.
This study seeks to replicate treatment reflective of regular clinical practice and there will be no 
pill counting to monitor treatment compliance in subjects in the OAP group.
8.
PRESTUDY AND CONCOMITANT THERAPY
All co-existent diseases or conditions will be treated in accordance with prevailing medical 
practice. 
Prestudy therapies taken by or administered to the subject up to 1 month (6 months for 
psychotropic medications other than antipsychotics, and life time for antipsychotics) before the 
first dose of study drug must be recorded at screening. 
Any prestudy OAP (except oral paliperidone ER or oral risperidone) will be tapered off and must 
be discontinued by Week 5 of Part I. Tapering of the previous OAP can start at the beginning of 
the screening period. Tapering and discontinuation of the previous OAP should be managed by 
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the investigator as clinically appropriate. All other medications (prescription or over-the-counter) 
that have been established as the treatment regimen for a particular subject may be continued 
during the course of the study. Subjects receiving psychotherapy prior to the study may continue 
existing therapy for the duration of the study at the same frequency as established prestudy.
Medications for treatment of minor concurrent illnesses that arise during the treatment phases 
may be allowed at the discretion of the investigator. Treatment with non-antipsychotic 
psychotropic medications, including mood stabilizers, antidepressants, anxiolytics, hypnotics, 
etc, is allowed if clinically indicated. Topical anesthetic preparations (ie, lidocaine 2% cream) 
are allowable for the treatment of injection site pain.
Supplemental OAPs should not be used as a sleeping aid or for sedation.
If breakthrough psychotic symptoms occur during Part II or Part III, supplemental OAP
treatment may be administered if considered clinically necessary based on the judgment of the 
investigator. However, antipsychotic monotherapy is encouraged throughout the study. If 
supplemental or added OAP treatment is initiated, the investigator must assess the subject for 
treatment failure (see Section 9.2.2.1, Treatment Failure). See Section 6, Dosage and 
Administration, for additional information on allowed antipsychotic use.
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study drug to the last study-related visit. Concomitant therapies should also be recorded 
beyond the last study-related visit only in conjunction with serious adverse events that meet the 
criteria outlined in Section 12.3.2. Serious Adverse Events.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies (see Section 4.3.1) are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of the efficacy, imaging,
pharmacogenomics, safety, and other exploratory measurements applicable to this study.
Additional urine pregnancy tests may be performed, as determined necessary by the investigator 
or required by local regulation, to establish the absence of pregnancy at any time during the 
subject's participation in the study.
Healthcare resource utilization data will be collected using RUQ. Refer to Section 9.4 for details.
The total blood volume to be collected from each subject will be approximately 50 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
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9.1.2.
Screening
The screening visit (Visit 1) will occur within 28 days prior to the first dose of study medication
in Part I. During the screening visit, written informed consent will be obtained and subject 
eligibility will be assessed based on the inclusion and exclusion criteria. The screening 
procedures, safety, efficacy, and other assessments detailed in the Time and Events Schedule will 
be completed. The informed consent must be completed before initiating any study procedures.
The subject’s designated individual must also sign an ICF.
A urine drug screen will be performed as part of the screening procedures. If a patient tests 
positive on the initial test, the subject may return and be enrolled in the study if they can achieve 
a clean urine screen within 7 days. 
Subjects may be inpatients or outpatients at the time of screening. Hospitalization during 
screening is allowed if the clinical condition of the prospective subject, in the opinion of the 
investigator, warrants hospitalization. If a subject is hospitalized, the investigator must discuss 
the need for continued hospitalization after 7 days and thereafter on a weekly basis with the 
medical monitor. 
A Screening Phase of up to 28 days is allowed for completion of all assessments. Tapering of the 
previous OAP other than oral risperidone or oral paliperidone ER can start at the beginning of 
the screening period. Tapering and discontinuation of the previous OAP should be managed by 
the investigator as clinically appropriate. Subjects may enter directly into Part I once all 
screening procedures are complete and the inclusion/exclusion criteria have been met.
9.1.3.
Part I: Oral Run-In
At the beginning of Part I (Visit 2, Day 1), safety, efficacy, and other study assessments will be 
performed as outlined in the Time and Events Schedule. 
The treating clinician will determine the appropriate dose of oral paliperidone ER or oral 
risperidone within the ranges specified and will provide the subject with a prescription (or send 
an electronic prescription to a local pharmacy) and a voucher that the subject can present at a 
local pharmacy to collect his/her medication. For countries where the voucher system is not 
applicable, the OAP will be dispensed by the study site or by a local pharmacy directly to the 
subject.
All prestudy OAP other than oral risperidone or oral paliperidone ER must be tapered off and 
must be discontinued by Week 5 of Part I. Tapering and discontinuation of the previous OAP 
should be managed by the investigator as clinically appropriate.
Subjects who find oral paliperidone ER or oral risperidone inadequately efficacious after 
treatment with an adequate duration and an adequate dosage per clinical judgment, may be 
switched to another protocol-specified OAP at the discretion of the investigator. Subjects who 
find either oral paliperidone ER or oral risperidone intolerable will be withdrawn from the study.
Note that medication changes made during the oral run-in phase will not be recorded as a 
treatment failure.
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Subjects will return to the site on Days 8, 15, 29, 43, and 57. The visit on Day 57 (Visit 7) will 
represent the final visit of Part I, and the first visit of Part II; details of this visit are described in 
Section 9.1.4 below.
9.1.4.
Part II: Disease Progression
At Visit 7 (Part I Day 57 or Part II Day 1), safety, efficacy and other assessments will be 
performed as described in the Time and Events Schedule. Results of the urine drug screen will be 
recorded; however, any subject that tests positive will remain eligible to continue in the study. 
Subjects will be randomized in a 1:2 ratio to either start PP treatment or to continue their OAP 
treatment from Part I. Before randomization of a subject, the investigator must decide whether it 
is suitable to initiate PP treatment in that subject, in the event that he/she is randomized to the PP
treatment group. If the investigator believes that starting PP1M treatment is not clinically 
appropriate in a given subject, the subject will be discontinued from the study prior to 
randomization. 
Subjects randomly assigned to the PP treatment group will then receive their first dose of 
paliperidone palmitate (PP1M), as described in Section 6.2.1. Subjects randomized to the OAP 
treatment group will receive a new prescription and voucher for their OAP.
Subjects will return to the study site at the time points indicated in the Time and Events 
Schedule. Subjects may also be brought in for unscheduled visits as necessary (Section 9.1.6, 
Unscheduled Visits). Contact should also be made with the subject’s designated individual at the 
time points indicated in the Time and Events Schedule to check on the subject’s well-being, such 
as subject’s general health, common daily activities and progress in personal or health goals. 
Contact with the designated individual can be made by telephone or in person.
The first post-randomization visit will occur 1 week after randomization (Visit 8; Day 8± 4 
days). Visits thereafter will occur at 4-weekly intervals. A visit window of ± 7 days will be 
allowed. However, after Visit 15 (Part II Day 204), a visit window of ±14 days will be allowed 
for subjects who are on PP or OAP treatment.
At each visit, efficacy, safety, and other assessments will be performed as detailed in the Time 
and Events schedule. Note that all study procedures (except MRI imaging) should be completed 
before OAPs are prescribed or PP1M/PP3M is injected. Use of concomitant medications (eg, 
mood stabilizers, antidepressants, anxiolytics, and hypnotic medication regimens) will be 
individualized as needed.
Subjects will be assessed for the occurrence of treatment failure at all post-randomization visits
(see Section 9.2.2.1, Treatment Failures, for definitions and exceptions). In addition, if a 
treatment failure event occurs or is suspected in between protocol-specified visits, an 
unscheduled visit must be performed. When a treatment failure occurs, the investigator will 
record the date of the treatment failure and the reason for the treatment failure in the CRF. 
Efficacy assessments (MCCB, PSP, CGI-S, CRDPSS, and MSQ) and MRI imaging (in the 
subgroup of subjects undergoing MRI assessment) must also be performed at the time of the 
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initial treatment failure event, or as soon as possible thereafter, even if these assessments are not 
scheduled to occur at the visit/unscheduled visit. At the time of any subsequent treatment 
failures (or as soon as possible thereafter), PSP, CGI-S, CRDPSS, and MSQ assessments should 
be performed. Subjects who experience a treatment failure should continue in the study, unless 
they meet criteria for withdrawal (see Section 10.2, Withdrawal From the Study).
Subjects still participating in the study at Visit 17 (Day 260) will be entered into Part III. 
Visit 17 will represent the final visit of Part II, and the first visit of Part III. Details of this visit 
are described in Section 9.1.5 below.  
Completion or discontinuation of Part II will be recorded in CRF.
9.1.5.
Part III: Extended Disease Progression and Disease Modification
At Visit 17 (Part II Day 260 or Part III Day 1), safety, efficacy and other assessments will be 
performed as described in the Time and Events Schedule. Results of the urine drug screen will be 
recorded; however, subjects who test positive on the drug screen will remain eligible to continue 
in the study.  Subjects in the OAP treatment group will be re-randomized in a 1:1 ratio to either 
continue OAP treatment or to switch to PP treatment. Before randomization, the investigator 
must decide whether it is suitable to initiate PP treatment in that subject, in the event that he/she 
is randomized to the PP treatment group. If the investigator believes that starting PP treatment is 
not clinically appropriate in a given subject in the OAP treatment group, the subject will be 
discontinued from the study prior to randomization.
The visit windows and the schedule and order of assessments will be the same as that described 
for Part II above. Refer to the Time and Events schedule for Part III for additional details.
The end-of study visit will be Visit 27 (Part III Day 260) [see Section 9.1.8].  
9.1.6.
Unscheduled Visits
Unscheduled visits, and contact by phone as needed, will be permitted throughout the study in 
order to assess continued response to study medication and to monitor subjects for safety and 
tolerability, as determined by the clinical judgment of the investigator.
An unscheduled visit must also take place if a treatment failure occurs or is suspected in between 
protocol-specified visits. At the time of first treatment failure, or as soon as possible thereafter, 
all efficacy assessments (MCCB, PSP, CGI-S, CRDPSS, and MSQ) and MRI imaging (in the 
subgroup of subjects undergoing MRI assessment) must be performed. At the time of any
subsequent treatment failures, or as soon as possible thereafter, PSP, CGI-S, CRDPSS, and 
MSQ assessments should be performed. Refer to the Time and Events schedule for the 
unscheduled visits.
Other procedures may also be performed at an unscheduled visit as deemed necessary according 
to the investigator.
Unscheduled visits will be documented on the appropriate page of the CRF.
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9.1.7.
Re-Entry Following Missed Injections or Visits
Subjects are allowed to continue the study if they have missed scheduled injections or visits as 
long as they come back within the same part of the study (ie, Part I, Part II or Part III) based on 
their original visit schedule, and they stay in the same assigned treatment group. In all cases of 
re-entry, the site should contact the medical monitor to determine the best way to re-enter the 
subject and re-initiate treatment. When a subject misses a visit, every possible effort should be 
made by the study site personnel (including contacting the subject or the subject’s designated 
individual) to determine if a treatment failure endpoint had occurred and, if applicable, the 
reason for absence from the study. Refer to Section 6.2.1.2 on how to manage missed doses of 
PP1M/PP3M.  
9.1.8.
End-of-Study or Early Termination Visit
Subjects who complete the study or withdraw from the study during any period other than the 
screening period will have end-of-study (EOS) procedures performed at the time of completion 
or withdrawal from the study. The EOS procedures are detailed in the Time and Events Schedule
(Visit 27/EOS). 
9.2.
Efficacy 
The efficacy assessments for this study include evaluation of treatment failure, cognition 
(MCCB), functioning (PSP), disease severity (CGI-S), schizophrenia symptoms (CRDPSS), and 
a patient-reported outcome of medication satisfaction (MSQ). 
9.2.1.
Efficacy Raters
Only qualified raters who are trained professionals may administer the SCID, MCCB, CGI-S, 
CRDPSS, and PSP. The rater administering each scale will be identified in the source 
documentation.
All raters should have clinical and/or research experience with the patient population in this 
study and participate in study-specific training. Certification is required for MCCB. A qualified 
rater must meet one of the following disciplines: 

Psychiatry (eg, MD or DO)

Senior Psychiatry Resident (eg, MD or DO) who fulfills the other requirements

Psychology (eg, PhD)

Clinical specialty (eg, B.A./B.S., MS or PhD) where patient care is a central component (eg, 
social work, counseling, psychology, and nurse practitioner), physician assistant, or 
registered nurse.
Exceptions to the above definition of a qualified rater will be made by the sponsor on a
case-by-case basis based on a rater’s previous experience.
Whenever possible, all efforts should be made to use the same raters at each site to assess the 
same subjects throughout the study. If this is not possible, review of the appropriate prior
examinations and communication with prior raters should be conducted as needed.
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9.2.2.
Efficacy Evaluations
9.2.2.1.
Treatment Failure
Subjects will be evaluated at the time points indicated in the Time and Events Schedule for the 
occurrence of any of the events below that are identified as treatment failures. Only treatment 
failure events occurring after randomization in Part II (up to the end of Part III) will be assessed. 
The investigator will determine whether the event meets one of the protocol definitions, and will 
provide documentation of dates and times associated with the event.  Treatment failure will be 
defined as any of the following:

Psychiatric hospitalization due to worsening symptoms (including Emergency Room visits 
≥23 hours, and not including hospitalization due to social reasons); 

Any deliberate self-injury, suicidal ideation or behavior, homicidal ideation or violent 
behavior that is clinically significant and needs immediate intervention as determined by the 
study physician; 

New arrest or incarceration (not related to probation or existing warrant); 

Discontinuation of antipsychotic treatment due to inadequate efficacy as determined by the 
study physician; 

Discontinuation of antipsychotic treatment due to safety or tolerability as determined by the 
study physician; 

Treatment supplementation with another antipsychotic due to inadequate efficacy as 
determined by the study physician (note: use of oral paliperidone ER or oral risperidone in 
the PP treatment group will not be considered a treatment failure unless supplemental use of 
oral paliperidone ER or oral risperidone exceeds the dose levels or treatment durations 
specified in Section 0);

Increase in the level of psychiatric services (such as from office visit to day hospitalization)
in order to prevent imminent psychiatric hospitalization as determined by the study 
physician.
Any changes in antipsychotic medications (switching, discontinuation, or add-on) must be 
evaluated against the treatment failure criteria. If any of these changes do not meet the treatment 
failure criteria, these must be documented and recorded in the eDC. 
At the time of first treatment failure, or as soon as possible thereafter, all efficacy assessments 
(MCCB, PSP, CGI-S, CRDPSS, and MSQ) and MRI imaging (in the subgroup of subjects 
undergoing MRI assessment) must be performed. At the time of any subsequent treatment 
failures (or as soon as possible thereafter), PSP, CGI-S, CRDPSS, and MSQ assessments should 
be performed.
Note that subjects who experience a treatment failure and do not withdraw consent or meet the 
criteria for withdrawal from the study (see Section 10.2, Withdrawal from the Study) will
continue in the study and be followed through to the end of the study.
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9.2.2.2.
MATRICS Consensus Cognitive Battery
The MATRICS Consensus Cognitive Battery (MCCB) was developed to provide a relatively 
brief evaluation of key cognitive domains relevant to schizophrenia and related disorders, and is 
recommended as the standard outcome measure for clinical trials of cognition-enhancing drugs 
for schizophrenia.16 The MCCB includes 10 tests that measure 7 cognitive domains (see 
Table 8).
Table 8:
MCCB Tests
Cognitive Domain
Test
Description
Speed of 
processing
Brief Assessment of Cognition in 
Schizophrenia (BACS): Symbol-
Coding 
Category Fluency: Animal 
Naming
Trail Making Test: Part A
Timed paper-and-pencil test in which respondent uses 
a key to write digits that correspond to nonsense 
symbols
Oral test in which respondent names as many animals 
as she/he can in 1 minute
Timed paper-and-pencil test in which respondent 
draws a line to connect consecutively numbered circles 
placed irregularly on a sheet of paper
Attention/Vigilance
Continuous Performance Test-
Identical Pairs (CPT-IP)
Computer-administered measure of sustained attention 
in which respondent presses a response button to 
consecutive matching numbers
Working memory
(nonverbal)
(verbal)
Wechsler Memory Scale®-3rd Ed. 
(WMS®-III): Spatial Span 
Letter-Number Span
Using a board on which 10 cubes are irregularly 
spaced, respondent taps cubes in same (or reverse) 
sequence as test administrator
Orally administered test in which respondent mentally 
reorders strings of number and letters and repeats them 
to administrator
Verbal learning
Hopkins Verbal Learning Test-
Revised™ (HVLT-R™)
Orally administered test in which a list of 12 words 
from three taxonomic categories is presented and the 
respondent is asked to recall as many as possible after 
each of three learning trials
Visual learning
Brief Visuospatial Memory Test-
Revised (BVMT-R™)
A test that involves reproducing six geometric figures 
from memory
Reasoning and
problem solving
Neuropsychological Assessment 
Battery® (NAB®): Mazes
Seven timed paper-and-pencil mazes of increasing 
difficulty that measure foresight and planning
Social cognition
Mayer-Salovey-Caruso Emotional 
Intelligence Test (MSCEIT™): 
Managing Emotions
Paper-and-pencil multiple-choice test that assesses 
how people manage their emotions
Source: MATRICS Assessment Inc. 82
The MCCB will be administered by a qualified rater at the time points indicated in the Time and 
Events Schedule. The MCCB assessment must also be performed at the time of first occurrence 
of treatment failure.
For each subject, best efforts should be made to begin all subsequent MCCB assessments within 
+/- 1 hour of the start time of administration of the MCCB assessments that occurred at Visit 1 
(Screening). If possible, the same person should administer the tests at each occasion.
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All MCCB data will be sent to central raters for review. Assessments will each be scored by 
central raters who are blinded to treatment information. Central raters will also review the 
neurocognitive data quality and correct any errors. The central raters will enter the final scores 
into the MCCB Scoring program to derive T-scores and composites scores. The central raters 
will enter the raw and derived MCCB scores to the eDC. 
9.2.2.3.
Personal and Social Performance Scale
The PSP scale88,89 is a clinician-rated instrument that assesses the degree of dysfunction a subject 
exhibits in the past month within 4 domains of behavior: a) socially useful activities, b) personal 
and social relationships, c) self-care, and d) disturbing and aggressive behavior. The results of 
the assessment are converted to a numerical score following the PSP scoring guideline. A score 
between 71 and 100 indicates a mild degree of dysfunction; a score between 31 and 70 indicates 
varying degrees of difficulty, and a subject with a score of 30 has functioning so poor that he or 
she requires intensive supervision.
The PSP scale is to be administered by a qualified rater at the time points indicated in the Time 
and Events Schedule. The PSP assessment must also be conducted at the time of first occurrence 
of treatment failure, and should also be performed at the time of subsequent occurrences of 
treatment failure. If possible, the same person should administer this scale at each occasion.
9.2.2.4.
Clinical Global Impression of Severity Scale
The CGI-S rating scale61 is used to rate the severity of a subject’s overall clinical condition on a 
7-point scale ranging from 1 (not ill) to 7 (among the most extremely ill). This scale permits a 
global evaluation of the subject’s condition at a given time. 
This scale will be administered by a qualified rater at the time points indicated in the Time and 
Events Schedule. The CGI-S assessment must also be conducted at the time of first occurrence of 
treatment failure, and should also be performed at the time of subsequent occurrences of 
treatment failure. If possible, the same person should administer this scale at each occasion.
9.2.2.5.
Clinician-Rated Dimensions of Psychosis Symptom Severity
The CRDPSS4 is an 8-item measure that assesses the severity of mental health symptoms that are 
important across psychotic disorders, including delusions, hallucinations, disorganized speech, 
abnormal psychomotor behavior, negative symptoms (ie, restricted emotional expression or
avolition), impaired cognition, depression, and mania. The severity of these symptoms can 
predict important aspects of the illness, such as the degree of cognitive and/or neurobiological 
deficits. This measure, developed by the APA, is intended to capture meaningful variation in the 
severity of symptoms, which may help with treatment planning, prognostic decision-making, and 
research on pathophysiological mechanisms. Each item asks the clinician to rate the severity of 
each symptom as experienced by the individual during the past 7 days. 
Each item on the measure is rated on a 5-point scale (0=none; 1=equivocal; 2=present, but mild; 
3=present and moderate; and 4=present and severe) with a symptom-specific definition of each 
rating level. The clinician may review all of the individual’s available information and, based on 
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clinical judgment, select the level that most accurately describes the severity of the individual’s 
condition. The clinician then indicates the score for each item in the “Score” column provided. 
The response on each item should be interpreted independently when assessing the severity of 
the psychotic disorder. 
The CRDPSS will be completed by a qualified rater at the time points indicated in the Time and 
Events Schedule. The CRDPSS assessment must also be conducted at the time of first 
occurrence of treatment failure, and should also be performed at the time of subsequent 
occurrences of treatment failure.
9.2.2.6.
Medication Satisfaction Questionnaire
Medication satisfaction will be assessed using the MSQ. The MSQ is a self-administered 
single-item questionnaire with responses on a 7-point Likert scale as follows: 1=extremely 
dissatisfied, 2=very dissatisfied, 3=somewhat dissatisfied, 4=neither satisfied nor dissatisfied, 
5=somewhat satisfied, 6=very satisfied, 7=extremely satisfied. The MSQ has demonstrated 
acceptable reliability and validity,112 making this single-item questionnaire appropriate and easy 
to use in clinical research. A 1-point change on the MSQ may be considered clinically 
meaningful.
The MSQ will be completed by the subject at the time points indicated in the Time and Events 
Schedule. The MSQ must also be conducted at the time of first occurrence of treatment failure, 
and should also be performed at the time of subsequent occurrences of treatment failure.
9.3.
MRI Brain Imaging Assessments
Selected sites will be performing MRI brain imaging. Approximately half of the enrolled 
subjects will undergo MRI scans. MRI scans are optional to subjects. All images will be sent to a 
central site for analysis. The imaging raters at the central site will be blind to clinical 
characteristics, treatment assignment, and demographic characteristics of subjects.
Brain imaging assessments will be performed in subjects with schizophrenia/schizophreniform 
disorder and in healthy control subjects. Subjects with schizophrenia or schizophreniform 
disorder who are not able to undergo scans (eg, unable to fit or difficulty fitting in MRI 
instrument, or MRI contraindicated due to presence of metallic objects [pacemaker, etc.]) will be 
excluded from participating in MRI scans, but will still be eligible to participate in all other 
aspects of this study. Healthy control subjects who are not able to undergo MRI scans will not be 
eligible to participate in this study (see Section 4.2, Selection Criteria for Healthy Controls). 
If the initial MRI is clinically abnormal and shows presence of a severe brain abnormality that 
would preclude analyses (eg, large hemangioma), the individual will be excluded from 
undergoing further MRI scans. If this occurs in a healthy control subject, the subject will be 
withdrawn from the study (see Section 10.2, Withdrawal from the Study). If the initial scan is 
abnormal in a subject with schizophrenia/schizophreniform disorder, the subject will be excluded 
from further MRI assessments but will continue in all other aspects of the study.
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A separate MRI manual will be provided to the relevant sites with detailed information regarding 
the MRI procedures. In brief, brain ICM volume will be measured by IR and SE MRI sequences 
focused on the frontal lobe. Cortical thickness, gray matter and white matter volumes will be 
measured by 3D MPRAGE MRI. Ventricular volume and intrasulcal CSF will be measured by 
SE MRI sequences. The subcortical myelin will be measured by MRI sequences optimized for 
DTI. The resting state fMRI will also be measured.
Brain imaging in subjects with schizophrenia or schizophreniform disorder will be performed at 
the time points indicated in the Time and Events Schedule. Brain imaging must also be 
conducted at the time of first occurrence of treatment failure or as soon as possible thereafter.
MRI assessments in healthy control subjects will be described in the MRI manual.
9.4.
Exploratory Assessments
Exploratory evaluations include assessment of medical resource use (based on the RUQ), and 
goal setting and daily activity evaluations. 
9.4.1.
Resource Utilization Questionnaire
The RUQ will be used in the study as an exploratory tool to assess utilization of resources, such 
as number of hospitalization days (refers to 1 overnight stay), emergency room visits without 
hospitalization, day or night clinic stays, and outpatient treatment, as well as daily living 
conditions and productivity of the subject. Healthcare resource utilization will be assessed 
through regular questioning of subject’s resource utilization during visits (via the RUQ) and will 
be objectively verified through medical records and emergency/crisis center documents obtained 
by investigative site staff. Work and living status will be assessed at baseline and at regular 
intervals throughout the study. 
9.4.2.
Goal Setting and Daily Activity Evaluations
Subjects will set up to 3 personal goals and 3 health goals at the beginning of each treatment 
phase, which will be reviewed with the subject and by the treating clinician. 
The patient goals are not binding, but progress towards attaining these goals will be followed 
throughout the study at the time points indicated in the Time and Events Schedule.
Patient Happiness Assessment and Goal Setting Preparation
The Patient Happiness Assessment and Goal Setting Preparation documents will be reviewed and 
completed by each subject at the Part I Baseline visit (Visit 2). 
Patient Goal Setting Documentation
The treating clinician will review the Goal Setting Preparation document with the subject and 
agree with up to 3 personal goals and up to 3 health goals for the subject at the start of each 
treatment phase. These goals will be documented on paper and shared with the subject and the 
subject’s designated individual. The original document will be filed at the investigative (study) 
site as part of the subject’s study source record. The patient goals are not binding.
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Patient Goals Attainment
Progress towards attaining the patient goals will be assessed by the subject at the time points 
indicated in the Time and Events Schedule. Satisfaction regarding the subject’s progress towards 
meeting the goals will be rated on a Likert scale ranging from ‘Extremely Dissatisfied’ to 
‘Extremely Satisfied’. 
Quantitative Assessment of Daily Activities
The Quantitative Assessment of Daily Activities is a patient-reported outcome that documents 
the time a subject spends in a broad array of common daily activities. Categories include sleep 
and rest, self-care, work, recreation and social activities. The period covered is the prior week.  
Refer to the Time and Event Schedule for frequency of assessment.
9.5.
Pharmacogenomic (DNA) Evaluations
DNA samples will be analyzed if it is hypothesized that this may help resolve issues with the 
clinical data. 
DNA samples will be used for research related to paliperidone palmitate or oral antipsychotics,
or schizophrenia and schizophreniform disorder. They may also be used to develop tests/assays 
related to paliperidone palmitate or oral antipsychotics and schizophrenia and schizophreniform 
disorder. Pharmacogenomic research may consist of the analysis of one or more candidate genes 
or of the analysis of genetic markers throughout the genome or analysis of the entire genome (as 
appropriate) in relation to paliperidone palmitate
or oral antipsychotic treatment,
or 
schizophrenia and schizophreniform disorder clinical endpoints.
9.6.
Safety Evaluations
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by the subject’s designated 
individual/caregiver) for the duration of the study. Adverse events will be followed by the 
investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology, and urine samples for urinalysis will be 
collected. The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event section of the 
CRF. The laboratory reports must be filed with the source documents.
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The following tests will be performed by the central laboratory:

Hematology Panel 
-hemoglobin
-platelet count
-red blood cell (RBC) count
-hemoglobin A1c
-white blood cell (WBC) count with 
differential

Serum Chemistry Panel 
-sodium
-alkaline phosphatase
-potassium
-total bilirubin
-chloride
-prolactin
-bicarbonate
-calcium
-blood urea nitrogen (BUN)
-albumin
-creatinine
-total protein
-aspartate aminotransferase (AST)
-C-Reactive Protein
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)

Metabolic Chemistry (all fasting)
-glucose
-triglycerides
-total cholesterol
-high density lipoprotein (HDL)
-low density lipoprotein (LDL)

Urinalysis
Dipstick
Sediment (if dipstick result is
-pH
abnormal)
-color
-RBCs
-glucose
-WBCs
-protein
-epithelial cells
-blood
-crystals
-ketones
-casts
-bilirubin
-bacteria
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, flow cytometry will be used to measure sediment. In case of 
discordance between the dipstick results and the flow cytometric results, the sediment will 
be examined microscopically.

Urine Pregnancy Testing, for women of childbearing potential only

Urine Drug Screen
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Electrocardiogram (ECG)
Twelve-lead ECGs will be obtained locally at screening and reviewed for data integrity and 
reasonableness by a licensed physician qualified to interpret ECG tracings.
A hard copy of the ECG recording must be filed with source documentation. Any findings 
deemed clinically significant and relevant by the investigator should be included on the Medical 
History case report form (CRF) and discussed with the medical monitor. ECGs should be 
performed prior to any scheduled blood draw.
Vital Signs
Blood pressure and pulse rate measurements will be assessed in a seated position with a 
completely automated device. Manual techniques will be used only if an automated device is not 
available.
Body Weight and Body Mass Index
Weight will be assessed at the times indicated in the Time and Events Schedule. Height will be 
recorded at screening only. BMI will be calculated from measurements of height and weight.
Physical Examination
A complete physical examination will be completed at the time points indicated in the Time and 
Events Schedule. 
Extrapyramidal Symptoms Rating Scale – Abbreviated
The ESRS-A is an abbreviated manualized version of the ESRS,21 a semistructured interview 
that rates parkinsonian symptoms, dystonia, dyskinesias, and akathisia over the previous 7 days. 
The ratings include a motor examination for rigidity, tremor, reduced facial expression or speech, 
impaired gait/posture, postural instability, and bradykinesia/hypokinesia. Twenty-four individual 
items are rated on a 6-point scale: 0=Absent, 1=Minimal, 2=Mild, 3=Moderate, 4=Severe, or 
5=Extreme. Frequency is included as an index of severity. Symptoms are divided into the 4 
corresponding subscales and each subscale is summarized in a Clinical Global Impression of 
Movement Severity (CGI-MS) score. 
A qualified clinician is required to administer the ESRS-A. A trained clinician rater for these 
scales must meet one the following criteria: a physician (MD or DO), advanced practice nurse 
(NP), physician assistant, or other allied health professional who is trained and holds a valid 
license to perform physical examinations. 
The ESRS-A will be administered at the time points indicated in the Time and Events Schedule. 
If possible, the same person should administer these scales at all visits.
InterSePT Scale for Suicidal Thinking – Plus
The ISST-Plus is a clinician-rated 4-part instrument for collecting data on suicidal thinking and 
behavior. The ISST-Plus Short Form is an abbreviated form of the ISST-Plus used to screen 
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subjects between ISST-Plus assessments. The ISST-Plus meets the requirements recently 
announced by FDA for assessment of suicidality.
The ISST-Plus includes 4 parts:

Part I is designed to collect information on the severity of suicidal ideation during the 
7 days (or other pre-defined time frame) prior to the subject’s visit. It is comprised of 
13 items, with three levels of severity: 0 (none), 1 (weak), or 2 (moderate or strong).  

Part II is designed to collect information on suicidal behaviors that have occurred since the 
last visit or the last assessment of suicidal behavior. 

Part III is a global rating of suicide ideation and behavior or status at the time of the 
subject interview as judged by a clinically experienced rater.  It includes and integrates both 
Part I and Part II of the scale. It should only be completed after Parts I and II have been 
completed and should take all available information into consideration.  

Part IV is collected at the end of the study to record whether or not the subject died by 
suicide during the study.  
Rating the ISST-Plus requires completion of a semistructured interview.  Subjects who exhibit a 
high suicide risk as evidenced by a total score of ≥7 on the ISST-Plus Part I or a score of 2 on 
items 7, 10, or 11, or an ISST-Plus Part III score of ≥2 must be evaluated by either a clinical 
psychologist or psychiatrist, and this must be documented in the source documents. If a subject 
answers in the affirmative (ie, “YES”) to any part of the suicidal behaviors section (Part II) of the 
ISST-Plus, completion of a detailed potential suicide attempt narrative is required.
The ISST-Plus Short Form will be administered at the study visits indicated in the Time and 
Events Schedule. If suicidality is identified (ie, ‘yes’ is answered to questions 1.0, 2.2, 2.3, or 2.4
of the ISST-Plus Short Form) the full ISST-Plus must be administered in its entirety.
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until reaching a clinically stable endpoint.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed assessments 
at Visit 27 (Day 260 of Part III), the end of the treatment phase. Completion and discontinuation 
will be examined and recorded in the CRF for each treatment phase.
10.2.
Withdrawal From the Study
Subjects with Schizophrenia or Schizophreniform Disorder
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent
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
Death

Discontinuation of study treatment. A subject's study treatment will be discontinued if:

The investigator or sponsor believes (eg, that for safety or tolerability reasons such as 
an adverse event) it is in the best interest of the subject to discontinue treatment.

The subject becomes pregnant.

The subject does not tolerate oral paliperidone ER or oral risperidone treatment during 
Part I (oral run-in).

The subject is randomly assigned to receive OAP, but the investigator considers it 
clinically necessary to switch the subject to an LAI agent.

The subject is randomly assigned to receive PP, but the investigator considers it is
clinically necessary to stop PP for any reason.
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study before the end of Part III, end-of-treatment assessments should 
be obtained.
A subject who withdraws from the study will have the following options regarding the optional 
pharmacogenomics DNA research sample:

The collected DNA sample will be retained and used in accordance with the subject's 
original separate informed consent for optional research samples.

The subject may withdraw consent for optional DNA research sample, in which case the 
sample will be destroyed and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study site contact of withdrawal 
of consent for the optional research samples and to request sample destruction. The sponsor 
study site contact will, in turn, contact the biomarker representative to execute sample 
destruction. If requested, the investigator will receive written confirmation from the sponsor 
that the sample has been destroyed.
Withdrawal From the Optional DNA Research Samples While Remaining in the Main 
Study
The subject may withdraw consent for optional DNA research samples while remaining in the 
study. In such a case, the optional research sample will be destroyed. The sample destruction 
process will proceed as described above.
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Withdrawal From the Use of DNA Samples in Future Research
The subject may withdraw consent for use of DNA samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the separate ICF for optional DNA research samples.
Healthy Control Subjects
A healthy control subject can be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

If the initial MRI is clinically abnormal and shows presence of a severe brain abnormality 
that would preclude analyses (eg, large hemangioma)

If the subject met any of the exclusion criteria during the course of the study
11.
STATISTICAL METHODS
The following presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) describing in detail the analyses to be conducted will be written and finalized before the 
Part II database lock. Unless otherwise specified, all statistical tests will be two-sided, and the 
Type I error will be fixed at 0.05 (two-sided), and all confidence intervals (CIs) will be two-sided 
with 95% coverage.
The overall primary hypothesis to be tested in this study (see Section 2.3) is that 9 months’ 
treatment with PP is superior to 9 months’ OAP treatment in delaying time to treatment failure in 
subjects with recent-onset schizophrenia or schizophreniform disorder. This will be assessed at 
the end of Part II.
Other hypotheses to be evaluated in this study (see Section 11.1) will assess whether LAI 
treatment with PP can slow down disease progression and possibly modify disease course in 
recent-onset subjects compared to OAP medications. This will be assessed by tracking changes 
in cognition (MCCB composite score), functioning (PSP), and brain imaging assessments (ICM 
volume).
The hypothesized effect of PP versus OAP on disease progression and disease modification is 
summarized in Figure 2, based on the predicted change from baseline in the MCCB composite 
score over time. Disease progression and disease modification will be assessed for MCCB 
composite score, PSP total score, and for ICM volume.
Part II (Disease Progression) will enroll all subjects who complete Part I. Subjects will be 
randomized in a 1:2 ratio to either start treatment with PP or to continue with their OAP
treatment from Part I. The early treatment effect identified after early start at the conclusion of 
Part II (δ21) represents the treatment effect after 9 months resulting from continuous treatment 
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with LAI compared with oral treatment. It seeks to identify differential treatment effects between 
the two alternative approaches on disease progression at the end of Part II. In particular, in 
addition to differences in time to first treatment failure, differences in cognition, functioning, and 
ICM volume will be assessed. At the conclusion of Part II, the database will be locked and data 
analyzed to determine if there is an early treatment effect (δ21= treatment effect on disease 
progression) demonstrating superiority of PP relative to oral treatment. 
At the onset of Part III, subjects in the OAP arm will be re-randomized to continued treatment 
with their prior oral treatment or to PP.  Subjects will be followed for an additional 9 months. 
Three effects will be assessed for a given endpoint: δ31, δ32, and δ33.  The quantity δ31 represents 
the lead treatment effect after an early start with 18 months of PP treatment and shows the lead 
effect remaining in the early start group over the delayed-start effect after a 9-month treatment 
duration. The quantity δ32 represents the delayed-start effect on disease progression for PP
compared to continuing OAP after 9 months of additional treatment. The quantity δ33 represents 
the cumulative effect on extended disease progression at the end of Part III following early start 
for PP compared to continuing OAP after a total of 18 months of treatment. At the conclusion of 
Part III, the database will again be locked and data analyzed to assess response in variables δ31,
δ32, and δ33. Positive results (δ33 is significant [a differential treatment effect is still evident] and
δ31 is significant [the lead effect remains significant after 9 months]) will be used to support a 
conclusion of disease modification using MCCB composite score. Similar observations for 
changes in PSP and ICM will be assessed.
In Part II, the overall Type I error rate for testing PP1M/PP3M versus OAP for both the primary 
efficacy endpoint and key secondary efficacy endpoints will be controlled at the 2-sided 0.05 
significance level using a combination of fixed sequence gatekeeper approach and Holm’s step-
down procedure. Time to first treatment failure will be tested first, followed by change in key 
secondary endpoints (MCCB, PSP, and ICM). Time to first treatment failure will be examined 
first using the log-rank test statistics, then using a Cox’s proportional hazards model to describe 
results based on hazard ratio. If the null hypothesis corresponding to time to first treatment 
failure is rejected, then the key secondary endpoints will be tested at the 5% level using Holm’s 
step-down procedure, thus maintaining an overall Type I error rate of 5%. If the primary null 
hypothesis is not rejected, testing of change in key secondary endpoints will still be performed, 
but no unqualified statements about the statistical significance regarding change will be made. In 
Holm’s procedure, p-values from analyses of MCCB, PSP, and ICM will be ordered from lowest 
to highest. Let p(1)<p(2)<p(3) to be order p-values corresponding null hypotheses H(1), H(2), 
and H(3). In Step 1, if p(1) < 0.05/3 then corresponding null hypothesis will be rejected and 
testing will be examined in second step; otherwise, none of the hypotheses will be rejected and 
we will stop testing. In Step 2, if p(2) < 0.05/2 then corresponding null hypothesis will be 
rejected and move onto third step; otherwise, H(2) and H(3) will not be rejected and we will stop 
testing. In Step 3, p(3) will be tested at 0.05 level. All other exploratory hypotheses will be tested 
at the 2-sided 0.05 significance level without adjustments for multiplicity.
In Part III, for the examination of extended disease progression and disease modification, there 
will be no adjustments for multiplicity. During this phase, we seek to show that subjects with 
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recent-onset schizophrenia or schizophreniform disorder who have a delayed start in their 
treatment with PP fail to catch up with subjects who start 9 months earlier in the course of their 
disease. We hypothesize that changes on measures of a pathophysiology biomarker (ICM), 
clinical symptoms (CGI), cognition (MCCB) and functioning (PSP) should be relatively better in 
subjects who initiate treatment earlier.
11.1.
Hypotheses
11.1.1.
Part II: Disease Progression
As described in Section 2.3, the overall primary hypothesis in this study is that 9 months’ 
treatment of subjects with recent-onset schizophrenia or schizophreniform disorder with PP is 
superior to 9 months’ treatment with OAP in delaying time to first treatment failure. The primary 
efficacy null hypothesis is that there is no difference in the distribution of time to first treatment 
failure in Part II between the PP and OAP treatment groups.
The key secondary hypotheses to be tested in Part II of this study are to demonstrate that 
9 months’ treatment of subjects with recent-onset schizophrenia or schizophreniform disorder 
with PP is superior to 9 months’ treatment with OAP in: 

improving or maintaining cognition (as measured by the change in MCCB composite score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in mean change 
from Part II baseline to the Part II end point in the MCCB composite score between PP
and OAP

maintaining functioning (as measured by time to 7-point worsening in the PSP total score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in time to 
7-point worsening in PSP total score in Part II between PP and OAP

increasing or preserving brain ICM volume of the frontal lobe as compared to baseline 

The key secondary efficacy null hypothesis is that there is no difference in mean change 
in ICM volume of the frontal lobe from Part II baseline to the Part II end point between 
PP and OAP 
11.1.2.
Part III: Extended Disease Progression and Disease Modification
11.1.2.1.
Extended Disease Progression 
Let it be assumed that the quantity δ33 in Figure 2 represents the cumulative effect on disease 
progression at the end of Part III following early start for PP compared to continuing OAP after a 
total of 18 months of treatment. The Extended Disease Progression hypotheses to be tested in 
Part III of this study are to demonstrate that 18 months’ treatment of subjects with recent-onset 
schizophrenia or schizophreniform disorder with PP is superior to 18 months’ treatment with 
OAP in:

improving or maintaining cognition (as measured by the change in MCCB composite score 
from baseline)
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
The primary efficacy null hypothesis is that there is no difference in mean change from 
Part II baseline to the Part III end point in the MCCB composite score between PP and 
OAP. In other words, H0: δ33 = 0 for MCCB composite score.

maintaining functioning (as measured by time to 7-point worsening from in the PSP total 
score from baseline)

The key secondary efficacy null hypothesis is that there is no difference in time to 
7-point worsening in PSP total score from Part II baseline to the Part III end point 

increasing or preserving brain ICM volume of the frontal lobe as compared to baseline

The key secondary efficacy null hypothesis is that there is no difference in mean change 
in ICM volume of the frontal lobe from Part II baseline to the Part III end point 
between PP and OAP 
11.1.2.2.
Disease Modification
In order to demonstrate disease modification, the following results are required: 

At the end point of Part II: Subjects treated with PP for 9 months (early-start group) must 
demonstrate better outcomes on MCCB than those treated with OAP for 9 months. Similar 
results for changes in functioning (PSP) and changes in brain anatomy (ICM) will be used to 
support this finding (ie, treatment effect on disease progression). 

At the end point of Part III: Subjects from Part II who have been treated with PP for 
18 months (early-start group) must continue to show better outcomes on MCCB compared 
with subjects treated with OAP for 18 months (a differential treatment effect is still evident), 
and compared with subjects treated with OAP for 9 months followed by PP for 9 months 
(the lead treatment effect remains significant after 9 months); ie, that late initiation of 
treatment with PP does not allow for achievement of the same level of cognition after 
9 months. [(See corresponding null hypotheis below (H0: δ31 – γ. δ21 ≤0)]. Similar results for 
changes in PSP and ICM will be used to support this finding for disease modification.
For each of the endpoints (MCCB, PSP, and ICM), the following hypotheses will be tested as a 
function of estimated changes in the Part II endpoint using the observed scores. Let δ21 denote 
the estimated mean differences between treatment groups at the end of Part II for a given 
endpoint, treatment effect on disease progression. Below, the parameter μPP-PP corresponds to the 
mean score for a given endpoint following 9 months’ of additional PP3M treatment in subjects 
originally randomized to PP and μOAP-PP corresponds to mean score for 9 months’ of delayed-
start PP treatment in subjects originally randomized to OAP treatment. Let δ31 denote the 
estimated difference between μPP-PP and μOAP-PP, lead treatment effect at the end of Part III. The 
corresponding null hypotheses for a given endpoint will be listed as:
H0: δ31 – γ. δ21 ≤0, where γ is a fixed number between 0 and 1 indicating the ratio of 
treatment effect in Part III compared to the Part II observed differences.
The quantity γ will be determined after Part II database lock and prior to finalization of Part III 
Statistical Analysis Plan. For γ, the quantities 0.25 and 0.50 will be considered principally. The γ 
could be different for a different endpoint.
In addition, for each of the endpoints, δ32 (delayed-start treatment effect on disease progression) 
will be tested in Part III using Part III baseline scores. Below, the parameter μOAP-PP corresponds 
to mean score for 9 months’ of delayed-start PP treatment in subjects originally randomized to 
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OAP treatment and μOAP-OAP corresponds to the mean score for a given endpoint following 
9 months’ of additional OAP treatment in subjects originally randomized to OAP. The 
corresponding null hypotheses for a given endpoint will be listed as:
H0: δ32 = μOAP-PP - μOAP-OAP = 0.
The quantity δ33 represents the cumulative effect on disease progression at the end of Part III 
following early start for PP compared to continuing OAP after a total of 18 months of treatment. 
At the conclusion of Part III, the database will again be locked and data analyzed to assess 
response in variables δ31, δ32, and δ33 (overall effect of treatment). Positive results (δ33 is 
significant [a differential treatment effect is still evident] and δ31 is significant [the lead effect 
remains significant after 9 months]) will be used to support a conclusion for disease 
modification.
11.2.
Sample Size Determination
The overall primary efficacy null hypothesis is that there is no difference in the distribution of 
time to treatment failure between the PP and OAP in the treatment of subjects with recent-onset 
schizophrenia or schizophreniform disorder in Part II. Treatment differences will be compared 
using a log-rank test. It is assumed that treatment failure rate in Part II is approximately 40% for 
the OAP group and 20% for the PP group at month 9 with a corresponding hazard ratio of 0.44. 
It is also assumed that the hazard rates of treatment failure for the two groups are proportional. 
Additional assumptions made to calculate the expected number of subjects that need to be 
randomized to obtain the required number of treatment failures are: 

In both treatment groups, 10% of the randomized subjects will be lost-to-follow-up.

Uniform accrual rate during the 15 month accrual period. 
With these assumptions, it is planned to randomize 225 (75 in PP and 150 in OAP group) 
subjects in a 1:2 ratio to receive either PP or OAP to obtain at least 62 treatment failures to show 
that PP is significantly different from OAP at the 2 sided significance level of 0.05, with 80% 
power to detect a hazard ratio of 0.44 using a log rank test. 
Blinded surveillance of the total number of events in Part II will be performed during the study 
to assess the appropriateness of the assumptions. The number of subjects enrolled and the 
number of subjects who discontinue before entering Part II will be closely monitored.
Assuming 20% attrition rate during the 2-month Run-in period (Part I), the total number of 
subjects to be enrolled in Part I will be approximately 275.
One of the key secondary efficacy null hypotheses in Part II (see Section 11.5.1) is that there is 
no difference in mean change from Part II baseline to the Part II end point in the MCCB 
composite score between PP and OAP in the treatment of subjects with recent-onset 
schizophrenia or schizophreniform disorder. The corresponding efficacy variable is the change in 
the MCCB composite score. This variable will be analyzed in Part II using mixed-effects 
repeated measures analysis of covariance (ANCOVA) model, described later. Similarly, the 
matching null hypothesis in Part III is that there is no difference in mean change from Part II 
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baseline to the Part III end point in the MCCB composite score between PP and OAP in the 
treatment of subjects with recent-onset schizophrenia or schizophreniform disorder. 
This is the first study to assess the efficacy of PP on cognition in subjects with recent-onset 
schizophrenia or schizophreniform disorder. A small study comparing the clinical efficacy of the 
LAI formulation of risperidone (RLAI) to the oral formulation of risperidone (oral Ris) in the 
early course of schizophrenia in UCLA Aftercare Research program showed an effect size of 
0.46 between the treatment groups in the MCCB composite score (change from baseline) at 
Month 6 end point. We consider an effect size of 0.3 and above to be clinically meaningful for 
cognition in a therapeutic area where there are no known effective treatments. 
Assuming an effect size of approximately 0.40 for the difference in the mean change from Part II 
baseline to Part II end point in the MCCB composite score between PP and OAP, with 1:2 
randomization ratio, sample sizes of 75 subjects in the PP group and 150 subjects in the OAP 
group are necessary to provide 80% power based on a two group t-test with a 0.05 two-sided 
significance level. This computation is also consistent with the time to treatment failure 
calculations ignoring correlations among these endpoints.
It is assumed that approximately 20% of subjects who entered Part II will not be transitioned to 
the Part III (Extended Disease Progression and Disease Modification) period in each treatment 
group. Approximately, a total of 180 subjects will be available at the Part III baseline. Subjects
in the OAP treatment arm will be re-randomized in a 1:1 ratio to continued treatment with their 
oral treatment or to PP (delayed-start PP arm). Subjects previously assigned to treatment with PP
in Part II will continue in that treatment in Part III. Thus, approximately 60 subjects will be 
available for each treatment group at the Part III baseline. Assuming approximately 5% of 
subjects will be missing either the Part III baseline or all post-baseline MCCB assessments, a 
sample size of 57 in each group will have 80% power to detect an effect size of 0.53 between PP
and OAP in the difference in the mean change from Part II baseline in the MCCB composite 
score using a two group t-test with a 0.05 two-sided significance level in Part III. The primary 
objective in Part III is to compare changes in cognition following 18 months’ treatment with PP
compared to 18 months’ treatment with OAP.
11.3.
Analysis Populations
Efficacy analyses will be based on the ITT and explanatory intent-to-treat (eITT) analysis sets. 
All safety analyses will be based on ITT analysis set. As there are different objectives for 
different periods of this study, separate ITT and eITT populations will be identified for the Part I 
(Run-in), Part II (Disease Progression), and Part III (Extended Disease Progression and Disease 
Modification) periods. eITT analysis set will not be included in Part I. The analysis sets are 
defined below.
Part I (Run-in) Intent-to-Treat Analysis Set
Efficacy and safety summaries for the Part I period will be based on the Part I ITT analysis set, 
which will include all subjects who receive at least one dose of study medication (or any portion 
of the dose) in Part I, regardless of their compliance with the protocol.
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Part II (Disease Progression) Analysis Sets
Efficacy and safety summaries for the Part II period will be based on the Part II ITT analysis set, 
which will include all randomized subjects who receive at least one dose of study medication (or 
any portion of the dose) in Part II, regardless of their compliance with the protocol. 
An explanatory ITT (eITT) analysis set will also be defined in Part II. The eITT analysis set will 
consist of all ITT subjects, as well as their study assessments for the time period between the 
date of randomization and the eITT end point. The eITT end point for subjects randomized to PP 
will be defined as the last PP1M injection date +28 days or the last PP3M injection date 
+84 days. For subjects randomized to OAP treatment, the eITT end point is defined as the last 
prescription date of the randomized oral medication + the number of days’ supply + 1 day. 
Changes in PSP, CGI-S, CRDPSS, and MSQ scales will also be analyzed using eITT analysis 
set.
The eITT analysis set for the primary efficacy endpoint in Part II consists of the 1st treatment 
failure time observed at or prior to the eITT endpoint, for all ITT subjects.  For subjects who did 
not experience any treatment failure at or prior to the eITT endpoint, their 1st treatment failure 
times would be censored at the eITT end point or the date of last contact, whichever was earlier. 
For any other efficacy endpoint (PSP, CGI-S, etc.), the eITT analysis set consists of only 
measures for that endpoint that were taken at or prior to the eITT end point. The eITT analysis 
set will be used for testing the primary as well as key secondary efficacy hypotheses.
Part III (Extended Disease Progression and Disease Modification) Analysis Sets
Efficacy and safety summaries for the Part III period will be based on the Part III ITT analysis 
set, which will include all randomized subjects who receive at least one dose of study medication 
(or any portion of the dose) in Part III, regardless of their compliance with the protocol. On 
Day 1 of Part III, subjects in the OAP treatment arm will be re-randomized in a 1:1 ratio to 
continued treatment with their oral treatment or to PP (delayed-start PP arm). Subjects previously 
assigned to treatment with PP in Part II will continue on that treatment; however, in order to be 
included in the ITT population, this group must have at least one post-baseline MCCB, ICM, or 
PSP assessment.
An explanatory ITT (eITT) analysis set will be defined in Part III. The eITT analysis set will 
consist of all ITT subjects, as well as their study assessments for the time period between the 
date of randomization and the eITT end point. The eITT end point for subjects randomized to PP 
will be defined as the last PP1M injection date +28 days or the last PP3M injection date 
+84 days. For subjects randomized to OAP treatment, the eITT end point is defined as the last 
prescription date of the randomized (start of Part III) oral medication + the number of days’ 
supply + 1 day. Changes in PSP, CGI-S, CRDPSS, and MSQ scales will be analyzed using the 
eITT analysis set.
11.4.
Subject Characteristics, Disposition, Study Medication 
Baseline subject characteristics will be summarized descriptively by study period, and the 
comparability of treatment groups at Part II and Part III baselines will be assessed using 
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Chi-square test for categorical variables and Analysis of Variance (ANOVA) for continuous 
variables. Particular interest will be given to the individual stratification factors for 
randomization: age, race, duration of previous antipsychotic usage prior to screening, baseline 
MCCB composite score, baseline PSP score, and substance use history.
Subject disposition including the timing of and reasons for discontinuation will be summarized 
by phase. Subjects’ exposure to study medications will be summarized. Duration of treatment 
with randomized study medication, defined as the time from subject randomization to 
discontinuation of the randomized study medication, will be summarized descriptively for the 
eITT subjects. For eITT subjects, the distribution of the number of injections for PP will be 
determined and summarized. A descriptive summary of mean daily dose will be presented for 
each of the randomized OAPs. Mean daily dose for a subject is calculated as the sum of total 
prescribed daily dose during the treatment period divided by the total number of days covered. 
11.5.
Efficacy Analyses 
11.5.1.
Part II: Disease Progression
At the end of Part II, the database will be locked and data analyzed.
Primary Analysis in Part II (Treatment Failure):
Subjects who meet at least 1 of the criteria for treatment failure while on Part II treatment at the 
time of or before Part II completion will be considered to have had an event. Treatment 
differences will be compared using a log-rank test. The cumulative distribution function of the 
time to treatment failure will be estimated by the Kaplan-Meier method. The 95% CIs for the 
median treatment failure rates, as well as the failure rates at 3 months, 6 months, and at 9 months 
will be provided. In addition, the estimate of the hazard ratio and its 95% CI will be provided by 
treatment group based on the Cox proportional hazards model. The reasons for first treatment 
failure and subsequent treatment failures will be summarized at each visit and end point. 
If the log-rank test result is statistically significant (p-value <0.05) in favor of PP, the null 
hypothesis would be rejected and we would conclude that PP is superior to OAP in delaying time 
to treatment failure. Hazard ratio and 95% CI will be used to describe reduction in risk treatment 
failure. 
In case of significant missing treatment failure information (ie, >20%), the tipping point analysis 
will be implemented to assess the robustness and consistency of findings. Subjects in the PP 
treatment arm with missing data will be assigned a value that inflates the hazard by a known 
factor. Events will be imputed 1,000 times assuming a Weibull distribution. Results will be 
combined using standard multiple imputation combining rules. The inflation factor will be 
increased until the upper limit of 95% confidence interval crosses 1.
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Key Secondary Analyses in Part II:
At the end of Part II, changes in MCCB composite score, PSP, and ICM volume will be analyzed 
to determine if there is an early treatment effect demonstrating disease progression of PP relative 
to OAP. The early treatment effect is illustrated by δ21 in Figure 2.
The change from baseline in MCCB composite score will be analyzed using a mixed model 
repeated measures (MMRM) ANCOVA model. The analysis will be based on observed data, ie,
data collected at each time point without carrying forward previous values. The data points from 
unscheduled visits will also be included. The response variable will be the change in MCCB total 
score. The model will include Part II baseline MCCB composite score as a fixed-effect covariate; 
treatment (PP and OAP) and site as fixed-effect (categorical) factors, time as a regression 
variable, and the interaction between time and treatment. Using this model, treatment effects at 
the Month 9 end point will be estimated based on differences between least squares (LS) means. 
Accompanying 95% CIs for the LS mean differences between PP and OAP will be presented. An 
unstructured matrix will be used for the covariance of the within-subject repeated measures as a 
base case. However, the following spatial covariance structures will also be evaluated, 
SP(POW), SP(GAU), and SP(SPH). Linearity of response over time will be examined. A random 
intercept and random slope for each subject will also be fitted. 
The purpose of this analysis is to examine treatment differences at Month 9 using LS means from 
the MMRM model. The treatment effect measures the deviation from the hypothesis of equality 
of means among treatments, “averaged” over the treatment duration. The time effect is a measure 
of deviation from the hypothesis of constancy of mean response over time for all treatment 
groups combined after aggregating over subjects. The treatment-by-time interaction tests the 
hypothesis of parallel response profiles over time in the treatment groups. A significant 
treatment-by-time interaction means that changes in response over time differ among treatments; 
in other words, there is a difference among the treatment groups, but the magnitude of the 
difference varies over time. The interaction will remain in the model, regardless of significance, 
in order to obtain an estimate of the treatment effect at the Month 9 time point. In the ITT 
analysis set, the model-based test for the mean treatment group difference will also be examined.
To assess missing data patterns, plots of mean MCCB change score from baseline over time for 
completers and for subjects who withdraw (by reason for withdrawal) will be generated. To 
assess normality, diagnostic plots such as normal quantile-quantile plots of residuals will be 
created. If a high degree of non-normality is suspected, remedies such as rank-based methods 
will be considered.
The eITT analysis set will also be used to test changes at end point. The eITT analysis set 
consists of MCCB score assessed at or prior to the eITT end point.
Changes in ICM volume will be analyzed using the same method as the MCCB analysis except 
the baseline MCCB score will be replaced by the corresponding ICM baseline score. 
The analysis of time to 7-point worsening in PSP total score will be similar in methodology to 
the primary efficacy analysis.  At each PSP assessment time point including the last eITT time 
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point, frequency counts, percentages, and cumulative percentages of subjects reporting each PSP 
level will be summarized by treatment group for the observed cases and LOCF data. Mean 
changes in PSP total score will be analyzed using the same method as the MCCB analysis except 
the baseline MCCB score will be replaced by the corresponding PSP baseline score. Additional 
PSP analyses include: Time to 10-point worsening; Categorical summary of frequency 
distribution of PSP total score and domain scores by time point; Shift from baseline scores by 
time point. Responses for PSP domain scores will also be dichotomized as absent to mild vs. 
manifest to very severe. The proportion of subjects in each group within domains will be 
calculated at each visit and compared between treatment groups using a CMH test.
Secondary Analyses in Part II: 
Frequency counts, percentages, and cumulative percentages of subjects reporting each CGI-S 
score, CRDPSS domain scores, and MSQ level will be summarized by treatment group. 
Difference between treatment groups will be evaluated using the Cochran-Mantel-Haenszel 
(CMH) mean score test using modified ridit scores. The ordinal repeated measures data will also 
be evaluated using Generalized Estimation Equations (GEE) for both the ITT and eITT analysis 
sets. Responses for MSQ will also be dichotomized as Satisfied and Dissatisfied when the 
observed response on the MSQ scale was between 1 and 4 and between 5 and 7, respectively. 
The proportion of subjects who were either satisfied or dissatisfied on the MSQ scale will be 
calculated at each visit and compared between treatment groups using a CMH test.
Continuous efficacy endpoints at each post-baseline time point (LOCF) will also be analyzed 
using an ANCOVA model including treatment as a fixed design factor and corresponding 
baseline score as a covariate. 
11.5.2.
Part III: Extended Disease Progression and Disease Modification
Subjects who complete Part II will be eligible to enter Part III. At the start of Part III, subjects 
treated with OAP during Part II will be re-randomized in a 1:1 ratio to either continue treatment 
with OAP (OAP-OAP group) or to switch to PP (OAP-PP or ‘Delayed-start PP’ group). Subjects
treated with PP during Part II will continue the same treatment (PP-PP group). The Part III 
treatment duration is 9 months.
The Extended Disease Progression analyses will focus on comparisons between the OAP-OAP 
and PP-PP groups; the Disease Modification analyses will focus on comparisons between the 
PP-PP and the OAP-PP groups (ie, subjects who started treatment with PP early vs. subjects who 
started PP treatment 9 months later).
11.5.2.1.
Extended Disease Progression
The cumulative effect on disease progression at the end of Part III is illustrated by the quantity 
δ33 in Figure 2. 
The change from Part II baseline in MCCB composite score at the end of Part III will be 
analyzed using a MMRM ANCOVA model. Changes in ICM volume and PSP total score will be 
analyzed using the same method as the MCCB analysis. Treatment differences for time to 
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7-point worsening in PSP score will be compared using a log-rank test, and Hazard Ratio along 
with 95% CI will be provided. 
Categorical summary of frequency distribution of PSP total score and domain scores by time 
point will be examined. Shifts in PSP total score and domain scores from baseline scores by time 
point will be provided. Frequency counts, percentages, and cumulative percentages of subjects 
reporting each CGI-S score, CRDPSS domain scores, and MSQ level will be summarized by 
treatment group. Difference between treatment groups will be evaluated using the CMH mean 
score test using modified ridit scores. The ordinal repeated measures data will also be evaluated 
using GEE for both the ITT and eITT analysis set. Responses for MSQ will also be dichotomized 
as Satisfied and Dissatisfied when the observed response on the MSQ scale was between 1 and 4 
and between 5 and 7, respectively. The proportion of subjects who were either satisfied or 
dissatisfied on the MSQ scale will be calculated at each visit and compared between treatment 
groups using a CMH test. Continuous and categorical endpoints at each post-baseline LOCF time 
point will also be examined.
11.5.2.2.
Disease Modification
In order to demonstrate disease modification, the following results are required: 

At the end point of Part II: Subjects treated with PP for 9 months (early-start group) must 
demonstrate better outcomes on MCCB than those treated with OAP for 9 months. Similar 
results for changes in functioning (PSP) and changes in brain anatomy (ICM) will be used to 
support this finding (ie, treatment effect on disease progression). 

At the end point of Part III: Subjects who have been treated with PP for 18 months 
(early-start group) must continue to show better outcomes on MCCB compared with 
subjects treated with OAP for 18 months (a differential treatment effect is still evident), and 
compared with subjects treated with OAP for 9 months followed by PP for 9 months (the 
lead treatment effect remains significant after 9 months); ie, that late initiation of treatment 
with PP does not allow for achievement of the same level of cognition after 9 months. [(See 
corresponding null hypothesis below (H0: δ31 – γ. δ21 ≤0)]. Similar results for changes in PSP 
and ICM will be used to support this finding for disease modification.
For each of the endpoints (MCCB, PSP, and ICM), the following hypotheses will be tested as a 
function of estimated changes in the Part II endpoint using the observed scores. Let δ21 denote 
the estimated mean differences between treatment groups at the end of Part II for a given 
endpoint, treatment effect on disease progression. Below, the parameter μPP-PP corresponds to the 
mean score for a given endpoint following 9 months of additional PP treatment in subjects 
originally randomized to PP and μOAP-PP corresponds to mean score for 9 months of delayed-start 
PP treatment in subjects originally randomized to OAP treatment. Let δ31 denote the estimated 
difference between μPP-PP and μOAP-PP, lead treatment effect at the end of Part III. The 
corresponding null hypotheses for a given endpoint will be listed as:
H0: δ31 – γ. δ21 ≤0, where γ is a fixed number between 0 and 1 indicating the ratio of 
treatment effect in Part III compared to the Part II observed differences.
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The quantity γ will be determined after Part II database lock and prior to finalization of Part III 
SAP. For γ, the quantities 0.25 and 0.50 will be considered principally. The γ could be different 
for a different endpoint.
In addition, for each of the endpoints, δ32 (delayed-start treatment effect on disease progression) 
will be tested in Part III using Part III baseline scores. Below, the parameter μOAP-PP corresponds 
to mean score for 9 months of delayed-start PP treatment in subjects originally randomized to 
OAP treatment and μOAP-OAP corresponds to the mean score for a given endpoint following 
9 months of additional OAP treatment in subjects originally randomized to OAP. The 
corresponding null hypotheses for a given endpoint will be listed as:
H0: δ32 = μOAP-PP - μOAP-OAP = 0.
The quantity δ33 represents the cumulative effect on disease progression at the end of Part III 
following early start for PP compared to continuing OAP after a total of 18 months of treatment.  
At the end of Part III, changes in MCCB composite score, PSP, and ICM volume will be 
analyzed to assess variables δ31, δ32, and δ33 (overall effect of treatment). Positive results (δ33 is 
significant [a differential treatment effect is still evident] and δ31 is significant [the lead effect 
remains significant after 9 months]) will be used to support a conclusion for disease 
modification. 
The quantity δ31 (lead treatment effect) will be examined as a function of δ21 (treatment effect on 
disease progression) at the end of Part III using Part III baseline scores. The observed differences 
in MCCB composite score will be analyzed using a MMRM ANCOVA model. The analytical 
models will account for differences in intercept. Changes in ICM volume and PSP total score 
will be analyzed using the same method as the MCCB analysis as a function of corresponding δ21
value. 
The quantity δ32 represents the delayed-start effect on disease progression for PP compared to 
continuing OAP after 9 months of additional treatment. The quantity δ33 represents the 
cumulative effect on extended disease progression at the end of Part III following early start for 
PP compared to continuing OAP after a total of 18 months of treatment.
The quantity δ32 (the delayed-start effect on disease progression) will be examined using change 
scores from Part III baseline to Part III end point. The differences in scale scores will be 
analyzed using MMRM ANCOVA models.
One of the objectives of Part I is to identify those subjects who have propensity to discontinue 
along with collecting and characterizing matching criteria. Patients who cannot tolerate oral 
paliperidone ER or oral risperidone will be discontinued in Part I. During Part II, patients are 
allowed to switch their OAP medications or adjust their dose levels in injectable arm. In other 
words, they are encouraged to stay in trial. These study features should minimize dropouts 
during Part II. However, there is still a potential that Part III subjects on PP-PP may not be 
comparable to subjects on OAP-PP or OAP-OAP with differential dropouts in Part II. For this 
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reason, additional sensitivity analysis using the Marginal Structural Models to describe study 
results will be considered.
The Disease Modification concept in Part III for each end point will also have corresponding 
Bayesian data analyses. This work will include all data points starting from Part II baseline and 
will utilize Bayesian Models with Hierarchy-Based Priors. The standard Markov Chain Monte 
Carlo methods including Gibbs and Langevin-Metropolis Hasting will be used to compute 
posterior estimates of δ21=μPP - μOAP and δ31=μPP-PP - μOAP-PP. The primary objective of this
analysis is to estimate posterior probability of P(δ31 – γ δ21 > 0 given data) accounting for 
inherent relationships between study visits within each endpoint. The quantity γ will be 
determined prior to Part III SAP finalization. Posterior median estimates and 90% credible 
intervals will be provided for μPP, μOAP, μPP-PP, and μOAP-PP. If the P(δ31 – γ δ21 > 0 given data) is 
greater than 80%, we will conclude that late initiation of treatment with PP does not allow for the 
same level of recovery after 9 months. In other words, subjects who start PP late do not catch up 
to those subjects who start PP 9 months earlier. 
11.6.
Safety Analyses 
Safety variables to be analyzed include treatment-emergent adverse event incidence, ESRS-A 
scores, laboratory parameters, vital signs, ECG measures, physical examination reports, and 
ISST-Plus. The ITT analysis sets will be used for analyses performed on safety parameters 
unless otherwise specified. Any statistical tests performed to explore the data will be used only to 
highlight any comparisons that may warrant further consideration. 
Adverse Events
The original terms used in the CRFs by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). The number of subjects with 
treatment-emergent adverse events, as well as the total number of events, will be displayed for 
each event within each phase. In addition, the severity of the event and its relationship to the 
study drug will be summarized by System Organ Class and preferred term. Incidence, type, 
timing, and resolution of serious adverse events will be reported. Special attention will be given 
to those subjects who discontinue treatment due to an adverse event or who experience a severe 
or a serious adverse event.
Clinical Laboratory Tests
Descriptive statistics will be provided for each laboratory analyte at the respective baseline and 
at each scheduled assessment time point. The criteria used to define markedly abnormal 
laboratory values will be defined in the SAP. The incidence of markedly abnormal laboratory 
values for each treatment group will be provided. A listing of subjects with any laboratory results 
outside the reference ranges will also be provided.
Electrocardiogram (ECG)
The effects on cardiovascular measurements will be evaluated using descriptive statistics and 
frequency tabulations. All important abnormalities from the ECG readings will be listed.
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Vital Signs and Physical Examination
Changes from baseline in vital signs measurements will be presented descriptively. The 
percentage of subjects with values beyond clinically important limits will be presented.
Continuous variables such as heart rate, blood pressure, and change from baseline will be 
summarized at each assessment time point and at end point. Descriptive statistics will be 
presented at each assessment point and at end point for vital signs, body weight, and BMI. Body 
mass index will be calculated as weight (kg)/(height [m])2.
For each of the vital signs parameters, the following categories for treatment-emergent 
abnormality will be tabulated with percentages by treatment group at each assessment time point 
and at end point. A treatment-emergent abnormality in vital sign is defined as a post-baseline 
value and change from baseline that meets any criteria in Table 9 with a normal or missing 
baseline value (ie, the baseline value must be above [in the case of abnormally low] or below [in 
the case of abnormally high] the value given in the table or missing). For example, when looking 
at abnormally low pulse, a normal baseline value would be considered any value >50 bpm.  
Similarly, when looking at abnormally high systolic blood pressure, a normal baseline value 
would be considered any value <180 mmHg.
Table 9:
Treatment-Emergent Abnormality Categories for Vital Signs
Post-baseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 
15 to a value 50
An increase from baseline of 
15 to a value 100
Systolic BP 
(mmHg)
A decrease from baseline of 
20 to a value 90
An increase from baseline of 
20 to a value 180
Diastolic BP  
(mmHg)
A decrease from baseline of 
15 to a value 50
An increase from baseline of 
15 to a value 105
BP = blood pressure
For body weight the incidence of increases/decreases from baseline 7% will be summarized in a 
frequency table by treatment group and by time point.
Extrapyramidal Symptom Rating Scale – Abbreviated (ESRS-A)
Descriptive statistics and frequency counts on changes from Part II or III baseline values will be 
provided for each measurement at each time of evaluation and at the subject’s last evaluation in 
each study period. 
InterSePT Scale for Suicidal Thinking-Plus (ISST-Plus) 
Descriptive summaries will be provided for each ISST-Plus item score at each assessment time 
point using both eITT and ITT analysis sets.
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12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.  
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For all paliperidone formulations (including oral 
paliperidone ER, oral risperidone, PP1M, and PP3M formulations), the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure. For
all other OAP treatments used in the OAP treatment arm, the expectedness of an adverse event 
will be determined by whether or not it is listed in the relevant package insert.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
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Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Unexpected therapeutic or clinical benefit from use of a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety). Serious adverse 
events, including those spontaneously reported to the investigator either at the End-of-Study Visit 
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or within 3 months after the last injection of study drug for the PP treatment groups, or within 
30 days of the last oral dose for the OAP treatment group, whichever is later, must be reported 
using the Serious Adverse Event Form. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 2.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
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and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

Study-designated hospitalizations, such as during the Screening Period.
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Pregnancy itself is not an adverse event; however, 
abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events and must be reported using 
the Serious Adverse Event Form. Any subject who becomes pregnant during the study must be 
promptly withdrawn from the study.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
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12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Paliperidone Palmitate
Paliperidone palmitate as a 1-month or a 3-month long-lasting IM formulation (ie, PP1M and 
PP3M, respectively) will be manufactured and provided under the responsibility of the sponsor. 
Medication labels will comply with the legal requirements of each country.
PP1M and PP3M injections will contain paliperidone palmitate aqueous injectable suspension. 
PP1M dose concentrations will be 78, 117, 156, and 234 mg (50, 75, 100, and 150 mg eq.) and 
PP3M dose concentrations will be 273, 410, 546, and 819 mg (175, 263, 350, or 525 mg eq.) [as 
described in Table 3 of this protocol].
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Please refer to the Investigator's Brochure for information on the physical and chemical 
characteristics of paliperidone palmitate, and for a list of excipients.102
Oral Antipsychotic Medications (Including Oral paliperidone ER and Oral Risperidone 
During Part I)
Oral antipsychotic medications (including oral paliperidone ER and oral risperidone during Part 
I) will not be provided directly by the sponsor. 
The investigator will apply feasible doses of each OAP within the approved dose range. The 
medication will be prescribed for self-administration. 
14.2.
Packaging
Paliperidone Palmitate
Paliperidone palmitate (PP1M and PP3M; at concentrations listed in Table 3) will be supplied in 
a carton containing 2 safety needles, instructions for use, and a blistered, pre-filled syringe 
assembled with a plunger rod. Each carton box and each syringe will be labeled.
Paliperidone palmitate will not be dispensed in child-resistant packaging. Since the study drug 
will be administered at the investigational site only, access by children will be very unlikely. 
Investigators will be asked to store medication at a secured place.
14.3.
Labeling
All study drugs provided by the sponsor will be labeled. Study drug labels will contain 
information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All formulations of paliperidone palmitate (PP1M and PP3M) should be stored between 15°C 
and 30°C (59°F and 86°F respectively). PP1M and PP3M injections will be administered by 
trained study-site personnel. Prior to administration, it is critical to shake the PP1M and PP3M
containing syringes vigorously for at least 10 and 15 seconds, respectively.
Please refer to the pharmacy manual for additional guidance on study drug preparation, handling, 
and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all paliperidone palmitate received at the site is 
inventoried and accounted for throughout the study. For subjects receiving paliperidone 
palmitate, accountability will be maintained in an injection log.
Paliperidone palmitate must be handled in strict accordance with the protocol and the container 
label and will be stored in a limited access area or in a locked cabinet under appropriate 
environmental conditions. Unused paliperidone palmitate must be available for verification by 
the sponsor’s site monitor during on-site monitoring visits. All paliperidone palmitate syringes, 
used and unused, returned for destruction will be documented on the Drug Return Form. When 
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the site is an authorized destruction unit and paliperidone palmitate is destroyed on site, this must 
also be documented on the Drug Return Form.
Hazardous materials such as used needles and syringes containing hazardous liquids, should be 
disposed of immediately in a safe manner and therefore will not be retained for drug 
accountability purposes. The immediate destruction of these drug supplies should be documented 
in the drug accountability records on site. 
Paliperidone palmitate should be dispensed under the supervision of the investigator, a qualified 
member of the investigational staff, or by a hospital/clinic pharmacist. Paliperidone palmitate 
will be supplied only to subjects participating in the study. Paliperidone palmitate may not be 
relabeled or reassigned for use by other subjects. The investigator agrees neither to dispense 
paliperidone palmitate, nor store it, at any site other than the study sites agreed upon with the 
sponsor. 
Oral antipsychotic medications will not be provided directly by the sponsor. At each visit the 
investigator will provide a voucher and prescription for oral antipsychotic medication to each 
subject to bring to a local pharmacy to receive his or her medication. As subjects in the OAP 
treatment group are expected to self-administer their own medications, subjects do not have to 
return unused study drug to the site. This study seeks to replicate treatment reflective of regular 
clinical practice and there will be no monitoring of treatment compliance in subjects in the OAP 
group, and drug accountability of OAPs used or unused by the subject will not be performed.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Blood collection tubes, storage tubes, preprinted labels (or tubes labeled with preprinted 
labels)

Urine pregnancy test kits

Urine collection kits

Urine drug screen test strip

eDC Completion Guidelines

Questionnaires/Rating Scales

Investigator Brochure for paliperidone

PI for risperidone, paliperidone ER, PP1M, and PP3M

Laboratory manual

IVRS/IWRS Manual 

MRI acquisition manual (for sites participating in MRI acquisition)
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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The potential advantage of PP3M over OAPs is that its administration would require outpatient 
clinic visits only 4 times a year, and is thus expected to facilitate treatment access and 
medication adherence among patients with schizophrenia with irregular or sporadic access to 
treatment. By extension, PP3M could potentially improve the feasibility of coordinating medical 
care with the patient’s primary physician and healthcare team, and ultimately improve the overall 
economic burden of healthcare costs for patients with schizophrenia.
Additionally, PP3M is supplied in prefilled syringes that do not require refrigeration. These 
characteristics, together with its long duration of action and 3-monthly dosing interval make this 
a promising treatment option for patients with limited access to healthcare because they either 
live in an underserved rural or inner city setting, or simply cannot coordinate biweekly or 
once-monthly transportation for injection visits.
In any clinical study there is always some risk to removing current psychotropic medications and 
starting an investigational compound. Only subjects that require treatment with an antipsychotic 
medication or a change in antipsychotic medication due to lack of efficacy, tolerability, safety 
issues or investigator/subject preference, will be eligible for the study. Subjects with a prior 
history of lack of response to oral or LAI risperidone or paliperidone treatment will not be 
eligible for the study. A screening phase of up to 4 weeks was chosen to allow adequate time for 
completion of all screening procedures with results available to the investigator before the first 
dose of oral paliperidone ER, and to allow for washout of the current OAP other than oral 
risperidone or oral paliperidone ER to occur. All subjects will initially be treated with oral 
paliperidone ER or oral risperidone during the Part I oral run-in phase, which will allow the 
investigator to evaluate efficacy and safety of paliperidone or oral risperidone and find an 
optimal dose. Subjects who find oral paliperidone ER or oral risperidone inadequately 
efficacious or who wish to change their OAP for reasons other than tolerability may be switched 
to another protocol-specified OAP. Subjects who find oral paliperidone ER or oral risperidone
intolerable will be withdrawn from the study. If the investigator believes that starting PP
treatment is not clinically appropriate in a given subject, the subject will be discontinued from 
the study prior to randomization. After randomization, treatment in the OAP treatment group will 
be provided in a similar fashion as in a regular practice, ie, switching or add-on of other OAPs is 
allowed. Seven commonly used OAPs are available to provide option to select the appropriate 
treatment for subjects. Subjects who switched off oral paliperidone ER or oral risperidone
treatment during Part I and II will be eligible to be randomized and continue treatment with OAP 
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or start treatment with PP when the investigator believes it is clinically appropriate. This 
approach is justifiable because studies have shown the clinical value of initiating LAI treatment 
in subjects who have not achieved adequate symptom control with an identical or chemically 
related oral antipsychotic, despite the similarities in mechanisms of action.1,46,87,106,111 This result 
may be explained by the assured knowledge of drug delivery with an LAI formulation. The 
relatively constant plasma paliperidone concentrations achieved over the dosing interval of 1 to 3 
months may also lead to longer sustained efficacy and improved tolerability.
Additional protective measures are incorporated into this protocol to assure safety of study 
subjects:

Only those subjects who have the capacity to provide informed consent will be allowed to 
enroll in the study;

Subjects will be carefully screened prior to enrollment, and subjects judged to be at high risk 
for AEs, violence, or self-harm will be excluded;

For optimal management of symptoms/tolerability, subjects receiving PP3M (during either 
Part II or Part III) may go back to treatment with PP1M (monthly injections of 78, 117, 156 
or 234 mg, flexibly dosed) for further dose adjustment or for the duration of the trial with 
the approval of the medical monitor;

Subjects should not be discontinued from their current antipsychotic, if effective, for the sole 
purpose of entering the study;

Subjects will receive any new information that may impact the benefit/risk of the 
investigational product and the subject’s willingness to continue in the study, as it becomes 
available;

Subjects may withdraw consent at any time and expect to receive regular, quality, 
conventional therapy;

Supportive psychotherapy, self-help, and educational programs are permitted to mitigate the 
potential effects of an ineffective dose of study medication;

Use of benzodiazepines and other rescue medications, and supplemental antipsychotic 
medications, are allowed to treat the symptoms that may emerge;

During the study, subjects will be monitored for any emergent medical and psychiatric 
illnesses, events, or symptoms that may introduce added health risks;

Subjects may be withdrawn from the study for any medical reason at the discretion of the 
investigator;

MRI uses no radiation. To date, no side effects from the magnetic fields and radio waves 
have been reported. Any subjects with metal implants that are incompatible with MRI 
scanning will be excluded from MRI scanning.
Additional risks may arise from the long-acting nature of the study drug. When an OAP is 
stopped, they are quickly eliminated from the body. This rapid elimination reduces the severity 
of most TEAEs. With LAI antipsychotics, the plasma concentrations are maintained for many 
weeks after injection. If a TEAE occurs, there is no effective way to accelerate the elimination. 
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However, many of the expected adverse effects can be managed with pharmacological 
intervention (eg, betablockers for akathisia, anticholinergics for EPS).
The total blood volume to be collected (approximately 50 mL) is considered to be less than a 
standard Red Cross blood donation and will be collected over the course of more than a year.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
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Approval for the collection of optional DNA samples for research and for the corresponding ICF 
must be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of 
this optional research component. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
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16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any 
study-related activity. The ICF(s) that is/are used must be approved by both the sponsor and by 
the reviewing IEC/IRB and be in a language that the subject can read and understand. The 
informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, including permission to obtain 
information about his or her survival status, and agrees to allow his or her study physician to 
recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for consent to provide optional DNA samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the subject 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the subject.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
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disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
DNA samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand paliperidone 
palmitate or oral antipsychotics, or schizophrenia and schizophreniform disorder. They may also 
be used to develop tests/assays related to paliperidone palmitate or oral antipsychotics and 
schizophrenia and schizophreniform disorder. The research may begin at any time during the 
study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2, Withdrawal From the Study (Withdrawal From the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
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sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement
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
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
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17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format.
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, scales other questionnaires) will be completed by the same 
individual who made the initial baseline determinations whenever possible. The investigator 
must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool.
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 3 
different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Site manager can generate a query for resolution by the study-site personnel.

Clinical data manager (CDM) can generate a query for resolution by the study-site 
personnel. 
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review CRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
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17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must 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 until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study center visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the CRF are known to the sponsor and 
study-site personnel and are accessible for verification by the sponsor study-site contact. If 
electronic records are maintained at the study site, the method of verification must be discussed 
with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
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In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
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17.11. Use of Information and Publication
All information, including but not limited to information regarding PP1M/PP3M or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomics or exploratory research data, 
generated as a result of this study, are considered confidential and remain the sole property of the 
sponsor. The investigator agrees to maintain this information in confidence and use this 
information only to accomplish this study, and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of PP1M/PP3M, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomics or 
exploratory MRI imaging analyses performed after the Clinical Study Report has been issued 
will be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
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Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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Clin Psychopharmacol. 2005;20:121–130.
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new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess 
routine social functioning. Acta Psychiatr Scand 2000;101:323-329.
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and Social Performance scale in patients with stable schizophrenia. Psychiatry Res. 2008;161:213-224. 
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long acting injectable formulations in the minipig (TOX10172). JRD, a division of Janssen Pharmaceutica 
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91.
Nonclinical Safety Study Report TOX8249. 12-Week local tolerance study of 2 paliperidone palmitate 
long acting injectable formulations in the minipig (TOX8249). Document No. EDMS-PSDB-7396388, 
issued September 2007. 
92.
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Developmental Processes in Schizophrenic Disorders: longitudinal studies of vulnerability and stress. 
Schizophr Bull. 1992;18(3):387-425.
93.
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selection, reliability, and validity. Am J Psychiatry. 2008;165:203-213.
94.
Nuechterlein KH, Subotnik KL, Ventura J, et al.  Long-acting injectable risperidone and medication 
adherence enhance cognition and work functioning after a first psychotic episode. Presented at the: 14th 
International Congress on Schizophrenia Research.  Orlando, Florida, USA, April 21-25, 2013.
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Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A 
meta-analysis of structural magnetic resonance imaging studies. Biological Psychiatry. 2011;70 (1):88-96. 
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interpretation of results of a pooled analysis of three Phase III trials of paliperidone extended-release 
tablets. Clin Ther. 2010 Feb;32(2):275-92.
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99.
Pompili M, Serafini G, Innamorati M, et al. Suicide risk in first episode psychosis: a selective review of 
the current literature. Schizophr Res. 2011 Jun;129(1):1-11.
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Schizophrenia. Janssen Research & Development. Document ID No.: EDMS-ERI-33981201:2.0.
101. Prouteau A, Verdoux H, Briand C, et al. Cognitive predictors of psychosocial functioning outcome in 
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Document ID No: EDMS-ERI-13413991, 9.0; Janssen Research & Development (24 February 2014).
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deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51:124–
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108. Subotnik KL, Nuechterlein KH, Ventura J, et al. Risperidone nonadherence and return of positive 
symptoms in the early course of schizophrenia. American Journal of Psychiatry. 2011;168:286-292.
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111. van Os J, Bossie CA, Lasser RA. Improvements in stable patients with psychotic disorders switched from 
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Attachment 1: Injection Site Guidelines
Guidelines for the intramuscular injection of paliperidone palmitate (1-month and 3-month 
formulations):

Doses should be given at approximately the same time each day

Prior to administration, it is critical to shake the PP1M and PP3M containing syringes 
vigorously for at least 10 and 15 seconds, respectively. 

The full content of the syringe should be injected

Muscle group (deltoid or gluteal) or side (right or left) should be alternated from one 
injection to the next
Site
Deltoid Injection Site
Gluteal Injection Site
Needle sizes 
for PP1M 
injections
<200 lbs (90 kg): 1 inch (23 gauge) needle
>200 lbs (90 kg): 1.5 inch (22 gauge) needle
All injections use 1.5 inch (22 gauge) needle
Needle sizes 
for PP3M 
injections
<200 lbs (90 kg): 1 inch (22 gauge) needle
>200 lbs (90 kg): 1.5 inch (22 gauge) needle
All injections use 1.5 inch (22 gauge) needle
Notes
Insert the needle at a 90 degree angle to the skin 
with a quick thrust. Insert the needle into the 
thickest portion of the deltoid muscle - above the 
level of the axilla and below the acromion.
Palpate the junction of the posterior iliac crest 
and sacrum. Then imagine drawing a line to the 
greater trochanter of the femur. Injection is 
given in the upper outer area bordered by this 
imaginary triangle.
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Attachment 2: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events: 
Schizophrenia
Psychotic disorder
Hallucination, auditory
Hallucination, visual 
Hallucination
Paranoia
Delusion
Apathy
Avolition
Drug use
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to health
authorities. However, if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
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INVESTIGATOR AGREEMENT
PPD
PPD
NCT02431702

SAP_001.pdf: 
1
Approved, Date: 6 December 2019
Janssen Research & Development, LLC
Statistical Analysis Plan
A Prospective, Matched-Control, Randomized, Open-Label, Flexible-Dose, Study in 
Subjects with Recent-Onset Schizophrenia or Schizophreniform Disorder to Compare 
Disease Progression and Disease Modification Following Treatment with Paliperidone 
Palmitate Long-Acting Injection or Oral Antipsychotics
Disease Recovery Evaluation and Modification (DREaM) Study
Phase 3b
Protocol R092670SCH3013
R092670 (paliperidone palmitate)
Status:
Approved
Date:
6 December 2019
Prepared by:
Janssen Research & Development, LLC  
Document No.:
EDMS-ERI-201245942, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design .................................................................................................................................... 10
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 16
1.3.1.
Part II: Disease Progression....................................................................................................... 17
1.3.2.
Part III: Extended Disease Progression and Disease Modification ............................................ 18
1.3.2.1.
Extended Disease Progression ............................................................................................... 18
1.3.2.2.
Disease Modification ............................................................................................................... 19
1.4.
Sample Size Determination ........................................................................................................... 20
1.5.
Randomization and Blinding .......................................................................................................... 21
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 23
2.1.
Analysis Phases............................................................................................................................. 23
TIME AND EVENTS SCHEDULE: SCREENING....................................................................................... 24
TIME AND EVENTS SCHEDULE: PART I, PART II, AND PART III......................................................... 25
2.1.1.
Study Reference Start and End Dates ....................................................................................... 27
2.1.2.
Analysis Phase Start and End Dates.......................................................................................... 27
2.1.3.
Study Day and Relative Day....................................................................................................... 28
2.2.
Baseline and End Point.................................................................................................................. 28
2.3.
Flagging Treatment Failures for Primary Analysis ..................................................................... 29
2.4.
Visit Windows................................................................................................................................. 29
2.5.
Analysis Sets.................................................................................................................................. 39
2.6.
Definition of Subgroups.................................................................................................................. 40
2.7.
Imputation Rules for Missing Dates ............................................................................................... 41
2.7.1.
Missing AE Dates ....................................................................................................................... 41
2.7.2.
Missing Concomitant Medication Dates ..................................................................................... 42
2.7.3.
Baseline Hospitalization Dates ................................................................................................... 42
2.7.4.
Baseline Characteristics and Prior Medications ......................................................................... 43
2.7.5.
Post Part I Baseline Hospitalization, Emergency Room Visit Dates .......................................... 43
3.
RULES FOR PRESENTATIONS....................................................................................................... 44
4.
SUBJECT INFORMATION................................................................................................................ 45
4.1.
Discontinuation/Completion Information ........................................................................................ 45
4.2.
Demographics and Baseline Characteristics ................................................................................. 45
4.3.
Extent of Treatment Exposure ....................................................................................................... 47
4.3.1.
Injections..................................................................................................................................... 47
4.3.2.
Oral Antipsychotics..................................................................................................................... 47
4.4.
Protocol Deviations ........................................................................................................................ 47
4.5.
Prior and Concomitant Medications ............................................................................................... 47
4.5.1.
Prior Psychotropic Medications .................................................................................................. 48
4.5.2.
Concomitant Benzodiazepines (Sedatives/Hypnotics/Anxiolytics)............................................. 48
4.5.3.
Concomitant Medications Other Than Benzodiazepines ........................................................... 49
4.5.4.
Concomitant Antiparkinsonian Medications................................................................................ 49
5.
EFFICACY ......................................................................................................................................... 49
5.1.
Level of Significance ...................................................................................................................... 49
5.2.
Part II, Primary Efficacy Endpoint .................................................................................................. 51
5.2.1.
Primary Estimand ....................................................................................................................... 52
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5.2.2.
Analysis Methods........................................................................................................................ 53
5.2.3.
Model Diagnostics ...................................................................................................................... 54
5.2.4.
Subgroup Analyses..................................................................................................................... 54
5.2.5.
Time to Treatment Failure by Reason........................................................................................ 54
5.2.6.
Multiple Events ........................................................................................................................... 55
5.3.
Part II, Key Secondary Endpoints .................................................................................................. 55
5.3.1.
MCCB – MATRICS Consensus Cognitive Battery ..................................................................... 56
5.3.1.1.
Definition.................................................................................................................................. 56
5.3.1.2.
Analysis Methods .................................................................................................................... 58
5.3.2.
PSP - Personal and Social Performance Scale ......................................................................... 59
5.3.2.1.
Definition.................................................................................................................................. 59
5.3.2.2.
Analysis Methods .................................................................................................................... 60
5.3.3.
MRI Brain Imaging Assessments ............................................................................................... 61
5.3.3.1.
Definition.................................................................................................................................. 61
5.3.3.2.
Analysis Methods .................................................................................................................... 63
5.4.
Secondary Endpoints..................................................................................................................... 64
5.4.1.
Treatment Failure ....................................................................................................................... 64
5.4.1.1.
Treatment Failure in EDP Phase............................................................................................. 64
5.4.1.2.
Treatment Failure in Part III..................................................................................................... 65
5.4.2.
MCCB – MATRICS Consensus Cognitive Battery ..................................................................... 67
5.4.2.1.
Definition.................................................................................................................................. 67
5.4.2.2.
Analysis Methods .................................................................................................................... 67
5.4.3.
PSP - Personal and Social Performance Scale ......................................................................... 69
5.4.3.1.
Definition.................................................................................................................................. 69
5.4.3.2.
Analysis Methods .................................................................................................................... 69
5.4.4.
MRI Brain Imaging Assessments ............................................................................................... 72
5.4.4.1.
Definition.................................................................................................................................. 72
5.4.4.2.
Analysis Methods .................................................................................................................... 72
5.4.5.
CGI-S - Clinical Global Impression of Severity Scale................................................................. 73
5.4.5.1.
Definition.................................................................................................................................. 73
5.4.5.2.
Analysis Methods .................................................................................................................... 73
5.4.6.
CRDPSS – Clinician-Rated Dimensions of Psychosis Symptom Severity................................. 74
5.4.6.1.
Definition.................................................................................................................................. 74
5.4.6.2.
Analysis Methods .................................................................................................................... 75
5.4.7.
MSQ – Medication Satisfaction Questionnaire........................................................................... 76
5.4.7.1.
Definition.................................................................................................................................. 76
5.4.7.2.
Analysis Methods .................................................................................................................... 76
5.5.
Part II, EDP Phase Exploratory Assessments ............................................................................... 77
5.5.1.
RUQ - Resource Utilization Questionnaire................................................................................. 77
5.5.1.1.
Definition.................................................................................................................................. 77
5.5.1.2.
Analysis Methods .................................................................................................................... 78
5.5.2.
Goal Setting and Daily Activity Evaluations................................................................................ 79
5.5.2.1.
Definition.................................................................................................................................. 79
5.5.2.2.
Analysis Methods .................................................................................................................... 80
6.
SAFETY............................................................................................................................................. 80
6.1.
Adverse Events .............................................................................................................................. 80
6.1.1.
EPS-Related Adverse Events.................................................................................................. 82
6.1.2.
Diabetes Mellitus and Hyperglycaemia-Related Adverse Events ........................................... 83
6.1.3.
Potentially Prolactin-Related Adverse Events......................................................................... 83
6.1.4.
Other Adverse Events of Special Interest ............................................................................... 83
6.2.
Clinical Laboratory ......................................................................................................................... 84
6.3.
Vital Signs, Weight, and BMI ......................................................................................................... 84
6.4.
ESRS-A - Extrapyramidal Symptoms Rating Scale – Abbreviated ............................................... 85
6.5.
ISST-Plus Short Form - InterSePT Scale for Suicidal Thinking – Plus.......................................... 86
REFERENCES............................................................................................................................................ 89
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LIST OF ATTACHMENTS.......................................................................................................................... 90
ATTACHMENT 1: Special Interest Adverse Events ................................................................................... 90
ATTACHMENT 2: Criteria of Markedly abnormal laboratory values........................................................... 98
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ABBREVIATIONS
ANCOVA
analysis of covariance
ANOVA
analysis of variance
bpm
Beats per minute
CMH
Cochran-Mantel-Haenszel
CRDPSS
Clinician-Rated Dimensions of Psychosis Symptom Severity scale (DSM-5)
CRF
case report form (paper or electronic as appropriate for this study)
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders (4th edition)
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
electrocardiogram
eDC
electronic data capture
ER
extended release
ESRS-A
Extrapyramidal Symptom Rating Scale-Abbreviated
GEE
Generalized Estimation Equations
GCP
Good Clinical Practice
ICF
informed consent form
ICM
intracortical myelin
IM
intramuscular
ISST-Plus
InterSePT Scale for Suicidal Thinking-Plus
ITT
intent-to-treat
IVRS
interactive voice response system
IWRS
interactive web response system
LAI
long-acting injectable
LOCF
last-observation-carried-forward
LS
least squares 
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia 
MCCB
MATRICS Consensus Cognitive Battery
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures
MRI
magnetic resonance imaging
MSQ
Medication Satisfaction Questionnaire
OAP
oral antipsychotic 
PPPP
paliperidone palmitate treatment sequence (PP1M followed by PP3M)
PP1M
paliperidone palmitate 1-month injection
PP3M
paliperidone palmitate 3-month injection
PSP
Personal and Social Performance scale
R076477
Sponsor's designation for study drug (paliperidone)
TEAE
treatment-emergent adverse event
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes study objectives, study design, and the sample size 
calculation based on protocol R092670-SCH-3013 (DREaM). This SAP also contains planned 
analyses, including definitions of analysis populations, derived variables, and statistical methods 
for the analysis of efficacy and safety data.
1.1.
Trial Objectives
The study includes 3 treatment phases: a 2-month, open-label, flexible-dose, oral run-in phase 
(Part I), and 2 sequential, 9-month, matched-control, randomized, open-label, active-controlled, 
flexible-dose treatment phases (Part II, referred to as the ‘Disease Progression Phase’ and 
Part III, referred to as the ‘Extended Disease Progression and Disease Modification Phase’). Part 
II and Part III each have their own objectives. 
An overview of the study design is provided in Figure 1.
Figure 1: Overview of the Study Design
   
                                   
                                      Part I                                                           Part II                                                                                Part III
                                     2-Months                                                    9 Months                                                                           9 Months
                                     Run-In                                                  Disease Progression                                                      Extended Disease Progression
                                                                                                                                                                                        and Disease Modification 
       = PP1M injection 
         = PP3M injection
a
All subjects will be started on paliperidone ER or oral risperidone. Subjects who find paliperidone ER/oral risperidone
intolerable will be withdrawn from the study; subjects who tolerate paliperidone ER/oral risperidone but find it inadequately 
efficacious may be switched to another protocol-specified OAP at the discretion of the investigator. 
b
Subjects randomized to the OAP treatment group will continue their OAP treatment (ie, paliperidone ER, or other OAP) from 
Part I. 
Note: For optimal management of symptoms/tolerability, subjects receiving PP3M (during either Part II or Part III) may go back
to treatment with PP1M (monthly injections of 78, 117, 156 or 234 mg, flexibly dosed) for further dose adjustment or for the
duration of the trial with the approval of the medical monitor.
OAP=oral antipsychotic; Pali ER=paliperidone extended-release; PP=paliperidone palmitate; PP1M=paliperidone palmitate
1-month injection; PP3M=paliperidone palmitate 3-month injection; SCZ=schizophrenia or schizophreniform disorder.
Part I Objectives: Run-In
The run-in phase is used to prospectively characterize the population enrolled and match subjects 
with similar characteristics so that, despite expected dropouts, subjects can be validly re-
randomized when the delayed-start treatment is initiated. This 2-month run-in phase will also be 
used to identify subjects who have a propensity to discontinue.
    PP
  OAP
(Pali ERa )
Subjects 
with
Recent-
Onset
SCZ
Randomize 
     (1:2)
Randomize 
      (1:1)
    PP (Delayed Start)
        PP
     OAP 
      OAPb
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Part II Objectives: Disease Progression
Subjects who complete the Part I oral run-in phase will enter Part II and will be randomized in a 
1:2 ratio to either start PP (paliperidone palmitate) treatment (ie, PP1M followed by PP3M) or to 
continue their OAP (oral antipsychotic) treatment from Part I. It is expected that most subjects 
will be receiving paliperidone ER at the start of Part II, but some subjects may be on an 
alternative OAP. The Part II treatment duration is 9 months.
Primary Objective

To compare the effectiveness of PP versus OAP treatment (ie, paliperidone ER, oral 
risperidone, or other OAP) in delaying time to first treatment failure over 9 months’ 
treatment in subjects with recent-onset schizophrenia or schizophreniform disorder.
Key Secondary Objectives:

To evaluate changes in cognition as measured by the Measurement and Treatment Research 
to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) 
composite score following 9 months’ treatment with PP compared to 9 months’ treatment 
with OAP.

To evaluate changes in functioning as measured by the Personal and Social Performance 
scale (PSP) following 9 months’ treatment with PP compared to 9 months’ treatment with 
OAP.

To evaluate changes in brain intracortical myelin (ICM) volume as measured by inversion 
recovery (IR) and spin echo (SE) magnetic resonance imaging (MRI) in the frontal lobe 
following 9 months’ treatment with PP compared to 9 months’ treatment with OAP.
Secondary Objectives:

To evaluate changes in cognition as measured by the individual domains of the MCCB (ie, 
working memory, verbal learning, speed of processing, attention/vigilance, visual learning, 
reasoning and problem solving, and social cognition) following 9 months’ treatment with PP 
compared to 9 months’ treatment with OAP.

To evaluate changes in illness severity as measured by the Clinical Global Impression-
Severity scale (CGI-S) following 9 months’ treatment with PP compared to 9 months’ 
treatment with OAP.

To evaluate changes in severity of psychotic symptoms, as measured by the 8 items of the 
Clinician-Rated Dimensions of Psychosis Symptom Severity scale (CRDPSS) (ie, delusions, 
hallucinations, disorganized speech, abnormal psychomotor behavior, negative symptoms 
[restricted emotional expression or avolition], impaired cognition, depression, and mania) 
following 9 months’ treatment with PP compared to 9 months’ treatment with OAP.

To evaluate changes in medication satisfaction as measured by the medication satisfaction 
questionnaire (MSQ) [patient-reported outcome] following 9 months’ treatment with PP 
compared to 9 months’ treatment with OAP.

To assess overall safety of PP.
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Exploratory Objectives:

To assess changes in resting state functioning MRI (fMRI), and changes in cortical 
thickness, gray matter volume, white matter volume, ventricular volume, intrasulcal CSF 
volume, and subcortical myelin integrity, as measured by MRI following 9 months’ 
treatment with PP compared to 9 months’ treatment with OAP.

To explore the overall healthcare resource utilization use as measured by the Resource 
Utilization Questionnaire (RUQ) following 9 months’ treatment with PP compared to 9 
months’ treatment with OAP.

To explore differences in satisfaction with goal setting following 9 months’ treatment with 
PP compared to 9 months’ treatment with OAP.

To explore quantitative assessments of daily activities following 9 months’ treatment with 
PP compared to 9 months’ treatment with OAP.

Additional objectives in Part II will include:
o
To evaluate changes in MCCB composite and domain scores by number of 
treatment failures.
o
To evaluate changes in PSP total and domain scores by number of treatment 
failures.
o
To examine correlations in change scores between MCCB and PSP total scores; 
and examine relationships on change scores among ICM volumes, MCCB scores, 
and PSP Total score.
Part III Objectives: Extended Disease Progression and Disease Modification 
Subjects who complete Part II will be eligible to enter Part III. At the start of Part III, subjects 
treated with OAP during Part II will be re-randomized in a 1:1 ratio to either continue treatment 
with OAP (OAP-OAP group) or to switch to PP (OAP-PP group). Subjects treated with PP 
during Part II will continue the same treatment (PP-PP group). The Part III treatment duration is 
9 months.
The Extended Disease Progression objectives will focus on comparisons between the OAP-OAP 
and PP-PP groups; the Disease Modification objectives will focus on comparisons between the 
PP-PP and OAP-PP groups (ie, subjects who started treatment with PP early vs. subjects who 
started PP treatment 9 months later).
Extended Disease Progression Objectives
Primary Objective

To compare the effectiveness of PP-PP versus OAP-OAP treatment in delaying time to first 
treatment failure over 18 months’ treatment in subjects with recent-onset schizophrenia or 
schizophreniform disorder.
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Key Secondary Objectives:

To evaluate changes in cognition as measured by the MCCB composite score following 
18 months’ treatment with PP compared to 18 months’ treatment with OAP in subjects with 
recent-onset schizophrenia or schizophreniform disorder.

To evaluate changes in functioning as measured by the PSP following 18 months’ treatment 
with PP compared to 18 months’ treatment with OAP.

To evaluate changes in brain ICM volume in the frontal lobe following 18 months’ 
treatment with PP compared to 18 months' treatment with OAP.
Secondary Objectives:

To evaluate changes in cognition as measured by the individual domains of the MCCB 
following 18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To evaluate changes CGI-S following 18 months’ treatment with PP compared to 
18 months’ treatment with OAP.

To evaluate changes in severity of psychotic symptoms, as measured by the 8 items of the 
CRDPSS following 18 months’ treatment with PP compared to 18 months’ treatment with 
OAP.

To evaluate changes in medication satisfaction as measured by the MSQ (patient-reported 
outcome) following 18 months’ treatment with PP compared to 18 months’ treatment with 
OAP.

To evaluate differences in time to first treatment failure and subsequent treatment failures 
over 18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To assess overall safety of PP. 
Exploratory Objectives:

To assess changes in resting state fMRI, and changes in cortical thickness, gray matter 
volume, white matter volume, ventricular volume, intrasulcal CSF volume, and subcortical 
myelin integrity, as measured by MRI following 18 months’ treatment with PP compared to 
18 months’ treatment with OAP.

To explore the overall healthcare resource utilization use as measured by the RUQ following 
18 months’ treatment with PP compared to 18 months’ treatment with OAP.

To explore differences in satisfaction with goal setting following 18 months’ treatment with 
PP compared to 18 months’ treatment with OAP.

To explore quantitative assessments of daily activities following 18 months’ treatment with 
PP compared to 18 months’ treatment with OAP.

Additional objectives in EDP phase will include:
o
To evaluate changes in MCCB composite and domain scores by number of 
treatment failures.
o
To evaluate changes in PSP total and domain scores by number of treatment 
failures.
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o
To examine correlations in change scores between MCCB and PSP total scores; 
and examine relationships on change scores among ICM volumes, MCCB scores, 
and PSP Total score.
Disease Modification Objectives:
Primary Objective

Using a delayed-start approach, to compare changes in cognition as measured by the MCCB 
composite score following 9 months’ additional PP treatment in subjects originally 
randomized to PP (PP-PP group) compared to 9 months’ delayed-start PP treatment in 
subjects originally randomized to OAP treatment (OAP-PP group).
Key Secondary Objectives:

Using a delayed-start approach, to compare changes in functioning as measured by the PSP 
following 9 months’ additional PP treatment in subjects originally randomized to PP (PP-PP 
group) compared to 9 months’ delayed-start PP treatment in subjects originally randomized 
to OAP treatment (OAP-PP group).

Using a delayed-start approach, to compare changes in brain ICM volume in the frontal lobe 
following 9 months’ additional PP treatment in subjects originally randomized to PP (PP-PP 
group) compared to 9 months’ delayed-start PP treatment in subjects originally randomized 
to OAP treatment (OAP-PP group).
Overall Primary Hypothesis
The overall primary hypothesis to be tested in this study is that 9 months’ treatment with PP is 
superior to 9 months’ treatment with OAP in delaying time to first treatment failure in subjects 
with recent-onset schizophrenia or schizophreniform disorder. The primary efficacy null 
hypothesis is that there is no difference in the distribution of time to first treatment failure in Part 
II between the PP and OAP treatment groups.
1.2.
Trial Design
This is a prospective, matched-control, randomized, open-label, active-controlled, flexible-dose, 
multi-center study designed to compare the effectiveness of PP versus OAP in delaying time to 
first treatment failure in subjects with recent-onset schizophrenia or schizophreniform disorder. 
The study will also evaluate whether long-acting injectable (LAI) treatment with PP can slow 
disease progression and possibly modify disease course compared to OAP medications, by 
tracking changes in cognition, functioning, and frontal lobe ICM volume. Other efficacy, safety, 
and exploratory endpoints will also be assessed. 
Approximately 275 men and women between the age of 18 and 35 years, who have a diagnosis 
of schizophrenia or schizophreniform disorder who experienced their first psychotic episode 
within 2 years of study entry will be enrolled. The total study duration for each subject will be 
approximately 86 weeks, including a screening phase (up to 4 weeks), a 2-month oral run-in 
phase (Part I), and two 9-month treatment phases (Part II and Part III). The study periods are 
briefly described below:
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
Screening (up to 4 weeks; Day -28 to -1): Subjects who provide written informed consent 
will undergo the screening procedures, including a review of the study entry criteria. Any 
prestudy OAP will be tapered off and must be discontinued by Week 5 of Part I. Tapering of 
the previous OAP can start at the beginning of the screening period. Tapering and 
discontinuation should be managed by the investigator, as clinically appropriate.

Part I, Oral Run-In Phase (2 months): After completing the screening period, subjects 
meeting the inclusion and exclusion criteria will be entered into Part I, a 2-month oral run-in 
phase. All subjects will initially receive flexible dosing with oral paliperidone ER (1.5-12 
mg/day) or oral risperidone (1-6 mg). Treatment with oral paliperidone ER or oral 
risperidone will enable investigators to establish tolerability prior to randomization to the 
LAI formulation in Part II. Subjects who find oral paliperidone ER or oral risperidone 
intolerable will be withdrawn from the study. Subjects who tolerate oral paliperidone ER or 
oral risperidone but find it inadequately efficacious after treatment for an adequate duration 
at an adequate dosage, may be switched to another protocol-specified OAP at the discretion 
of the investigator. Any of the following 7 OAPs are permitted: aripiprazole, haloperidol, 
olanzapine, paliperidone ER, perphenazine, quetiapine, and risperidone. The following 
demographic and baseline characteristics and clinical data will be collected during Part I to 
be used for matching during randomization into Part II and Part III: age, gender, race, prior 
antipsychotic exposure, substance use history, MCCB composite score, and PSP total score.  

Part II, Disease Progression Phase (9 months): Subjects who complete Part I will be 
eligible to enter Part II. On Day 1 of Part II (Day 57 of Part I), subjects will be randomized 
in a 1:2 ratio to open-label treatment with either PP or to continued OAP treatment for 9 
months. Dynamic central randomization will be performed, based on matching criteria 
determined in Part I. It is estimated that approximately 225 subjects will be randomized in 
Part II, ie, approximately 75 subjects will be randomized to the PP treatment group and 150 
subjects to the OAP treatment group.

Subjects randomly assigned to the OAP treatment group will continue their OAP 
treatment from Part I. It is expected that most subjects will be receiving oral 
paliperidone ER or oral risperidone, but some subjects may be receiving an alternative 
OAP. Investigators are encouraged to continue the original OAP (ie, the OAP at Part II 
baseline) as monotherapy throughout the remainder of the study but, if clinically 
indicated, a switch to an alternative OAP or add-on of an additional OAP is permitted 
after the first randomization visit. Switching or add-on of another OAP due to 
inadequate efficacy, tolerability, or safety will be assessed as a treatment failure. 
Subjects with treatment failure will continue participation in the study. Multiple 
switches (ie, treatment failures) are permitted during the study. The same 7 OAPs 
identified in Part I are allowed (ie, aripiprazole, haloperidol, olanzapine, paliperidone 
ER, perphenazine, quetiapine, and risperidone). 

Subjects randomly assigned to the PP treatment group will receive 5 doses of PP1M 
followed by PP3M once every 12 weeks. PP1M initiation dosing (first injection 234 mg 
[150 mg eq.] on Day 1 of Part II and second injection 156 mg [100 mg eq.] on Day 8, 
both in the deltoid muscle) followed by 3 injections of flexible doses of PP1M 
(78-234 mg [50-150mg eq.]) on Days 36, 64, and 92, either in the deltoid or gluteal 
muscle. On Day 120, subjects will receive an injection of PP3M (using a 3.5-fold 
multiple of the PP1M dose received on Day 92) either in the deltoid or gluteal muscle. 
On Day 204, subjects will receive a flexible dose of PP3M (273-819 mg [175-525 mg 
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eq.]) either in the deltoid or gluteal muscle. Investigators are encouraged to use PP1M 
and PP3M as antipsychotic monotherapy and to adjust the injection dose for 
management of symptoms/tolerability. If required, supplemental oral paliperidone ER
(up to 6 mg/day) or oral risperidone (up to 3 mg/day) may be given. It should be noted 
that adding oral paliperidone/oral risperidone will not be considered a treatment failure 
unless supplemental paliperidone ER/oral risperidone is given for a combined total of 
more than 84 days or if paliperidone ER doses exceed 6 mg/day or oral risperidone 
doses exceed 3 mg/day (see further details in the Dosage and Administration Section). 
Adding any other antipsychotic will also be considered a treatment failure. Subjects 
with treatment failures will continue the study unless the PP injection is discontinued 
permanently. 

Part III, Extended Disease Progression and Disease Modification Phase (9 months): 
Subjects who complete Part II will be entered into Part III. On Day 1 of Part III (Day 260 of 
Part II), subjects in the OAP treatment arm will be re-randomized in 1:1 ratio to continued 
treatment with their OAP (OAP-OAP group) or to PP (OAP-PP or ‘Delayed-start PP’ arm). 
The Delayed-start PP arm will receive PP1M and PP3M treatment as described in Part II (ie, 
5 doses of PP1M followed by PP3M once every 12 weeks). Subjects previously assigned to 
treatment with PP in Part II will continue in that treatment group with PP3M injections 
every 12 weeks for a total of 3 injections (PP-PP group). Randomization will be based on 
matched criteria identified in Part I. Subjects will be followed for an additional 9 months.  
Subjects will be assessed for treatment failure at all visits during Part II and Part III. Other 
efficacy assessments (MCCB, PSP, CGI-S, CRDPSS, and MSQ) will be performed as specified 
in the Time and Events Schedule. Safety will be monitored through evaluation of AEs, clinical 
laboratory parameters, vital signs, body weight, ESRS, ISST-Plus, and physical examination 
findings. Resource use (measured using the RUQ), goal setting experience, and quantitative 
assessment of daily activities will be assessed as exploratory endpoints. A pharmacogenomic 
blood sample will be collected from subjects who consent separately to this component of the 
study (where local regulations permit). Subject participation in pharmacogenomic research is 
optional.
Approximately half of the enrolled subjects will also undergo brain MRI scans for assessment of 
ICM volume and other exploratory MRI endpoints. In addition, approximately 20 healthy control 
subjects (comparable in age, sex, and race to the subjects with schizophrenia/schizophreniform
disorder undergoing MRI scans) will be identified at each MRI center and followed as controls 
for the MRI machine calibration for the duration of the study without treatment. 
Note that subjects who experience a treatment failure and do not withdraw consent or meet the 
criteria for withdrawal from the study will continue in the study and be followed through to the 
end of the study.
Subjects who miss scheduled injections or visits are allowed to re-enter the same assigned 
treatment group of the study.
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Treatment Failure Criteria
Subjects will be assessed at each visit during Part II and Part III for the occurrence of treatment 
failure. Treatment failure is defined as any of the following: 1) Psychiatric hospitalization due to 
worsening symptoms (including Emergency Room visits ≥23 hours, and not including 
hospitalization due to social reasons); 2) Any deliberate self-injury, suicidal ideation or behavior, 
homicidal ideation or violent behavior that is clinically significant and needs immediate 
intervention as determined by the study physician; 3) New arrest/incarceration (not related to 
probation or existing warrant); 4) Discontinuation of antipsychotic treatment due to inadequate 
efficacy as determined by the study physician; 5) Discontinuation of antipsychotic treatment due 
to safety or tolerability as determined by the study physician; 6) Treatment supplementation with 
another antipsychotic due to inadequate efficacy as determined by the study physician (note: use 
of oral paliperidone ER or oral risperidone in the PP treatment group will not be considered a 
treatment failure unless supplemental treatment with oral paliperidone ER or oral rispedone is 
longer than 84 days or if paliperidone ER doses exceed 6 mg/day or oral risperidone doses 
exceed 3 mg/day); 7) Increase in the level of psychiatric services (such as from office visit to day 
hospitalization) in order to prevent imminent psychiatric hospitalization as determined by the 
study physician.
Any changes in antipsychotic medications (switching, discontinuation, or add-on) must be 
evaluated against the treatment failure criteria. If any of these changes do not meet the treatment 
failure criteria, these must be documented and recorded in the eDC.
Subject Population
Subjects with schizophrenia or schizophreniform disorder: Approximately 275 subjects who 
meet all of the inclusion and none of the exclusion criteria will be enrolled in the study. Refer to 
the main text for a complete list of inclusion and exclusion criteria.  
The major inclusion criteria include the following: men and women aged 18 to 35 years, 
inclusive, current diagnosis of schizophrenia (295.90) or schizophreniform disorder (295.40) as 
defined by DSM-5 and confirmed by the Structured Clinical Interview for DSM-5 Disorders 
(SCID) with a first psychotic episode within the last 24 months, and requiring treatment with an 
antipsychotic medication or a change in antipsychotic medication due to lack of efficacy, 
tolerability, safety issues, or investigator/subject preference. 
The major exclusion criteria include: positive urine drug screen test for cocaine, amphetamines, 
opiates, or PCP at screening; current DSM-5 diagnosis of dissociative disorder, bipolar disorder, 
major depressive disorder, schizoaffective disorder, autistic disorder, or intellectual disabilities; 
and meets the DSM-5 definition of moderate or severe substance use disorder (except for 
nicotine) within 2 months prior to screening.
Healthy Control Subjects: Each MRI site will identify and enroll approximately 20 healthy 
control subjects who will undergo MRI assessments only. These healthy control subjects should 
be comparable in age, sex, and race to the cohort of subjects with schizophrenia/schizophrenia 
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disorder undergoing MRI scans. Refer to the main text for a complete list of inclusion and 
exclusion criteria.
Major exclusion criteria are: evidence of a known psychiatric disorder, neurological disorder (eg, 
epilepsy) or significant head injury; first degree relative who has schizophrenia, 
schizophreniform, schizoaffective, or bipolar disorder; or meets the DSM-5 definition of 
moderate or severe substance use disorder (except for nicotine) within 2 months prior to 
screening. Subjects who are unable to undergo MRI scan for any reason, including because of 
body size (unable or difficult to fit in MRI instrument) or MRI contraindicated due to presence of 
metallic objects (pacemaker, etc.) will also be excluded.
Dosage and Administration
Part I, Oral Run-In Phase
During Part I, all subjects will initially be treated with paliperidone ER (1.5 to 12 mg/day) or oral 
risperidone (1-6 mg/day). Any prestudy OAP other than risperidone or oral paliperidone ER will 
be tapered off and must be discontinued by Week 5 of Part I. Subjects already being treated with 
oral risperidone or oral paliperidone ER should be continued at the dose deemed to be most appropriate 
by the investigator). Adjustment of the dosage will be done at the investigator’s discretion, based on the
individual subject’s clinical response to and tolerability of the study drug. To be eligible for
randomization in Part II, subjects must be able to tolerate a minimum dose of 3 mg of oral paliperidone or 
2 mg of oral risperidone for at least 2 weeks prior to entry to Part II. Subjects who find either oral
paliperidone ER or oral risperidone intolerable will be withdrawn from the study. Subjects who tolerate
oral paliperidone ER/oral risperidone but find it inadequately efficacious after treatment for an adequate
duration at an adequate dosage (per clinical judgment), may be switched to another protocol-specified
OAP at the discretion of the investigator. The following 7 OAPs are permitted: aripiprazole, haloperidol,
olanzapine, oral paliperidone ER, perphenazine, quetiapine, and risperidone.
Part II and Part III, Active-Controlled Treatment Phases
Paliperidone Palmitate (PP1M/PP3M) 
All drug injections must be administered by an individual who has received appropriate medical 
training to administer an IM injection. 
Subjects who are randomly assigned to the PP treatment group at the start of Part II will 
discontinue their OAP treatment from Part I and will be started on PP1M. Subjects will be 
subsequently switched to PP3M following 5 injections of PP1M. A transition period of a 
maximum of 5 weeks will be allowed for the previous OAP.
PP1M will be administered IM once-monthly, after the first 2 injections that are given one week 
apart (Day 1 and Day 8). The first two doses will be administered through a deltoid injection on 
alternating arms. The subsequent injections can be given either in the deltoid or the gluteal 
muscle. The first dose of PP1M will be 234 mg given in the deltoid muscle at Day 1 of the 
treatment phase. The second dose of PP1M will be 156 mg given in the deltoid muscle at Day 8 
of the treatment phase. Subsequent doses of PP1M on Days 36, 64, and 92 will be given every 28 
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(±7) days in either the deltoid or gluteal muscle. The investigator may select from 78, 117, 156, 
or 234 mg, according to the subjects’ clinical needs. Subjects will continue to return to the study 
site every 4 weeks for injections and for study evaluations. 
At the Day 120 visit (±7 days), subjects will start PP3M treatment. The initial PP3M dose will be 
calculated as 3.5 fold multiple of the final PP1M dose administered on Day 92. Subjects will 
receive PP3M injections once every 12 weeks (±14 days). Investigators will be permitted to 
flexibly adjust the dose of PP3M as clinically necessary with the dose options for PP3M being 
273, 410, 546, or 819 mg. Injections of PP3M may be administered in either the deltoid muscle 
or the upper outer portion of the gluteal muscle. The side of each injection (left or right) should 
be alternated and recorded. 
Supplemental OAP Use in the PP Treatment Group: Investigators are strongly encouraged to use 
PP1M and PP3M as antipsychotic monotherapy and to adjust the injection dose for management 
of symptoms/tolerability. Subjects in the PP treatment group who are tolerating the medication 
but experience symptom exacerbation during the study will be allowed to have supplemental 
antipsychotic medication, ie, oral paliperidone ER (up to 6 mg/day or oral risperidone (up to 3 
mg/day, for no longer than a total of 84 days during the total PP treatment period. If the 
supplemental treatment with oral paliperidone ER/oral risperidone is longer than 84 days or if 
oral paliperidone ER doses exceed 6 mg/day or oral risperidone doses exceed 3 mg/day, the 
subject will be considered a treatment failure. Adding any other antipsychotic will also be 
considered a treatment failure.
A switch to an alternative antipsychotic is not permitted in the PP treatment group. If it is 
deemed clinically necessary to stop PP1M or PP3M in a subject assigned to PP treatment, the 
subject will be withdrawn from the study and discontinuation of PP will be recorded as a 
treatment failure.  
Oral Antipsychotic Treatment 
Subjects randomly assigned to the OAP treatment group at the start of Part II will continue their 
OAP treatment from Part I. It is expected that most subjects will be receiving oral paliperidone 
ER or oral risperidone, but some subjects may be receiving an alternative OAP at entry into Part 
II. 
Investigators are encouraged to continue the same OAP (ie, the OAP at Part II baseline) as 
monotherapy throughout the remainder of the study, and to adjust the OAP dose for management 
of symptoms/tolerability at any time. After the initial randomization visit, a switch to a different 
OAP or the addition of another OAP is allowed in the OAP treatment arm if clinically indicated; 
however, switching or add-on of another OAP due to inadequate efficacy, tolerability, or safety 
will be assessed as a treatment failure. The same 7 OAPs specified for Part I (aripiprazole, 
haloperidol, olanzapine, paliperidone ER, perphenazine, quetiapine, and risperidone) will be 
permitted. Multiple switches to other protocol-specified OAPs will be allowed during the study. 
Any change in antipsychotic medication (switching, discontinuation, or add-on) must be 
evaluated against the treatment failure criteria.
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Administration of PP or an alternative LAI antipsychotic is prohibited in subjects assigned to 
OAP treatment. If an LAI agent is deemed clinically necessary for subjects assigned to the OAP 
group, their data will be censored as a treatment failure and they will be discontinued from the
study.
Subjects should generally be treated within the approved label for all OAPs. Any exceptions 
should first be discussed with the Medical Monitor.
1.3.
Statistical Hypotheses for Trial Objectives
The overall primary hypothesis to be tested in this study is that 9 months’ treatment with PP is 
superior to 9 months’ OAP treatment in delaying time to treatment failure in subjects with 
recent-onset schizophrenia or schizophreniform disorder. This will be assessed at the end of Part 
II.
Other hypotheses to be evaluated in this study will assess whether LAI treatment with PP can 
slow down disease progression and possibly modify disease course in recent-onset subjects 
compared to OAP medications. This will be assessed by tracking changes in cognition (MCCB 
composite score), functioning (PSP), and brain imaging assessments (ICM volume). 
Hypothetical outcomes of the DREaM study are shown schematically in Figure 2. Panels A and 
B differ with respect to the size of δ31 (i.e., the Part 3 difference between delayed-start and 
patients on PP throughout the trial). Panel A is titled, “Treatment Effect on Disease Progression 
and Modification”; Panel B is titled, “Delayed-Start Treatment Effect”. Numerically higher 
scores are assumed to correspond to better outcomes. Based on prior experience and the 
likelihood that patients randomized to OAP will be less compliant with taking their medications, 
we expect that in Part 2 patients randomly assigned to OAP's will experience a greater degree of 
disease progression than those receiving PP. In Part 3, if PP has disease modifying effects, the 
two PP groups (immediate start and delayed-start) will have similar slopes and will be parallel, 
such that differences that develop after an early start are not overcome and the between groups 
measures of disease progression do not catch up (Panel A). If early introduction of PP does not 
have disease-modifying effects, the size of δ31 will significantly decrease compared to δ21 (the 
difference between treatment groups at the start of Part 3) (Panel B). The delayed-start treatment 
benefit is measured by the size of the difference between δ31 and δ21.
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Figure 2: Hypothetical outcomes of DREaM, assuming higher scores correspond to better
outcomes
1.3.1.
Part II: Disease Progression
The overall primary hypothesis in this study is that 9 months’ treatment of subjects with recent-
onset schizophrenia or schizophreniform disorder with PP is superior to 9 months’ treatment 
with OAP in delaying time to first treatment failure. The primary efficacy null hypothesis is that 
there is no difference in the distribution of time to first treatment failure in Part II between the PP 
and OAP treatment groups.
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The key secondary hypotheses to be tested in Part II of this study are to demonstrate that 9 
months’ treatment of subjects with recent-onset schizophrenia or schizophreniform disorder with 
PP is superior to 9 months’ treatment with OAP in: 

improving or maintaining cognition (as measured by the change in MCCB composite score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in mean change 
from Part II baseline to the Part II end point in the MCCB composite score between PP 
and OAP

maintaining functioning (as measured by time to 7-point worsening in the PSP total score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in time to 
7-point worsening in PSP total score in Part II between PP and OAP

increasing or preserving brain ICM volume of the frontal lobe as compared to baseline 

The key secondary efficacy null hypothesis is that there is no difference in mean change 
in ICM volume of the frontal lobe from Part II baseline to the Part II end point between 
PP and OAP 
1.3.2.
Part III: Extended Disease Progression and Disease Modification
1.3.2.1.
Extended Disease Progression 
Let it be assumed that the quantity δ33 in Error! Reference source not found. represents the 
cumulative effect on disease progression at the end of Part III following early start for PP 
compared to continuing OAP after a total of 18 months of treatment. The Extended Disease 
Progression hypotheses to be tested in Part III of this study are to demonstrate that 18 months’ 
treatment of subjects with recent-onset schizophrenia or schizophreniform disorder with PP is 
superior to 18 months’ treatment with OAP in:

the overall primary hypothesis to be tested in this phase of the study is that 18 months’ 
treatment with PP-PP is superior to 18 months’ OAP-OAP treatment in delaying time to 
treatment failure in subjects with recent-onset schizophrenia or schizophreniform disorder.

improving or maintaining cognition (as measured by the change in MCCB composite score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in mean change 
from Part II baseline to the Part III end point in the MCCB composite score between 
PP and OAP. In other words, H0: δ33 = 0 for MCCB composite score.

maintaining functioning (as measured by time to 7-point worsening in the PSP total score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in time to 
7-point worsening in PSP total score from Part II baseline to the Part III end point 
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
increasing or preserving brain ICM volume of the frontal lobe as compared to baseline

The key secondary efficacy null hypothesis is that there is no difference in mean change 
in ICM volume of the frontal lobe from Part II baseline to the Part III end point 
between PP and OAP 
1.3.2.2.
Disease Modification
In order to demonstrate disease modification, the following results are required: 

At the end point of Part II: Subjects treated with PP for 9 months (early-start group) must 
demonstrate better outcomes on MCCB than those treated with OAP for 9 months. Similar 
results for changes in functioning (PSP) and changes in brain anatomy (ICM) will be used to 
support this finding (ie, treatment effect on disease progression).

At the end point of Part III: Subjects from Part II who have been treated with PP for 
18 months (early-start group) must continue to show better outcomes on MCCB compared 
with subjects treated with OAP for 18 months (a differential treatment effect is still evident), 
and compared with subjects treated with OAP for 9 months followed by PP for 9 months 
(the lead treatment effect remains significant after 9 months); ie, that late initiation of 
treatment with PP does not allow for achievement of the same level of cognition after 
9 months. [(See corresponding null hypothesis below (H0: δ31 – γ. δ21 ≤0)]. Similar results 
for changes in PSP and ICM will be used to support this finding for disease modification.
For each of the endpoints (MCCB, PSP, and ICM), the following hypotheses will be tested as a 
function of estimated changes in the Part II endpoint using the observed scores. Let δ21 denote 
the estimated mean differences between treatment groups at the end of Part II for a given 
endpoint, treatment effect on disease progression. Below, the parameter μPP-PP corresponds to the 
mean score for a given endpoint following 9 months’ of additional PP3M treatment in subjects 
originally randomized to PP and μOAP-PP corresponds to mean score for 9 months’ of delayed-
start PP treatment in subjects originally randomized to OAP treatment. Let δ31 denote the 
estimated difference between μPP-PP and μOAP-PP, lead treatment effect at the end of Part III. The 
corresponding null hypotheses for a given endpoint will be listed as:
H0: δ31 – γ. δ21 ≤0, where γ is a fixed number between 0 and 1 indicating the ratio of 
treatment effect in Part III compared to the Part II observed differences.
The quantity γ will be determined after Part II database lock and prior to finalization of Part III 
Statistical Analysis Plan. For γ, the quantities 0.75 and 0.50 will be considered principally. The γ 
could be different for a different endpoint. The quantity γ is called conditional noninferiority 
margin.
In addition, for each of the endpoints, δ32 (delayed-start treatment effect on disease progression) 
will be tested in Part III using Part III baseline scores. Below, the parameter μOAP-PP corresponds 
to mean score for 9 months’ of delayed-start PP treatment in subjects originally randomized to 
OAP treatment and μOAP-OAP corresponds to the mean score for a given endpoint following 
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
20
Approved, Date: 6 December 2019
9 months’ of additional OAP treatment in subjects originally randomized to OAP. The 
corresponding null hypotheses for a given endpoint will be listed as:
H0: δ32 = μOAP-PP - μOAP-OAP = 0.
The quantity δ33 represents the cumulative effect on disease progression at the end of Part III 
following early start for PP compared to continuing OAP after a total of 18 months of treatment. 
At the conclusion of Part III, the database will again be locked and data analyzed to assess 
response in variables δ31, δ32, and δ33 (overall effect of treatment). Positive results (δ33 is 
significant [a differential treatment effect is still evident] and δ31 is significant [the lead effect 
remains significant after 9 months]) will be used to support a conclusion for disease 
modification.
1.4.
Sample Size Determination
The overall primary efficacy null hypothesis is that there is no difference in the distribution of 
time to treatment failure between the PP and OAP in the treatment of subjects with recent-onset 
schizophrenia or schizophreniform disorder in Part II. Treatment differences will be compared 
using a log-rank test. It is assumed that treatment failure rate in Part II is approximately 40% for 
the OAP group and 20% for the PP group at month 9 with a corresponding hazard ratio of 0.44. 
It is also assumed that the hazard rates of treatment failure for the two groups are proportional. 
Additional assumptions made to calculate the expected number of subjects that need to be 
randomized to obtain the required number of treatment failures are: 

In both treatment groups, 10% of the randomized subjects will be lost-to-follow-up.

Uniform accrual rate during the 15 month accrual period. 
With these assumptions, it is planned to randomize 225 (75 in PP and 150 in OAP group) 
subjects in a 1:2 ratio to receive either PP or OAP to obtain at least 62 treatment failures to show 
that PP is significantly different from OAP at the 2 sided significance level of 0.05, with 80% 
power to detect a hazard ratio of 0.44 using a log rank test. 
Blinded surveillance of the total number of events in Part II will be performed during the study 
to assess the appropriateness of the assumptions. The number of subjects enrolled and the 
number of subjects who discontinue before entering Part II will be closely monitored.
Assuming 20% attrition rate during the 2-month Run-in period (Part I), the total number of 
subjects to be enrolled in Part I will be approximately 275.
One of the key secondary efficacy null hypotheses in Part II is that there is no difference in mean 
change from Part II baseline to the Part II end point in the MCCB composite score between PP 
and OAP in the treatment of subjects with recent-onset schizophrenia or schizophreniform 
disorder. The corresponding efficacy variable is the change in the MCCB composite score. This 
variable will be analyzed in Part II using mixed-effects repeated measures analysis of covariance 
(ANCOVA) model, described later. Similarly, the matching null hypothesis in Part III is that 
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
21
Approved, Date: 6 December 2019
there is no difference in mean change from Part II baseline to the Part III end point in the MCCB 
composite score between PP and OAP in the treatment of subjects with recent-onset 
schizophrenia or schizophreniform disorder.
This is the first study to assess the efficacy of PP on cognition in subjects with recent-onset 
schizophrenia or schizophreniform disorder. A small study comparing the clinical efficacy of the 
long-acting injectable formulation of risperidone (RLAI) to the oral formulation of risperidone 
(oral Ris) in the early course of schizophrenia in UCLA Aftercare Research program showed an 
effect size of 0.46 between the treatment groups in the MCCB composite score (change from 
baseline) at Month 6 end point. We consider an effect size of 0.3 and above to be clinically 
meaningful for cognition in a therapeutic area where there are no known effective treatments. 
Assuming an effect size of approximately 0.40 for the difference in the mean change from Part II 
baseline to Part II end point in the MCCB composite score between PP and OAP, with 1:2 
randomization ratio, sample sizes of 75 subjects in the PP group and 150 subjects in the OAP 
group are necessary to provide 80% power based on a two group t-test with a 0.05 two-sided 
significance level. This computation is also consistent with the time to treatment failure 
calculations ignoring correlations among these endpoints.
It is assumed that approximately 20% of subjects who entered Part II will not be transitioned to 
the Part III (Extended Disease Progression and Disease Modification) period in each treatment 
group. Approximately, a total of 180 subjects will be available at the Part III baseline. Subjects 
in the OAP treatment arm will be re-randomized in a 1:1 ratio to continued treatment with their 
oral treatment or to PP (delayed-start PP arm). Subjects previously assigned to treatment with PP 
in Part II will continue in that treatment in Part III. Thus, approximately 60 subjects will be 
available for each treatment group at the Part III baseline. Assuming approximately 5% of 
subjects will be missing either the Part III baseline or all post-baseline MCCB assessments, a 
sample size of 57 in each group will have 80% power to detect an effect size of 0.53 between PP 
and OAP in the difference in the mean change from Part II baseline in the MCCB composite 
score using a two group t-test with a 0.05 two-sided significance level in Part III. The primary 
objective in Part III is to compare changes in cognition following 18 months’ treatment with PP 
compared to 18 months’ treatment with OAP.
1.5.
Randomization and Blinding
Procedures for Randomization and Stratification
There will be 2 randomizations in this study, once at the start of Part II and once at the start of 
Part III. Randomization will be used to minimize bias in the assignment of subjects to treatment 
groups, to increase the likelihood that known and unknown subject attributes (eg, demographic 
and baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups.
Matching will be performed using dynamic central randomization. In Part II, subjects will be 
assigned to receive either PP or OAP in a 1:2 ratio based on an algorithm implemented in the 
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
22
Approved, Date: 6 December 2019
interactive voice response system (IVRS) or interactive web response system (IWRS) before the 
study. It is estimated that approximately 225 subjects will be randomized in Part II; therefore 
approximately 75 subjects will be randomized to the PP treatment group and 150 subjects to the 
OAP treatment group. Dynamic central randomization minimizes the imbalance in the 
distribution of the number of subjects across treatment groups within the levels of each 
individual stratification factor: age, race, gender, duration of previous antipsychotic usage prior 
to screening, baseline MCCB composite score, baseline PSP score, substance use history, MRI 
participation, and site. Based on the algorithm, the IVRS/IWRS will assign a unique treatment 
code, which will dictate the treatment assignment. The requestor must use his or her own user 
identification and personal identification number when contacting the IVRS/IWRS, and will then 
give the relevant subject details to uniquely identify the subject. To eliminate the predictability 
of randomization for the next subject, treatment assignment probabilities will also be utilized. 
Subjects who complete Part II will be entered into Part III. On Day 1 of Part III (Day 260 of 
Part II), subjects in the OAP treatment arm will be re-randomized in a 1:1 ratio to continued 
treatment with their oral treatment or to PP (Delayed-start PP arm). The Delayed-start PP arm 
will receive PP1M and PP3M treatment as described in Part II (ie, 5 doses of PP1M followed by 
PP3M once every 12 weeks). Subjects previously assigned to treatment with PP in Part II will 
continue in that treatment group with PP3M injections every 12 weeks for a total of 3 injections. 
Randomization will be based on matched criteria identified in Part I. Similar to the Part II 
randomization, dynamic central randomization will be implemented for Part III. Stratification 
factors will include age, race, gender, duration of previous antipsychotic usage prior to 
screening, baseline PSP score at Part I, baseline MCCB score at Part I, substance abuse history, 
and site. 
Subjects who re-enter the study after missing scheduled injections or visits must stay in the same 
assigned treatment group.
Blinding 
No blinding of investigators or subjects will be used in this study. 
Centralized blinded evaluations will be utilized for the assessment of imaging endpoints (eg, 
ICM volume) to reduce potential bias during data collection and evaluation. For the imaging 
endpoints, the assessment of the MRI images will be performed by a rater who is blinded to 
drug-treatment information and to clinical and demographic characteristics of the subjects. 
MCCB assessments will be performed by raters at each study site and there is no blinding for the 
local MCCB raters. All MCCB data collected at each study site will be sent to central raters for 
review. Assessments will each be scored by central raters who are blinded to treatment 
information. Central raters will also review the neurocognitive data quality and correct any 
errors. The central raters will enter the final scores into the MCCB Scoring program to derive 
T-scores and composites scores and enter the raw and derived MCCB scores to the eDC.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
23
Approved, Date: 6 December 2019
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Analysis Phases
There are 4 analysis phases defined in this study, see Time and Event Schedule: 

Screening: Up to 4 weeks, Day -28 to Day -1.

Part I, Oral Run-In Phase: 2 Months

Part II, Disease Progression Phase: 9 Months

Part III, Extended Disease Progression and Disease Modification Phase: 9 Months. Extended 
Disease Progression part and Disease Modification part differs with respect to duration of 
examination period.
Each analysis phase has its own analysis phase start and end dates.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
24
Approved, Date: 6 December 2019
TIME AND EVENTS SCHEDULE: SCREENING
Treatment Phase
Screening
Visit:
1
Day (Part I)
-28 to -1
Screening/Administrative
Informed consent
X
Informed consent for optional genetic research samples
X
Inclusion/exclusion criteria
X
Medical and psychiatric history
X
SCID
X
Pre-morbid IQ estimate (WTAR)a
X
Urine Drug Screen
X
Informed consent for the subject's designated individual
X
Efficacy Assessments
MCCB
X
PSP
X
CRDPSS (DSM-5)
X
CGI-S
X
MSQ
X
Safety Assessments
Physical examination
X
ECG
X
Clinical laboratory tests
X
Urine Pregnancy test
X
ESRS-A
X
ISST-Plus Short formb
X
Vital signs (blood pressure, pulse rate) and weight
X
Adverse Events
X
Concomitant medication
X
a
An alternative test will be defined by the sponsor if the study is conducted in countries 
other than the United States.
b
If suicidality is identified (ie, ‘yes’ is answered to questions 1.0, 2.2, 2.3, or 2.4 of the 
ISST-Plus Short Form) the full ISST-Plus must be administered in its entirety.
KEY: CGI-S=Clinical Global Impression-Severity scale; CRDPSS=Clinician-Rated 
Dimensions of Psychosis Symptom Severity; DSM-5=Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition; ECG=electrocardiogram; ESRS-A=Extrapyramidal Symptom
Rating Scale-Abbreviated; IQ=intelligence quotient; ISST-Plus=InterSePT Scale for Suicidal 
Thinking-Plus; MCCB=MATRICS Consensus Cognitive Battery; MSQ=Medication 
Satisfaction Questionnaire; PSP=Personal and Social Performance scale; SCID=Structured 
Clinical Interview for DSM-5 Disorders; UV=unscheduled visit; WTAR=Wechsler Test of 
Adult Reading
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
25
Approved, Date: 6 December 2019
TIME AND EVENTS SCHEDULE: PART I, PART II, AND PART III
Treatment Phase:
Part Ia 
(Oral Run-in)
Part II
(Disease Progression)
Part III 
(Extended Disease Progression and Disease Modification)
Visit: 2
3
4
5
6
7p
8
9
10
11
12
13s
14
15
16s
17p
18
19o
20
21
22
23s
24
25
26s
27/EOSp UVm
Day (Part I) 1
8
15 29 43
57
Day (Part II)
1
8
36
64
92
120 148
176
204
232
260
Day (Part III)
1
8
36
64
92
120
148 176
204
232
260
Visit window
±4 ±4 ±4 ±4
±7
±4
±7
±7
±7
±7
±7
±7
±7n
±7
±7
±4
±7n
±7
±7
±7n
±7
±7
±7n
±7
Administrative
Inclusion/exclusion criteria
X
Urine Drug Screen
X
X
X
Randomization
Xb
Xc
Contact designated individuald
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample collection for DNAr
X
Study Drug Administration/Prescriptione
Administer study drug (PP)f
or provide prescription (O)g
O
O
O
O
O
1M 1M
1M
1M
1M
3M
-
-
3M
-
-
-s
3M
-
-
3M
-
-
3M
-
-
O
Os
O
O
O
O
O
O
O
O
1M
1M
1M
1M
1M
3M
-
-
3M
-
-
O
Os
O
O
O
O
O
O
O
O
-
Efficacy Assessmentsh
Assessment for treatment failure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
MCCBi
X
X
X
X
X
X
X
X
Xh
PSP
X
X
X
X
X
X
X
X
Xh
CRDPSS (DSM-5)
X
X
X
X
X
X
X
X
X
Xh
CGI-S
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
MSQ
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Imagingh,t
MRI 
X
X
X
X
X
Xh
Exploratory Assessments
Goal setting and reviewj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of daily activities
X
X
X
X
X
X
X
X
RUQ
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
EC
X
X
X
Clinical laboratory tests
X
X
X
Urine Pregnancy test
X
X
X
ESRS-A
X
X
X
X
X
X
X
ISST-Plus Short formk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsl and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
26
Approved, Date: 6 December 2019
a
During Part I, all subjects will initially receive flexible doses of paliperidone ER (1.5-12 mg/day) or 1-6 mg/day of oral risperidone. Subjects who find paliperidone ER or oral 
risperidone intolerable will be withdrawn from the study. Subjects who tolerate paliperidone ER or oral risperidone but find it inadequately efficacious may be switched to another 
protocol-specified OAP. Any of the following 7 OAPs will be permitted during Part I: aripiprazole, haloperidol, olanzapine, paliperidone ER, perphenazine, quetiapine, and 
risperidone.  
b
At the start of Part II, subjects will be randomized in a 1:2 ratio to start PP injections or to continue OAP treatment from Part I. 
c
At the start of Part III, subjects who were randomized to OAP in Part II will be re-randomized in a 1:1 ratio to continue OAP from Part II  (OAP-OAP group) or switch to PP injections 
(OAP-PP group). Subjects randomized to PP in Part II will continue the same treatment (PP-PP group). 
d
The subject’s designated individual should be contacted to check on the subject’s wellbeing, such as subject’s general health, common daily activities and progress in personal or 
health goals. Contact may be by telephone if the designated individual does not accompany the subject at the scheduled visit.
e
All procedures should be performed prior to study drug administration/prescription, except for MRI, which does not need be performed on the day of a scheduled visit, but should be 
completed within ±7 days.
f
Subjects who are randomly assigned to start PP treatment will receive PP1M injections on Day 1, Day 8 (±4 days), Day 36 (±7 days), Day 64 (±7 days), and Day 92 (±7 days). The 
first dose of PP3M will be given on Day 120 (±7 days) and then every 12 weeks (±14 days) thereafter. If these windows are exceeded, contact the medical monitor. Refer to Section 
Error! Reference source not found. of the Protocol for details on PP dosing as well as re-initiation of PP in cases of missed doses. 
g
Subjects who are randomly assigned to the OAP treatment group will continue their OAP treatment from Part I. Subjects will be provided a voucher to present at a local pharmacy to 
receive their assigned study drug. Following the initial randomization visit, a switch to a different OAP or the addition of another OAP is allowed in the OAP treatment group if 
clinically indicated; however, switching or add-on of another OAP due to inadequate efficacy, safety, or tolerability will be assessed as a treatment failure. Refer to Section Error! 
Reference source not found. of the Protocol for definition of Treatment Failure. Any of the following 7 agents will be permitted during Part II and Part III: aripiprazole, haloperidol, 
olanzapine, paliperidone ER, perphenazine, quetiapine, and risperidone. Multiple switches to alternative OAPs (ie, multiple treatment failures) are allowed during the study. 
h
All efficacy assessments and MRI scans (in the subgroup of subjects undergoing MRI assessment) must be completed at the first occurrence of treatment failure, or as soon as possible, 
even they are not scheduled to be done for the visit or for the unscheduled visit. At subsequent treatment failures, PSP, CGI-S, CRDPSS, and MSQ assessments should be performed. 
i
For every individual subject, MCCB should be administered at the same time of day (within a 2-hour window) for every assessment.
j
Patient Happiness Assessment and Goal Setting Preparation will be performed at Day 1 Part I only; Patient Goal Setting Documentation will be completed on Day 1 of Part I, II, and 
III; Assessment of Patient Goal Attainment will be assessed by the subject every month.
k 
If suicidality is identified (ie, ‘yes’ is answered to questions 1.0, 2.2, 2.3, or 2.4 of the ISST-Plus Short Form) the full ISST-Plus must be administered in its entirety.
l
Blood pressure and pulse rate.
m
Unscheduled visits should be performed, as necessary for the following reasons:

Unscheduled visits that are clinically indicated: Unscheduled visits should be performed as necessary in the judgment of the physician for appropriate clinical care, including 
reasons of safety or tolerability.

Unscheduled visits for investigational purposes: Any subject who experiences a protocol-defined treatment failure event after randomization to Part II (Visit 7) should undergo 
an unscheduled visit. This applies to every treatment failure episode; not just the initial one. If an unscheduled visit can’t be performed before the next scheduled protocol visit, 
applicable unscheduled visit procedures should be performed during the scheduled visit even when they are not normally part of the scheduled visit. Note that subjects who 
experience a treatment failure event should continue in the study, unless they meet study withdrawal criteria.
n
At these visits (Visit 15, 19, 22, and 25), the treatment window for PP3M dosing will be ±14 days, except for the first PP3M injection, which will be ±7 days.
o
In order to synchronize visit dates for all 3 treatment arms, Visit 19 occurs 92 days (instead of 84 days, ie, 12 weeks) after the previous PP3M injection. However, it is still within the 
±14-day window.
p
Note that completion and discontinuation will be recorded in the CRF for each treatment phase. 
r
The pharmacogenomic (DNA) sample should be collected at the specified time point, however if necessary it may be collected at a later time point without constituting a protocol 
deviation.
s
These visits can be conducted by telephone.
t
Approximately half the subjects will undergo MRI scans at selected study sites. MRI assessments are optional to subjects. MRI scans will also be performed in the healthy control 
group; the schedule for MRI assessments in healthy control subjects will be provided in a separate MRI manual.
KEY: CGI-S=Clinical Global Impression-Severity scale; CRDPSS=Clinician-Rated Dimensions of Psychosis Symptom Severity; ECG=electrocardiogram; EOS=end of study; 
ESRS-A=Extrapyramidal Symptom Rating Scale-Abbreviated; ISST-Plus= InterSePT Scale for Suicidal Thinking-Plus; MCCB=MATRICS Consensus Cognitive Battery; MRI=magnetic 
resonance imaging; MSQ=Medication Satisfaction Questionnaire; O=oral antipsychotic; 1M=paliperidone palmitate 1-month formulation; 3M=paliperidone palmitate 3-month 
formulation; PP=paliperidone palmitate; PSP=Personal and Social Performance scale; RUQ=Resource Use Questionnaire; UV=unscheduled visit 
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
27
Approved, Date: 6 December 2019
2.1.1.
Study Reference Start and End Dates
The trial reference start date will be the Part I Start Date. The trial reference end date will be the 
date of the last trial-related procedure. Specifically, it will be the maximum of the last study 
medication date, or last visit date (scheduled or unscheduled), or End-of-Treatment/Early 
Withdrawal visit date. At each scheduled visit, all the assessments need to be completed before 
the study drug administration.
2.1.2.
Analysis Phase Start and End Dates
Screening Phase
The start date of the screening phase is the informed consent date. The screening phase end date
is the Part I start date.
Part I, Oral Run-In Phase
The oral run-in phase will begin on the day (referred to as, ‘Part I Start Date’) of Visit 2. The oral 
run-in phase end date (denoted as ‘Part I End Date’) is the date of Part II randomization (for 
OAP subjects) or the first PP injection date in Part II for subjects who enter the Part II; 
otherwise, subjects who withdraw during the Part I, the Part I End Date is the same as the 
Reference End Date.
Part II, Disease Progression Phase
The Part II will begin on the day (referred to as, ‘Part II Start Date’) of the first randomization 
(for OAP subjects) or the first paliperidone palmitate injection date, which is Day 1 in Part II.
For subjects who complete/discontinue from the Part II, the Part II end date (denoted as ‘Part II 
End Date’) is the maximum of the date of last visit in Part II. Specifically, for those subjects who 
enter the Part III and randomized, the end date will be the date of Part III randomization. Those 
subjects who are assigned to PP in Part II and continue to be in PP, the end date will be the date 
of Visit 17. For subjects who withdraw during the Part II, the Part II End Date is the same as the 
Reference End Date.
Part III, Extended Disease Progression and Disease Modification Phase
The Part III will begin on the day (referred to as, ‘Part III Start Date’) of the second 
randomization for OAP subjects from Part II. For those subjects who are assigned to PP in Part 
II, the Part III Start Date will be the earliest Visit 17 date.
For subjects who complete/discontinue from the Part III, the Part III end date (denoted as ‘Part 
III End Date’) is the maximum of the date of last visit in Part III. The Part III End Date is the 
same as the Reference End Date.
The extended disease progression phase will start with Part II Start Date and will continue into 
Part III. The objective of this phase to examine differences (i.e., 33 for efficacy endpoints) 
between patients given OAPs vs. those given PP up to 18 months. The end date for the extended 
disease progression phase will be same as the Part III end date.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
28
Approved, Date: 6 December 2019
2.1.3.
Study Day and Relative Day
Study day is calculated relative to the reference start date for the study. Relative day is calculated 
relative to the analysis phase start date of the analysis phase in which the data are captured. A 
minus (-) sign indicates days prior to the start of study or prior to the start of the analysis phase.
Study day for an event on or after the start of the study is calculated as:
event date- reference start date+1.
Study day for an event prior to the start of the study is calculated as:
event date-reference start date 
Relative day for an event on or after the analysis phase start date is calculated as:
event date – analysis phase start date + 1.
Relative day for an event prior to the analysis phase start date is calculated as:
event date – analysis phase start date.
There is no study day 0 or relative day 0.
2.2.
Baseline and End Point
Baseline is defined for each parameter/assessment.
Part I: The ‘Baseline Part I’ value for the Part I is defined as the last assessment on or before the 
Visit 2 date. Note that the baseline is defined for each parameter of interest whereas the Part I
Start Date is defined at subject level and remains the same for all parameters of interest. The 
baseline scores may consist of information from the Screening phase. 
Part II: The last observation prior to or on the start date of Part II is denoted as, ‘Baseline Part II’.
It is defined for all efficacy variables as well as for the safety variables. Baseline Part II will also 
be listed as baseline for the Extended Disease Progression phase.
Part III: The last observation prior to or on the start date of Part III is denoted as, ‘Baseline Part 
III’. It is defined for all efficacy variables as well as for the safety variables.
For each variable measured over time, the ‘End Point Part I’ value is defined as the last 
postbaseline assessment value during the run-in Phase. This value will be the same as the 
Baseline Part II value for subjects who continue into the Part II phase.
The ‘End Point Part II’ value is defined as the last postbaseline assessment value during the 
disease progression phase. This value will be the same as the Baseline Part III value for subjects 
who continue into the Part III phase.
The ‘End Point Part III’ value is defined as the last postbaseline assessment value during the Part 
III phase. The End Point Part III will also serve for the end point for the Disease Progression 
Phase.
NCT02431702


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Statistical Analysis Plan R092670SCH3013
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Approved, Date: 6 December 2019
A subject will be included in the end point analysis if they have both a baseline assessment and a 
post-baseline assessment.
2.3.
Flagging Treatment Failures for Primary Analysis
All treatment failures that occur within 1 day from the Part II period discontinuation date will be 
used in the primary analysis in Part II. Treatment failures will also be captured in Part III.
Treatment failures will also be identified during the combined Part II and III periods which is 
referred to as Extended Disease Progression phase using event and censoring dates. Timing and 
reasons for only repeated treatment failures will be determined by the Treatment Failure Board.
Corresponding analysis set from the Treatment Failure Board will only be used in repeated 
events analysis in Parts II and EDP phases.
2.4.
Visit Windows
As subjects may participate in more than one period in this trial, little knowledge is gained by 
presenting patient data with a treatment group in the listings. Thus, the following coding has 
been devised to compactly and efficiently describe a patient's treatment history in the trial. 
Although data summaries will be carried out for Part I, the treatment history information starts 
from Part II randomization to aid treatment group comparisons. Those subjects who are listed 
with codes OAPOAP and PPPP will by definition also be part of the Extended Disease 
Progression phase.
Code
Treatment History
PP
Entered Part II, randomized to paliperidone palmitate, 
OAP
Entered Part II, randomized to oral antipsychotics
OAPPP
Entered Part III, randomized to paliperidone palmitate
OAPOAP
Entered Part III, randomized to oral antipsychotics
PPPP
Entered Part III, no second randomization
Because subjects do not always adhere to the protocol visit schedule, the following rules are 
applied to assign actual visits to protocol visits. Listed below are the visit windows for analysis 
and the target days for each visit. These windows are distinct from the visit windows specified in 
the Time and Event (T&E) Schedule in the protocol to inform the conduct of the study. The 
reference day for each phase is the corresponding first day. For those subjects who are 
randomized in Part III (PPPP treatment group), there will be another visit window schedule using 
the Part II Start Date (Part II Day 1) as the reference day. This will allow us compare OAPOAP 
and PPPP treatment groups starting from Part II through Part III treatment phase.
If a subject has 2 or more scheduled or unscheduled visits in one visit window, the visit closest to 
the target day will be used as the protocol visit for that visit window. If 2 actual visits are 
equidistant from the target day within a visit window, the later visit is used. If a visit window has 
no scheduled visits but does have unscheduled visits, then the unscheduled visit closest to the 
scheduled visit will be used.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
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Approved, Date: 6 December 2019
All assignments will be made in chronological order. Once a visit is assigned to a visit window, 
it will no longer be used for a later time point except for the end point. 
The last non-missing post-baseline value will be carried forward and will be defined as the last 
observation carried forward (LOCF) endpoint for all efficacy and safety parameters within each 
study phase. It is important that the carry-forward procedure only be applied within a phase and 
not across multiple phases.  A subject will be included in the LOCF efficacy analysis if they have 
both a baseline assessment (except where a baseline assessment is not done) and a post-baseline 
assessment. Hence baseline assessment will not be carried forward. The LOCF assessments will 
be created for each post-baseline visit. If there are multiple visits within the last available time 
window, the last visit will be carried forward assuming the last visit took place within the 
reference end date. The imputed LOCF time points will be labeled ‘XX LOCF’.  For OAPOAP 
and PPPP treatment group comparisons, 18-month study (Extended Disease Progression phase), 
the absolute last visit scores will be listed as ‘XX LOCF’ where XX refers to visit label. The 
objective with the Extended Disease Progression phase is to show differences between those 
subjects who have been treated with PP for up to 18 months (early start group) compared with 
patients treated with OAP for up to18months. Extended Disease Progression phase will be 
labeled as EDP for the rest of the document. Listed below are the visit windows and the target 
days (if applicable) for each visit defined in the protocol for all phases (Error! Reference 
source not found.).
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
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Approved, Date: 6 December 2019
Table 1a: Time Intervals for Visits for MCCB, PSP
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Screening
1
-28 to -1
Screening
<1
-28 to -1
Part I 
1
Baseline Part Ia
<= 1
1
5
29
Day 29 (Part I)
2 - 42
29
7
57
Day 57 (Part I)
43 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
21
92
Day 92 (Part III)
2-134
92
24
176
Day 176 (Part III)
135-218
176
27
260
Day 260 (Part III)
219 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPb
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
21
352
Day 92 (Part III)
2-134
92
24
436
Day 176 (Part III)
135-218
176
27
520
Day 260 (Part III)
219 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
a Screening visit window or Visit 2 assessment will be listed as Part I Baseline.
b Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
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Approved, Date: 6 December 2019
Table 1b: Time Intervals for Visits for CRDPSS
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Screening
1
-28 to -1
Screening
<1
-28 to -1
Part I 
2
1
Baseline Part I
<= 1
1
5
29
Day 29 (Part I)
2 - 42
29
7
57
Day 57 (Part I)
43 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
21
92
Day 92 (Part III)
2-134
92
24
176
Day 176 (Part III)
135-218
176
27
260
Day 260 (Part III)
219 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPa
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
21
352
Day 92 (Part III)
2-134
92
24
436
Day 176 (Part III)
135-218
176
27
520
Day 260 (Part III)
219 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
a Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
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Approved, Date: 6 December 2019
Table 1c: Time Intervals for Visits for CGI-S, MSQ
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Screening
1
-28 to -1
Screening
<1
-28 to -1
Part I 
2
1
Baseline Part I
<= 1
1
3
8
Day 8 (Part I)
2 - 12
8
4
15
Day 15 (Part I)
13 – 22
15
5
29
Day 29 (Part I)
23 – 36
29
6
43
Day 43 (Part I)
37 – 50
43
7
57
Day 57 (Part I)
51 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II 
1
1
9
36
Day 36 (Part II)
2 – 50
36
9+i
36+28*i
(i=1..7)
Day 36+28*i (Part 
II)
50+28*(i-1)+1 
to 50+28*i
36+28*i
17
260
Week 260 (Part II)
247 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
19
36
Day 36 (Part III)
2-50
36
19+i
36+28*i 
(i=1..7)
Day 36+28*i (Part 
III)
50+28*(i-1)+1
to 50+28*i
Day 36+28*i
27
260
Week 260 (Part III)
247 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPa
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
9
36
Day 36 (Part II)
2 – 50
36
9+i
36+28*i 
(i=1..8)
Day 36+28*i (Part 
II)
50+28*(i-1)+1 
to 50+28*i
36+28*i
19
296
Day 36 (Part III)
2-50
36
19+i
296+28*i 
(i=1..7)
Day 36+28*i (Part 
III)
50+28*(i-1)+1 
to 50+28*i
Day 36+28*i
27
520
Week 260 (Part III)
247 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
a Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
34
Approved, Date: 6 December 2019
Table 1d: Time Intervals for Visits for MRI
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Part II
7
1
Baseline Part II 
<=42
1
11
92
Day 92 (Part II)
43 – 176
92
17
260
Week 260 (Part II)
177 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
43 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
21
92
Day 92 (Part III)
2-176
92
27
260
Week 260 (Part III)
177 to End of 
Part II
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPa
7
1
Baseline 
EDP=Baseline Part 
II 
<=42
1
11
92
Day 92 (Part II)
43 – 176
92
17
260
Week 260 (Part III)
177 to End of 
Part III
260
21
352
Day 92 (Part III)
2-176
92
27
520
Week 260 (Part III)
177 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit. The last post-baseline assessment in Part II will be used as Part III baseline.
a Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
35
Approved, Date: 6 December 2019
Table 1e: Time Intervals for Visits for Goal Setting and Review
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Part I 
2
1
Baseline Part I
<= 1
1
5
29
Day 29 (Part I)
2 – 42
29
7
57
Day 57 (Part I)
43 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II 
1
1
9
36
Day 36 (Part II)
2 – 50
36
9+i
36+28*i 
(i=1..7)
Day 36+28*i (Part 
II)
50+28*(i-1)+1 
to 50+28*i
36+28*i
17
260
Week 260 (Part II)
247 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
19
36
Day 36 (Part III)
2-50
36
19+i
36+28*i 
(i=1..7)
Day 36+28*i (Part 
III)
50+28*(i-1)+1 
to 50+28*i
Day 36+28*i
27
260
Week 260 (Part III)
247 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPa
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
9
36
Day 36 (Part II)
2 – 50
36
9+i
36+28*i 
(i=1..8)
Day 36+28*i (Part 
II)
50+28*(i-1)+1 
to 50+28*i
36+28*i
19
296
Day 36 (Part III)
2-50
36
19+i
296+28*i 
(i=1..7)
Day 36+28*i (Part 
III)
50+28*(i-1)+1 
to 50+28*i
Day 36+28*i
27
520
Week 260 (Part III)
247 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
a Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
36
Approved, Date: 6 December 2019
Table 1f: Time Intervals for Visits for Daily Activities, RUQ
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Part I 
2
1
Baseline Part I
<= 1
1
7
57
Day 57 (Part I)
2 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
21
92
Day 92 (Part III)
2-134
92
24
176
Day 176 (Part III)
135-218
176
27
260
Day 260 (Part III)
219 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPa
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
21
352
Day 92 (Part III)
2-134
92
24
436
Day 176 (Part III)
135-218
176
27
520
Day 260 (Part III)
219 to End of 
Part III
260
EDP Final 
Visit
End Point EDP = 
End Point Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
a Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
37
Approved, Date: 6 December 2019
Table 1g: Time Intervals for Visits for ESR-A
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Screening
1
-28 to -1
Screening
<1
-28 to -1
Part I 
1
Baseline Part Ia
<= 1
1
7
57
Day 57 (Part I)
2 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
21
92
Day 92 (Part III)
2-134
92
24
176
Day 176 (Part III)
135-218
176
27
260
Day 260 (Part III)
219 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPb
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
11
92
Day 92 (Part II)
2-134
92
14
176
Day 176 (Part II)
135-218
176
17
260
Day 260 (Part II)
219 to End of 
Part II
260
21
352
Day 92 (Part III)
2-134
92
24
436
Day 176 (Part III)
135-218
176
27
520
Day 260 (Part III)
219 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
a Screening visit window or Visit 2 assessment will be listed as Part I Baseline.
b Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
38
Approved, Date: 6 December 2019
Table 1h: Time Intervals for Visits for ISST Plus, Vital Signs, and Weight
Analysis 
Phase
Scheduled
Visit
Number
Scheduled 
Day
Time Interval
(label on output)
Time Interval
(Day)
Target Time 
Point from start 
of
each phase
(Day)
Screening
1
-28 to -1
Screening
<1
-28 to -1
Part I 
2
1
Baseline Part I
<= 1
1
3
8
Day 8 (Part I)
2 - 12
8
4
15
Day 15 (Part I)
13 – 22
15
5
29
Day 29 (Part I)
23 – 36
29
6
43
Day 43 (Part I)
37 – 50
43
7
57
Day 57 (Part I)
51 to End of 
Part I
57
Part I Final 
Visit
End Point Part I
2 to End of 
Part I
Part II
7
1
Baseline Part II 
1
1
8
8
Day 8 (Part II)
2 - 22
8
9
36
Day 36 (Part II)
23 – 50
36
9+i
36+28*i 
(i=1..7)
Day 36+28*i (Part 
II)
50+28*(i-1)+1 
to 50+28*i
36+28*i
17
260
Week 260 (Part II)
247 to End of 
Part II
260
Part II Final 
Visit
End Point Part II
2 to End of 
Part II
Part III
17
1
Baseline Part III 
1
1
18
8
Day 8 (Part III)
2 - 22
8
19
36
Day 36 (Part III)
23 - 50
36
19+i
36+28*i 
(i=1..7)
Day 36+28*i (Part 
III)
50+28*(i-1)+1 
to 50+28*i
Day 36+28*i
27
260
Week 260 (Part III)
247 to End of 
Part III
260
Part III Final 
Visit
End Point Part III
2 to End of 
Part III
EDPa
7
1
Baseline 
EDP=Baseline Part 
II 
1
1
8
8
Day 8 (Part II)
2 - 22
8
9
36
Day 36 (Part II)
23 – 50
36
9+i
36+28*i 
(i=1..8)
Day 36+28*i (Part 
II)
50+28*(i-1)+1 
to 50+28*i
36+28*i
18
268
Day 8 (Part III)
2 - 22
8
19
296
Day 36 (Part III)
23 - 50
36
19+i
296+28*i 
(i=1..7)
Day 36+28*i (Part 
III)
50+28*(i-1)+1 
to 50+28*i
Day 36+28*i
27
520
Week 260 (Part III)
247 to End of 
Part III
260
EDP Final 
Visit
End Point EDP 
Phase= End Point 
Part III
2 to End of 
Part III
Note: The time intervals and target time point days are relative to the respective phase. Final post-
baseline assessment during the preceding phase will be used as the value for the current phase 
baseline visit.
b Extended Disease Progression phase starts from Part II and extends into Part III for only those 
subjects who are on PPPP and OAPOAP.
NCT02431702


R092670 (paliperidone palmitate)
Statistical Analysis Plan R092670SCH3013
39
Approved, Date: 6 December 2019
LABs
Laboratory assessments will be slotted to visit windows according to sample date rather than the 
visit date. Clinical laboratories will be summarized at the following visits: Baseline Part I, End 
Point Part I, Baseline Part II, End Point Part II, Baseline Part III, and End Point Part III. Baseline 
for the Part I will be captured during the screening period. 
Combination of Part II and Part III scores will be utilized for the Extended Disease Progression 
phase. Extended Disease Progression phase starts from Part II and extends into Part III for only 
those subjects who are on PPPP and OAPOAP. Part II baseline will serve as EDP Baseline and 
Part III end point will serve as EDP end point.
Observations from local labs with missing units will be omitted.
2.5.
Analysis Sets
Efficacy analyses will be based on the intent-to-treat (ITT) and explanatory intent-to-treat (eITT) 
analysis sets. All safety analyses will be based on ITT analysis set. As there are different 
objectives for different periods of this study, separate ITT and eITT populations will be 
identified for the Part I (Run-in), Part II (Disease Progression), Part III (Disease Modification)
and EDP (Extended Disease Progression) periods. The eITT analysis set will not be included in 
Part I. The analysis sets are defined below.
Part I (Run-in) Intent-to-Treat Analysis Set
Efficacy and safety summaries for the Part I period will be based on the Part I ITT analysis set, 
which will include all subjects who receive at least one dose of study medication (or any portion 
of the dose) in Part I, regardless of their compliance with the protocol.
Part II (Disease Progression) Analysis Sets
Efficacy and safety summaries for the Part II period will be based on the Part II ITT analysis set, 
which will include all randomized subjects who receive at least one dose of randomized study 
medication (or any portion of the dose) in Part II, regardless of their compliance with the 
protocol. 
An explanatory ITT (eITT) analysis set will also be defined in Part II. The eITT analysis set will 
consist of all ITT subjects, as well as their study assessments for the time period between the 
date of randomization and the eITT end point. The eITT end point for subjects who had a 
treatment failure will be defined as 1st treatment failure date +7 days. For those subjects who did 
not have treatment failure, the eITT end point will be same as the Part II end point. Changes in 
MCCB, PSP, ICM volumes, and CGI-S will also be analyzed using eITT analysis set. 
The MRI ITT analysis set in Part II will include those subjects who are part of the Part II ITT 
analysis set and had a confirmed MRI scan anytime during Part II.
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Part III Analysis Sets
Efficacy and safety summaries for the Part III period will be based on the Part III ITT analysis 
set, which will include all randomized subjects who receive at least one dose of study medication 
(or any portion of the dose) in Part III, regardless of their compliance with the protocol. On 
Day 1 of Part III, subjects in the OAP treatment arm will be re-randomized in a 1:1 ratio to 
continued treatment with their oral treatment or to PP (delayed-start PP arm). Subjects previously 
assigned to treatment with PP in Part II will continue on that treatment; however, in order to be 
included in the ITT population, this group must have at least one post-baseline MCCB or PSP 
assessment.
An explanatory ITT (eITT) analysis set will be defined in Part III. The eITT analysis set will 
consist of all ITT subjects, as well as their study assessments for the time period between the 
date of randomization and the eITT end point. The eITT end point for subjects who had a 
treatment failure will be defined as 1st treatment failure date +7 days. For those subjects who did 
not have treatment failure, the eITT end point will be same as the Part III end point. Changes in 
MCCB, PSP, ICM volumes, and CGI-S will also be analyzed using eITT analysis set. 
The MRI ITT analysis set in Part III will include those subjects who are part of the Part III ITT 
analysis set and had a confirmed MRI scan anytime during Part III.
EDP (Extended Disease Progression) Analysis Sets
Efficacy and safety summaries for the EDP period will be based on the Part III ITT analysis set, 
which will include all randomized subjects who receive at least one dose of study medication (or 
any portion of the dose) in Part III, regardless of their compliance with the protocol. 
An explanatory ITT (eITT) analysis set for EDP phase will be same as eITT for Part III.
The MRI ITT analysis set for the EDP period will be based on Part III MRI ITT analysis set.
2.6.
Definition of Subgroups
Analyses will be provided for the overall primary endpoint, time to treatment failure, by the 
following subgroups.

Sex

Race (White, Black, Other)

Age Group in years (<20 years, 20 to 24 years, >24 years)

Prior Antipsychotic Exposure (<6 months, 6 to 12 months, >12 months)

MCCB Composite Score using the Part I – Visit 5 assessment (<25, 25-35, >35) 

PSP Score using the Part I – Visit 5 assessment (<=70, >70)
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
Substance Abuse History (0 years, >0 to 2 years, > 2 years)

Current Primary DSM-5 Diagnosis (schizophrenia and schizophreniform)

Subjects who continued into Part III and those who did not.
2.7.
Imputation Rules for Missing Dates
2.7.1.
Missing AE Dates
A conservative approach will be used to handle any missing portion of dates for adverse events. 
The rules for handling the incomplete AE onset dates will be as follows:
(1) The missing day of the month will be estimated as follows:  If the month and year are 
known, compare the month with the month of Part I start date, Part II start date, and Part III 
start date.
If the month of AE is equal to the month of Part I start date then the estimated day is the 
start day of Part I.  
If the month of AE is equal to the month of Part II start date then the estimated date is the 
start day of Part II. 
If the month of AE is equal to the month of Part III start date then the estimated date for AE 
will be the start day of the Part III.  
If the month of AE is different (greater than or less than) from the month of Part I, or Part II, 
or Part III then the estimated day for AE is the 1st day of the month. 
(2) If both the day and the month are missing: NO estimation is to be performed. 
For incomplete AE recovery dates, the rules are:
1. The missing day of the month will be estimated as follows:  If the month and year are 
known then the missing day will be imputed as the last day of that month.
2. If both the day and the month are missing then the imputed date will be the date of the 
reference end date (provided the AE start date is not missing and after the Part I start date).
3. If the AE end date is missing however and the AE outcome says the AE is not recovered/not 
resolved then the AE end date = reference end date.
If the imputed AE date is greater than the reference end date then the imputed AE will be cutoff 
at the reference end date.
Treatment-emergent flags will be created for identifying AEs that occurred in each phases of the 
study. Treatment-emergent adverse events (TEAEs) and serious treatment-emergent adverse 
events (SAEs) will be defined as adverse events (AEs) with start dates on or after the start of a 
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period and prior to 30 days after the permanent discontinuation of the study medication. An 
ongoing AE diagnosed prior to the start date of treatment in a period will be included in that 
period if there is an increase in its severity or change in relationship to study medication on or 
after the beginning of the period. Adverse events with completely missing onset dates will not be 
included in the summarizations. In addition to TEAE flags based on AE start dates, another flag 
will be created to identify those AEs that last more than one period.
2.7.2.
Missing Concomitant Medication Dates
If the start or end date of the drug intake is missing, the following rules will be applied. If only 
the day is missing (month and year are not missing) then the first day of the month will be used 
as the start day and the last day of the month will be used as an end day. If month or year is 
missing, then no imputation will be made. Exceptions are: when the drug intake is marked as 
“prior” or “continuing”, the end date of the respective period is the last day of study medication.  
The first day of the year will be used if only the year is present for a start date.  This convention 
is similar to prior medications date imputation rule.
Concomitant medications will be defined as medications with a start date equal to or greater than 
the first date of each period or with a start date prior to the first date of each period that are either 
ongoing or have a stop date greater than the first date of each period or a stop date that is 
missing.  In this way, concomitant medications will be carried forward from previous periods 
based on their stop date and ongoing status. Medications started on the Visit 27 date (trial 
termination visit) or after the Visit 27 date will not be considered concomitant since subjects are 
allowed to use any medication after trial completion.
If a partial date is reported, it is assumed the medication (or therapy) was taken in all phases that 
overlap with the partial date. If both start and end dates are missing but this concomitant 
medication was taken both prior to the study entry and still ongoing at study end, it is assumed 
medication was taken in all phases.
2.7.3.
Baseline Hospitalization Dates
The duration (days) of the index hospitalization will be calculated as (hospitalization end date 
from RUQ page – hospitalization start date +1). The current hospitalization duration will be 
computed matching the RUQ Hospitalization Start Date to the Date of Current Hospitalization 
Admission in the Psychiatric History page. The corresponding STOP date will be identified from 
the RUQ page. Index hospitalization start and stop dates can be identified from the RUQ page.
If the hospitalization start/stop date is completely missing, or the year is missing, then no 
imputation will be performed for the prior hospitalizations. If the start/stop dates of 
hospitalization are partially missing the following rule will apply:
Hospitalization start date: 

If only the day is missing, it is imputed using the first day of the month. 

If only the month is missing, it is imputed using January. 
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
If only both the day and month are missing, it is imputed using January 1. 
Hospitalization stop date: 
The earlier of the date before the current hospitalization admission and the following imputed 
date:

If only the day is missing, it is imputed using the last day of the month.

If only the month is missing, it is imputed using December. 

If only both the day and the month are missing, it is imputed using December 31.
2.7.4.
Baseline Characteristics and Prior Medications
Partial dates will be imputed as follows for analysis of prior medication dose administration, 
demographic and background characteristics:

The first day of the month will be used if only the month and year are present for a start 
date. The same scheme will be applied for the date of first schizophrenia disorder diagnosis, 
the onset date of first psychotic episode, prior medications, etc.

The first day of the year will be used if only the year is present for a start date. The same 
scheme will be applied for the date of first schizophrenia disorder diagnosis, the onset date 
of first psychotic episode, prior medications, etc.

The last day of the month will be used if only the month and year are present for a stop date 
and if the month is prior to month of Day 1 (Part I). If the month of a stop date and month of 
Day 1 (Part I) is the same, then the screening date will be used as the stop date.
The last day of the year will be used if only the year is present for a stop date and if year is prior 
to Day 1 (Part I) year. If the year of a stop date and year of Day 1 (Part I) is the same, then the 
screening date will be used as the stop date.
2.7.5.
Post Part I Baseline Hospitalization, Emergency Room Visit Dates
The post Part I baseline hospitalization related dates should not be missing. In case of partial 
dates, the following rules will be applied. However, prior to implementing this rule, all the 
available data correction tactics must be considered to capture the missing day field.
Hospitalization start date or emergency room visit:

If the trial medication started during that month, then set the start date equal to the trial 
medication date.

If the trial medication started prior to that month, then set the start date equal to the 1st day 
of that month.
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
If the study medication has not been administered during that month, then set the start date 
equal to the 1st day of that month.

If the month is split over phases, then set the start date equal to the trial medication date.

If the day and month of the start date are missing, then leave date as missing.
Hospitalization end date:

If the trial medication stopped during that month, then set the end date equal to the stop date 
of the trial medication.

If the trial medication stopped after that month, then set the end date equal to the last day of 
that month.

If the trial medication stopped prior to that month, then set the end date equal to the 1st day 
of that month. 

If the day and month of the end date are missing, then leave end date as missing.
3.
RULES FOR PRESENTATIONS
The overall primary efficacy end point is the time between subject randomization and the first 
documentation of a treatment failure during the Part II phase. Treatment failures will also be 
examined in Part III and during the 18-month EDP study period. The primary efficacy null 
hypothesis is that there is no difference in distribution of time to treatment failure between 
paliperidone palmitate and oral antipsychotics. There will be no interim analysis. 
Summary statistics will be presented to give a general description of the patients studied and an 
overview of the efficacy and safety results. Data from all sites will be combined in the 
computation of these descriptive summaries. Categorical variables will be summarized by 
presenting the number and percentage of patients in each category.  All percentages will be 
presented to one decimal point.  Continuous variables will be summarized using n, mean, 
standard deviation (SD), median, minimum, and maximum values.
All statistical tests will be two-sided. All p-values will be rounded to three decimal places; p-
values less than 0.001 will be presented as <0.001 in all tables; p-values greater than 0.999 will 
be presented as 1.000. All group comparisons from analysis of variance (ANOVA) and analysis 
of covariance (ANCOVA) models will be based on Type III sums of squares. All confidence 
intervals will be two-sided with 95% coverage. The primary analysis will be evaluated for 
statistical significance at the 0.05 level. 
All data from the Part I phase will be categorized and presented in three main columns: ALL (all 
Part I subjects), those patients who entered Part II, and those patients who did not enter Part II. 
There will be no statistical testing to compare these groups.
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All data from the Part II phase will be categorized and presented using two columns: those 
patients who are randomized to paliperidone palmitate (PP) and those patients who are 
randomized to oral antipsychotics (OAP). 
All data from the Part III phase will be categorized and presented using three columns: those 
patients who are not re-randomized (PPPP) were on PP in Part II, those patients who are re-
randomized to paliperidone palmitate (OAPPP), and those patients who are re-randomized to 
oral antipsychotics (OAPOAP). 
All data from 18-month EDP phase of the study will be categorized and presented using two 
columns: those patients who are NOT re-randomized (PPPP) in Part III, and those patients who 
are re-randomized to oral antipsychotics (OAPOAP) in Part III. The differences at Month 18 
represent the cumulative effect on disease progression.
Computations for all of the results will be performed using the SAS® Version 9.2 or higher 
computer software package or R.
4.
SUBJECT INFORMATION
4.1.
Discontinuation/Completion Information
The numbers and percentage of subjects entering the Part I, Part II, Part III, and EPD phase will 
be summarized for the ITT Analysis Set. Those subjects including healthy controls undergoing 
MRI assessments will also be summarized.
The number and percentage of subjects who completed the trial, and those who prematurely 
discontinued from the trial along with the reason for discontinuation, will be summarized by 
period and treatment group. In addition, the number of subjects who withdrew by visit will be 
provided. For Part II, additional summaries will be generated for the subgroups of patients in the 
PP treatment group based on patterns of dose modifications/transitions.
Time to all cause discontinuation in Part II, Part III, and EDP phase (expressed as number of 
days from randomization or Day 1 to termination) will be analyzed using Kaplan-Meier 
estimated time-to-event curves, and compared among treatment groups using log-rank tests. 
Time to discontinuation excluding treatment failure will also be derived for Part II, Part III, and
EDP phase.
Subject enrollment by country and study sites will also be listed.
4.2.
Demographics and Baseline Characteristics
Demographics baseline characteristics, psychiatric history, medical history, and nicotine and 
substance use will be presented for the ITT populations in all periods. 
Demographic and clinical characteristics, including age (years), age category (<20 years, 20- 24
years, >24 years), gender, race, ethnicity, height (cm), weight (kg) and body mass index (BMI) 
(kg/m2), and BMI category (normal: BMI< 25, overweight: 25≤ BMI< 30, and obese: BMI≥30), 
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education, employment status, and living situation at study entry will be summarized
descriptively by study phase and treatment group. Baseline values of efficacy variables, 
including MCCB, PSP, CRDPSS, CGI-S, and MSQ score will be summarized. Randomization 
factors, specifically, age group in years (<20 years, 20 to 24 years, >24 years), prior 
antipsychotic exposure (<6 months, 6 to 12 months, >12 months), MCCB composite score using 
the Part I – Visit 5 assessment (<25, 25-35, >35), PSP Score using the Part I – Visit 5 assessment 
(<=70, >70), and substance abuse history (0 years, >0 to 2 years, > 2 years) summaries will also 
be provided for Parts II and III, and EDP phase. 
Psychiatric history, including current primary diagnosis, duration of illness (≤ 5 years vs. >5 
years - using date of first schizophrenia or schizophreniform diagnosis), duration since first 
psychiatric episode (years), age (years) at first psychiatric episode, age (years) at first psychiatric 
diagnosis, age (years) at first pharmacological treatment for psychiatric symptoms, prior 
psychiatric diagnosis, setting of current psychiatric treatment, duration (days) of current 
hospitalization, age at first psychiatric hospitalization, number of total psychiatric 
hospitalizations (both continuous and categorical summaries, 0, 1, 2, 3, and >3 times), time since 
last psychiatric hospitalization discharge, any suicide attempts, number of suicide attempts, time 
since last suicide attempt, and birth history will be summarized.
In Part II, demographic and clinical characteristics and psychiatric history summaries will be 
repeated for the following subgroups: 1-) Current Primary DSM-5 Diagnosis (schizophrenia and 
schizophreniform); 2-) Subjects who continued into Part III and those who did not.
Previous and current use of tobacco and previous substance use will be summarized. If an 
imputed date for last substance use is later than the screening date, the imputed date will be set 
equal to the screening date when calculating the time since last substance use. Post-baseline 
tobacco related summaries will also be presented.
Medical history will be summarized for each study period using corresponding ITT analysis sets. 
The number of abnormalities will be displayed for medical histories that are both not currently 
active and currently active. 
Prior medications will be defined as medications with start dates prior to the start of study 
medication or medications with prior flag. Prior medications will be coded to ATC level 4 and 
generic terms using the World Health Organization (WHO) Drug Dictionary, version 2017[1] or 
higher version. Psychotropic medications will be further classified based on sponsor-defined 
medication classes (see Appendix Table 2) and sponsor-defined preferred terms that combine 
like medications. Prior non-psychotropic and psychotropic medications will be summarized 
separately. Prior non-psychotropic medications will be summarized by ATC Level 4 and generic 
term using frequencies and percentages by treatment group. Prior psychotropic medications will 
be presented by sponsor-defined class and sponsor-defined preferred term.  Additionally, the 
number of subjects taking 0, 1, 2, or >2 medications will be presented.
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Psychotropic medications taken at baseline only for Part I, defined as medications taken (present) 
within 7 days prior to the screening date and one day following the screening date will also be 
summarized.
Hospital admission and discharge information will be summarized for the ITT population using 
the RUQ page. It will include the duration of the hospital stay for the index episode and the 
cumulative duration of rehospitalizations.
4.3.
Extent of Treatment Exposure
4.3.1.
Injections
The number and percent of subjects who receive 1, 2, 3, etc. injections of PP will be listed. The 
total exposure (days) to paliperidone palmitate will also be summarized.  This summary will be 
presented separately for each of the study periods. The number and percent of subjects at each
dose level will be summarized. For each month during the Parts II and III, and during EDP 
phase, a frequency distribution will be presented showing the number of subjects who receive the 
injection in the deltoid or gluteal muscle. The treatment exposure, mean dose, mode dose, and 
final dose will be presented both continuously and categorically for each period separately.
4.3.2.
Oral Antipsychotics
The number and percentage of subjects who receive study drug will be summarized for each 
study period.  Total OAP exposure from study phases Part I, Part II, Part III, and EDP will also 
be presented. The total duration of exposure will be based on the relative day and study day 
fields which were described in earlier sections. Frequency distribution of the duration will be 
presented separately for each study phase. Mode and last dose levels will also be summarized. 
Cumulative frequency distribution will also be presented. Additionally, the average dose, mean 
modal dose, and the last dose of OAPs will be summarized.
4.4.
Protocol Deviations
The frequency and percent of protocol violations excluding screen failures will be presented for 
each of the study phases separately using corresponding ITT populations.  Important protocol 
violations will be identified by a clinical review of the data prior to data base lock.  Protocol 
violations include, but are not limited to, taking a medication other than those allowed by the 
protocol, failure to satisfy inclusion/exclusion criteria or stabilization criteria, wrong treatment 
given, and efficacy scales are performed by non-qualified personnel.
4.5.
Prior and Concomitant Medications
Concomitant medications will be defined as medications with a start date equal to or greater than 
the first study phase date of each phase or with a start date prior to the first study date of each 
phase that are either ongoing or have a stop date greater than the first study date of each phase or 
a stop date that is missing.  In this way, concomitant medications will be carried forward from 
previous phases based on their stop date and ongoing status.  Medications started on the Visit 27
date (trial termination visit) or after the Visit 27 date will not be considered concomitant since 
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subjects are allowed to use any medication after trial completion.  Concomitant medications will 
be coded to ATC class and generic name using the World Health Organization (WHO) Drug 
Dictionary. Concomitant medication use will be summarized by number of medications (None 
(if any), 1, 2, ≥3) as well as by the ATC class and generic name using frequencies and 
percentages for each of the ITT populations. Psychotropic medications will be further classified 
based on sponsor-defined medication classes (see Appendix Table 2) and sponsor-defined 
categorization of preferred terms that combine like medications and will be summarized. The 
number and percentage of subjects taking psychotropic medications due to an adverse event will 
also be included.  Patients with multiple occurrences of a medication in an ATC class and/or 
generic name will only be counted once within each ATC class and/or generic name. 
4.5.1.
Prior Psychotropic Medications
The number and percentage of subjects who received psychotropic medications prior to the 
screening date will be presented by the generic term category within the psychotropic group. 
Each medication will be categorized into one of the following psychotropic groups: 
Acetylcholinesterase inhibitors, Antidepressants, Anti-extrapyramidal symptoms (EPS), 
Antihistamines, Atypical antipsychotics, Benzodiazepines, Beta blockers, Depot antipsychotics, 
Mood stabilizers and antiepileptics, Non-benzodiazepines hypnotics and anxiolytics, Stimulants, 
and Typical antipsychotics. These summaries will be presented for the Parts I, II, III, and EDP 
phase ITT population analysis sets.
The number and percentage of subjects who received prior antiparkinsonian medications 
(anticholinergics [anti-EPS] or antihistamines) will be provided by the generic term category 
within the psychotropic group. 
4.5.2.
Concomitant Benzodiazepines (Sedatives/Hypnotics/Anxiolytics)
The number and percentage of subjects who received benzodiazepines during the Parts II and III, 
and EDP phase will be provided by generic term category for the ITT analysis sets. 
For each subject, the total duration of each benzodiazepine therapy will be calculated.
Descriptive statistics of the duration (days) of benzodiazepine therapy use during the study 
periods will be presented for the ITT analysis sets. Duration of concomitant medication is 
defined as stop date – start date +1, where stop and start dates of the concomitant medication 
during the respective phases are defined below.
For the summary of duration of concomitant medication during the Part II phase, if the start date 
of concomitant medication is prior to the Part II start date, the Part II start date will be used as 
concomitant medication start date for duration calculation. If the end date of concomitant 
medication is after the Part II end date or indicated as continuing, then the Part II end date will be 
used as the concomitant medication end date for duration calculation. 
For the summary of duration of concomitant medication during the Part III phase, if the start date 
of concomitant medication is prior to the Part II start date, then the Part III start date will be used 
as concomitant medication start date for duration calculation.  If the end date of concomitant 
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medication is after the Part III end date or indicated as continuing, then the Part III end date will 
be used as the concomitant end date in calculating duration.
For the summary of duration of concomitant medication during the EDP phase, Part II start date 
and Part III end dates will be used to compute duration.
4.5.3.
Concomitant Medications Other Than Benzodiazepines
The number and percentage of subjects who receive concomitant therapies other than 
benzodiazepines during the study will be provided by generic term category for the ITT analysis 
sets. Those concomitant medications, other than benzodiazepines, received by at least 5% of the 
subjects in either study treatment group will be presented for the Part II, III, and EDP phase ITT 
analysis sets.
4.5.4.
Concomitant Antiparkinsonian Medications
The number and percentage of subjects who received concomitant antiparkinsonian medications 
(anticholinergics [anti-EPS] or antihistamines) will be provided by the generic term category 
within the psychotropic group for each of the study phase using the ITT analysis sets. 
5.
EFFICACY
5.1.
Level of Significance
The overall primary hypothesis to be tested in this study is that 9 months’ treatment with PP is 
superior to 9 months’ OAP treatment in delaying time to treatment failure in subjects with 
recent-onset schizophrenia or schizophreniform disorder. This will be assessed at the end of Part 
II.
Other hypotheses to be evaluated in this study will assess whether LAI treatment with PP can 
slow down disease progression and possibly modify disease course in recent-onset subjects 
compared to OAP medications. This will be assessed by tracking changes in cognition (MCCB 
composite score), functioning (PSP), and brain imaging assessments (ICM volume). 
The hypothesized effect of PP versus OAP on disease progression and disease modification is 
summarized in Error! Reference source not found.. Disease progression and disease 
modification will be assessed for MCCB composite score, PSP total score, and for ICM volume. 
Part II (Disease Progression) will enroll all subjects who complete Part I. Subjects will be 
randomized in a 1:2 ratio to either start treatment with PP or to continue with their OAP 
treatment from Part I. The early treatment effect identified after early start at the conclusion of 
Part II (δ21) (Figure 2) represents the treatment effect after 9 months resulting from continuous 
treatment with LAI compared with oral treatment. It seeks to identify differential treatment 
effects between the two alternative approaches on disease progression at the end of Part II. In 
particular, in addition to differences in time to first treatment failure, differences in cognition, 
functioning, and ICM volume will be assessed. At the conclusion of Part II, the database will be 
soft-locked and data analyzed to determine if there is an early treatment effect (δ21= treatment 
effect on disease progression) demonstrating superiority of PP relative to oral treatment. 
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At the onset of Part III, subjects in the OAP arm will be re-randomized to continued treatment 
with their prior oral treatment or to PP.  Subjects will be followed for an additional 9 months. 
Three effects will be assessed for a given endpoint: δ31, δ32, and δ33.  The quantity δ31 represents 
the lead treatment effect after an early start with 18 months of PP treatment and shows the lead 
effect remaining in the early start group over the delayed-start effect after a 9-month treatment 
duration. The quantity δ32 represents the delayed-start effect on disease progression for PP 
compared to continuing OAP after 9 months of additional treatment. The quantity δ33 represents 
the cumulative effect on extended disease progression at the end of Part III following early start 
for PP compared to continuing OAP after a total of 18 months of treatment. At the conclusion of 
Part III, the database will be locked and data analyzed to assess response in variables δ31, δ32, and 
δ33. Positive results (δ33 is significant [a differential treatment effect is still evident] and δ31 is 
significant [the lead effect remains significant after 9 months]) will be used to support a 
conclusion of disease modification using MCCB composite score in addition to examining 
difference between δ31 and δ21. Similar observations for changes in PSP and ICM will be 
assessed. 
In Part II, the overall Type I error rate for testing PP (PP1M/PP3M) versus OAP for both the 
primary efficacy endpoint and key secondary efficacy endpoints will be controlled at the 2-sided 
0.05 significance level using a combination of fixed sequence gatekeeper approach and Holm’s 
step-down procedure[2]. Time to first treatment failure will be tested first, followed by change in 
key secondary endpoints (MCCB, PSP, and ICM). Time to first treatment failure will be 
examined first using the log-rank test statistics, then using a Cox’s proportional hazards model to 
describe results based on hazard ratio. If the null hypothesis corresponding to time to first 
treatment failure is rejected, then the key secondary endpoints will be tested at the 5% level 
using Holm’s step down procedure, thus maintaining an overall Type I error rate of 5%. If the 
primary null hypothesis is not rejected, testing of change in key secondary endpoints will still be 
performed, but no unqualified statements about the statistical significance regarding change will 
be made. In Holm’s procedure, p-values from analyses of MCCB, PSP, and ICM will be ordered 
from lowest to highest. Let p(1)<p(2)<p(3) to be ordered p-values corresponding null hypotheses 
H(1), H(2), and H(3). In Step 1, if p(1) < 0.05/3 then corresponding null hypothesis will be 
rejected and testing will be examined in second step; otherwise, none of the hypotheses will be 
rejected and we will stop testing. In Step 2, if p(2) < 0.05/2 then corresponding null hypothesis 
will be rejected and move onto third step; otherwise, H(2) and H(3) will not be rejected and we 
will stop testing. In Step 3, p(3) will be tested at 0.05 level. All other exploratory hypotheses will 
be tested at the 2-sided 0.05 significance level without adjustments for multiplicity.
For the examination of extended disease progression and disease modification, there will be no 
adjustments for multiplicity. During these phases, we seek to show that subjects with recent-
onset schizophrenia or schizophreniform disorder who have a delayed start in their treatment 
with PP fail to catch up with subjects who start 9 months earlier in the course of their disease. 
We hypothesize that changes on measures of a pathophysiology biomarker (ICM), clinical 
symptoms (CGI), cognition (MCCB) and functioning (PSP) should be relatively better in 
subjects who initiate treatment earlier.
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5.2.
Part II, Primary Efficacy Endpoint
The primary efficacy endpoint is the time from Day 1 Part II (randomization) to the first 
treatment failure during the Part II phase.
Subjects will be evaluated at the time points indicated in the Time and Events Schedule for the 
occurrence of any of the events below that are identified as treatment failures. Only treatment 
failure events occurring after randomization in Part II (up to the end of Part III) will be assessed. 
The investigator will determine whether the event meets one of the protocol definitions, and will 
provide documentation of dates and times associated with the event.  Treatment failure will be 
defined as any of the following:

Psychiatric hospitalization due to worsening symptoms (including Emergency Room visits 
≥23 hours, and not including hospitalization due to social reasons); 

Any deliberate self-injury, suicidal ideation or behavior, homicidal ideation or violent 
behavior that is clinically significant and needs immediate intervention as determined by the 
study physician; 

New arrest/incarceration (not related to probation or existing warrant); 

Discontinuation of antipsychotic treatment due to inadequate efficacy as determined by the 
study physician; 

Discontinuation of antipsychotic treatment due to safety or tolerability as determined by the 
study physician; 

Treatment supplementation with another antipsychotic due to inadequate efficacy as 
determined by the study physician (note: use of oral paliperidone ER in the PP treatment 
group will not be considered a treatment failure unless supplemental use of paliperidone ER
or oral risperidone exceeds the dose levels or treatment durations specified in study protocol 
- Section Error! Reference source not found.); and

Increase in the level of psychiatric services (such as from office visit to day hospitalization) 
in order to prevent imminent psychiatric hospitalization as determined by the study 
physician.
Any changes in antipsychotic medications (switching, discontinuation, or add-on) must be 
evaluated against the treatment failure criteria. If any of these changes do not meet the treatment 
failure criteria, these must be documented and recorded in the eDC. 
At the time of first treatment failure, or as soon as possible thereafter, all efficacy assessments 
(MCCB, PSP, CGI-S, CRDPSS, and MSQ) and MRI imaging (in the subgroup of subjects 
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undergoing MRI assessment) must be performed. At the time of any subsequent treatment 
failures (or as soon as possible thereafter), PSP, CGI-S, CRDPSS, and MSQ assessments should 
be performed.
Note that subjects who experience a treatment failure and do not withdraw consent or meet the 
criteria for withdrawal from the study will continue in the study and be followed through to the 
end of the study.
Subject status during Part II
Time to First Treatment Failure/Censoring
Censoring 
indicator
Randomized subjects who 
experienced treatment failure
during Part II
(Date of treatment failure – Part II start
date) + 1
No
Randomized subjects who remained 
treatment failure-free at the end of
the Part II
(End of Part II date – Part II start date) + 1
Yes
Early withdrawal/discontinued 
during the Part II without treatment 
failure
(Date of early withdrawal – Part II start
date) + 1
Yes
5.2.1.
Primary Estimand
The primary efficacy estimand, the main clinical quantity of interest to be estimated in the study, 
is defined by the following components:
The treatment condition in Part II is:

Paliperidone Palmitate (PP) treatment group including PP1M for a minimum 4 months 
(five to eight injections) followed by PP3M treatment. 

Oral Antipsychotics (OAP) treatment group includes oral paliperidone or risperidone or 
another protocol-specified oral AP: aripiprazole, haloperidol, perphenazine, quetiapine, 
or olanzapine.
The population is restricted to subjects with recent-onset schizophrenia or schizophreniform 
disorder who were randomized in Part II and took any study medication regardless of compliance 
with study protocol.
The variable is time to first treatment failure during the disease progression phase (Part II).
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The intercurrent events and corresponding strategy are the following:
• Treatment discontinuation – Hypothetical Strategy: After treatment discontinuation in Part II, 
assume similar efficacy for subjects who discontinued as those subjects from the same 
treatment group who did not discontinue the treatment.
The population-level summary is the Kaplan-Meier estimate of the survival function. The 
primary analysis will be based on the Part II ITT analysis set.
5.2.2.
Analysis Methods
Under the primary estimand, only treatment failures occurring during the Part II phase prior to 
treatment discontinuation will be counted as events in the primary analysis. Treatment 
differences will be compared using a log-rank test. The cumulative distribution function of the 
time to treatment failure will be estimated by the Kaplan-Meier method [3,4]. The 95% CIs for the 
median treatment failure rates, as well as the failure rates at 3 months, 6 months, and at 9 months 
will be provided. Standard Error (SE) estimates will be computed using Greenwood’s formula. 
The estimate of the hazard ratio and its 95% CI will be provided by treatment group based on the 
Cox proportional hazards model[5]. The reasons for first treatment failure and subsequent 
treatment failures will be summarized at each visit and end point. 
If the log-rank test result is statistically significant (p-value <0.05) in favor of PP, the null 
hypothesis would be rejected, and we would conclude that PP is superior to OAP in delaying 
time to treatment failure. Hazard ratio and 95% CI will be used to describe reduction in risk 
treatment failure. 
The main analysis relies on the assumption of ignorable censoring. Therefore, sensitivity 
analyses will be performed to stress-test the robustness of results to deviations from ignorable 
censoring for the Part II ITT analysis population. Specifically, it is assumed that subjects on PP 
who discontinue prematurely from the Part II phase have a higher event hazard starting from the 
discontinuation time, compared with similar subjects who remain in this phase. The higher event 
hazard is determined by single sensitivity parameter Delta, representing the ratio of subject-
specific hazard at any given time point t following discontinuation compared to that same 
subject’s hazard at the same time t if he or she had remained in the Part II. A Kaplan-Meier 
multiple imputation (KMMI) non-parametric approach will be used for the imputation of 
treatment failure events as described by Taylor et al. (2002)[6] and Lipkovich et al. (2016)[7]. The 
number of multiple imputations (MI) will be set to 1000 and a seed equal to 234 will be used for 
MI. A sequence of Delta values will be used for all subjects with non-administrative censoring 
from the PP group (i.e. subjects censored due to other reasons than the end of Part II phase cut-
off), starting with 1 (ignorable censoring) and increasing by 1 until the point until the tipping 
point, where the results are no longer significant. For the OAP group, the sensitivity parameter 
Delta will be set to one, i.e. maintaining the ignorable censoring assumption.
An additional analysis will also be carried out for time to early discontinuation of study 
medication during the Part II for any reason including treatment failure and for any reason not 
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including treatment failure. This analysis will be similar in methodology to the primary efficacy 
analysis.
5.2.3.
Model Diagnostics
To assess the appropriateness of the proportional hazards assumption, a log-log survival plot of 
the Kaplan-Meier estimates will be generated.  If the proportional hazards assumption is correct, 
this plot should present approximately parallel lines corresponding to the two treatment groups.  
Cumulative sums of Schoenfeld residuals[8] over time may also be used to assess the proportional 
hazards assumption.
5.2.4.
Subgroup Analyses
Additional analysis of the time to treatment failure will be also be evaluated by age groups, race, 
sex, baseline BMI group, and randomization factors. Separate Cox’s proportional hazard models 
will be used to individually assess the effect of these covariates (including treatment and one 
covariate at a time). 
In Part II, primary time to treatment failure summaries will be repeated for the following 
subgroups: 1-) Current Primary DSM-5 Diagnosis (schizophrenia and schizophreniform); 2-) 
Subjects who continued into Part III and those who did not.
5.2.5.
Time to Treatment Failure by Reason
The reasons for treatment failure will be summarized at each visit and endpoint.  Exploratory 
time to event endpoints of interest include:
-
Time to 1st psychiatric hospitalization.
-
Time to 1st any deliberate self-injury, suicidal ideation or behavior, homicidal ideation or 
violent behavior.
-
Time to 1st new arrest/incarceration.
-
Time to 1st discontinuation of antipsychotic treatment due to inadequate efficacy.
-
Time to 1st discontinuation of antipsychotic treatment due to safety or tolerability.
-
Time to 1st treatment supplementation with another antipsychotic due to inadequate 
efficacy.
-
Time to 1st increase in the level of psychiatric services.
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The same analysis methods described for the primary efficacy endpoint will be used to analyze 
the above exploratory time to event endpoints. No multiplicity adjustment will be made to these 
tests.
5.2.6.
Multiple Events
Multiple treatment failures from the same subject will be analyzed as recurrent events. The 
cumulative mean function (CMF)[9] of treatment failure is a function of time and will be defined 
as the expected number of treatment failures per subject in a given time interval since 
randomization. A proportional rates/means model including a term for treatment will be used to 
compare the CMFs of treatment failure between the two treatment groups. Multiple treatment 
failure related data points will be captured from the Treatment Failure Board data set.
5.3.
Part II, Key Secondary Endpoints
The key secondary hypotheses to be tested in Part II of this study are to demonstrate that 9 
months’ treatment of subjects with recent-onset schizophrenia or schizophreniform disorder with 
PP is superior to 9 months’ treatment with OAP in: 

improving or maintaining cognition (as measured by the change in MCCB composite score 
from baseline)

The key secondary efficacy null hypothesis is that there is no difference in mean change 
from Part II baseline to the Part II end point in the MCCB composite score between PP 
and OAP

maintaining functioning (as measured by time to at least 7-point worsening in the PSP total 
score from baseline)

The key secondary efficacy null hypothesis is that there is no difference in time to 
7-point worsening in PSP total score in Part II between PP and OAP

increasing or preserving brain ICM volume of the frontal lobe as compared to baseline 

The key secondary efficacy null hypothesis is that there is no difference in mean change 
in ICM volume of the frontal lobe from Part II baseline to the Part II end point between 
PP and OAP 
At the end of Part II, changes in MCCB composite score, PSP, and ICM volume will be analyzed 
to determine if there is an early treatment effect demonstrating disease progression of PP relative 
to OAP. The early treatment effect is illustrated by δ21 in Error! Reference source not found.. 
In Part II, the overall Type I error rate for testing PP versus OAP for both the primary efficacy 
endpoint and key secondary efficacy endpoints will be controlled at the 2-sided 0.05 significance 
level using a combination of fixed sequence gatekeeper approach and Holm’s step-down 
procedure. Time to first treatment failure will be tested first, followed by change in key 
secondary endpoints (MCCB, PSP, and ICM). Time to first treatment failure will be examined 
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first using the log-rank test statistics. If the null hypothesis corresponding to time to first 
treatment failure is rejected, then the key secondary endpoints will be tested at the 5% level 
using Holm’s step down procedure, thus maintaining an overall Type I error rate of 5%. If the 
primary null hypothesis is not rejected, testing of change in key secondary endpoints will still be 
performed, but no unqualified statements about the statistical significance regarding change will 
be made. In Holm’s procedure, p-values from analyses of MCCB, PSP, and ICM will be ordered 
from lowest to highest. Let p(1)<p(2)<p(3) to be order p-values corresponding null hypotheses 
H(1), H(2), and H(3). In Step 1, if p(1) < 0.05/3 then corresponding null hypothesis will be 
rejected and testing will be examined in second step; otherwise, none of the hypotheses will be 
rejected and we will stop testing. In Step 2, if p(2) < 0.05/2 then corresponding null hypothesis 
will be rejected and move onto third step; otherwise, H(2) and H(3) will not be rejected and we 
will stop testing. In Step 3, p(3) will be tested at 0.05 level.
5.3.1.
MCCB – MATRICS Consensus Cognitive Battery
5.3.1.1.
Definition
The MATRICS Consensus Cognitive Battery (MCCB) was developed to provide a relatively 
brief evaluation of key cognitive domains relevant to schizophrenia and related disorders and is 
recommended as the standard outcome measure for clinical trials of cognition-enhancing drugs 
for schizophrenia. The MCCB includes 10 tests that measure 7 cognitive domains.
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MCCB Tests
Cognitive Domain
Test
Description
Speed of 
processing
Brief Assessment of 
Cognition in Schizophrenia
(BACS): Symbol-Coding 
Category Fluency: Animal 
Naming
Trail Making Test: Part A
Timed paper-and-pencil test in which 
respondent uses a key to write digits that 
correspond to nonsense symbols
Oral test in which respondent names as 
many animals as she/he can in 1 minute
Timed paper-and-pencil test in which 
respondent draws a line to connect 
consecutively numbered circles placed 
irregularly on a sheet of paper
Attention/Vigilance
Continuous Performance 
Test-Identical Pairs (CPT-
IP)
Computer-administered measure of 
sustained attention in which respondent 
presses a response button to consecutive 
matching numbers
Working memory
(nonverbal)
(verbal)
Wechsler Memory Scale®-
3rd Ed. 
(WMS®-III): Spatial Span 
Letter-Number Span
Using a board on which 10 cubes are 
irregularly spaced, respondent taps cubes 
in same (or reverse) sequence as test 
administrator
Orally administered test in which 
respondent mentally reorders strings of 
number and letters and repeats them to 
administrator
Verbal learning
Hopkins Verbal Learning 
Test-Revised™ (HVLT-
R™)
Orally administered test in which a list of 
12 words from three taxonomic categories 
is presented and the respondent is asked to 
recall as many as possible after each of 
three learning trials
Visual Learning
Brief Visuospatial Memory 
Test-Revised (BVMT-R™)
A test that involves reproducing six 
geometric figures from memory
Reasoning and
problem solving
Neuropsychological 
Assessment Battery®
Seven timed paper-and-pencil mazes of 
increasing difficulty that measure 
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(NAB®): Mazes
foresight and planning
Social cognition
Mayer-Salovey-Caruso 
Emotional Intelligence Test
(MSCEIT™): Managing 
Emotions
Paper-and-pencil multiple-choice test that 
assesses how people manage their 
emotions
The MCCB will be administered by a qualified rater at the time points indicated in the Time and 
Events Schedule. The MCCB assessment must also be performed at the time of first occurrence 
of treatment failure.
For every individual subject, MCCB should be administered at the same time of day (within a 
2-hour window) for every assessment. If possible, the same person should administer the tests at 
each occasion.
All MCCB data will be sent to central raters for review. Assessments will each be scored by 
central raters who are blinded to treatment information. Central raters will also review the 
neurocognitive data quality and correct any errors. The central raters will enter the final scores 
into the MCCB Scoring program to derive T-scores and composites scores. The central raters 
will enter the raw and derived MCCB scores to the eDC.
5.3.1.2.
Analysis Methods
Part II
The change from baseline in MCCB composite score will be analyzed using a mixed model 
repeated measures (MMRM) ANCOVA model[10,11,12,13]. The analysis will be based on observed 
data, ie, data collected at each time point without carrying forward previous values. The data 
points from unscheduled visits will also be included. The response variable will be the change in 
MCCB composite score. The model will include Part II baseline MCCB composite score as a 
fixed-effect covariate; treatment (PP and OAP) and country and time as fixed-effect (categorical) 
factors, and the interaction between time and treatment. Using this model, treatment effects at the 
Month 9 end point will be estimated based on differences between least squares (LS) means. 
Accompanying 95% CIs for the LS mean differences between PP and OAP will be presented. An 
unstructured matrix will be used for the covariance of the within-subject repeated measures as a 
base case. 
The purpose of this analysis is to examine treatment differences at Month 9 using LS means from 
the MMRM model. The treatment effect measures the deviation from the hypothesis of equality 
of means among treatments, “averaged” over the treatment duration. The time effect is a measure 
of deviation from the hypothesis of constancy of mean response over time for all treatment 
groups combined after aggregating over subjects. The treatment-by-time interaction tests the 
hypothesis of parallel response profiles over time in the treatment groups. A significant 
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treatment-by-time interaction means that changes in response over time differ among treatments; 
in other words, there is a difference among the treatment groups, but the magnitude of the 
difference varies over time. The interaction will remain in the model, regardless of significance, 
in order to obtain an estimate of the treatment effect at the Month 9 time point. In the ITT 
analysis set, the model-based test for the mean treatment group difference will also be examined.
To assess normality, diagnostic plots such as normal quantile-quantile plots of residuals will be 
created. If a high degree of non-normality is suspected, remedies such as rank-based methods 
will be considered.
The eITT analysis set will also be used to test changes at end point. The eITT analysis set 
consists of MCCB score assessed at or prior to the eITT end point.
Similar analysis will also be repeated using the observed scores (not the change) and domain 
scores.
In addition, the actual values and change from baseline scores will be summarized for both 
observed data as well as LOCF data by treatment group. The treatment group differences will be 
analyzed using an ANCOVA model. The model will include treatment and country as fixed 
effect design factors, and baseline MCCB composite score as a covariate.  Using this model, 
treatment effects will be estimated based on differences between least squares (LS) means. 
Accompanying 95% CIs (not adjusted for multiplicity) for the LS mean differences will be 
presented. Within treatment group difference for change from baseline will be evaluated using a 
paired t-test. Plots of the LS-Mean (± standard error (SE)) change from baseline in MCCB total 
score over time will also be presented for both the observed and LOCF data.
Primary MCCB composite score summaries will be repeated for the following subgroups: 1-) 
Current Primary DSM-5 Diagnosis (schizophrenia and schizophreniform); 2-) Subjects who 
continued into Part III and those who did not.
5.3.2.
PSP - Personal and Social Performance Scale
5.3.2.1.
Definition
The PSP scale is a clinician-rated instrument that assesses the degree of dysfunction a subject 
exhibits in the past month within 4 domains of behavior: a) socially useful activities, b) personal 
and social relationships, c) self-care, and d) disturbing and aggressive behavior. The results of 
the assessment are converted to a numerical score following the PSP scoring guideline. A score 
between 71 and 100 indicates a mild degree of dysfunction; a score between 31 and 70 indicates 
varying degrees of difficulty, and a subject with a score of 30 has functioning so poor that he or 
she requires intensive supervision.
The PSP scale is to be administered by a qualified rater at the time points indicated in the Time 
and Events Schedule. The PSP assessment must also be conducted at the time of first occurrence 
of treatment failure, and should also be performed at the time of subsequent occurrences of 
treatment failure. If possible, the same person should administer this scale at each occasion.
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5.3.2.2.
Analysis Methods
Part II
The analysis of time to at least 7-point worsening in PSP total score will be similar in 
methodology to the primary efficacy analysis.
Subject status during Part II
Time to First >= 7-point worsening in PSP 
Total Score
Censoring 
indicator
Randomized subjects who 
experienced at least 7-point 
worsening during Part II
(Date of event – Part II start date) + 1
No
Randomized subjects who remained 
event free at the end of the Part II
(End of Part II date – Part II start date) + 1
Yes
Early withdrawal/discontinued 
during the Part II without an event
(Date of early withdrawal – Part II start 
date) + 1
Yes
Mean changes in PSP total score will be analyzed using the same method as the MCCB analysis 
except the baseline MCCB score will be replaced by the corresponding PSP baseline score in 
MMRM and ANCOVA models. Primary PSP summaries will be repeated for the following 
subgroups: 1-) Current Primary DSM-5 Diagnosis (schizophrenia and schizophreniform); 2-) 
Subjects who continued into Part III and those who did not.
Time to 10-point worsening in PSP total score will also be analyzed.
Frequency counts, percentages, and cumulative percentages of subjects reporting each PSP 
deciles, 3 PSP categories (Poor, Variable, Good), and domain levels will be summarized for both 
observed data and LOCF data by treatment group. In addition to 3 PSP categories, subjects who 
achieve a PSP score ≥ 71 vs. <70 will be identified and summarized. The incidence of PSP 
responders (PSP score ≥ 71 vs. <70) will be compared between active treatment group and 
placebo. Differences between treatment groups will be evaluated based on the Cochran-Mantel-
Haenszel mean score (CMH)[14] test using the modified ridit scores, stratifying on site.
At each post-baseline assessment and LOCF, a shift from baseline table will summarize the 
worsening, no change, and improvement relative to baseline PSP categories. Within group 
differences will be evaluated using the McNemar’s test.
Each PSP domain was assessed on a 6-point severity scale of dysfunction: 1 = absent, 2 = mild, 3 
= manifest, 4 = marked, 5 = severe, and 6 = very severe. We define no impairment to mild 
impairment as a PSP domain score of absent or mild dysfunction; moderate to severe impairment 
is defined as manifest, marked, severe, or very severe dysfunction. For these binomial 
summaries, differences between treatment groups will be evaluated based on the Cochran-
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Mantel-Haenszel mean score (CMH) test using the modified ridit scores, stratifying on site. At 
each post-baseline assessment and LOCF, a shift from baseline table will summarize the changes 
relative to baseline PSP categories. Within group differences will be evaluated using the 
McNemar’s test.
5.3.3.
MRI Brain Imaging Assessments
5.3.3.1.
Definition
Selected sites will be performing MRI brain imaging. Approximately half of the enrolled 
subjects will undergo MRI scans. MRI scans are optional to subjects. All images will be sent to a 
central site for analysis. The imaging raters at the central site will be blind to clinical 
characteristics, treatment assignment, and demographic characteristics of subjects. 
Brain imaging assessments will be performed in subjects with schizophrenia/schizophreniform 
disorder and in healthy control subjects. Subjects with schizophrenia or schizophreniform 
disorder who are not able to undergo scans (eg, unable to fit or difficulty fitting in MRI 
instrument, or MRI contraindicated due to presence of metallic objects [pacemaker, etc.]) will be 
excluded from participating in MRI scans, but will still be eligible to participate in all other 
aspects of this study. Healthy control subjects who are not able to undergo MRI scans will not be 
eligible to participate in this study. 
If the initial MRI is clinically abnormal and shows presence of a severe brain abnormality that 
would preclude analyses (eg, large hemangioma), the individual will be excluded from 
undergoing further MRI scans. If this occurs in a healthy control subject, the subject will be 
withdrawn from the study. If the initial scan is abnormal in a subject with 
schizophrenia/schizophreniform disorder, the subject will be excluded from further MRI 
assessments but will continue in all other aspects of the study. 
A separate MRI manual will be provided to the relevant sites with detailed information regarding 
the MRI procedures. In brief, brain ICM volume will be measured by inversion recovery (IR) 
and spin echo (SE) MRI sequences focused on the frontal lobe. Cortical thickness, gray matter 
and white matter volumes will be measured by 3D MPRAGE MRI. Ventricular volume and 
intrasulcal CSF will be measured by SE MRI sequences. The subcortical myelin will be 
measured by MRI sequences optimized for DTI. The resting state fMRI will also be measured.
Brain imaging in subjects with schizophrenia or schizophreniform disorder will be performed at 
the time points indicated in the Time and Events Schedule. Brain imaging must also be 
conducted at the time of first occurrence of treatment failure or as soon as possible thereafter.
MRI assessments in healthy control subjects will be described in the MRI manual.
The MRI data set will include both raw and adjusted measures. Adjusted Intracortical Myelin 
Fraction (ICM_div_ICV_adj) will be considered as primary variable of interest.
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Variable Name
Description
Notes
ICV_cc
Intracranial volume
Data units are cubic centimeters 
(cm3)
Total_cc
Total brain tissue volume 
(WM+GM)
Data units are cubic centimeters 
(cm3)
IR_cc
WM volume measured on IR 
image
Data units are cubic centimeters 
(cm3)
PD_cc
WM volume measured on PD 
image
Data units are cubic centimeters 
(cm3)
ICM_old_cc
Intracortical myelin volume (old 
version)
Data units are cubic centimeters 
(cm3)
ICM_cc
Intracortical myelin volume
Data units are cubic centimeters 
(cm3)
Total_div_ICV
Total brain tissue fraction 
(WM+GM)
Data as fraction of intracranial 
volume
IR_div_ICV
WM fraction measured on IR 
image
Data as fraction of intracranial 
volume
PD_div_ICV
WM fraction measured on PD 
image
Data as fraction of intracranial 
volume
ICM_old_div_ICV
Intracortical myelin fraction (old 
version)
Data as fraction of intracranial 
volume
ICM_div_ICV
Intracortical myelin fraction
Data as fraction of intracranial 
volume
ICV_cc_adj
Adjusted Intracranial volume
Volume after adjusting using HC 
group (e.g. age, machine drift)
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5.3.3.2.
Analysis Methods
Part II
The number and percentage of subjects who completed the trial, prematurely discontinued from 
the trial along with the reason for discontinuation, will be summarized based on the Part II MRI 
ITT analysis set. Demographics baseline characteristics and psychiatric history will also be 
presented for the MRI ITT Population. Correlations between the MRI variables and MCCB 
composite score including domain scores will be listed.
The actual values and change from baseline for each variable will be summarized for both 
observed data as well as the LOCF data. Box plots will be generated at each time point for 
observed and change scores separately by treatment group.
Both the change from baseline and observed scores in MRI variables will be analyzed using a 
mixed model repeated measures (MMRM) ANCOVA model. These models will be repeated for 
both raw scores and adjusted scores. The analysis will be based on observed data, ie, data 
collected at each time point without carrying forward previous values. The data points from 
unscheduled visits will also be included. The response variable will be the change or observed 
score in MRI scores. The model will include corresponding Part II baseline as a fixed-effect 
covariate; treatment (PP and OAP) and country and time as fixed-effect (categorical) factors, and 
the interaction between time and treatment. Using this model, treatment effects at the Month 9 
end point will be estimated based on differences between least squares (LS) means. 
Accompanying 95% CIs for the LS mean differences between PP and OAP will be presented. An 
unstructured matrix will be used for the covariance of the within-subject repeated measures as a 
base case. 
To assess normality, diagnostic plots such as normal quantile-quantile plots of residuals will be 
created. If a high degree of non-normality is suspected, remedies such as rank-based methods 
will be considered.
In addition, the actual values and change from baseline scores will be summarized for both 
observed data as well as LOCF data by treatment group. The treatment group differences will be 
analyzed using an ANCOVA model. The model will include treatment and country as fixed 
effect design factors, and corresponding baseline MRI score as a covariate.  Using this model, 
treatment effects will be estimated based on differences between least squares (LS) means. 
Accompanying 95% CIs (not adjusted for multiplicity) for the LS mean differences will be 
presented. Within treatment group difference for change from baseline will be evaluated using a 
paired t-test. Plots of the LS-Mean (± standard error (SE)) change from baseline in MRI 
variables over time will also be presented.
The eITT analysis set will also be used to test changes at end point for the primary MRI variable. 
The eITT analysis set consists of MRI variables assessed at or prior to the eITT end point.
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5.4.
Secondary Endpoints
No multiplicity adjustments will be made for secondary endpoints.  All p-values are considered 
nominal.
5.4.1.
Treatment Failure 
5.4.1.1.
Treatment Failure in EDP Phase
Subjects will be evaluated at the time points indicated in the Time and Events Schedule for the 
occurrence of treatment failures. Only treatment failure events occurring after randomization in 
Part II until the end of Part III will be assessed. 
Note that subjects who experience a treatment failure and do not withdraw consent or meet the 
criteria for withdrawal from the study will continue in the study and be followed through to the 
end of the study.
Subject status during EDP Phase
Time to First Treatment Failure/Censoring
Censoring 
indicator
Randomized subjects who 
experienced treatment failure
during EDP Phase
(Date of treatment failure – Part II start 
date) + 1
No
Randomized subjects who remained 
treatment failure-free at the end of
the Part III
(End of Part III date – Part II start date) + 1
Yes
Early withdrawal/discontinued 
during the Part III without treatment 
failure
(Date of early withdrawal in Part III – Part 
II start date) + 1
Yes
Treatment differences will be compared using a log-rank test. The cumulative distribution 
function of the time to treatment failure will be estimated by the Kaplan-Meier method. The 95% 
CIs for the median treatment failure rates, as well as the failure rates at months 3, 6, 9, 12, 15, 
and 18 will be provided. Standard Error (SE) estimates will be computed using Greenwood’s 
formula. Group differences will be evaluated using the log-rank test. The estimate of the hazard 
ratio and its 95% CI will be provided by treatment group based on the Cox proportional hazards 
model. The reasons for first treatment failure and subsequent treatment failures will be 
summarized at each visit and end point. 
To assess the appropriateness of the proportional hazards assumption, a log-log survival plot of 
the Kaplan-Meier estimates will be generated.  If the proportional hazards assumption is correct, 
this plot should present approximately parallel lines corresponding to the two treatment groups.  
Cumulative sums of Schoenfeld residuals over time may also be used to assess the proportional 
hazards assumption. 
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Additional analysis of the time to treatment failure will be also be evaluated by age groups, race, 
sex, and baseline BMI group. Separate Cox’s proportional hazard models will be used to 
individually assess the effect of these covariates (including treatment and one covariate at a 
time). 
The reasons for treatment failure will be summarized at each visit and endpoint.  These time to 
event endpoints of interest include:
-
Time to 1st psychiatric hospitalization.
-
Time to 1st any deliberate self-injury, suicidal ideation or behavior, homicidal ideation or 
violent behavior. 
-
Time to 1st new arrest/incarceration. 
-
Time to 1st discontinuation of antipsychotic treatment due to inadequate efficacy.
-
Time to 1st discontinuation of antipsychotic treatment due to safety or tolerability. 
-
Time to 1st treatment supplementation with another antipsychotic due to inadequate 
efficacy.
-
Time to 1st increase in the level of psychiatric services.
For each of the reasons for treatment failure, the Kaplan-Meier estimates, log-rank test, 
hazard ratios will be provided to differentiate treatment groups.
Multiple treatment failures from the same subject will be analyzed as recurrent events. The 
cumulative mean function (CMF) of treatment failure is a function of time and will be defined as 
the expected number of treatment failures per subject in a given time interval since 
randomization. A proportional rates/means model including a term for treatment will be used to 
compare the CMFs of treatment failure between the two treatment groups. Multiple treatment 
failure related data points will be captured from the Treatment Failure Board data set.
5.4.1.2.
Treatment Failure in Part III
Subjects will be evaluated at the time points indicated in the Time and Events Schedule for the 
occurrence of treatment failures. Only treatment failure events occurring after Part III start date 
will be assessed. 
Note that subjects who experience a treatment failure and do not withdraw consent or meet the 
criteria for withdrawal from the study will continue in the study and be followed through to the 
end of the study.
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Subject status during Part III
Time to First Treatment Failure/Censoring
Censoring 
indicator
Subjects who experienced treatment 
failure during Part III
(Date of treatment failure – Part III start 
date) + 1
No
Subjects who remained treatment 
failure-free at the end of the Part III
(End of Part III date – Part III start date) + 1
Yes
Early withdrawal/discontinued 
during the Part III without treatment 
failure
(Date of early withdrawal in Part III – Part 
III start date) + 1
Yes
In Part III, there are three treatment groups, PPPP, OAPPP, and OAPOAP. Treatment differences 
among three groups will be compared using a log-rank test. The cumulative distribution function 
of the time to treatment failure will be estimated by the Kaplan-Meier method. The 95% CIs for 
the median treatment failure rates, as well as the failure rates at months 3, 6, and 9 will be 
provided. Standard Error (SE) estimates will be computed using Greenwood’s formula. Group 
differences will be evaluated using the log-rank test. The estimate of the hazard ratio and its 95% 
CI will be provided by treatment group based on the Cox proportional hazards model. The 
reasons for first treatment failure and subsequent treatment failures will be summarized at each 
visit and end point. 
To assess the appropriateness of the proportional hazards assumption, a log-log survival plot of 
the Kaplan-Meier estimates will be generated.  If the proportional hazards assumption is correct, 
this plot should present approximately parallel lines corresponding to the two treatment groups.  
Cumulative sums of Schoenfeld residuals over time may also be used to assess the proportional 
hazards assumption. 
Additional analysis of the time to treatment failure will be also be evaluated by age groups, race, 
sex, and baseline BMI group. Separate Cox’s proportional hazard models will be used to 
individually assess the effect of these covariates (including treatment and one covariate at a 
time). 
The reasons for treatment failure will be summarized at each visit and endpoint.  These time to 
event endpoints of interest include:
-
Time to 1st psychiatric hospitalization.
-
Time to 1st any deliberate self-injury, suicidal ideation or behavior, homicidal ideation or 
violent behavior. 
-
Time to 1st new arrest/incarceration. 
-
Time to 1st discontinuation of antipsychotic treatment due to inadequate efficacy.
-
Time to 1st discontinuation of antipsychotic treatment due to safety or tolerability. 
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-
Time to 1st treatment supplementation with another antipsychotic due to inadequate 
efficacy.
-
Time to 1st increase in the level of psychiatric services.
For each of the reasons for treatment failure, the Kaplan-Meier estimates, log-rank test, 
hazard ratios will be provided to differentiate treatment groups.
Multiple treatment failures from the same subject will be analyzed as recurrent events. The 
cumulative mean function (CMF) of treatment failure is a function of time and will be defined as 
the expected number of treatment failures per subject in a given time interval since 
randomization. A proportional rates/means model including a term for treatment will be used to 
compare the CMFs of treatment failure between the two treatment groups. Multiple treatment 
failure related data points will be captured from the Treatment Failure Board data set.
5.4.2.
MCCB – MATRICS Consensus Cognitive Battery
5.4.2.1.
Definition
Definition is listed in Section 5.3.3.1.
5.4.2.2.
Analysis Methods
Part I
The actual values and change from baseline in MCCB composite score and domain scores will 
be summarized for both observed data as well as LOCF data. Within treatment group difference 
for change from baseline will be evaluated using a paired t-test. The MCCB composite score will 
also be categorized into three groups as <25, 25-35, >35. Frequency counts, percentages, and 
cumulative percentages of subjects reporting each MCCB composite score categories will be 
summarized. Shifts from baseline to each visit including LOCF by categories will also be 
displayed.
Part II
Part II analysis is listed as a segment of the Key Secondary Efficacy analysis section, see Section 
5.3.
Treatment group differences will also be evaluated by number of treatment failures in Part II.
EDP Phase
The change from baseline in MCCB composite score and domain scores will be analyzed using a 
mixed model repeated measures (MMRM) ANCOVA model. The analysis will be based on 
observed data, ie, data collected at each time point without carrying forward previous values. 
The data points from unscheduled visits will also be included. The response variable will be the 
change in MCCB composite score or domain scores. The model will include Part II baseline 
MCCB composite score as a fixed-effect covariate; treatment (PPPP and OAPOAP) and country
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and time as fixed-effect (categorical) factors, and the interaction between time and treatment. 
Using this model, treatment effects at each visit and at Month 18 end point will be estimated 
based on differences between least squares (LS) means. Accompanying 95% CIs for the LS 
mean differences between PPPP and OAPOAP will be presented. An unstructured matrix will be 
used for the covariance of the within-subject repeated measures as a base case. 
The eITT analysis set will also be used to test changes at end point. The eITT analysis set 
consists of MCCB score assessed at or prior to the eITT end point.
Similar analysis will also be repeated using the observed scores (not the change) and domain 
scores.
In addition, the actual values and change from baseline scores will be summarized for both 
observed data as well as LOCF data by treatment group. The treatment group differences will be 
analyzed using an ANCOVA model. The model will include treatment and country as fixed 
effect design factors, and baseline MCCB composite score or domain score as a covariate.  Using 
this model, treatment effects will be estimated based on differences between least squares (LS) 
means. Accompanying 95% CIs (not adjusted for multiplicity) for the LS mean differences will 
be presented. Within treatment group difference for change from baseline will be evaluated using 
a paired t-test. Plots of the LS-Mean (± standard error (SE)) change from baseline in MCCB total 
score over time will also be presented for both the observed and LOCF data. Treatment group 
differences will also be evaluated by number of treatment failures in EDP phase.
Part III
All data from the Part III phase of the study will be categorized and presented using three 
columns: those patients who are not re-randomized (PPPP) were on PP in Part II, those oral 
patients in Part II who are re-randomized to paliperidone palmitate (OAPPP), and those patients 
who are re-randomized to oral antipsychotics (OAPOAP). 
Part III analyses of MCCB composite and domain scores will be analyzed using the Part II 
analyses strategies.
For the MCCB composite score, the following hypotheses will also be tested as a function of 
estimated changes in the Part II endpoint using the observed scores to demonstrate disease 
modification. This analysis assumes at minimum that subjects treated with PP for 9 months (early-
start group) demonstrated better outcomes on MCCB composite score than those treated with OAP for 9
months at the end of Part II. Let δ21 denote the estimated mean differences between treatment 
groups at the end of Part II, treatment effect on disease progression. Let δ31 denote the estimated 
mean difference between PPPP and OAPOP groups at the end of Part III. The following 
hypotheses will be tested using observed scores:
H0: δ31 – 0.5. δ21 ≤0 and H0: δ31 – 0.75. δ21 ≤0 where the fractions 0.5 and 0.75 are the conditional
noninferiority margins which indicate the ratio of treatment effect in Part III compared to the 
Part II observed differences.
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These hypotheses will be tested using a mixed model repeated measures (MMRM) ANCOVA 
models. The analysis will be based on observed data. The model will include corresponding Part 
II baseline as a fixed-effect covariate; treatment and country and time as fixed-effect 
(categorical) factors, and the interaction between time and treatment. Using this model, treatment 
effects at the Month 9 and Mont 18 end point will be estimated based on differences between 
least squares (LS) means. An unstructured matrix will be used for the covariance of the within-
subject repeated measures. 
5.4.3.
PSP - Personal and Social Performance Scale
5.4.3.1.
Definition
Definition is listed in Section 5.3.2.1.
5.4.3.2.
Analysis Methods
Part I
The actual values and change from baseline in PSP score will be summarized for both observed 
data as well as LOCF data. Within treatment group difference for change from baseline will be 
evaluated using a paired t-test. Frequency counts, percentages, and cumulative percentages of 
subjects reporting each PSP deciles and domain level will be summarized. Additionally, at each 
post-baseline assessment and LOCF data, a shift from baseline table will summarize the 
worsening, no change, and improvement relative to baseline for the PSP 10-point categories. 
Worsening in the PSP change from baseline score is defined as a decrease by one 10-point scale 
or more, and an improvement in the PSP change from baseline score is defined as an increase by 
one 10-point scale or more.  No testing will be done for this shift summary. The PSP score will 
also be categorized into three groups as Poor (PSP score ≤30), Variable (>30 PSP score ≤70), 
and Good (PSP score >70). Frequency counts, percentages, and cumulative percentages of 
subjects reporting each PSP categories will be summarized. Shifts from baseline to each visit 
including LOCF by PSP categories will also be listed.
Part II
Part II analysis is listed as a segment of the Key Secondary Efficacy analysis section, see Section 
5.3.
Treatment group differences will also be evaluated by number of treatment failures in Part II.
EDP Phase
The analysis of time to at least 7-point worsening in PSP total score will be similar in 
methodology to the primary efficacy analysis.
Subject status during EDP Phase
Time to First >= 7-point worsening in PSP 
Total Score
Censoring 
indicator
Randomized subjects who 
(Date of event – Part II start date) + 1
No
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experienced at least 7-point 
worsening during EDP phase
Randomized subjects who remained 
event free at the end of the Part III
(End of Part III date – Part II start date) + 1
Yes
Early withdrawal/discontinued 
during the Part III without an event
(Date of early withdrawal in Part III – Part 
II start date) + 1
Yes
Mean changes in PSP total score will be analyzed using the same method as the MCCB analysis 
except the baseline MCCB score will be replaced by the corresponding PSP baseline score.
Treatment group differences will also be evaluated by number of treatment failures in EDP 
phase.
Time to 10-point worsening in PSP total score will also be analyzed.
Frequency counts, percentages, and cumulative percentages of subjects reporting each PSP 
deciles, 3 PSP categories (Poor, Variable, Good), and domain levels will be summarized for both 
observed data and LOCF data by treatment group. In addition to 3 PSP categories, subjects who 
achieve a PSP score ≥ 71 vs. <70 will be identified and summarized. The incidence of PSP 
responders (PSP score ≥ 71 vs. <70) will be compared between active treatment group and placebo. 
Differences between treatment groups will be evaluated based on the Cochran-Mantel-Haenszel 
mean score (CMH) test using the modified ridit scores, stratifying on site.
At each post-baseline assessment and LOCF, a shift from baseline table will summarize the 
worsening, no change, and improvement relative to baseline PSP categories. Within group 
differences will be evaluated using the McNemar’s test.
Each PSP domain was assessed on a 6-point severity scale of dysfunction: 1 = absent, 2 = mild, 3 
= manifest, 4 = marked, 5 = severe, and 6 = very severe. We define no impairment to mild 
impairment as a PSP domain score of absent or mild dysfunction; moderate to severe impairment 
is defined as manifest, marked, severe, or very severe dysfunction. For these binomial 
summaries, differences between treatment groups will be evaluated based on the Cochran-
Mantel-Haenszel mean score (CMH) test using the modified ridit scores, stratifying on site. At 
each post-baseline assessment and LOCF, a shift from baseline table will summarize the changes
relative to baseline PSP categories. Within group differences will be evaluated using the 
McNemar’s test.
Part III
All data from the Part III phase of the study will be categorized and presented using three 
columns: those patients who are not re-randomized (PPPP) were on PP in Part II, those oral 
patients in Part II who are re-randomized to paliperidone palmitate (OAPPP), and those patients 
who are re-randomized to oral antipsychotics (OAPOAP). 
The analysis of time to at least 7-point worsening in PSP total score will be similar in 
methodology to the primary efficacy analysis.
Subject status during Part III
Time to First >= 7-point worsening in PSP 
Censoring 
indicator
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Total Score
Subjects who experienced at least 
7-point worsening during Part III
(Date of event – Part III start date) + 1
No
Subjects who remained event free at 
the end of the Part III
(End of Part III date – Part III start date) + 1
Yes
Early withdrawal/discontinued 
during the Part III without an event
(Date of early withdrawal in Part III – Part 
III start date) + 1
Yes
Mean changes in PSP total score will be analyzed using the same method as the MCCB analysis 
except the baseline MCCB score will be replaced by the corresponding PSP baseline score.
Time to 10-point worsening in PSP total score will also be analyzed.
Frequency counts, percentages, and cumulative percentages of subjects reporting each PSP 
deciles, 3 PSP categories (Poor, Variable, Good), and domain levels will be summarized for both 
observed data and LOCF data by treatment group. In addition to 3 PSP categories, subjects who 
achieve a PSP score ≥ 71 vs. <70 will be identified and summarized. The incidence of PSP 
responders (PSP score ≥ 71 vs. <70) will be compared between active treatment group and placebo. 
Differences between treatment groups will be evaluated based on the Cochran-Mantel-Haenszel 
mean score (CMH) test using the modified ridit scores, stratifying on site.
At each post-baseline assessment and LOCF, a shift from baseline table will summarize the 
worsening, no change, and improvement relative to baseline PSP categories. Within group 
differences will be evaluated using the McNemar’s test.
Each PSP domain was assessed on a 6-point severity scale of dysfunction: 1 = absent, 2 = mild, 3 
= manifest, 4 = marked, 5 = severe, and 6 = very severe. We define no impairment to mild 
impairment as a PSP domain score of absent or mild dysfunction; moderate to severe impairment
is defined as manifest, marked, severe, or very severe dysfunction. For these binomial 
summaries, differences between treatment groups will be evaluated based on the Cochran-
Mantel-Haenszel mean score (CMH) test using the modified ridit scores, stratifying on site. At 
each post-baseline assessment and LOCF, a shift from baseline table will summarize the changes
relative to baseline PSP categories. Within group differences will be evaluated using the 
McNemar’s test.
For the PSP total score, the following hypotheses will also be tested as a function of estimated 
changes in the Part II endpoint using the observed scores to demonstrate disease modification. 
This analysis assumes at minimum that subjects treated with PP for 9 months (early-start group) 
demonstrated better outcomes on PSP total score than those treated with OAP for 9 months at the 
end of Part II. Let δ21 denote the estimated mean differences between treatment groups at the end 
of Part II, treatment effect on disease progression. Let δ31 denote the estimated mean difference 
between PPPP and OAPOP groups at the end of Part III. The following hypotheses will be tested 
using observed scores:
H0: δ31 – 0.5. δ21 ≤0 and H0: δ31 – 0.75. δ21 ≤0 where the fractions 0.5 and 0.75 are the conditional
noninferiority margins which indicate the ratio of treatment effect in Part III compared to the 
Part II observed differences.
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These hypotheses will be tested using a mixed model repeated measures (MMRM) ANCOVA 
models. The analysis will be based on observed data. The model will include corresponding Part 
II baseline as a fixed-effect covariate; treatment and country and time as fixed-effect 
(categorical) factors, and the interaction between time and treatment. Using this model, treatment 
effects at the Month 9 and Mont 18 end point will be estimated based on differences between 
least squares (LS) means. An unstructured matrix will be used for the covariance of the within-
subject repeated measures. 
5.4.4.
MRI Brain Imaging Assessments
5.4.4.1.
Definition
Definition is listed in Section 5.3.3.1.
5.4.4.2.
Analysis Methods
Part I
There is no imaging data collected in Part I.
Part II
Part II analysis is listed as a segment of the Key Secondary Efficacy analysis section, see Section 
5.3.
EDP Phase
Changes in ICM volume will be analyzed using the same method as the MCCB analysis except 
for the baseline MCCB score which will be replaced by the corresponding ICM baseline score. 
Treatment groups will be listed as PPPP and OAPOAP. The objective is to examine the 
cumulative effect on extended disease progression at the end of Part III following early start for 
PP compared to continuing OAP after a total of 18 months of treatment.
Part III
All data from the Part III phase of the study will be categorized and presented using three 
columns: those patients who are not re-randomized (PPPP) were on PP in Part II, those oral 
patients in Part II who are re-randomized to paliperidone palmitate (OAPPP), and those patients 
who are re-randomized to oral antipsychotics (OAPOAP). 
Part III analyses of MRI scores will be analyzed using the Part II analyses strategies.
For the Adjusted Intracortical Myelin Fraction (ICM_div_ICV_adj) score, the following 
hypotheses will also be tested as a function of estimated changes in the Part II endpoint using the 
observed scores to demonstrate disease modification. This analysis assumes at minimum that 
subjects treated with PP for 9 months (early-start group) demonstrated better outcomes on
Adjusted Intracortical Myelin Fraction score than those treated with OAP for 9 months at the end 
of Part II. Let δ21 denote the estimated mean differences between treatment groups at the end of 
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Part II, treatment effect on disease progression. Let δ31 denote the estimated mean difference 
between PPPP and OAPOP groups at the end of Part III. The following hypotheses will be tested 
using observed scores:
H0: δ31 – 0.5. δ21 ≤0 and H0: δ31 – 0.75. δ21 ≤0 where the fractions 0.5 and 0.75 are the conditional
noninferiority margins which indicate the ratio of treatment effect in Part III compared to the 
Part II observed differences.
These hypotheses will be tested using a mixed model repeated measures (MMRM) ANCOVA 
models. The analysis will be based on observed data. The model will include corresponding Part 
II baseline as a fixed-effect covariate; treatment and country and time as fixed-effect 
(categorical) factors, and the interaction between time and treatment. Using this model, treatment 
effects at the Month 9 and Mont 18 end point will be estimated based on differences between 
least squares (LS) means. An unstructured matrix will be used for the covariance of the within-
subject repeated measures. 
5.4.5.
CGI-S - Clinical Global Impression of Severity Scale
5.4.5.1.
Definition
The CGI-S rating scale is used to rate the severity of a subject’s overall clinical condition on a 
7-point scale ranging from 1 (not ill) to 7 (among the most extremely ill). This scale permits a 
global evaluation of the subject’s condition at a given time. 
This scale will be administered by a qualified rater at the time points indicated in the Time and 
Events Schedule. The CGI-S assessment must also be conducted at the time of first occurrence of 
treatment failure and should also be performed at the time of subsequent occurrences of 
treatment failure. If possible, the same person should administer this scale at each occasion.
5.4.5.2.
Analysis Methods
Part I
The actual values and change from baseline in CGI-S score will be summarized for both 
observed data as well as LOCF data. Within treatment group difference for change from baseline 
will be evaluated using a paired t-test. Frequency counts, percentages, and cumulative 
percentages of subjects reporting each CGI-S level will be summarized for both observed data as 
well as LOCF data.
Part II
The actual values and change from baseline scores of CGI-S will be summarized for both 
observed data as well as LOCF data by treatment group. The treatment group differences will be 
analyzed using an ANCOVA model. The model will include treatment and country as fixed 
effect design factors, and the baseline CGI-S score as a covariate.  Using this model, treatment 
effects will be estimated based on differences between least squares (LS) means. Accompanying 
95% CIs (not adjusted for multiplicity) for the LS mean differences will be presented. Within 
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treatment group difference for change from baseline will be evaluated using a paired t-test. Plots 
of the LS-Mean (± standard error (SE)) change from baseline in CGI-S score over time will also 
be presented for the observed data. The assumptions of the ANOVA / ANCOVA models--errors 
are normally distributed with equal variances--will be tested by examining the model residuals 
with histograms, normal probability plot and plots of residuals versus fitted values. If there is 
strong evidence that the assumptions are not satisfied then the p-value from Friedman's Chi-
Square Test will also be presented for the ANOVA case, and the p-value from the stratified 
Mantel-Haenszel test for the ANCOVA case, using the methodologies described in Stokes, 
Davis, and Koch (1997)[15]. The ordinal observed repeated measures data will also be evaluated 
using Generalized Estimation Equations (GEE)[15].
Frequency counts, percentages, and cumulative percentages of subjects reporting CGI-S level 
will be summarized for both observed data as well as LOCF data by treatment group. Differences 
between treatment groups will be evaluated based on the Cochran-Mantel-Haenszel mean score 
(CMH) test using the modified ridit scores, stratifying on site.
At each post-baseline assessment and LOCF data, a shift from baseline table will summarize the 
worsening, no change, and improvement relative to baseline for the CGI-S. Worsening in the 
CGI-S change from baseline score is defined as a decrease by one grade or more, and an 
improvement in the CGI-S change from baseline score is defined as an increase by one grade or 
more.  
EDP Phase
CGI-S score will be analyzed using the same method as the Part II analysis. Treatment groups 
will be listed as PPPP and OAPOAP. The objective is to examine the cumulative effect on 
extended disease progression at the end of Part III following early start for PP compared to 
continuing OAP after a total of 18 months of treatment.
Part III
CGI-S score will be analyzed using the same method as the Part II analysis. Treatment groups 
will be listed as PPPP, OAPPP, and OAPOAP. All data from the Part III phase of the study will 
be categorized and presented using three columns: those patients who are not re-randomized 
(PPPP) were on PP in Part II, those oral patients in Part II who are re-randomized to paliperidone 
palmitate (OAPPP), and those patients who are re-randomized to oral antipsychotics (OAPOAP). 
5.4.6.
CRDPSS – Clinician-Rated Dimensions of Psychosis Symptom 
Severity
5.4.6.1.
Definition
The CRDPSS is an 8-item measure that assesses the severity of mental health symptoms that are 
important across psychotic disorders, including delusions, hallucinations, disorganized speech, 
abnormal psychomotor behavior, negative symptoms (ie, restricted emotional expression or 
avolition), impaired cognition, depression, and mania. The severity of these symptoms can 
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predict important aspects of the illness, such as the degree of cognitive and/or neurobiological 
deficits. This measure, developed by the APA, is intended to capture meaningful variation in the 
severity of symptoms, which may help with treatment planning, prognostic decision-making, and 
research on pathophysiological mechanisms. Each item asks the clinician to rate the severity of 
each symptom as experienced by the individual during the past 7 days. 
Each item on the measure is rated on a 5-point scale (0=none; 1=equivocal; 2=present, but mild; 
3=present and moderate; and 4=present and severe) with a symptom-specific definition of each 
rating level. The clinician may review all of the individual’s available information and, based on 
clinical judgment, select the level that most accurately describes the severity of the individual’s 
condition. The clinician then indicates the score for each item in the “Score” column provided. 
The response on each item should be interpreted independently when assessing the severity of 
the psychotic disorder. 
The CRDPSS will be completed by a qualified rater at the time points indicated in the Time and 
Events Schedule. The CRDPSS assessment must also be conducted at the time of first 
occurrence of treatment failure and should also be performed at the time of subsequent 
occurrences of treatment failure.
5.4.6.2.
Analysis Methods
Part I
Frequency counts, percentages, and cumulative percentages of subjects reporting each CRDPSS
level will be summarized for both observed data as well as LOCF data.
Part II
Frequency counts, percentages, and cumulative percentages of subjects reporting each CRDPSS 
level will be summarized for both observed data as well as LOCF data by treatment group. 
Differences between treatment groups will be evaluated based on the Cochran-Mantel-Haenszel 
mean score (CMH) test using the modified ridit scores, stratifying on site.
At each post-baseline assessment and LOCF data, a shift from baseline table will summarize the 
worsening, no change, and improvement relative to baseline for the each CRDSS item. 
Worsening in the CRDSS item change from baseline score is defined as a decrease by one grade 
or more, and an improvement in the CRDSS item change from baseline score is defined as an 
increase by one grade or more.  No testing will be done for this shift summary.
EDP Phase
CRDPSS items will be analyzed using the same method as the Part II analysis. Treatment groups 
will be listed as PPPP and OAPOAP. The objective is to examine the cumulative effect on 
extended disease progression at the end of Part III following early start for PP compared to 
continuing OAP after a total of 18 months of treatment.
Part III
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CRDPSS items will be analyzed using the same method as the Part II analysis. Treatment groups 
will be listed as PPPP, OAPPP, and OAPOAP. All data from the Part III phase of the study will 
be categorized and presented using three columns: those patients who are not re-randomized 
(PPPP) were on PP in Part II, those oral patients in Part II who are re-randomized to paliperidone 
palmitate (OAPPP), and those patients who are re-randomized to oral antipsychotics (OAPOAP). 
5.4.7.
MSQ – Medication Satisfaction Questionnaire
5.4.7.1.
Definition
Medication satisfaction will be assessed using the MSQ. The MSQ is a self-administered 
single-item questionnaire with responses on a 7-point Likert-scale as follows: 1=extremely 
dissatisfied, 2=very dissatisfied, 3=somewhat dissatisfied, 4=neither satisfied nor dissatisfied, 
5=somewhat satisfied, 6=very satisfied, 7=extremely satisfied. The MSQ has demonstrated 
acceptable reliability and validity,Error! Reference source not found. making this single-item questionnaire 
appropriate and easy to use in clinical research. A 1-point change on the MSQ may be 
considered clinically meaningful.
The MSQ will be completed by the subject at the time points indicated in the Time and Events 
Schedule. The MSQ must also be conducted at the time of first occurrence of treatment failure, 
and should also be performed at the time of subsequent occurrences of treatment failure.
5.4.7.2.
Analysis Methods
Part I
The actual values and change from baseline in MSQ score will be summarized for both observed 
data as well as LOCF data. Within treatment group difference for change from baseline will be 
evaluated using a paired t-test. Frequency counts, percentages, and cumulative percentages of 
subjects reporting each MSQ level will be summarized for both observed data as well as LOCF 
data.
Part II
The actual values and change from baseline scores of MSQ score will be summarized for both 
observed data as well as LOCF data by treatment group. The treatment group differences will be 
analyzed using an ANCOVA model. The model will include treatment and country as fixed 
effect design factors, and the baseline MSQ score as a covariate. Within treatment group 
difference for change from baseline will be evaluated using a paired t-test. The assumptions of 
the ANOVA / ANCOVA models--errors are normally distributed with equal variances--will be 
tested. If there is strong evidence that the assumptions are not satisfied then the p-value from 
Friedman's Chi-Square Test will also be presented for the ANOVA case, and the p-value from 
the stratified Mantel-Haenszel test for the ANCOVA case. The ordinal repeated measures data 
will also be evaluated using Generalized Estimation Equations (GEE).
Frequency counts, percentages, and cumulative percentages of subjects reporting each MSQ 
levels will be summarized for both observed data and LOCF data by treatment group. 
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Differences between treatment groups will be evaluated based on the Cochran-Mantel-Haenszel 
mean score (CMH) test using the modified ridit scores, stratifying on site. At each post-baseline 
assessment and LOCF, a shift from baseline table will summarize the worsening, no change, and 
improvement relative to baseline MSQ categories. Within group differences for shifts will be 
evaluated using the McNemar’s test. 
Responses for MSQ will also be dichotomized as Satisfied and Dissatisfied when the observed 
response on the MSQ scale was between 1 and 4 and between 5 and 7, respectively. The 
proportion of subjects who were either satisfied or dissatisfied on the MSQ scale will be 
calculated at each visit and compared between treatment groups using a CMH test. Within group 
differences for satisfaction vs. dissatisfaction will be evaluated using the McNemar’s test.
EDP Phase
MSQ score will be analyzed using the same method as the Part II analysis. Treatment groups will 
be listed as PPPP and OAPOAP. The objective is to examine the cumulative effect on extended 
disease progression at the end of Part III following early start for PP compared to continuing 
OAP after a total of 18 months of treatment.
Part III
MSQ score will be analyzed using the same method as the Part II analysis. Treatment groups will 
be listed as PPPP, OAPPP, and OAPOAP. All data from the Part III phase of the study will be 
categorized and presented using three columns: those patients who are not re-randomized (PPPP) 
were on PP in Part II, those oral patients in Part II who are re-randomized to paliperidone 
palmitate (OAPPP), and those patients who are re-randomized to oral antipsychotics (OAPOAP). 
5.5.
Part II, EDP Phase Exploratory Assessments
Exploratory evaluations include assessment of medical resource use (based on the RUQ), and 
goal setting and daily activity evaluations. 
5.5.1.
RUQ - Resource Utilization Questionnaire
5.5.1.1.
Definition
The RUQ will be used in the study as an exploratory tool to assess utilization of resources, such 
as number of hospitalization days (refers to 1 overnight stay), emergency room visits without 
hospitalization, day or night clinic stays, and outpatient treatment, as well as daily living 
conditions and productivity of the subject. Healthcare resource utilization will be assessed 
through regular questioning of subject’s resource utilization during visits (via the RUQ) and will 
be objectively verified through medical records and emergency/crisis center documents obtained 
by investigative site staff. Work and living status will be assessed at baseline and at regular 
intervals throughout the study.
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5.5.1.2.
Analysis Methods
Part I
Descriptive statistics, counts, and percentages will be presented at baseline and at end point. The 
NA values will not be considered in the examination of RUQ assessments for all categorical and 
non-ordinal measure data summaries. The calculated percentages will be determined using only 
patients who provided an applicable answer to the referred questions.
All cause and psychiatric-related hospitalizations will be summarized by reason, by the total 
number hospitalizations (none, once, twice, and >twice), and overall. For emergency room visits, 
the number and percent of subjects with ER visits will be summarized by reasons of visit, by the 
total number of visits (none, once, twice and >twice), and by overall. Data points for day clinic 
or day treatment programs, outpatient services, daily living, and productivity will also be 
summarized.
Part II
Descriptive statistics, counts, and percentages will be presented at each assessment time point, 
end point and each LOCF visit. The NA values will not be considered in the examination of 
RUQ assessments for all categorical and non-ordinal measure data summaries. The calculated 
percentages will be determined using only patients who provided an applicable answer to the 
referred questions.
All cause and psychiatric-related hospitalizations will be summarized by reason, by the total 
number hospitalizations (none, once, twice, and >twice), and by overall. Hospitalizations due to
social reasons will be excluded. The cumulative distribution function of time from Day 1 to first 
hospitalization for psychiatric reasons will be estimated by the Kaplan-Meier method. The null 
hypothesis that there is no difference between treatment groups in the time to hospitalization 
over 9 months will be tested using a log-rank test. In addition, descriptive analysis will also be 
conducted by hospital types and by the type of ward or unit during hospitalization. Since date of 
admission and discharge are collected for hospitalization, length of stay (LOS) will be derived 
and summarized descriptively.
For emergency room visits, the number and percent of subjects with ER visits will be 
summarized overall, by reasons of visit and by the total number of visits (none, once, twice and 
>twice) per treatment group. The cumulative distribution function of time from Day 1 to first ER 
visit for psychiatric reasons will be estimated by the Kaplan-Meier method. The null hypothesis 
that there is no difference between treatment groups in the time to ER distributions over 9 
months will be tested using a log-rank test. 
Data points for day clinic or day treatment programs, outpatient services, daily living, and 
productivity will also be summarized by treatment group.
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EDP Phase
RUQ data points will be analyzed using the same method as the Part II analysis. Treatment 
groups will be listed as PPPP and OAPOAP. The objective is to examine the cumulative effect 
on extended disease progression at the end of Part III following early start for PP compared to 
continuing OAP after a total of 18 months of treatment.
Part III
RUQ data will be analyzed using the same method as the Part II analysis. Treatment groups will 
be listed as PPPP, OAPPP, and OAPOAP. All data from the Part III phase of the study will be 
categorized and presented using three columns: those patients who are not re-randomized (PPPP) 
were on PP in Part II, those oral patients in Part II who are re-randomized to paliperidone 
palmitate (OAPPP), and those patients who are re-randomized to oral antipsychotics (OAPOAP). 
Baseline summary for prior hospitalizations and ER visit will go back to 12 month prior to Part 
III start date. 
5.5.2.
Goal Setting and Daily Activity Evaluations
5.5.2.1.
Definition
Subjects will set up to 3 personal goals and 3 health goals at the beginning of each treatment 
phase, which will be reviewed with the subject and by the treating clinician. 
The patient goals are not binding, but progress towards attaining these goals will be followed 
throughout the study at the time points indicated in the Time and Events Schedule.
Patient Happiness Assessment and Goal Setting Preparation
The Patient Happiness Assessment and Goal Setting Preparation documents will be reviewed and 
completed by each subject at the Part I Baseline visit (Visit 2). 
Patient Goal Setting Documentation
The treating clinician will review the Goal Setting Preparation document with the subject and 
agree with up to 3 personal goals and up to 3 health goals for the subject at the start of each 
treatment phase. These goals will be documented on paper and shared with the subject and the 
subject’s designated individual. The original document will be filed at the investigative (study) 
site as part of the subject’s study source record. The patient goals are not binding.
Patient Goals Attainment
Progress towards attaining the patient goals will be assessed by the subject at the time points 
indicated in the Time and Events Schedule. Satisfaction regarding the subject’s progress towards 
meeting the goals will be rated on a Likert scale ranging from ‘Extremely Dissatisfied’ to 
‘Extremely Satisfied’. 
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Quantitative Assessment of Daily Activities
The Quantitative Assessment of Daily Activities is a patient reported outcome that documents 
the time a subject spends in a broad array of common daily activities. Categories include sleep 
and rest, self-care, work, recreation and social activities. The period covered is the prior week.  
Refer to the Time and Event Schedule for frequency of assessment.
5.5.2.2.
Analysis Methods
At each assessment time point and LOCF data, descriptive statistics will be presented for each of 
the domains for all the phases.
6.
SAFETY
Safety variables to be analyzed include treatment-emergent adverse events, serious adverse 
events, ESRS-A scores, laboratory parameters, vital signs, physical examination reports, and 
ISST-Plus. The ITT analysis sets will be used for analyses performed on safety parameters 
unless otherwise specified. Any statistical tests performed to explore the data will be used only to 
highlight any comparisons that may warrant further consideration. 
6.1.
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) (version 18.1 or above)[16] will be 
used to classify AEs by system organ class and preferred term. Treatment-emergent adverse 
events (TEAEs) that occurred in each study phase will be summarized by system organ class and 
preferred term. 
A treatment-emergent adverse event (TEAE) is an event that is new in onset or increased in 
severity following treatment initiation. An event that starts prior to and ends after the initiation of 
study drug (Day 1 of each study phase) is to be considered treatment-emergent only if the 
severity increases after the start of medication. Treatment-emergent flags will be defined 
separately for Part I, Part II, EDP, and Part III. 
Treatment-emergent AE in the Part I are defined as the adverse events with onset date on or after 
the first study date (onset date >= Part I Start Date and <= Part I End Date) or increase in 
severity during the same period. An event that starts prior to the Part I Start Date and ends 
afterwards will be considered treatment emergent in the Part I Phase only if the severity 
increases on or after the Part I Start Date.
Treatment-emergent AE in the Part II are defined as the adverse events with onset date on or 
after the first study date (onset date >= Part II Start Date and <= Part II End Date) or increase in 
severity during the same period. An event that starts prior to the Part II Start Date and ends 
afterwards will be considered treatment emergent in the Part II Phase only if the severity 
increases on or after the Part II Start Date.
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Treatment-emergent AE in the Part III are defined as the adverse events with onset date on or 
after the first study date (onset date >= Part III Start Date and <= Part III End Date) or increase 
in severity during the same period. An event that starts prior to the Part III Start Date and ends 
afterwards will be considered treatment emergent in the Part III Phase only if the severity 
increases on or after the Part III Start Date.
Treatment-emergent AE in the EDP phase are defined as the adverse events with onset date on or 
after the first study date (onset date >= Part II Start Date and <= Part III End Date) or increase in 
severity during the same period. An event that starts prior to the Part II Start Date and ends 
afterwards will be considered treatment emergent in the EDP only if the severity increases on or 
after the Part II Start Date. This phase simply contains information from both Parts II and III.
AEs will be included as TEAEs 30 days after the permanent discontinuation of the study 
medication. 
The number of subjects with at least one TEAE as well as the number of subjects and total 
number of events for each preferred term and SOC will be summarized regardless of severity and 
relationship to study medication. For each subject, multiple reports of events that map to a 
common MedDRA preferred term and SOC will be condensed into a single AE for incidence 
counts, while each occurrence will be counted for the number of events. Within each summary, 
TEAEs will be sorted alphabetically. 
Severity for AEs is classified in the case report form (CRF) as ‘mild’, ‘moderate’, or ‘severe’. 
Incidence of TEAEs will be summarized by preferred term, SOC, and maximum severity for 
each treatment group. If a subject has more than one AE within a preferred term and SOC, the 
subject will be counted at most once by the maximum severity. Adverse events with missing 
severity will be classified as ‘not specified’ and will be considered the least severe in cases where 
a subject has the same event with a specified severity.
Relationship to study medication for AEs is classified in the CRF as ‘not related’, ‘doubtful’, 
‘possible’, ‘probable’, or ‘very likely’. Incidence of TEAEs will be summarized by the preferred 
term, SOC, and maximum relationship for each treatment group. If a subject has more than one 
AE within a preferred term and SOC, the subject will be counted at most once by the maximum 
relationship to study medication. Adverse events with missing relationship will be classified as 
‘not specified’ and will be considered the least related in cases where a subject has the same 
event with a specified relationship. 
An additional summary will display incidence of TEAEs by ‘not related’ and ‘related’. The 
responses of ‘not related’ and ‘doubtful’ will be pooled to create the ‘not related’ to study 
medication group category. The following three responses (‘possible’, ‘probable’, or ‘very 
likely’) will be pooled to create the ‘related’ to study medication group category. If an event has 
missing relationship it will be classified as ‘not specified’ and will not be considered ‘related’ or 
‘not related’.
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Action taken for AEs is classified in the CRF as ‘dose increased’, ‘dose not changed’, ‘drug 
interrupted, ‘drug withdrawn’, and ‘not applicable’. Incidence of TEAEs will be summarized by 
the preferred term, SOC, and action taken for each treatment group. If a subject has more than 
one AE within a preferred term and SOC, the subject will be counted at most once by the worst 
outcome. Adverse events with missing action taken will be classified as ‘not specified’.
The incidence of TEAEs will be presented for subjects who discontinue the study for an AE, as 
well as for subjects who experience a SAE. These AE summaries will be summarized in each 
study phase separately.
Listings of subjects who discontinue the study for an AE and subjects who experience a SAE will 
be presented. 
Summaries of treatment-emergent adverse events for categories of clinical interest will be 
provided as discussed in the following sections. The preferred terms for each category are given 
in Attachment 1. 
6.1.1.
EPS-Related Adverse Events 
Treatment-emergent AEs that are related to extrapyramidal symptoms (EPS) will be 
summarized. The EPS AEs will be categorized into 5 subgroups (tremor, dystonia, hyperkinesia, 
parkinsonism, and dyskinesia) that include the following MedDRA preferred terms:
Tremor (preferred terms: Tremor, Essential tremor, Intention tremor)
Dystonia (preferred terms: Oculogyration, Oculogyric crisis, Trismus, Tongue spasm, Tongue 
paralysis, Cervical spasm, Emprosthotonus, Myotonia, Pleurothotonus, Risus sardonicus, 
Muscle spasms, Blepharospasm, Dystonia, Opisthotonus, Torticollis, Facial spasm, Muscle 
contracture)
Hyperkinesia (preferred terms: Akathisia, Hyperkinesia, Periodic limb movement disorder, 
Restless legs syndrome, Restlessness) 
Parkinsonism (preferred terms: Hypertonia, Bradykinesia, Cogwheel rigidity, Drooling, 
Musculoskeletal stiffness, Akinesia, Hypokinesia, Nuchal rigidity, Parkinsonian gait, 
Parkinsonian rest tremor, Parkinsonism, Muscle rigidity, Muscle tightness, Glabellar reflex 
abnormal, On and off phenomenon, Parkinson's disease, Parkinsonian crisis, Extrapyramidal 
disorder, Masked facies)
Dyskinesia (preferred terms: Dyskinesia, Muscle contractions involuntary, Movement 
disorder, Muscle twitching, Athetosis, Chorea, Choreoathetosis, Tardive dyskinesia, 
Myoclonus, Protrusion tongue, Rabbit syndrome, Buccoglossal syndrome).
The incidence for each EPS subgroup will be calculated, and no overall incidence for the 
EPS-related AEs will be presented.
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6.1.2.
Diabetes Mellitus and Hyperglycaemia-Related Adverse Events 
Treatment-emergent adverse events that may be associated with diabetes mellitus and 
hyperglycaemia will be summarized. MedDRA preferred terms related to diabetes mellitus and 
hyperglycaemia are defined as follows: 
Acquired lipoatrophic diabetes, Diabetic hepatopathy, Fulminant type 1 diabetes mellitus, 
Hyperglycaemic seizure, Hyperglycaemic unconsciousness, Type 3 diabetes mellitus, Blood 
1,5-anhydroglucitol decreased, Blood glucose increased, Diabetes complicating pregnancy, 
Diabetes mellitus, Diabetes mellitus inadequate control, Diabetes with hyperosmolarity, 
Diabetic coma, Diabetic hyperglycaemic coma, Diabetic hyperosmolar coma, Diabetic 
ketoacidosis, Diabetic ketoacidotic hyperglycaemic
coma, Fructosamine increased, 
Gestational diabetes, Glucose tolerance impaired, Glucose tolerance impaired in pregnancy, 
Glucose urine present, Glycosuria, Glycosuria during pregnancy, Glycosylated haemoglobin 
increased, Hyperglycaemia, Hyperglycaemic hyperosmolar nonketotic syndrome, Impaired 
fasting glucose, Insulin resistance, Insulin resistance syndrome, Insulin resistant diabetes, 
Insulin-requiring type 2 diabetes mellitus, Ketoacidosis, Ketonuria, Ketosis, Latent 
autoimmune diabetes in adults, Metabolic syndrome, Neonatal diabetes mellitus, 
Pancreatogenous diabetes, Type 1 diabetes mellitus, Type 2 diabetes mellitus, Urine ketone 
body present, Diabetes mellitus insulin-dependent, Diabetes mellitus non-insulin-dependent, 
Insulin-requiring type II diabetes mellitus.
6.1.3.
Potentially Prolactin-Related Adverse Events
Treatment-emergent adverse events that may be associated with changes in serum prolactin 
levels will be summarized. MedDRA preferred terms considered as being potentially related to 
serum prolactin levels are defined as below: 
Amenorrhoea, 
Amenorrhoea-galactorrhoea 
syndrome, 
Galactorrhoea, 
Gynaecomastia, 
Hyperprolactinaemia, Oligomenorrhoea, Blood prolactin increased, Anorgasmia, Ejaculation 
delayed, Ejaculation disorder, Erectile dysfunction, Female sexual dysfunction, Libido 
decreased, Libido disorder, Loss of libido, Male sexual dysfunction, Orgasm abnormal, 
Orgasmic sensation decreased, Sexual dysfunction, Breast discharge, Breast enlargement, 
Breast pain, Prolactin-producing pituitary tumour, Prolactinoma, Blood prolactin, Blood 
prolactin abnormal, Breast tenderness, Hypertrophy breast, Menstruation irregular.
These adverse events will also be tabulated separately by sex.
6.1.4.
Other Adverse Events of Special Interest
Incidence of other treatment-emergent adverse events of clinical interest will be presented. 
Search terms relevant to the adverse events of clinical importance are listed in Attachment 1. 
These terms are classified into the following groups: 
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Suicidality, Aggression and Agitation, Somnolence and Sedation, Seizures and Convulsions, 
Neuroleptic Malignant Syndrome, Cardiac Arrhythmias, Orthostatic Hypotension, Adverse 
Events Suggestive of Proarrhythmic Potential, Ischemia-related, Potential Rhabdomyolysis-
related, Overdose-related, Weight Gain-related, Tachycardia-related, and Injection-site Related.
6.2.
Clinical Laboratory
Descriptive statistics (N, mean, median, minimum, maximum and range) for values and changes 
from baseline will be provided for clinical laboratory tests (hematology, chemistry and 
urinalysis) for all the phases.
Clinical laboratories will be summarized at the following visits: Part I Baseline, Part I End Point, 
Part II Baseline, Part II End Point, Part III Baseline, Part III End Point, EDP Baseline, and EDP 
End Point. Baseline for the Part II period will be defined as the last Part I data point on or before 
the randomization date, similar to other efficacy and safety scales. If there are no Part I post-
baseline laboratory assessments the baseline for the Part II period will consist of data from the 
screening period. Part II baseline will serve as the baseline score for the EDP Phase.
Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
each treatment phase. The incidence of treatment-emergent markedly abnormal laboratory values 
that occurred at any time during each treatment phase will be presented. Clinical laboratory test 
values will be considered “TEMA using the criteria defined by the Sponsor (Janssen Research 
& Development, LLC)” listed in Attachment 2. The identification of TEMA laboratory values is 
based on the postbaseline value being out of range while the baseline value (defined above) is 
either missing or within the range given in Attachment 2. If post-baseline laboratory results are 
above the upper limit and the baseline value is below the lower limit, then the post-baseline 
abnormality will also be considered TEMA. The same applies to the postbaseline value being 
below the lower limit with the baseline value being above the upper limit. 
For prolactin laboratory results, values over time and treatment-emergent abnormal results based 
on the laboratory reference range will be presented by sex.
6.3.
Vital Signs, Weight, and BMI
Vital signs will be assessed at each visit, and will consist of body temperature, sitting blood 
pressure, and pulse. Body weight will also be assessed at each visit. Height will be recorded at 
screening only. Height will be recorded at screening only. BMI will be calculated from 
measurements of height and weight, (kg)/(height (m))2.
Actual and change from baseline in vital signs will be summarized at each assessment time point 
including LOCF end points within each phase. Data summaries will be listed by treatment group.
For body weight, the incidence of increases/decreases from baseline to endpoint by 7% will be 
summarized for each study period using the corresponding baseline score. For each of the vital 
signs parameters, the following categories for abnormality will be tabulated and presented with 
percentages by treatment group at each assessment time point and at end point for all the study 
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phases. The tabulation of weight abnormality classes will be repeated by baseline BMI category 
(OL Baseline) [Normal=<25; Overwieght= 25 - <30; Obese= 30].
Treatment-emergent abnormality categories for vital signs are defined as follows:
Period Post-baseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 15 
to a value 50
An increase from baseline of 15 
to a value 100
Systolic BP (mmHg)
A decrease from baseline of 20 
to a value 90
An increase from baseline of 20 
to a value 180
Diastolic BP  (mmHg)
A decrease from baseline of 15 
to a value 50
An increase from baseline of 15 
to a value 105
Body Weight (kg)
A decrease from baseline of 7%  An increase from baseline of 7%  
BP = blood pressure
Physical examinations will be performed at screening and the end of study, including 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, 
lungs, abdomen, lymph nodes, extremities, and nervous system. The number and percent of 
subjects with abnormal values will be summarized for each system at baseline and study 
endpoint.
6.4.
ESRS-A - Extrapyramidal Symptoms Rating Scale – Abbreviated 
The ESRS-A is an abbreviated manualized version of the ESRS, a semistructured interview that 
rates parkinsonian symptoms, dystonia, dyskinesias, and akathisia over the previous 7 days. The 
ratings include a motor examination for rigidity, tremor, reduced facial expression or speech, 
impaired gait/posture, postural instability, and bradykinesia/hypokinesia. Twenty-four individual 
items are rated on a 6-point scale: 0=Absent, 1=Minimal, 2=Mild, 3=Moderate, 4=Severe, or 
5=Extreme. Frequency is included as an index of severity. Symptoms are divided into the 4 
corresponding subscales and each subscale is summarized in a Clinical Global Impression of 
Movement Severity (CGI-MS) score. 
A qualified clinician is required to administer the ESRS-A. A trained clinician rater for these 
scales must meet one the following criteria: a physician (M.D. or D.O.), advanced practice nurse 
(NP), physician assistant (PA), or other allied health professional who is trained and holds a 
valid license to perform physical examinations. 
The ESRS-A will be administered at the time points indicated in the Time and Events Schedule. 
If possible, the same person should administer these scales at all visits.
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Part I
CGI-MS scores will be presented for parkinsonism, dystonia, dyskinesia, and akathisia. The 
actual values and change from screening in numeric CGI-MS scores will be summarized for both 
observed data as well as LOCF data. 
Part II
The actual values and change from baseline scores of CGI-MS domains will be summarized for 
both observed data as well as LOCF data by treatment group in each phase separately. Frequency 
counts, percentages, and cumulative percentages of subjects reporting each CGI-MS level will be 
summarized for both observed data as well as LOCF data by treatment group. At each post-
baseline assessment and LOCF, a shift from baseline table will summarize the worsening, no 
change, and improvement relative to baseline for the CGI-MS. Worsening in the CGI-MS
change from baseline score is defined as a decrease by one grade or more, and an improvement 
in the CGI-MS change from baseline score is defined as an increase by one grade or more.  No 
testing will be done for this shift summary. Individual ESRS-A items for each domain will be 
summarized using frequency counts, percentages, and cumulative percentages of subjects 
reporting each level of the score within each phase as well.
EDP Phase
ESRS-A items will be analyzed using the same method as the Part II analysis. Treatment groups 
will be listed as PPPP and OAPOAP. The objective is to examine the cumulative effect on 
extended disease progression at the end of Part III following early start for PP compared to 
continuing OAP after a total of 18 months of treatment.
Part III
ESRS-A items will be analyzed using the same method as the Part II analysis. Treatment groups 
will be listed as PPPP, OAPPP, and OAPOAP. All data from the Part III phase of the study will 
be categorized and presented using three columns: those patients who are not re-randomized 
(PPPP) were on PP in Part II, those oral patients in Part II who are re-randomized to paliperidone 
palmitate (OAPPP), and those patients who are re-randomized to oral antipsychotics (OAPOAP). 
6.5.
ISST-Plus Short Form - InterSePT Scale for Suicidal Thinking – Plus
The ISST-Plus is a clinician-rated 4-part instrument for collecting data on suicidal thinking and 
behavior. The ISST-Plus Short Form is an abbreviated form of the ISST-Plus used to screen 
subjects between ISST-Plus assessments. The ISST-Plus meets the requirements recently 
announced by FDA for assessment of suicidality. 
The ISST-Plus includes 4 parts:

Part I is designed to collect information on the severity of suicidal ideation during the 
7 days (or other pre-defined time frame) prior to the subject’s visit. It is comprised of 
13 items, with three levels of severity: 0 (none), 1 (weak), or 2 (moderate or strong).  
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
Part II is designed to collect information on suicidal behaviors that have occurred since the 
last visit or the last assessment of suicidal behavior. 

Part III is a global rating of suicide ideation and behavior or status at the time of the 
subject interview as judged by a clinically experienced rater.  It includes and integrates both 
Part I and Part II of the scale. It should only be completed after Parts I and II have been 
completed and should take all available information into consideration.  

Part IV is collected at the end of the study to record whether or not the subject died by 
suicide during the study.  
Rating the ISST-Plus requires completion of a semi-structured interview.  Subjects who exhibit a 
high suicide risk as evidenced by a total score of ≥7 on the ISST-Plus Part I or a score of 2 on 
items 7, 10, or 11, or an ISST-Plus Part III score of ≥2 must be evaluated by either a clinical 
psychologist or psychiatrist, and this must be documented in the source documents. If a subject 
answers in the affirmative (ie, “YES”) to any part of the suicidal behaviors section (Part II) of the 
ISST-Plus, completion of a detailed potential suicide attempt narrative is required.
The ISST-Plus Short Form will be administered at the study visits indicated in the Time and 
Events Schedule. If suicidality is identified (ie, ‘yes’ is answered to questions 1.0, 2.2, 2.3, or 2.4
of the ISST-Plus Short Form) the full ISST-Plus must be administered in its entirety.
Part I
ISST-Plus item scores will be presented for both observed data as well as LOCF data. Frequency 
counts and percentages of subjects reporting each item level will be summarized. Additionally, 
Total Score of Suicidal Thinking Part will be computed. The actual values and change from 
baseline in total score will be summarized. Within group difference for change from baseline 
will be evaluated using a paired t-test. 
Part II
Frequency counts and percentages of subjects reporting each item level will be summarized for 
both observed data as well as LOCF data by treatment group. 
Total Score of Suicidal Thinking Part will be computed. The actual values and change from 
baseline in total score will be summarized. Within treatment group difference for change from 
baseline will be evaluated using a paired t-test. The actual values and change from baseline 
scores of total score will be summarized. The treatment group differences will be analyzed using 
an ANCOVA model. The model will include treatment and country as fixed effect design 
factors, and the baseline score as a covariate.
EDP Phase
ISST-Plus items will be analyzed using the same method as the Part II analysis. Treatment 
groups will be listed as PPPP and OAPOAP. The objective is to examine the cumulative effect 
on extended disease progression at the end of Part III following early start for PP compared to 
continuing OAP after a total of 18 months of treatment.
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Part III
ISST-Plus items will be analyzed using the same method as the Part II analysis. Treatment 
groups will be listed as PPPP, OAPPP, and OAPOAP. All data from the Part III phase of the 
study will be categorized and presented using three columns: those patients who are not re-
randomized (PPPP) were on PP in Part II, those oral patients in Part II who are re-randomized to 
paliperidone palmitate (OAPPP), and those patients who are re-randomized to oral antipsychotics 
(OAPOAP). 
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REFERENCES
1.
WHO drug dictionary. WHO Collaborating Centre for International Drug Monitoring. Uppsala, Sweden, 
(Box 26, S-751 03), 1993. http://www.who-umc.org/
2.
Demitrienko A, Tamhane A, Bretz F. Multiple testing problems in pharmaceutical statistics. 2010, 
Chapman&Hall/CRC Biostatistics Series.
3.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations. Journal of the American 
Statistical Association, 1958: 53; 457-8112.
4.
Kalbfleisch, J.D. and Prentice, R.L.  The Statistical Analysis of Failure Time Data. New York:  John Wiley 
& Sons, Inc.; 1980.
5.
Cox DR. Regression models and life tables. J Royal Stat Soc 1972; 34: 87-220.
6.
Taylor M., Murray S., Hsu C-H. Survival estimation and testing via multiple imputation. Statistics and 
Probability letters. 2002; 58:221-232. 
7.
Lipkovich I., Ratitch, B., Kelly, M. Sensitivity to censored-at-random assumption in the analysis of time-
to-event endpoints. Pharmaceutical Statistics. 2016; 15:216-229.
8.
Schoenfeld D. Chi-squared goodness of fit test for the proportional hazards regression model. Biometrika
1981, 67:147-53. 
9.
Nelson, W. B. (2003), Recurrent Events Analysis for Product Repairs, Disease Recurrences, and Other 
Applications, The ASA-SIAM Series on Statistics and Applied Probability.
10. Siddiqui O, James Hung HM, O’Neill R. MMRM vs. LOCF: Comprehensive Comparison Based on 
Simultion Study and 25 NDA Datasets. Journal of Biopharmaceutical Statistics. 2009, 19:2, 227-246. 
11. Verbeke G, Molenberghs G.  Linear Mixed Models for Longitudinal Data.  Springer-Verlag, 2000.
12. Diggle P, Heagerty P, Lian KY, and Zeger S.  Analysis of Longitudinal Data, Second Edition. Oxford 
University Press, USA.  August 2002
13. Neter J, Wasserman W, Kutner M.  Applied linear statistical models. Richard D. Irwin, Inc., Homewood, 
Illinois, 1990: 1037-1049
14. Mantel N, Haenszel W.  Statistical aspects of the analysis of data from retrospective studies of disease. 
Journal of the National Cancer Institute, 1959: 22; 719-48.
15. Stokes, Maura E., Davis, Charles S., Koch, Gary G., Categorical Data Analysis Using the SAS® System, 
Cary, NC: SAS Institute Inc., 1997 (3rd Printing).
16. Medical Dictionary for Regulatory Activities (MedDRA), Version 18.1. IFPMA, International Committee 
on Harmonization. Geneva, Switzerland.
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LIST OF ATTACHMENTS
ATTACHMENT 1: Special Interest Adverse Events
MAGCAT
AEDECOD
AGITATION
Agitation
AGITATION
Psychomotor agitation
AGITATION
Psychomotor hyperactivity
AGGRESSION Aggression
AGGRESSION Homicidal ideation
AGGRESSION Hostility
AGGRESSION Homicide
MCARCAT
AEDECOD
CARDIOVASCULAR
Torsade de pointes
CARDIOVASCULAR
Sudden death
CARDIOVASCULAR
Ventricular tachycardia
CARDIOVASCULAR
Ventricular fibrillation
CARDIOVASCULAR
Ventricular flutter
CARDIOVASCULAR
Syncope
CARDIOVASCULAR
Presyncope
CARDIOVASCULAR
Syncope vasovagal
MISCCAT
AEDECOD
ISCHAEMIA
Acute coronary syndrome
ISCHAEMIA
Acute myocardial infarction
ISCHAEMIA
Angina pectoris
ISCHAEMIA
Angina unstable
ISCHAEMIA
Subendocardial ischaemia
ISCHAEMIA
Myocardial ischaemia
ISCHAEMIA
Cardiac ischaemia
ISCHAEMIA
Coronary artery disease
ISCHAEMIA
Coronary artery insufficiency 
ISCHAEMIA
Myocardial infarction
ISCHAEMIA
Myocardial ischaemia
ISCHAEMIA
Papillary muscle infarction
ISCHAEMIA
Postinfarction angina
ISCHAEMIA
Prinzmetal angina
ISCHAEMIA
Silent myocardial infarction
ISCHAEMIA
Subendocardial ischaemia
ISCHAEMIA
Amaurosis fugax
ISCHAEMIA
Brain stem infarction
ISCHAEMIA
Brain stem ischaemia
ISCHAEMIA
Cerebellar infarction
ISCHAEMIA
Cerebral infarction
ISCHAEMIA
Cerebral ischaemia
ISCHAEMIA
Cerebrovascular accident
ISCHAEMIA
Cerebrovascular disorder
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ISCHAEMIA
Cerebrovascular insufficiency
ISCHAEMIA
Embolic cerebral infarction
ISCHAEMIA
Embolic stroke
ISCHAEMIA
Haemorrhagic cerebral infarction
ISCHAEMIA
Haemorrhagic stroke
ISCHAEMIA
Ischaemic cerebral infarction
ISCHAEMIA
Ischaemic stroke
ISCHAEMIA
Subclavian steal syndrome
ISCHAEMIA
Thromboembolic stroke
ISCHAEMIA
Thrombotic stroke
ISCHAEMIA
Lacunar infarction
ISCHAEMIA
Reversible ischaemic neurological deficit
ISCHAEMIA
Transient ischaemic attack
ISCHAEMIA
Vascular encephalopathy
ISCHAEMIA
Vertebrobasilar insufficiency
ISCHAEMIA
Ischaemia
ISCHAEMIA
Ischaemic cardiomyopathy
ISCHAEMIA
Thrombotic cerebral infarction
ISCHAEMIA
Cerebral microangiopathy
ISCHAEMIA
Cerebellar ischaemia
MORTHCAT
AEDECOD
Orthostatic Hypotension
Blood pressure orthostatic abnormal
Orthostatic Hypotension
Blood pressure orthostatic decreased
Orthostatic Hypotension
Dizziness postural
Orthostatic Hypotension
Orthostatic hypotension
Orthostatic Hypotension
Orthostatic intolerance
Orthostatic Hypotension
Orthostatic heart rate response increased
MOVCAT AEDECOD
Overdose Accidental overdose
Overdose Intentional overdose
Overdose Multiple drug overdose
Overdose Multiple drug overdose accidental
Overdose Multiple drug overdose intentional 
Overdose Overdose
MQTCAT
AEDECOD
TORSADE DE POINTES
Torsade de pointes
SUDDEN DEATH
Cardiac arrest
SUDDEN DEATH
Cardiac death
SUDDEN DEATH
Cardio-respiratory arrest
SUDDEN DEATH
Sudden death
SUDDEN DEATH
Sudden cardiac death
SUDDEN DEATH
Ventricular asystole
VENTRICULAR TACHYCARDIA
Accelerated idioventricular rhythm
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VENTRICULAR TACHYCARDIA
Ventricular tachycardia
VENTRICULAR TACHYCARDIA
Ventricular tachyarrhythmia
VENTRICULAR FIBRILLATION AND FLUTTER
Cardiac fibrillation
VENTRICULAR FIBRILLATION AND FLUTTER
Ventricular arrhythmia
VENTRICULAR FIBRILLATION AND FLUTTER
Ventricular fibrillation
VENTRICULAR FIBRILLATION AND FLUTTER
Ventricular flutter
SYNCOPE
Circulatory collapse
SYNCOPE
Loss of consciousness
SYNCOPE
Syncope
SYNCOPE
Presyncope
SYNCOPE
Syncope vasovagal
SEIZURES
Clonic convulsion
SEIZURES
Convulsion
SEIZURES
Epilepsy
SEIZURES
Grand mal convulsion
SEIZURES
Tonic clonic movements
SEIZURES
Tonic convulsion
SEIZURES
Status epilepticus
SEIZURES
Atonic seizures
SEIZURES
Complex partial seizures
SEIZURES
Generalised non-convulsive epilepsy
MRHACAT
AEDECOD
RHABDOMYOLYSIS
Rhabdomyolysis
RHABDOMYOLYSIS
Blood creatine phosphokinase increased
RHABDOMYOLYSIS
Myoglobinuria
RHABDOMYOLYSIS
Myoglobin urine
MSEIZCAT
AEDECOD
SEIZURES
Acquired epileptic aphasia
SEIZURES
Alcoholic seizure
SEIZURES
Atonic seizures
SEIZURES
Atypical benign partial epilepsy
SEIZURES
Automatism epileptic
SEIZURES
Baltic myoclonic epilepsy
SEIZURES
Clonic convulsion
SEIZURES
Complex partial seizures
SEIZURES
Convulsion
SEIZURES
Convulsion in childhood
SEIZURES
Convulsion neonatal
SEIZURES
Convulsions local
SEIZURES
Convulsive threshold lowered
SEIZURES
Deja vu
SEIZURES
Dreamy state
SEIZURES
Drug withdrawal convulsions
SEIZURES
Eclampsia
SEIZURES
Epilepsy
SEIZURES
Epilepsy congenital
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SEIZURES
Epileptic aura
SEIZURES
Epileptic psychosis
SEIZURES
Febrile convulsion
SEIZURES
Frontal lobe epilepsy
SEIZURES
Generalised non-convulsive epilepsy
SEIZURES
Grand mal convulsion
SEIZURES
Hypoglycaemic seizure
SEIZURES
Infantile spasms
SEIZURES
Lafora's myoclonic epilepsy
SEIZURES
Lennox-Gastaut syndrome
SEIZURES
Myoclonic epilepsy
SEIZURES
Myoclonic epilepsy and ragged-red fibres
SEIZURES
Myoclonic epilepsy and ragged-red fibers
SEIZURES
Partial seizures
SEIZURES
Partial seizures with secondary generalisation
SEIZURES
Petit mal epilepsy
SEIZURES
Post-traumatic epilepsy
SEIZURES
Psychomotor seizures
SEIZURES
Seizure anoxic
SEIZURES
Simple partial seizures
SEIZURES
Status epilepticus
SEIZURES
Sudden unexplained death in epilepsy
SEIZURES
Temporal lobe epilepsy
SEIZURES
Tonic clonic movements
SEIZURES
Tonic convulsion
SEIZURES
Uncinate fits
MSOMCAT
AEDECOD
SOMNOLENCE Somnolence
SOMNOLENCE Sedation
SOMNOLENCE Lethargy
SOMNOLENCE Hypersomnia
MSUICAT
AEDECOD
SUICIDALITY
Depression suicidal
SUICIDALITY
Intentional overdose
SUICIDALITY
Intentional self-injury
SUICIDALITY
Multiple drug overdose intentional
SUICIDALITY
Poisoning deliberate
SUICIDALITY
Self injurious behavior
SUICIDALITY
Self-injurious ideation
SUICIDALITY
Completed suicide
SUICIDALITY
Suicidal ideation
SUICIDALITY
Suicide attempt
SUICIDALITY
Suicidal behavior
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MNMSCAT
AEDECOD
NMS
Hyperthermia malignant
NMS
Neuroleptic malignant syndrome
NMS
Serotonin syndrome
NMS
Body temperature increased
NMS
Hyperpyrexia
NMS
Pyrexia
NMS
Catatonia
NMS
Dyskinesia
NMS
Dystonia
NMS
Freezing phenomenon
NMS
Hyperkinesia
NMS
Hypertonia
NMS
Muscle necrosis
NMS
Muscle rigidity
NMS
Oculogyric crisis
NMS
Oculogyration
NMS
Opisthotonus
NMS
Rhabdomyolysis
NMS
Altered state of consciousness
NMS
Autonomic nervous system imbalance
NMS
Blood creatine phosphokinase abnormal
NMS
Blood creatine phosphokinase increased
NMS
Blood creatine phosphokinase MM increased
NMS
Blood pressure abnormal
NMS
Blood pressure decreased
NMS
Blood pressure fluctuation
NMS
Blood pressure increased
NMS
Cardiovascular insufficiency
NMS
Coma
NMS
Confusional state
NMS
Consciousness fluctuating
NMS
Delirium
NMS
Depressed level of consciousness
NMS
Disorientation
NMS
Extrapyramidal disorder
NMS
Heart rate abnormal
NMS
Heart rate increased
NMS
Hyperhidrosis
NMS
Hypertension
NMS
Hypotension
NMS
Labile blood pressure
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NMS
Labile hypertension
NMS
Leukocytosis
NMS
Loss of consciousness
NMS
Muscle enzyme increased
NMS
Myoclonus
NMS
Myoglobin blood increased
NMS
Myoglobin blood present
NMS
Myoglobin urine present
NMS
Myoglobinaemia
NMS
Myoglobinuria
NMS
Parkinsonian crisis
NMS
Parkinsonian rest tremor
NMS
Parkinsonism
NMS
Parkinson's disease
NMS
Stupor
NMS
Tachycardia
NMS
Tremor
NMS
Unresponsive to stimuli
NMS
White blood cell count abnormal
NMS
White blood cell count increased
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MTACCAT
AEDECOD
Tachycardia
Heart rate increased
Tachycardia
Sinus tachycardia
Tachycardia
Tachycardia
Tachycardia
Tachycardia paroxysmal
MWEICAT
AEDECOD
WEIGHT GAIN
Increased appetite
WEIGHT GAIN
Hyperphagia
WEIGHT GAIN
Obesity
WEIGHT GAIN
Overweight
WEIGHT GAIN
Abnormal weight gain
WEIGHT GAIN
Waist circumference increased
WEIGHT GAIN
Weight above normal
WEIGHT GAIN
Weight increased
WEIGHT GAIN
Waist circumference increased
MINJCAT
AEDECOD
INJECTION SITE
Injection site abscess
INJECTION SITE
Injection site abscess sterile
INJECTION SITE
Injection site anaesthesia
INJECTION SITE
Injection site atrophy
INJECTION SITE
Injection site bruising
INJECTION SITE
Injection site calcification
INJECTION SITE
Injection site cellulitis
INJECTION SITE
Injection site coldness
INJECTION SITE
Injection site cyst
INJECTION SITE
Injection site dermatitis
INJECTION SITE
Injection site desquamation
INJECTION SITE
Injection site discharge
INJECTION SITE
Injection site discolouration
INJECTION SITE
Injection site discomfort
INJECTION SITE
Injection site eczema
INJECTION SITE
Injection site erosion
INJECTION SITE
Injection site erythema
INJECTION SITE
Injection site extravasation
INJECTION SITE
Injection site fibrosis
INJECTION SITE
Injection site haematoma
INJECTION SITE
Injection site haemorrhage
INJECTION SITE
Injection site hypersensitivity
INJECTION SITE
Injection site hypertrophy
INJECTION SITE
Injection site induration
INJECTION SITE
Injection site infection
INJECTION SITE
Injection site inflammation
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INJECTION SITE
Injection site injury
INJECTION SITE
Injection site irritation
INJECTION SITE
Injection site ischaemia
INJECTION SITE
Injection site lymphadenopathy
INJECTION SITE
Injection site mass
INJECTION SITE
Injection site movement impairment
INJECTION SITE
Injection site necrosis
INJECTION SITE
Injection site nerve damage
INJECTION SITE
Injection site nodule
INJECTION SITE
Injection site oedema
INJECTION SITE
Injection site pain
INJECTION SITE
Injection site pallor
INJECTION SITE
Injection site papule
INJECTION SITE
Injection site paraesthesia
INJECTION SITE
Injection site phlebitis
INJECTION SITE
Injection site photosensitivity reaction
INJECTION SITE
Injection site pruritus
INJECTION SITE
Injection site pustule
INJECTION SITE
Injection site rash
INJECTION SITE
Injection site reaction
INJECTION SITE
Injection site scab
INJECTION SITE
Injection site scar
INJECTION SITE
Injection site swelling
INJECTION SITE
Injection site thrombosis
INJECTION SITE
Injection site ulcer
INJECTION SITE
Injection site urticaria
INJECTION SITE
Injection site vesicles
INJECTION SITE
Injection site warmth
INJECTION SITE
Buttock pain
INJECTION SITE
Pain in extremity
INJECTION SITE
Puncture site pain
INJECTION SITE
Administration site pain
INJECTION SITE
Application site pain
INJECTION SITE
Injection site dryness
INJECTION SITE
Injection site dysaesthesia
INJECTION SITE
Injection site exfoliation
INJECTION SITE
Injection site granuloma
INJECTION SITE
Injection site hyperaesthesia
INJECTION SITE
Injection site laceration
INJECTION SITE
Injection site macule
INJECTION SITE
Injection site plaque
INJECTION SITE
Injection site streaking
INJECTION SITE
Injection site vasculitis
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ATTACHMENT 2: Criteria of Markedly abnormal laboratory values
Laboratory Parameter[unit]
Markedly Abnormal Limits
Low
High
Albumin [g/L]
24
60
Alkaline phosphatase [U/L]
N/A
250
Alanine Aminotransaminase (SGPT) [U/L]
N/A
200
Aspartate Aminotransaminase (SGOT) [U/L]
N/A
250
Bicarbonate [mmol/L]
15.1
34.9
Blood urea nitrogen  [mmol/L]
N/A
17.9
Calcium [mmol/L]
1.5
3
Chloride [mmol/L]
94
112
Cholesterol [mmol/L]
N/A
7.8
Creatinine [mol/L]
N/A
265.2
Gamma glutamyl transferase [U/L]
N/A
300
Glucose [mmol/L]
2.2
16.7
HDL (mmol/L)
0.9
N/A
LDL (mmol/L)
2.3
4.1
Lactate Dehydrogenase[U/L]
N/A
500
Phosphate [mmol/L]
0.7
2.6
Potassium [mmol/L]
3.0
5.8
Sodium [mmol/L]
125
155
Bilirubin, total [mol/L]
N/A
51.3
Protein, total  (g/L)
50
N/A
Triglycerides [mmol/L]
N/A
5.7
Urate  [mol/L]
89.2
594.8
Hematocrit  (fraction) -- female
0.28
0.5
                                    -- male
0.24
0.55
Hemoglobin [g/L]
80
190
Neutrophils, Segmented [%]
30
90
Monocytes [%]
N/A
20
Eosinophils [%]
N/A
10
Basophils [%]
N/A
6
Lymphocytes [%]
10
60
Platelet count [x109/L]
100
600
Erythrocytes [x1012/L] -- female
3.0
5.5
                                     -- male
3.0
6.4
Leukocytes [x109/L]
2.5
15.0
Note:  The same limits apply to both males and females unless gender is 
indicated; N/A = Not applicable.
NCT02431702