Conditions: Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 841
Healthy volunteers: no

Brief summary:
The purpose of this study is to demonstrate that injection cycles consisting of a single administration of paliperidone palmitate 6-month (PP6M) are not less effective than 2 sequentially administered injections of paliperidone palmitate 3-month PP3M) (350 or 525 mg eq.) for the prevention of relapse in participants with schizophrenia previously stabilized on corresponding doses of paliperidone palmitate 1-month (PP1M) (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

Detailed description:
The primary hypothesis of this study is that the efficacy of PP6M is non-inferior to PP3M for preventing relapse in participants with schizophrenia who were previously stabilized on corresponding doses of PP1M or PP3M. The study consists of mainly 3 phases: a screening phase (up to 28 days), a maintenance phase (of 1 or 3 months), and a double-blind phase (of 12 months \[neither the researchers nor the participants know what treatment the participant is receiving\]). Additional/conditional phases include a transition phase (before maintenance phase). Study evaluations include efficacy, pharmacokinetics, pharmacodynamics, and safety. The study duration will vary from approximately 13 months to 19 months.

Arms:
arm 1: Participants who previously have not achieved stability with moderate to higher doses of Paliperidone palmitate 1-month (PP1M) or Paliperidone palmitate 3-month (PP3M) will enter into a transition period of up to 4 months. During transition period participants will receive 1 to 5 injections of PP1M 50 to 100 milligrams equivalent (mg eq.). The participants who achieved stability (stability is defined as at least 3 months of injections with the last 2 doses being the same strength) with PP1M 100 mg eq. will precede from transition phase to maintenance phase. arm 2: All the participants will receive only 1 dose of PP1M 100 or 150 mg eq. or PP3M 350 or 525 mg eq. The participants will precede from maintenance phase to double-blind phase. arm 3: Participants will receive intramuscular injection of PP6M in left gluteal muscle on Day 1 and right gluteal muscle on Day 183 with alternating placebo in right gluteal muscle on Day 92 and left gluteal muscle on Day 274. arm 4: Participants will receive intramuscular injections of PP3M at dose of 350 mg eq. or 525 mg eq. in left gluteal muscle on Day 1 and 274 and right gluteal muscle on Day 92 and 183.

Interventions: intervention 1: PP6M intervention 2: PP3M 350 mg eq. intervention 3: PP3M 525 mg eq. intervention 4: PP1M intervention 5: Placebo
Intervention descriptions: intervention 1: Participants will receive intramuscular injection of PP6M. intervention 2: Participants will receive intramuscular injection of PP3M 350 mg eq. intervention 3: Participants will receive intramuscular injection of PP3M 525 mg eq. intervention 4: Participants will receive intramuscular injection of PP1M 50 to 150 mg eq. intervention 5: Participants will receive matching placebo.

Protocol document:
Prot_002.pdf: 
1
Status: Approved, Date: 11 February 2019
Janssen Research & Development *
Clinical Protocol
A Double-blind, Randomized, Active-controlled, Parallel-group Study of 
Paliperidone Palmitate 6-Month Formulation
Protocol R092670PSY3015; Phase 3
Amendment 3
R092670 (paliperidone palmitate)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the Sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. 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 United States (US) Food & Drug Administration (FDA) 
Investigational New Drug (IND) regulations (21 Code of Federal Regulations [CFR] Part 312).
EudraCT Number: 2017-001941-28
Status:
Approved
Date:
11 February 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number: EDMS-ERI-130495167, 5.0
Compliance: This study will be conducted in compliance with Good Clinical Practice (GCP), 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.
NCT03345342


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
SYNOPSIS.................................................................................................................................................. 26
TIME AND EVENTS SCHEDULES ............................................................................................................ 33
A.
Screening, Transition, and Maintenance Phases .......................................................................... 33
A.i.
Subjects With Prestudy PP1M or PP3M Stability....................................................................... 33
A.ii.
Subjects Without Prestudy PP1M or PP3M Stability.................................................................. 34
B.
Double-blind Phase (12 Months) ................................................................................................... 35
C.
Follow-up Phase (for Subjects Who Discontinue, Withdraw, or Relapse During the 
Double-blind Phase)....................................................................................................................... 36
D.
Keys and Footnotes (for All Time and Events Schedules) ............................................................ 37
ABBREVIATIONS AND TERMS................................................................................................................ 39
1.
INTRODUCTION................................................................................................................................ 41
1.1.
Background .................................................................................................................................... 41
1.2.
Overall Rationale for the Study...................................................................................................... 44
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 45
2.1.
Objectives and Endpoints .............................................................................................................. 45
2.1.1.
Objectives ................................................................................................................................... 45
2.1.2.
Endpoints.................................................................................................................................... 46
2.1.2.1.
Primary Endpoint ..................................................................................................................... 46
2.1.2.2.
Relapse Criteria....................................................................................................................... 46
2.1.2.3.
Secondary Endpoints .............................................................................................................. 47
2.2.
Hypothesis ..................................................................................................................................... 47
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 47
3.1.
Overview of Study Design.............................................................................................................. 47
3.2.
Study Design Rationale.................................................................................................................. 52
4.
SUBJECT POPULATION.................................................................................................................. 55
4.1.
Inclusion Criteria ............................................................................................................................ 56
4.2.
Exclusion Criteria ........................................................................................................................... 59
4.3.
Criteria for Entry Into the Maintenance Phase............................................................................... 63
4.4.
Criteria for Entry Into the Double-blind Phase ............................................................................... 64
4.5.
Prohibitions, Restrictions, and Strong Recommendations............................................................. 65
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 66
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 68
6.1.
Dosage........................................................................................................................................... 68
6.1.1.
Screening Phase ........................................................................................................................ 68
6.1.2.
Transition Phase......................................................................................................................... 68
6.1.3.
Maintenance Phase.................................................................................................................... 76
6.1.4.
Double-blind Phase .................................................................................................................... 80
6.1.5.
Treatment After the Study or in the Follow-up Phase ................................................................ 80
6.2.
Administration ................................................................................................................................ 80
6.2.1.
Administration During the Open-label Phases ........................................................................... 80
6.2.2.
Administration During the Double-blind Phase........................................................................... 81


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7.
TREATMENT COMPLIANCE............................................................................................................ 81
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 81
8.1.
Prestudy Medical Therapy and Psychotherapy ............................................................................. 81
8.2.
Concomitant Therapy..................................................................................................................... 82
8.3.
Prohibited Concomitant Medications ............................................................................................. 83
9.
STUDY EVALUATIONS .................................................................................................................... 84
9.1.
Study Procedures........................................................................................................................... 84
9.2.
Efficacy Evaluations....................................................................................................................... 86
9.2.1.
Qualified Raters .......................................................................................................................... 86
9.2.2.
Positive and Negative Syndrome Scale ..................................................................................... 87
9.2.3.
Clinical Global Impression - Severity.......................................................................................... 87
9.2.4.
Personal and Social Performance Scale.................................................................................... 88
9.2.5.
Satisfaction With Participation in Social Roles ........................................................................... 88
9.2.6.
Abbreviated Treatment Satisfaction Questionnaire for Medication ............................................ 88
9.3.
Pharmacokinetic and Pharmacodynamic Evaluations................................................................... 88
9.3.1.
Pharmacokinetic Evaluations ..................................................................................................... 88
9.3.2.
Analytical Procedures................................................................................................................. 89
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 89
9.3.4.
Pharmacodynamic Evaluations .................................................................................................. 90
9.4.
Safety Evaluations ......................................................................................................................... 90
9.4.1.
Adverse Events........................................................................................................................... 90
9.4.2.
Clinical Laboratory Tests ............................................................................................................ 90
9.4.3.
Electrocardiograms..................................................................................................................... 92
9.4.4.
Vital Signs................................................................................................................................... 93
9.4.5.
Physical Examinations................................................................................................................ 93
9.4.6.
Extrapyramidal Symptoms.......................................................................................................... 93
9.4.6.1.
Abnormal Involuntary Movement Scale................................................................................... 93
9.4.6.2.
Barnes Akathisia Rating Scale ................................................................................................ 94
9.4.6.3.
Simpson Angus Scale ............................................................................................................. 94
9.4.7.
Columbia Suicide Severity Rating Scale .................................................................................... 94
9.4.8.
Evaluations of the Injection Site ................................................................................................. 94
9.4.8.1.
Injection Site Evaluations by Subjects..................................................................................... 94
9.4.8.2.
Injection Site Evaluations and Follow-up by Investigators ...................................................... 95
9.5.
Benefit-risk Evaluations.................................................................................................................. 96
9.6.
Other Exploratory Evaluations ....................................................................................................... 96
9.6.1.
Healthcare Resource Utilization Questionnaire.......................................................................... 96
9.6.2.
Involvement Evaluation Questionnaire....................................................................................... 97
9.6.3.
Concomitant Substances Questions .......................................................................................... 97
9.6.4.
Illness Management and Recovery Scale .................................................................................. 97
9.6.5.
Schizophrenia Quality of Life Scale (Revision 4) ....................................................................... 98
10.
SUBJECT COMPLETION / DISCONTINUATION OF STUDY DRUG / WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 98
10.1.
Completion ..................................................................................................................................... 98
10.2.
Discontinuation of Study Drug / Withdrawal From the Study......................................................... 98
10.3.
Antipsychotic Therapy After the Study or in the Follow-up Phase............................................... 100
10.4.
Process for Planned Study Closure............................................................................................. 102
11.
STATISTICAL METHODS............................................................................................................... 103
11.1.
Subject Information ...................................................................................................................... 103
11.2.
Sample Size Determination ......................................................................................................... 103
11.3.
Efficacy Analyses ......................................................................................................................... 104
11.3.1.
Primary Hypothesis and Efficacy Analyses .............................................................................. 104
11.3.1.1.
Double-blind Intent-to-Treat Analysis Population.................................................................. 104
11.3.1.1.1.
Primary Estimand............................................................................................................... 104
11.3.1.1.2.
Primary Efficacy Analyses.................................................................................................. 105


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11.3.1.1.3.
Sensitivity Analyses for Primary Efficacy........................................................................... 105
11.3.1.2.
Per-protocol Analysis Population........................................................................................... 105
11.3.1.2.1.
Estimand ............................................................................................................................ 105
11.3.1.2.2.
Analyses............................................................................................................................. 105
11.3.2.
Secondary Efficacy Analyses ................................................................................................... 106
11.4.
Pharmacokinetic and Pharmacodynamic Analyses..................................................................... 106
11.5.
Safety Analyses ........................................................................................................................... 108
11.5.1.
Adverse Events......................................................................................................................... 108
11.5.2.
Clinical Laboratory Tests .......................................................................................................... 108
11.5.3.
Electrocardiograms................................................................................................................... 108
11.5.4.
Vital Signs................................................................................................................................. 109
11.5.5.
Physical Examinations.............................................................................................................. 109
11.5.6.
Extrapyramidal Symptom Scales.............................................................................................. 109
11.5.7.
Columbia Suicide Severity Rating Scale .................................................................................. 109
11.5.8.
Evaluations of the Injection Sites.............................................................................................. 109
11.5.9.
Anticipated Event Review Committee ...................................................................................... 110
11.6.
Benefit-risk Analyses.................................................................................................................... 110
11.7.
Other Exploratory Analyses ......................................................................................................... 110
12.
ADVERSE EVENT REPORTING .................................................................................................... 110
12.1.
Definitions .................................................................................................................................... 111
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 111
12.1.2.
Attribution Definitions................................................................................................................ 112
12.1.3.
Severity Criteria ........................................................................................................................ 112
12.2.
Special Reporting Situations........................................................................................................ 113
12.3.
Procedures................................................................................................................................... 113
12.3.1.
All Adverse Events.................................................................................................................... 113
12.3.2.
Serious Adverse Events ........................................................................................................... 114
12.3.3.
Pregnancy................................................................................................................................. 115
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 116
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 116
13.1.
Procedures................................................................................................................................... 116
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 116
14.
STUDY DRUG INFORMATION....................................................................................................... 116
14.1.
Physical Description of Study Drugs............................................................................................ 116
14.2.
Packaging .................................................................................................................................... 117
14.3.
Labeling........................................................................................................................................ 117
14.4.
Preparation, Handling, and Storage............................................................................................. 117
14.5.
Drug Accountability ...................................................................................................................... 117
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 118
16.
ETHICAL ASPECTS ....................................................................................................................... 119
16.1.
Study-specific Design Considerations ......................................................................................... 119
16.2.
Regulatory Ethics Compliance..................................................................................................... 120
16.2.1.
Investigator Responsibilities ..................................................................................................... 120
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 120
16.2.3.
Informed Consent ..................................................................................................................... 122
16.2.4.
Privacy of Personal Data .......................................................................................................... 123
16.2.5.
Country Selection ..................................................................................................................... 123
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 123
17.1.
Protocol Amendments.................................................................................................................. 123
17.2.
Regulatory Documentation .......................................................................................................... 124
17.2.1.
Regulatory Approval/Notification .............................................................................................. 124
17.2.2.
Required Prestudy Documentation........................................................................................... 124
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 125


R092670 (paliperidone palmitate)
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17.4.
Source Documentation................................................................................................................. 125
17.5.
Electronic Case Report Form Completion ................................................................................... 126
17.6.
Data Quality Assurance / Quality Control .................................................................................... 126
17.7.
Record Retention ......................................................................................................................... 127
17.8.
Monitoring .................................................................................................................................... 127
17.9.
Study Completion/Termination..................................................................................................... 128
17.9.1.
Study Completion (End of Study) ............................................................................................. 128
17.9.2.
Study Termination..................................................................................................................... 128
17.10.
On-Site Audits .............................................................................................................................. 128
17.11.
Use of Information and Publication.............................................................................................. 129
REFERENCES.......................................................................................................................................... 131
ATTACHMENTS....................................................................................................................................... 133
INVESTIGATOR AGREEMENT ............................................................................................................... 137
LIST OF ATTACHMENTS
Attachment 1:
Guidelines for the Intramuscular Injection of Paliperidone Palmitate or 
Placebo During the Double-blind Phase .................................................................. 133
Attachment 2:
Relapse Criteria for PANSS Total Score.................................................................. 134
Attachment 3:
Anticipated Events for Study R092670PSY3015 ..................................................... 136
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Conversions Between Doses of the 1-, 3-, and 6-Month Formulations of Paliperidone 
Palmitate; Study R092670PSY3015......................................................................................... 41
Table 2:
Doses of Paliperidone ER/PR Tablets and PP1M Needed to Attain Similar Steady-
state Paliperidone Exposure..................................................................................................... 71
Table 3:
Dosage and Administration Schedule for PP1M During the Transition Phase (Before 
Meeting the PP3M Prerandomization Target); Study R092670PSY3015................................ 73
Table 4:
Dosage and Administration Schedule for PP1M During the Transition Phase (After 
Meeting the PP3M Prerandomization Target); Study R092670PSY3015................................ 74
Table 5:
Administration of Study Agent During the Double-blind Phase; Study 
R092670PSY3015 .................................................................................................................... 81
Table 6:
Maximum Allowable Benzodiazepine Daily Dosages; Study R092670PSY3015..................... 83
Table 7:
Timing of Resumption of PP1M/3M after the Double-blind Study or in Follow-Up 
Phase...................................................................................................................................... 102
Table 8:
Switching Conversion Table (Oral and LAI Paliperidone and Oral Risperidone) ................... 102
FIGURES
Figure 1:
Schematic Overview; Study R092670PSY3015....................................................................... 50
Figure 2:
Schematic Overview, Showing Additional Details for the Screening Phase and 
Transition Phase; Study R092670PSY3015............................................................................. 70
Figure 3:
Schematic Overview, Showing Additional Details for the Maintenance Phase (Before 
Meeting the PP3M Prerandomization Target); Study R092670PSY3015................................ 78
Figure 4:
Schematic Overview, Showing Additional Details for the Maintenance Phase (After 
Meeting the PP3M Prerandomization Target); Study R092670PSY3015................................ 79
Figure 5:
Post Study Medication Algorithm............................................................................................ 101


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PROTOCOL AMENDMENTS
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (11 February 2019)
The overall reason for the amendment: To limit the duration of the Double-blind Phase to 12 months by 
eliminating the double-blind extension period, which is currently of a variable length of 12-24 months; and to 
increase the estimated number of subjects entering the Transition/Maintenance Phases from a target sample size 
of 765 to 840.
Applicable Section(s)
Description of Change(s)
Rationale: The rationale for limiting the Double-blind Phase to a fixed duration of 12 months is to align it with 
the primary endpoint, ie, time to relapse during the Double-blind Phase which is based on the Kaplan-Meier 
estimate of percentage of subjects who remain relapse-free at Month 12. 
Synopsis: 
Secondary Endpoints
OVERVIEW OF 
STUDY DESIGN
Dosage: Double-blind 
Phase
Removed the greater than or equal to sign ‘≥’ to reflect that secondary endpoints beyond 
12 months of the Double-blind Phase are no longer applicable.
Removed text related to subjects participating in additional double-blind treatment of 
variable duration beyond the 12-month Double-blind Phase.
Removed text related to study procedures beyond the 12 months of the Double-blind 
Phase.
Deleted text stating that the Follow up Phase will end at 6-month time points thereafter 
if the subject has already participated past the first 12 months of the Double-blind Phase.
Revised the text to state that that the longest expected duration is ~19 months and not 
>31 months for subjects who complete the study without relapse as the variable duration 
of double-blind phase beyond the first 12 months has been removed.
Deleted text describing treatment beyond the first 12 months of the Double-blind Phase
Time and Events 
Schedules C
Time and Events 
Schedule C 
(originally Time and 
Events Schedule D)
Deleted the original Time and Events Schedule C. Double-blind Phase (After the First 
12 Months) in its entirety as the Double-blind Phase is limited to 12 months per this 
amendment.
In the EOP column, removed “18 or 24” months after the subject’s first double-blind 
injection; removed text “(or at 6-Month Time Points Thereafter, if Applicable)”; deleted text 
in the footnote describing an example of Follow up Phase visits for a subject who 
withdraws from the study in the Double-blind Phase beyond the 12 months. Also deleted 
text stating “… or at 6-month time points thereafter if the subject has already 
participated past the first 12 months of the Double-blind Phase”.
Protocol Version
Issue Date
Original Protocol
28 August 2017
Amendment 1
Amendment 2
Amendment 3
21 March 2018
28 September 2018
11 February 2019


R092670 (paliperidone palmitate)
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Time and Events 
Schedule D: Keys and 
Footnotes (for All 
Time and Events 
Schedules) (originally 
Time and Events 
Schedule E)
2.1.2.3. Secondary 
Endpoints
3.1 Overview of 
Study Design
Figure 1
3.2. Study Design 
Rationale
Study Phases
6.1.2. Transition 
Phase: Figure 2
6.1.3. Maintenance 
Phase: Figure 3 and 
Figure 4
6.1.4. Double-blind 
Phase
6.2.2. Administration 
During the Double-
blind Phase: Table 5
Deleted footnote “aa” in Amendment 2 as it no longer applies with the elimination of 
variable double-blind phase beyond the 12 months.
Removed secondary endpoints beyond the 12-month Double-blind Phase.
Removed the greater than or equal to sign ‘≥’ to reflect that secondary endpoints beyond 
12 months of the Double-blind Phase are no longer applicable.
Removed text related to subjects participating in additional double-blind treatment of 
variable duration beyond the 12-month Double-blind Phase.
Removed text related to study procedures beyond the 12 months of the Double-blind 
Phase.
Deleted text stating that the Follow up Phase will end at 6-month time points thereafter 
if the subject has already participated past the first 12 months of the Double-blind Phase.
Revised text to reflect that the length of the Double-blind Phase is 12 months and a 
subject could have 19 months of participation with exposure to paliperidone palmitate 
for subjects without relapse.
Limited the length of Double-blind Phase to 12 months only to align with the primary 
endpoint.
Footnote d: Removed text describing treatment during Double-blind Phase beyond 12 
months and revised text on study closure to account for possibilities of the last subject 
randomized being lost to follow-up or withdrawing consent.
Note: Deleted text stating that the Follow up Phase will end at 6-month time points 
thereafter if the subject has already participated past the first 12 months of the Double-
blind Phase.
Deleted text stating that the Follow up Phase will end at 6-month time points thereafter 
if the subject has already participated past the first 12 months of the Double-blind Phase.
Limited the length of Double-blind Phase to 12 months only to align with the primary 
endpoint.
Limited the length of Double-blind Phase to 12 months only to align with the primary 
endpoint.
Deleted text describing treatment beyond the first 12 months of the Double-blind Phase.
Deleted last column of Table 5 that is related to pattern of injection sites beyond the first 
12 months of the Double-blind Phase.


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9.1. Study 
Procedures:
Double-blind Phase
10.2. Discontinuation 
of Study 
Drug/Withdrawal 
From the Study
10.3. Antipsychotic 
Therapy After the 
Study or in the 
Follow-up Phase: 
Figure 5
10.4. Process for 
Planned Study 
Closure
Deleted text related to study procedures beyond the first 12 months of the Double-blind 
Phase.
Removed potential scheduled assessments beyond the 12-month Double-blind Phase (ie, 
Visits beyond Visit 33a). Removed text describing a scenario of withdrawal in which a 
subject has not entered the Double-blind Phase when the Sponsor terminates the study.
Removed Double-blind Time Point that is beyond 12-month (last column).
(Note: section numbering has been updated as the original section 10.3 Withdrawal 
From the Use of Research Samples is now deleted.)
Removed odd-numbered injections (5th, etc.) that are beyond the 12-month Double-blind 
Phase. Revised text on study closure to account for possibilities of the last subject 
randomized being lost to follow-up or withdrawing consent
Rationale: To increase the estimated number of subjects entering the Transition and Maintenance Phases from 
approximately 765 to 840 to match current dropout/enrollment rates and to meet the randomization target of 549 
subjects in the Double-blind Phase. Current enrollment rates project that the number of subjects entering the 
Transition/Maintenance Phases will exceed the previous target. The increase in the estimated number needed to 
achieve the randomization target is primarily due to an increased dropout rate during Transition and Maintenance 
Phases.
3.1 Overview of 
Study Design;
11.2. Sample Size 
Determination
Specified that the number of subjects entering the Transition/Maintenance will be 
approximately 840.
Rationale: To indicate data collection for “Concomitant substance testing and questions” at Visit 13 during the 
Double-blind Phase for consistency with footnote e and f of Time and Events Schedule B and with the text in 
section 9.4.2. 
Time and Events 
Schedule B
Added a time point for data collection at Visit 13 in the row of Concomitant substance 
testing and questions.
Rationale: To remove ECG collection at Visit 4 of the Maintenance Phase as routine ECG monitoring at this 
timepoint is not expected to enhance safety monitoring for subjects who are continuing the same medications in 
the Maintenance Phase.
Time and Events 
Schedule Ai
Time and Event 
Schedule Aii
Removed ECG data collection at Visit 4.
Removed ECG data collection at Visit 4.
Rationale: To provide guidance on the timing of EOP after relapse confirmation.
Time and Events 
Schedule D, footnote 
f 
9.1. Study Procedures
Added text to state that the EOP visit is to occur as soon as possible after relapse 
confirmation (preferably the same day).
Rationale: To remove the EOP Visit from the Follow-up Phase to minimize potential confusions with the EOP 
visit at the Double-blind Phase (33a) and at the end of the Maintenance Phase (7a).


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Time and Events 
Schedule C
(Originally Time and 
Events Schedule D)
Time and Events 
Schedule D
(Originally Time and 
Events Schedule E)
Figure 1
Section 10 .4
Deleted the EOP Visit column from the Follow-up Phase.
Deleted footnote “bb” in Amendment 2
Deleted text related to the EOP Visit of the Follow-up Phase in Footnote d. 
Deleted text related to the EOP Visit of the Follow-up Phase
Rationale: To clarify that in inclusion criterion 11, the method of contraception referred to above (ie, criterion 
10) is for the female partner(s) of male subjects.
4.1 Inclusion Criteria
Modified inclusion criterion 11 to clarify that a male subject must agree that his female 
partner(s), rather than himself, use method of contraception as described in criterion 10.
Rationale: To remove the introduction sentence under Exclusion Criteria for clarity.
4.2 Exclusion Criteria
Deleted the introduction sentence under Exclusion Criteria
Rationale: To clarify that the excluded injectable formulations of neuroleptic drugs are long-acting injectable 
formulations.
4.2. Exclusion 
Criteria
Added “long-acting” to exclusion criterion 6 to state excluded injectable formulation of 
neuroleptic drugs as long-acting formulations.
Rationale: To clarify that the full content of the study drug should be administered as a single injection.
6.2. Administration 
Added text to state that the full content is to be administered in one injection, using only 
the supplies provided in the study drug kit.
Rationale: To add text to instruct the site of the first injection during the Maintenance Phase.
6.2.1. Administration 
During the Open-
label Phases
Added a note to state Day 1 injection should not be administered at the same site as the 
last injection during the Maintenance Phase.
Rationale: To add tricyclic anti-depressants, known to prolong QT interval, to the list of Prohibited Concomitant 
Medications; to minimize the risk of concomitant amantadine use, it is now explicitly cited as an example of a 
dopamine agonist; to add non-antipsychotic dopamine antagonists to the list of Prohibited Concomitant 
Medications to minimize risk of EPS and akathisia.
8.3. Prohibited 
Concomitant 
Medications
Added tricyclic antidepressants, amantadine, and nonantipsychotic dopamine 
antagonists to the list of Prohibited Concomitant Medications.
Rationale: To provide additional details for injection site assessments.
9.4.8.2. Injection Site 
Evaluations and 
Follow-up by 
Investigators
Added anchor point scores for injection site evaluations regarding tenderness, 
erythema/redness, and induration/swelling.
Rationale: To provide investigators with detailed information on antipsychotic treatment options after the study 
or in the Follow-up Phase.


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10.3. Antipsychotic 
Therapy After the 
Study or in the 
Follow-up Phase
Diagram in Figure 5 replaced with the Post Study Medication Algorithm; added Table 7, 
Timing of Resumption of PP1M/PP3M after the Double-blind Study or in Follow-Up 
Phase; added Table 8, Switching Conversion Table (Oral and LAI Paliperidone and oral 
risperidone).
Rationale: With a fixed duration of 12 months for the Double-blind Phase, there will be fewer relapse events 
than anticipated to detect a biomarker signal that could reliably predict relapse events. Therefore, collection of 
blood biomarkers is now removed from the protocol.
Time and Events 
Schedules A.i., A.ii. 
and B
Time and Events 
Schedule D: Keys and 
footnotes (Originally 
Time and Events 
Schedule E)
2.1.1 Objectives
Exploratory Objectives
3.2. Study Design 
Rationale
4.5. Prohibitions, 
Restrictions, and Strong 
Recommendations
9.1. Study Procedures
9.6. Biomarker 
Evaluations
10.3. Withdrawal From 
the Use of Research 
Samples
11.7. Biomarker 
Analysis
15. STUDY SPECIFIC 
MATERIALS
16.2.4.Privacy of 
Personal Data
16.2.5. Long-term 
Retention of Samples 
for Additional Future 
Research
17.11. Use of 
Information and 
Publication
Removed text related to blood biomarkers under Collection of biofluids
Under footnote f, removed text related to blood biomarker sample collections.
Removed footnote “r” in Amendment 2 which was related to sample collections for 
blood biomarkers.
Removed text related to the exploratory objective to measure blood-based biomarkers.
Removed the Biomarkers subsection.
Removed text related to strong recommendations for blood biomarker sample 
collections.
Removed text related to blood sample collections for biomarkers.
Removed original section 9.6 Biomarker Evaluations.
Deleted the entire original section 10.3 that was related to biomarker research samples.
Removed original section 11.7. Biomarker Analysis.
Removed text related to biomarkers under “Documentations” and “Supplies”.
Removed text related to exploratory biomarker research.
Removed the entire original section 16.2.5. that was related to biomarkers.
Removed text related biomarker research data analysis and report.


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Rationale: To add secondary endpoints in Synopsis and section 2.1.2.3. Secondary Endpoints of the protocol to 
align secondary endpoints with section 9 Study Evaluations related to secondary endpoints to maintain 
consistency throughout the protocol.
Synopsis;
2.1.2.3. Secondary 
Endpoints
Listed additional secondary endpoints as described in section 9 of the protocol.
Rationale: To include an additional trade name of risperidone LAI.
6.1.2. Transition Phase
Listed the trade name of risperidone LAI in certain countries.
Rationale: To include a list of Investigational Medicinal Products (IMPs) and Noninvestigational Medicinal 
Products (NIMPs) used in the study to facilitate protocol review.
Abbreviations and 
Terms
Listed IMPs and NIMPs used in the study
Rationale: Minor errors were noted/
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 2 (28 September 2018)
The overall reasons for the amendment:

To revise the number of prerandomization injections of PP1M from a total of 6 (ie, 5-month duration) to a 
total of 5 (ie. 4-month duration) required before subjects are randomized to either PP3M or PP6M treatment 
group in the Double-blind Phase. This change applies to subjects in the study’s Open-label phases being 
treated with PP1M after the PP3M prerandomization target has been met, since these subjects will be 
randomized directly from PP1M treatment. The change aligns with the minimum of 4-month treatment with 
PP1M prior to the initiation of PP3M in previously completed pivotal PP3M trials and the approved posology 
for PP3M.  

To update and clarify supporting text, figures, and tables for consistency and corrects conflicting portions of 
the protocol that inadvertently increased the minimum duration of PP1M treatment from 4 months to 5 months

To remove text related to optional salivary biomarkers research since the sample size for this portion of the 
study is expected to be too low to generate conclusive results.

Other changes to the protocol are also made for clarity, consistency, or operational feasibility. (Note: in this 
table, newly added text to the protocol is in bold font and deleted text is in strikethrough.)
Applicable Section(s)
Description of Change(s)
Rationale: To revise the minimum number of PP1M injections from 6 (ie,5 months) to 5 (ie, 4 months) prior to 
random assignment to treatment with either PP6M or PP3M in the Double-blind Phase.  This is to realign the protocol 
with the intended design in which subjects receive a minimum of 4-month treatment with PP1M in order to determine 
dose stability and to maintain clarity and consistency throughout the protocol.
6.1.2 Transition Phase, Figure 2, 
Table 3
Revised Figure 2 and Table 3 (which now becomes Table 3 and Table 4 to 
illustrate the Dosage and Administration Schedule for PP1M During the 
Transition Phase before and after meeting the PP3M prerandomization target, 
respectively) to specify the minimum numbers of PP1M injections prior to 
randomization before or after the PP3M prerandomization target has been met. 
(Footnote f of Table 3 and 4 is revised so the interval from the last prestudy 
PP1M injection is now 30±7 days to align with section 6.1.3).
6.1.2. Transition Phase: Subjects 
Previously Treated With Oral 
Antipsychotics
The following text was added to explain and clarify the changes to the visit 
schedule after the PP3M prerandomization target is met: 
“After the PP3M prerandomization target is met, these subjects will skip 
Visit 2e and proceed to Visit 2f if the subject is eligible to enter the 
Maintenance Phase (see Section 4.3, Criteria for Entry Into the 
Maintenance Phase). If not eligible to enter the Maintenance Phase, the 
subject will be withdrawn from the study.”


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6.1.2. Transition Phase: Subjects 
Previously Stabilized on Injectable 
Risperidone (Biweekly – Risperdal 
CONSTA™ formulation)
6.1.2. Transition Phase: Subjects 
Previously Initiated (But Not on a 
Stable Regimen) With Moderate or 
Higher Doses of PP1M (Invega 
Sustenna ™ or Xeplion ™ 
formulation)
6.1.3. Maintenance Phase, Figure 4
Time and Events Schedules, A.ii.
The following text was added: “After the PP3M prerandomization target is 
met, these subjects will skip Visit 2e and proceed to Visit 2f, if eligible to 
enter the Maintenance Phase (see Section 4.3, Criteria for Entry Into the 
Maintenance Phase).  If not eligible to enter the Maintenance Phase, the 
subject will be withdrawn from the study.”
The following text was added: “After the PP3M prerandomization target is 
met, subjects previously initiated on PP1M (but not on a stable regimen) 
who enter the study at Visit 2c or 2d will skip Visit 2e and proceed to Visit 
2f, if eligible to enter the Maintenance Phase (see Section 4.3, Criteria for 
Entry Into the Maintenance Phase). Subjects with ≥4 prestudy PP1M 
injections with the last 2 doses being the same strength will enter the study 
at Visit 2f.  Subjects with ≥4 prestudy PP1M injections with the last 2 doses 
being different (ie, do not have dose stability) will enter the study at Visit 2e.  
If not eligible to enter the Maintenance Phase, the subject will be withdrawn 
from the study.”
Revised Figure 4 to reflect the minimum number of PP1M injections during the 
Transition Phase from a total of 5 to a total of 4. (A footnote was also updated to 
reflect that the prerandomization targets of PP3M and PP1M groups were 
changed to approximately one-half from each group.)
Added the footnote cc for Visit number 2e of Transition Phase to state “After
the PP3M prerandomization target is met, subjects who entered the study at 
Visits 2a, 2b, 2c, or 2d, will skip Visit 2e and proceed to Visit 2f if the 
subject is eligible to enter the Maintenance Phase (see Section 4.3, Criteria 
for Entry Into the Maintenance Phase).  If not eligible to enter the 
Maintenance Phase, the subject will be withdrawn from the study. Visit 2e 
remains available for subjects with ≥4 prestudy PP1M injections but do not 
have dose stability.”
Rationale: To update the visit window for Visits 8, 21, 34, and 43 to avoid overlaps with the window of their 
respective previous visit.
Time and Events Schedules, B and 
C
Changed visit window for Visits 8, 21, 34, and 43 from ± 1 to -1 to +3. 
Rationale: To update footnotes in Time and Event Schedule, E to align with text in section 6.1.3.
Time and Events Schedules, E
Revised footnote g so that the intervals from the last prestudy PP1M and PP3M 
injections are now 30±7 days and 90±14 days, respectively.
Revised footnote w to indicate that the interval from the last prestudy PP1M 
injection is now 30±7 days and “Table 3” is changed to “Tables 3 and 4”.
Rationale: To achieve greater balance between the prerandomization proportions of each medication group. 
3.1. Overview of Study Design
The following text was revised as follows:
“Of subjects entering the Double-blind Phase, the prerandomization targets are 
approximately one-half one quarter to one-third entering from a PP3M group, 
and one-half three-quarters to two-thirds entering from a PP1M group.


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6.1.3. Maintenance Phase
Figure 3
Similar changes were also made to reflect the approximately one-half pre-
randomization target from PP1M and PP3M groups. In addition, text was added 
to the number of PP3M entering the study if needed to maintain the approximate 
balance of PP1M and PP3M prerandomization targets: “In order to 
appropriately balance the number of PP1M and PP3M subjects in the 
Maintenance Phase and to complete the study in a timely manner, the 
pathway to study enrollment that includes subjects who enter the study with 
previous PP3M stability will be open for only a limited time. The Sponsor 
will inform the sites when this pathway has closed to enrollment.”
Figure 3 updated so that the appearance and position of the box containing the 
“Low- dose exclusion groups” are aligned with those in Figure 1. A footnote 
was also updated to reflect the approximately one-half prerandomization target 
for the PP1M and PP3M group. 
Rationale: To simplify the sequence of procedures to be performed so that non-invasive safety assessments are 
completed before invasive tests to avoid influencing results and the sequence of procedures that is critical to quality is 
kept.    
9.1. Study Procedures
The Time and Events Schedules summarize the frequency and timing of 
measurements applicable to this study. If multiple assessments are scheduled for 
the same visit, then ECG and vital signs should be collected prior to blood 
sample collections (eg, PK, biomarkers, and/or laboratory tests) and blood 
sample collections should be collected prior to procedures should be 
performed in the following sequence: subject-reported efficacy or exploratory 
scales; ECG; vital signs; sample collection for PK, biomarkers, and/or laboratory 
tests; clinical assessments of efficacy and safety; study drug injection.  
Evaluations of the injection site occur after study drug injection, as 
described in Section 9.4.8. and then assessments of injection sites.  Actual dates 
and times of assessments will be recorded in the source documentation.
Rationale: To clarify the need to maintain the same dose level for eligibility, whether continuing PP1M or 
switching to PP3M.
4.3. Criteria for Entry Into the 
Maintenance Phase
The following text was modified in criterion for entry into the Maintenance 
Phase #2
2. Criterion modified per Amendment 2
2.1. For subjects proceeding from the Transition Phase to the Maintenance 
Phase, the PP1M dose prior to entering the Maintenance Phase must have 
been 100 or 150 mg eq. and, in the investigator’s judgment, the subject 
should continue on the same dose level (ie, either the equivalent PP3M 
dose [before the PP3M prerandomization target is met] or the same PP1M 
dose [after the PP3M prerandomization target is met]). must not be planned 
for adjustment in the foreseeable future and must have been 100 or 150 mg eq. 
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Rationale: To ensure a subject has dose stability to enter the DB Phase.
10.2. Discontinuation of Study 
Drug/Withdrawal From the Study
The following text is added:

For subjects in the Maintenance Phase:
o
If the dose at Visit 2f is different from the preceding dose or is 
not a dose equivalent of the preceding dose
Rationale: To remove text related to optional saliva biomarkers as the sample size for this optional portion of the study 
is expected to be too low to generate conclusive results.
Time and Events Schedules A.i.
Time and Events Schedules A.ii.
Time and Events Schedule B and 
C
Time and Events Schedule E: 
Keys and footnotes
2.1.1 Objectives
Exploratory Objectives
3.2. Study Design Rationale
4.1. Inclusion Criteria
4.5. Prohibitions, Restrictions, and 
Strong Recommendations
9.1. Study Procedures
9.6. Biomarker Evaluations
10.3. Withdrawal From the Use of 
Research Samples
15. STUDY SPECIFIC 
MATERIALS
16.2.2.Independent Ethics 
Committee or Institutional Review 
Board
16.2.3. Informed Consent
Removed text related to saliva biomarkers for the Optional ICF under 
Screening/Administrative.
Removed text related to optional saliva biomarkers under Collection of biofluids
Removed text related to saliva biomarkers for the Optional ICF under 
Screening/Administrative.
Removed text related to optional saliva biomarkers under Collection of biofluids
Removed text related to optional saliva biomarkers under Collection of biofluids
Under footnote g, removed text related to optional saliva biomarker sample 
collections.
Removed text related to optional saliva based biomarkers.
Removed text related to sample collections for optional saliva biomarkers under 
the Biomarkers subheading.
Deleted Inclusion Criterion 15 which is related to signing the ICF for the optional 
saliva biomarkers.
Removed text related to sample collections for optional saliva biomarkers.
Removed text related to sample collections for optional saliva biomarkers.
Removed text related to sample collections for optional saliva biomarkers.
Deleted text related to the optional saliva biomarker research samples.
Deleted text related to optional saliva sample collections.
Removed text related to approval for the collection of optional saliva samples for 
research and for the corresponding ICF.
Removed text related to signing the ICF for the optional saliva biomarker 
research.


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Rationale: To explicitly state that rescreening may be considered for some subjects who were withdrawn during the 
Transition or Maintenance Phases.
4. SUBJECT POPULATION
4.3. Criteria for Entry Into the 
Maintenance Phase
4.4. Criteria for Entry Into the 
Double-blind Phase
Added the following text: “Rescreening is permitted with the medical 
monitor’s approval for subjects who were withdrawn during the Transition 
Phase or Maintenance Phase due to an incomplete injection or an 
unintended dosing or administration of a study drug.”
Added the following text: “If withdrawal is due to an incomplete injection or 
an unintended dosing or administration of a study drug, rescreening is 
permissible with the medical monitor’s approval.”
Added the following text: “If withdrawal is due to an incomplete injection or 
an unintended dosing or administration of a study drug, rescreening is 
permissible with the medical monitor’s approval.”
Rationale: To minimize the risk of confusion related to the process of study closure.
9.1. Study Procedures
Under the Double-blind Phase subtitle, removed text that may be confusing and 
instead provide a reference to section 10.5 where the process for study closure is 
described in detail.
Rationale: To monitor for appropriate eligibility on the basis of exclusionary medications and for correct timing and 
dosing of study injections with respect to prestudy PP1M and PP3M injections, where applicable. 
8.2.
Concomitant Therapy
Text revised to include that therapies from 90 days prior to the study are also to 
be recorded.
Rationale: To state that although the form used to record concomitant substances use includes alcohol, nicotine, and 
illicit substances, only nicotine data will be analyzed.
9.7.3. Concomitant Substances 
Questions
Removed “alcohol” and “illicit substances” from analysis.
Rationale: To clarify the approximate number of subjects entering the Transition/Maintenance Phases
3.1. Overview of Study Design
11.2. Sample Size Determination
Revised the following text as follows: “The approximate participation targets are 
903 subjects entering the Screening Phase, 765 subjects entering the 
Transition/Maintenance Phases, and 549 subjects entering the Double-blind 
Phase.”
Revised the following text as follows: “Given these assumptions for 
discontinuation, the study targets approximately 765 subjects to enter the 
Transition/Maintenance Phases.”
Rationale: To include measurements of thyroid stimulating hormone to the Serum Chemistry Panel
9.4.2. Clinical Laboratory Tests
Added thyroid stimulating hormone to the Serum Chemistry Panel. 
Rationale: Improvements in the conduct of the protocol.
Throughout the protocol 
Changes for consistency between sections and for clarification were made that 
had no impact on safety.


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Amendment 1 (21 March 2018)
This amendment is considered to be nonsubstantial 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, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reasons for the amendment:
to clarify which version of the Columbia Suicide Severity Rating Scale (C-SSRS) will be used at the 
screening and baseline visits, and all other visits;
to update the visit window for Visit 3 to avoid overlap with Visit 2;
to clarify that an alcohol breath test, and not a saliva test, will be performed to test for concomitant 
substances;
Figure 1 was updated;
to clarify that vital signs to be collected every 3 months (Q3) during double-blind (DB) phase;
to minimize risk of fetal exposure to study drug;
to remove renal insufficiency as part of exclusion criterion #7;
to prevent unnecessary exclusion of patients with gaps in historical medical documents;
to include exclusion criterion #26 as per Food and Drug Administration (FDA) request for clarification;
to maximize patient safety, exclude clinically unstable patients, and align with the R092670PSY3011 
protocol;
the first 3 bullets in Section 2.1.2.2 (Relapse Criteria) were previously in a different order and are now 
included in Section 4.3 (Criteria For Entry Into the Maintenance Phase) and in Section 4.4 (Criteria For 
Entry Into the Double-blind Phase);
to include risperidone 3 mg/day as a valid alternative at an equivalent dose in countries for which the 
paliperidone extended-release (ER)/prolonged-release (PR) formulations are not available;
to include additional text to the section subtitle, to clarify the frequency of prestudy Risperdal injections,
and to clarify that subjects taking branded long-acting injectables (LAI) of risperidone or paliperidone 
palmitate will be permitted to enter this phase of the study;
to clarify that the actual dates and times of electrocardiogram (ECG) and laboratory tests are not recorded 
in electronic case report form (eCRF);
to update text in the protocol for clarity and consistency with Time and Events Schedules;
to provide clearer guidance on timing of the end-of-phase (EOP) visit;
to clarify text to include an accurate description of the Satisfaction With Participation in Social Roles 
Short Form 8a (SPSR), and to allow flexibility for regions to begin enrollment despite lack of translation 
availability;
to modify text to prevent the risk of unblinding study treatment while collecting prolactin samples for 
clinical laboratory testing;
to update Attachment 1 with clear instructions regarding the administration of injection;
to remove controlling stratification by the maintenance dose level in the primary efficacy analysis; and
to add a formula to clarify the calculation of percent change of total PANSS score.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify which version of the C-SSRS will be used at the screening and baseline visits, and all other 
visits.


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Applicable Section(s)
Description of Change(s)
Synopsis, Safety 
Evaluations; Time and 
Events Schedules –
Section A.i. Subjects 
with prestudy PP1M or 
PP3M stability;
Section A.ii. Subjects 
without prestudy PP1M 
or PP3M stability; 
Section E. Keys and 
Footnotes (for All Time 
and Events Schedules)
In Sections A.i. (Subjects with prestudy PP1M or PP3M stability), A.ii. (Subjects 
without prestudy PP1M or PP3M stability), and E (Keys and Footnotes [for All Time 
and Events Schedules]), the following footnote was modified for C-SSRS 
(strikethrough text deleted):
m. The C-SSRS is administered as the "Baseline" version during screening and as the 
"Since Last Visit" version at all other visits.  At the patients first study visit, the 
C-SSRS Baseline/Screening Form will be used; for all other visits, the C-SSRS Since 
Last Visit Form will be used.
Removed the other visits in this row (Sections A.i and A.ii) and X, once before first 
dose (Section A.ii).
In Sections A.i. and A.ii., the Suicidality (C-SSRS)f,m row has been changed to 
Suicidality (C-SSRS Baseline/Screening)f,m, and added a row to include Suicidality 
(C-SSRS Since Last Visit)f,m for all other visits.
The following text was modified in the Synopsis (Safety Evaluations)(bold text 
added):
The study's standard safety evaluations will be physical examinations, vital signs, 
adverse events, electrocardiograms (ECGs), the Columbia Suicide Severity Rating 
Scale (C-SSRS Baseline/Screening and C-SSRS Since Last Visit), the Abnormal 
Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the 
Simpson Angus Scale (SAS), clinical laboratory assessments (in full [including 
prolactin] at some time points, or for prolactin only at other time points), and injection 
site evaluations.
Rationale: To update the visit window for Visit 3 to avoid overlap with Visit 2.
Time and Events
Schedules –
Section A.i. Subjects 
with prestudy PP1M or 
PP3M stability
In the Time and Events Schedules (Section A.i, For Subjects with prestudy PP1M or 
PP3M stability), the visit window was changed from ±2 days to -1 to +2 days for 
Visit 3.
Rationale: To clarify that an alcohol breath test, and not a saliva test, will be performed to test for concomitant 
substances.


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Applicable Section(s)
Description of Change(s)
Time and Event 
schedule- Section E-
Keys and Footnotes; 
9.1. Study Procedures; 
9.4.2. Clinical 
Laboratory Tests; 15. 
Study Specific 
Materials
The following text was modified in footnote e (bold text added; deleted text 
strikethrough):
e. These tests for concomitant substances (both an saliva test for alcohol breath test
and a urine drug screen for illicit substances), including marijuana (even where legal). 
Alcohol and illicit substances are strongly discouraged but are not exclusionary and 
are not cause for withdrawal from the study.
The following text was modified in footnote f (bold text added; deleted text 
strikethrough):
f. In addition to the indicated visits, suspected relapses during the Double-blind Phase 
should prompt all of the following assessments at all associated clinic visits, even if 
not designated on these schedules: a pharmacokinetics (PK) sample, the biomarker 
samples (plasma and serum for all subjects, and saliva for subjects who are 
participating in that optional part of the study), a full PANSS assessment, a CGI-S 
assessment, a C-SSRS assessment, and testing for concomitant substances (both an 
saliva test for alcohol breath test and a urine drug screen for illicit substances).
In Section 9.1 (Study Procedures), the following bullet point text was modified (bold 
text added; deleted text strikethrough):
Testing for concomitant substances (both an saliva test for alcohol breath test and a 
urine drug screen for illicit substances), per Section 9.4.2 (Clinical Laboratory Tests).
In Section 9.4.2 (Clinical Laboratory Tests), the following bullet point text was 
modified (bold text added; deleted text strikethrough):
Urine drug screen kits (for illicit substances, including marijuana, even where legal) 
and alcohol saliva test kits breath tests will be provided for local use at the time 
points specified in the Time and Events Schedules.
In Section 15 (Study Specific Materials), the following bullet point text was modified 
(bold text added; deleted text strikethrough):
Alcohol breath testSaliva alcohol test kit
Rationale: Figure 1 was updated.
3.1. Overview of Study 
Design
Replaced Figure 1 with a new figure.
Rationale: To clarify that vital signs to be collected Q3 during DB phase.
Time and Events
Schedules, Section B.
Double-blind Phase 
(First 12 Months);
Section C. Double-
blind Phase (After the 
First 12 Months)
In the Time and Events Schedules, vital signs measurements (body weight and waist 
circumference) were added to Visit 13 (Section B, Double-blind Phase [First 12 
Months]), and also to Visit 39 (Section C, Double-blind Phase [After the First 12 
Months]).  
Rationale: To minimize risk of fetal exposure to study drug.


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Applicable Section(s)
Description of Change(s)
4.1. Inclusion Criteria
The note following inclusion criterion #10 was modified (bold text added; deleted text 
strikethrough):
10. Criterion modified per Amendment 1
10.1…
Note: If the childbearing potential changes after start of the study or the risk of 
pregnancy changes (eg. A woman who is not heterosexually active becomes sexually 
active) a woman must begin consent to starting a highly effective method of 
contraception as described throughout this inclusion criterion after a negative 
pregnancy test. If reproductive status is questionable, additional evaluation 
should be considered. If the subject declines consent for start of a highly effective 
method of contraception, the subject must be withdrawn from the study.
Rationale: To remove renal insufficiency as part of exclusion criterion #7.
Synopsis, Subject 
Population; 4.2. 
Exclusion Criteria
The following text was modified in the Synopsis (Subject Population) and under 
exclusion criterion #7 (bold text added; deleted text strikethrough):
7. Criterion modified per Amendment 1
7.1 Must not have a clinically significant and unstable medical illness in history or at 
screening, including (but not limited to) cardiac arrhythmias or other cardiac disease, 
hematologic disease, coagulation disorders (including any abnormal bleeding or blood 
dyscrasias), significant pulmonary disease including bronchospastic respiratory 
disease, diabetes mellitus (poorly controlled or requiring insulin), renal or hepatic 
insufficiency, thyroid disease (poorly controlled based on recent thyroid stimulating 
hormone [TSH] level),
Rationale: To prevent unnecessary exclusion of patients with gaps in historical medical documents.  
4.2. Exclusion Criteria
The following text was modified in exclusion criterion #12 (bold text added;
strikethrough text deleted):
12. Criterion modified per Amendment 1
12.1 Must not have a history of treatment resistance, defined as failure to respond to 2 
adequate trials with adequate doses of different antipsychotic medications (where an 
adequate trial is defined as a minimum of 4 weeks at a therapeutic dosage)., based on 
the available medical records. Final determination of eligibility is based on 
investigator judgment.
Rationale: To include exclusion criterion #26 as per FDA request for clarification.
4.2. Exclusion Criteria
The following bullet point text was added to exclusion criterion #26:
Must not have moderate to severe renal impairment (ie, creatinine clearance, as 
estimated by the Cockcroft-Gault method, of <60 mL/min).
Rationale: To maximize patient safety, exclude clinically unstable patients, and align with the R092670PSY3011
protocol.


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Applicable Section(s)
Description of Change(s)
4.2. Exclusion Criteria; 
8.3. Prohibited 
Concomitant 
Medications
The following bullet point text was included in exclusion criterion #27:
Subjects must not have the following:
-Electroconvulsive therapy (ECT) within 60 days before screening
-Nonselective/irreversible monoamine oxidase inhibitors (MAOI) antidepressants 
within 30 days prior to screening.
-Other antidepressants unless at a stable dosage for 30 days before screening (If the 
dosage has been stable for less than 30 days and the subject does not require the 
antidepressant, it can be washed out by the baseline visit; if the dosage has been stable 
for less than 30 days and the subject requires antidepressant treatment, the subject 
should not be included in this study).
The following bullet point text was included in exclusion criterion #28:
Must not be concomitantly treated with mood stabilizers including lithium, or 
valproate, or other antiepileptics/anticonvulsants within 14 days of the first screening 
visit.
The exclusion criterion #29 was added:
Must not have been treated with a dopamine agonist (eg, ropinirole or pramipexole) 
within 90 days of the first screening visit.
The following bullet point text was included in Section 8.3 (Prohibited Concomitant 
Medications):
-
Mood stabilizers and anticonvulsants including, but not limited to: lithium, 
valproate, lamotrigine, carbamazepine, phenytoin, and gabapentin.
-
Antidepressants not taken at a stable dosage for 30 days before screening, and all 
nonselective/irreversible MAOIs. Throughout the study, an antidepressant (other than 
a nonselective MAOI) may be initiated in rare circumstances only after consultation 
with the Medical Monitor. 
-
Any prescription, herbal, or over-the-counter agents with psychotropic actions 
including any substances with stimulant and cognitive-enhancing properties.
-
Dopamine agonists, including, but not limited to: ropinirole, pramipexole, 
pergolide, cabergoline, and lisuride.
Rationale: The first 3 bullets in Section 2.1.2.2 (Relapse Criteria) were previously in a different order and are 
now included in Section 4.3 (Criteria For Entry Into the Maintenance Phase) and in Section 4.4 (Criteria For 
Entry Into the Double-blind Phase).


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Applicable Section(s)
Description of Change(s)
4.3. Criteria For Entry 
Into the Maintenance 
Phase; 4.4. Criteria For 
Entry Into the Double-
blind Phase
The following text was modified in Section 4.3 (Criteria For Entry Into the 
Maintenance Phase)(bold text added; strikethrough text deleted):
3. For subjects proceeding from the Transition Phase to the Maintenance Phase, they 
must not have during the Transition Phase: met any of the first 3 bullet points in 
Section 2.1.2.2 (Relapse Criteria) during the Transition Phase
a. required psychiatric hospitalization (involuntary or voluntary admission to a 
psychiatric hospital for decompensation of the subject’s schizophrenic 
symptoms), or 
b. inflicted deliberate self-injury or exhibited violent behavior resulting in 
suicide, clinically significant injury to him/her self or another person, or 
significant property damage, or
c. had suicidal or homicidal ideation and aggressive behavior that is clinically 
significant (in frequency and severity) in the investigator’s judgment
The following text was modified in Section 4.4 (Criteria For Entry Into the Double-
blind Phase)(bold text added; strikethrough text deleted):
5. Subjects must not have during the Maintenance Phase: met any of the first 3 
bullet points in Section 2.1.2.2 (Relapse Criteria) during the Maintenance Phase
The sub-bullet points presented in Section 4.3 (Criteria For Entry Into the 
Maintenance Phase) are also presented in Section 4.4 (Criteria For Entry Into the 
Double-blind Phase).
Rationale: Paliperidone ER/PR are not available in all study countries.  Risperidone 3 mg/day is a valid 
alternative at an equivalent dose.
6.1.1. Screening Phase
The following text was modified in Section 6.1.1 (Screening Phase) (bold text added; 
strikethrough text deleted):
To demonstrate oral tolerability, pPaliperidone ER/PR 6 mg tablets or risperidone 
3 mg/day (dose may be divided) will be given during the Screening Phase for 4 to 6 
consecutive days with the last dose swallowed on or before Day -1. The 
recommended dose is paliperidone ER/PR of 6 mg/day or risperidone 3 mg/day 
(dose may be divided), but higher doses of paliperidone or risperidone may be 
used if clinically indicated, based on investigator judgment.
Rationale: To include additional text to the section subtitle, to clarify the frequency of prestudy Risperdal 
injections, and to clarify that subjects taking branded LAI of risperidone or paliperidone palmitate will be 
permitted to enter this phase of the study.  


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Applicable Section(s)
Description of Change(s)
6.1.2. Transition Phase
The following subtitle was modified (bold text added):
Transition Phase: Subjects Previously Stabilized on Injectable Risperidone (Biweekly 
– Risperdal CONSTA™ formulation)
The following subtitle was modified and text was included (bold text added):
Transition Phase: Subjects Previously Initiated (But Not on a Stable Regimen) With 
Moderate or Higher Doses of PP1M (Invega Sustenna ™ or Xeplion ™ 
formulation)
In the Transition Phase, subjects who entered the study on PP1M as 100 or 150 mg 
eq., but who do not yet meet criteria for stabilization with those doses, are treated with 
additional doses of PP1M during the Transition Phase, as shown in Table 3.
Owing to potential differences in release characteristics, only subjects who are 
taking Invega Sustenna ™ or Xeplion ™ PP1M formulations will be permitted to 
enter this phase of the study. Subjects who are taking non-branded formulations 
of once monthly paliperidone LAI or other once monthly LAIs will not be 
permitted to enter this phase.
Rationale: Actual dates and times of ECG and laboratory tests are not recorded in eCRF. This information would 
be recorded by CROs.
9.1. Study Procedures
The following text was modified in Section 9.1 (Study Procedures, Overview)
(strikethrough text deleted):
Actual dates and times of assessments will be recorded in the source documentation.
and eCRF
Rationale: Text was updated in the protocol for clarity and consistency with Time and Events Schedule.
Time and Events
Schedule, Section D.
Follow-up Phase; 
11.5.7. Columbia 
Suicide Severity Rating 
Scale
The following text was added to the Time and Events Schedule (Section D, Follow-up 
Phase) (bold text added):
12, 18 or 24 Months after the Subject’s First Double-blind Injection (or at 6-Month 
Time Points Thereafter, if Applicable)
The following text was added to Section 11.5.7 (Columbia Suicide Severity Rating 
Scale) (bold text added):
C-SSRS Baseline/Screening Form will be used at screening. C-SSRS Since Last 
Visit Form will be used at other visits, as per Time and Events Schedules.  
Suicide-related thoughts and behaviors based on the C-SSRS scale will be summarized 
by treatment group in incidence and shift tables.  
Rationale: To provide clearer guidance on timing of the EOP visit.


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Applicable Section(s)
Description of Change(s)
Time and Events 
Schedule, Section C. 
Double-blind Phase 
(After the First 12 
Months); Section E. 
Keys and Footnotes 
(for All Time and 
Events Schedules)
In Section C, the visit window of the EOP visit was changed from “Variable” to 
“±7bb”.
The following text was modified in Section E, footnote aa (bold text added; 
strikethrough text deleted):
After completing the first 12 months of the Double-blind Phase, subjects who cannot 
proceed further in the Double-blind Phase (eg, if the study is closed) will complete the 
EOP Visit as an End-of-Study Visit. For subjects who can proceed to further treatment 
in the Double-blind Phase, Visit 33a is the same as Visit 33b, with the addition of 
another dose of study drug. Thereafter, subjects continue with this schedule until the 
Sponsor informs the sites that the study is closing, at which time subjects should be 
asked to return as soon as possible to the site for an EOP Visit, which becomes the 
End-of-Study Visit. The planned closure will be 12 months after the last subject has 
been randomized in the Double-blind Phase.  Refer to section 10.4 (Antipsychotic 
Therapy After the Study or in the Follow-up Phase) and 10.5 (Process for 
Planned Study Closure) for more information.
Footnote bb was added:
bb. For EOP visits occurring during study closure (ie, not a result of withdrawal or 
relapse), the visit window is specified as ±7 days.  In the event of study withdrawal or 
relapse, a visit window (in days) for the EOP visit is not specified but is to occur as 
soon as possible.
Rationale: Text was updated to include an accurate description of the SPSR Short Form 8a, and to allow 
flexibility for patient enrollment to begin in regions where translations are not yet available.
Time and Events 
Schedules, Section E. 
Keys and Footnotes; 
Synopsis, Efficacy 
Evaluations; 9.2.5. 
Satisfaction With 
Participation in Social 
Roles
In Section E, footnote u, the following text was added:
For subjects that require translation of the SPSR into their local language, the 
collection of the SPSR is optional until the final, approved translation is available.
The following text was modified in the Synopsis (Efficacy Evaluations) (bold text 
added; deleted text strikethrough):
Subject-reported efficacy evaluations include the Satisfaction With Participation in 
Social Roles scale Short Form 8a (SPSR) and the abbreviated 9-item Treatment 
Satisfaction Questionnaire for Medication (TSQM-9).
The following text was modified in Section 9.2.5 (Satisfaction With Participation in 
Social Roles) (bold text added; deleted text strikethrough):
The Patient-Reported Outcomes Measurement Information System (PROMIS) group 
developed and evaluated the Satisfaction With Participation in Social Roles scale
Short Form 8a (SPSR) with funding from the US National Institutes of Health (NIH) 
and other academic and research grants.15 A study in a diverse clinical population 
demonstrated the SPSR's responsiveness to change.15 The SPSR asks subjects to 
consider the past 7 days and to rate 14 8 items on 5-point Likert scales with higher 
scores representing higher satisfaction. An example of the SPSR is provided in the 
Manual of Assessments.
Note: For subjects that require translation of the SPSR into their local language, 
the collection of the SPSR is optional until the final, approved translation is 
available.


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Applicable Section(s)
Description of Change(s)
Rationale: To prevent the risk of unblinding study treatment while collecting prolactin samples for clinical 
laboratory testing.
9.4.2. Clinical 
Laboratory Tests
The following text was modified in Section 9.4.2 (Clinical Laboratory Tests)
(strikethrough text deleted):
-prolactin, which will be blinded to the study-site personnel and Sponsor except by 
request due to an adverse event; some samples will be for prolactin only (not the other 
analytes listed above), as designated in the Time and Events Schedules
Rationale: Because the choice of dose level in the maintenance was determined on the appropriate dose that 
subjects had been stabilized on, and which the investigators consider as appropriate from both efficacy and safety 
point of view, the KM curves analysis by treatment group is thus by regimen and not by individual dose level.  
This is consistent with the previous registration studies (R092670PSY3001, R092670PSY3011, and 
R092670PSY3012).
11.3.1.1.2. Primary 
Efficacy Analyses
The following sentence was removed in Section 11.3.1.1.2 (Primary Efficacy 
Analyses): 
The tests above are adjusted by the stratification factor used during randomization (for 
moderate or higher dose).
Rationale: To update Attachment 1 with clear instructions regarding the administration of injection.
Attachment 1
The following text was added to the Notes of the figure in Attachment 1:
Injections should be administered in the dorso-gluteal injection site only. 
Ventrogluteal injections are not permitted.
Rationale: To add a formula to clarify the calculation of percent change of total PANSS score.
Attachment 2
A formula for calculating percent change of total PANSS score was added.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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SYNOPSIS
A Double-blind, Randomized, Active-controlled, Parallel-group Study of Paliperidone 
Palmitate 6-Month Formulation
Paliperidone is a monoaminergic antagonist that exhibits the characteristic dopamine Type 2 and 
serotonin Type 2A antagonism of the newer, or second-generation, atypical antipsychotic medications. 
Paliperidone is the active metabolite of risperidone and is available as a daily-dose oral formulation. 
Paliperidone palmitate is an ester of paliperidone, and is available for intramuscular injection in the 
paliperidone palmitate 1-month (PP1M) product as the F013 formulation and the paliperidone palmitate 
3-month (PP3M) product as the F015 formulation. To further improve adherence and convenience, a 
paliperidone palmitate 6-month (PP6M) product is now under development.
 
 
 (ie, PP3M may be administered into either the deltoid or the 
gluteal muscle, but the larger volume associated with a PP6M dose requires injection into the larger 
gluteal muscle).
Doses can be expressed in milligrams of paliperidone palmitate or in milligrams equivalent (mg eq.) to 
paliperidone. Conversions between products and between units are described in the table below.
Conversions Between Doses of the 1-, 3-, and 6-Month Formulations of Paliperidone Palmitate; Study R092670PSY3015
PP1M Dose
PP3M Dose
PP6M Dose
mg
mg eq.
mg
mg eq.
mg
mg eq.
Lowest-dose groups a
78 mg
50 mg eq.
Not used in this study
- - - - Not available - - - -
Lower-dose groups
117 mg
75 mg eq.
Not used in this study
- - - - Not available - - - -
Moderate-dose groups
156 mg
100 mg eq.
546 mg
350 mg eq.
1092 mg
700 mg eq.
Higher-dose groups
234 mg
150 mg eq.
819 mg
525 mg eq.
1560 mg
1000 mg eq.
Key: mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); PP1M = paliperidone palmitate 1-month 
(product); PP3M = paliperidone palmitate 3-month (product); PP6M = paliperidone palmitate 6-month (product).
a
Some countries may also have an ultralow dose of PP1M (below the lowest dose stated here), but the ultralow dose is not 
used in this study.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective

The primary efficacy objective is to demonstrate that injection cycles consisting of a single 
administration of PP6M (700 or 1000 mg eq.) are not less effective than 2 sequentially administered 
injections of PP3M (350 or 525 mg eq.) for the prevention of relapse in subjects with schizophrenia 
previously stabilized on corresponding doses of PP1M (100 or 150 mg eq.) or PP3M (350 or 
525 mg eq.).
Secondary Objectives

To evaluate the safety and tolerability of PP6M (700 or 1000 mg eq.) in subjects with schizophrenia 
who have switched from corresponding doses of PP1M (100 or 150 mg eq.) or PP3M (350 or 
525 mg eq.).

To assess the pharmacokinetic (PK) profile of PP6M (700 or 1000 mg eq.) administered in the 
gluteal muscle in subjects with schizophrenia who have switched from corresponding doses of PP1M 
(100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

To evaluate the clinically assessed efficacy of PP6M (700 or 1000 mg eq.) versus PP3M (350 or 
525 mg eq.) in maintaining symptom control, functioning personally and socially, and achieving or 
CCI


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sustaining remission in subjects with schizophrenia who were previously stabilized on corresponding 
doses of PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

To evaluate the subject-reported efficacy outcomes of PP6M (700 or 1000 mg eq.) or PP3M (350 or 
525 mg eq.) compared with treatment with previous oral antipsychotics in terms of satisfaction with 
medication and with participation in social roles.
Exploratory Objectives
Exploratory objectives are also defined in the full protocol, but are excluded from this synopsis for 
brevity.
Endpoints
Primary Endpoint
The primary endpoint is time to relapse during the Double-blind Phase. This noninferiority primary 
endpoint will be based on the difference in Kaplan-Meier 12-month estimate of survival (ie, percentage of 
subjects remaining relapse-free) between PP6M and PP3M.
Relapse Criteria
Relapse is defined as 1 or more of the following:

Psychiatric hospitalization (involuntary or voluntary admission to a psychiatric hospital for 
decompensation of the subject’s schizophrenic symptoms), or

For Positive and Negative Syndrome Scale for Schizophrenia (PANSS) total score:

The subject has an increase of 25% in total PANSS score from randomization for 2 consecutive 
assessments separated by 3 to 7 days if the score at randomization was >40, or

The subject has a 10-point increase in the total PANSS score from randomization for 
2 consecutive assessments separated by 3 to 7 days if the score at randomization was ≤40, or

The subject inflicts deliberate self-injury or exhibits violent behavior resulting in suicide, clinically 
significant injury to him/her self or another person, or significant property damage, or 

The subject has suicidal or homicidal ideation and aggressive behavior that is clinically significant 
(in frequency and severity) in the investigator’s judgment, or

For PANSS items P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behavior), 
P6 (suspiciousness/persecution), P7 (hostility), and G8 (uncooperativeness):

The subject has a score of ≥5 after randomization for 2 consecutive assessments separated by 
3 to 7 days on any of the above items if the maximum score for the above PANSS items was ≤3 
at randomization, or

The subject has a score of ≥6 after randomization for 2 consecutive assessments separated by 
3 to 7 days on any of the above items if the maximum score for the above PANSS items was 4 
at randomization.
The date of the relapse will be the date of the first assessment for symptoms of relapse (not the date of 
confirmation).
Secondary Endpoints
The secondary efficacy endpoints include the changes from baseline during the 12-month Double-blind 
Phase in the following scales: the PANSS total score and subscale scores, the Clinical Global Impression 
- Severity (CGI-S), and the Personal and Social Performance (PSP) scale. Additionally, the proportion of 


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subjects during the Double-blind Phase who meet criteria for symptomatic remission will be summarized; 
the definition of remission is provided in the full protocol.
The secondary PK endpoint is plasma paliperidone exposure.
The secondary endpoints for satisfaction with medication and with participation in social roles are 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) and Satisfaction with 
Participation in Social Roles (SPSR), respectively.
The secondary endpoints that measure safety and tolerability include physical examinations, vital signs, 
adverse events, electrocardiograms (ECGs), the Columbia Suicide Severity Rating Scale (C-SSRS 
Baseline/Screening and C-SSRS Since Last Visit), the Abnormal Involuntary Movement Scale (AIMS), 
the Barnes Akathisia Rating Scale (BARS), the Simpson Angus Scale (SAS), clinical laboratory 
assessments (in full [including prolactin] at some time points, or for prolactin only at other time points), 
and injection site evaluations.
Hypothesis
The primary hypothesis is that the efficacy of PP6M is noninferior to PP3M for preventing relapse in 
subjects with schizophrenia who were previously stabilized on corresponding doses of PP1M or PP3M.
SUBJECT POPULATION
Eligibility criteria are presented as a detailed list in the full protocol. A few important highlights are 
presented here in the synopsis:

Must be 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking 
place) to 70 years of age, inclusive, at the time of informed consent.

Must meet the diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) for at least 6 months before screening.

Must be receiving treatment with paliperidone palmitate (as either the PP1M or PP3M formulation), 
or injectable risperidone, or any oral antipsychotic.
a. If the treatment is paliperidone palmitate, then:
1) The dose strength must be PP1M as 100 or 150 mg eq. or PP3M as 350 or 525 mg eq.
2) The dose timing must fit the study schedule. The next injection must be due within 28 days of 
the first screening (or first rescreening) visit.
b. If the treatment is injectable risperidone, then the dose strength must be 50 mg, the dosing cycle 
must be every 2 weeks, the efficacy and tolerability must have been established as adequate with 
the same strength and frequency for at least 3 injection cycles before screening, and the subject 
must have a preference for a longer-acting injectable medication.
c. If the treatment is an oral antipsychotic, then the subject must have a valid reason to discontinue 
the previous treatment, such as problems with efficacy, safety, or tolerability, or preference for a 
long-acting injectable medication.

Criterion modified per Amendment 1

7.1 Must not have a clinically significant and unstable medical illness in history or at screening,
including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, 
coagulation disorders (including any abnormal bleeding or blood dyscrasias), significant pulmonary 
disease including bronchospastic respiratory disease, diabetes mellitus (poorly controlled or 
requiring insulin), hepatic insufficiency, thyroid disease (poorly controlled based on recent thyroid 


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stimulating hormone [TSH] level), neurologic or other psychiatric disease (except schizophrenia), 
infection, cancer, or any other illness that the investigator considers should exclude the subject or 
that could interfere with the interpretation of the efficacy or safety measurements.
If a subject does not meet all inclusion criteria (is a screen failure) with respect to dose level, dose 
duration, or dose timing of prestudy treatment with paliperidone palmitate or injectable risperidone, but at 
some point in the future is expected to meet these inclusion criteria, then the subject may be rescreened on 
1 occasion. If a subject meets any exclusion criteria (is a screen failure) with respect to safety parameters,
then rescreening is not allowed.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, active-controlled, multicenter, interventional, parallel-group study. 
All eligible subjects who progress without relapse will participate in a Screening Phase (of up to 28 days), 
a Maintenance Phase that includes 1 injection cycle with either PP1M or PP3M (yielding a phase duration 
of 1 or 3 months, accordingly), and a Double-blind Phase (of 12 months). The Double-blind Phase is 
designed to include 2 injection cycles of PP6M (investigational drug with alternating placebo) or 
4 injection cycles of PP3M (active control). In addition to standard participation as described above, 
further conditional/additional participation is possible as follows:

Before the Maintenance Phase, some subjects will participate in a Transition Phase, with 1 to 
5 injections of PP1M, if they entered the study on an oral antipsychotic, on injectable risperidone, or 
on PP1M previously initiated but not yet stabilized.

The planned closure will be 12 months after the last subject has been randomized in the Double-
blind Phase.

If a subject has already received at least 1 dose of double-blind study drug but then has relapsed or 
has met other relevant conditions for withdrawal or discontinuation, then the subject should enter a
Follow-up Phase. The Follow-up Phase ends 12 months after the subject's first double-blind 
injection. The Follow-up Phase collects supplementary poststudy data from willing affected subjects, 
in an effort to document minimum safety information (ie, adverse events) and minimum efficacy 
information (ie, relapse status). The Follow-up Phase is designed to be as low-burden and 
noninvasive as possible, in order to encourage participation by the affected subjects.
The duration of exposure to study drug (ie, the number of injections) and the duration of study 
participation are variable based on a subject's flow through treatment types, on participation in conditional 
phases or parts as described in the 3 bullet points above, and on whether a subject experiences a relapse 
during the study.
For subjects who complete the study without relapse, the longest expected duration is ~19 months and the 
shortest expected duration is ~13 months, as described in the full protocol. For subjects who complete the 
study with relapse, the duration of exposure and participation depend on the timing of the relapse, and 
could even be (for example) only ~2 months of injections with a variable duration of assessments 
thereafter, as described in the full protocol.
DOSAGE AND ADMINISTRATION
Dosage: Screening Phase
During the Screening Phase, subjects must have already been receiving PP1M at 100 or 150 mg eq., 
PP3M at 350 or 525 mg eq., injectable risperidone at 50 mg, or an oral antipsychotic at any dosage with a 
reason to change, as described in the inclusion criteria.


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Dosage: Transition Phase
The Transition Phase is applicable only to subjects who entered the Screening Phase without previous 
PP1M or PP3M stability. These subjects may have been previously treated with oral antipsychotics,
injectable risperidone, or a moderate or higher dose of PP1M with previous initiation but without
previous stabilization (where stabilization is defined is at least 3 months of injections with the last 2 doses 
being the same strength). A table in the full protocol provides further information about the PP1M 
administration schedule for subjects who participate in the Transition Phase.
Dosage: Maintenance Phase
For all subjects, the Maintenance Phase includes only 1 dose of PP1M as 100 or 150 mg eq. or PP3M as 
350 or 525 mg eq. Each subject's Maintenance Phase dose will be matched by straightforward progression 
(PP1M to PP1M, or PP3M to PP3M) or will be matched by established conversion (PP1M to PP3M) to 
the same dose that they had been receiving during the Screening Phase or at the end of the Transition
Phase. Progression versus conversion will depend on prestudy treatment types and on the need to balance 
the PP1M and PP3M groups in the Maintenance Phase, as described in the full protocol.
Dosage: Double-blind Phase
The PP1M and PP3M dose levels that were administered in the Maintenance Phase will be converted to 
PP3M or PP6M dose levels for the Double-blind Phase as follows:

For the active control group,

The open-label PP1M doses (100 or 150 mg eq.) will be converted to double-blind PP3M doses 
(350 or 525 mg eq.) in accordance with the approved prescribing information for PP3M.

The open-label PP3M doses (350 or 525 mg eq.) will continue at the same double-blind dose 
level.

For the investigational drug group,

The open-label 100 mg eq. PP1M and 350 mg eq. PP3M doses will be converted to double-
blind 700 mg eq. PP6M doses.

The open-label 150 mg eq. PP1M and 525 mg eq. PP3M doses will be converted to double-
blind 1000 mg eq. PP6M doses.
To maintain the blind, the subjects who are assigned to treatment with PP6M will receive injections of 
placebo at the 3-month time points between their 6-month doses of investigational drug. The placebo is 
20% Intralipid® (200 mg/mL) injectable emulsion. Therefore, the Double-blind Phase should include a 
total of 4 doses at 3-month intervals, no matter which treatment group.
Administration
During the Transition Phase and Maintenance Phase, injections will be in the deltoid or gluteal muscles in 
accordance with the prescribing information for PP1M or PP3M, and will use injection kits equivalent to 
commercially available kits. During the Double-blind Phase, injections will be in the gluteal muscles
only, will use study-specific injection kits, and will rotate across sides of the body as described in the full 
protocol.
PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATIONS
Venous blood samples of approximately 4 mL will be collected to obtain approximately 2 mL of plasma, 
for measurement of plasma concentrations of paliperidone (and on selected samples, paliperidone 
palmitate). The aim of the PK evaluations will be to characterize the time course of plasma paliperidone 
concentrations and PK parameters such as maximum and minimum plasma concentrations and timing. 


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Therefore, 3 PK samples are scheduled weekly around the expected paliperidone peak at approximately 1 
month after the PP6M dose, and 6 PK samples are scheduled weekly when approaching the end of the 
6-month dosing interval. For paliperidone palmitate, PK evaluations will be performed on samples
collected 2 days after the injections indicated in the Time and Events Schedules, to check for any prodrug 
in the bloodstream from possible partial intravascular injections.
In addition to PK sampling time points indicated in the Time and Events Schedules, sites should collect 
unscheduled PK samples associated with important efficacy or safety events, as described in the full 
protocol.
EFFICACY EVALUATIONS
The clinically assessed efficacy evaluations include the PANSS (full and abbreviated), the CGI-S, the 
PSP scale, and other relapse criteria as described above. Subject-reported efficacy evaluations include the 
Satisfaction With Participation in Social Roles Short Form 8a (SPSR) and the abbreviated 9-item 
Treatment Satisfaction Questionnaire for Medication (TSQM-9).
SAFETY EVALUATIONS
The study's standard safety evaluations will be physical examinations, vital signs, adverse events, 
electrocardiograms (ECGs), the Columbia Suicide Severity Rating Scale (C-SSRS Baseline/Screening 
and C-SSRS Since Last Visit), the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia 
Rating Scale (BARS), the Simpson Angus Scale (SAS), clinical laboratory assessments (in full [including 
prolactin] at some time points, or for prolactin only at other time points), and injection site evaluations. In 
addition those standard evaluations, conditional evaluations also are described for special safety situations
that may occur; these include evaluations of injection site reactions or evaluations associated with 
initiations or changes in concomitant medications to manage extrapyramidal symptoms (EPS).
EXPLORATORY EVALUATIONS
Exploratory evaluations are described in the full protocol, they are excluded from this synopsis for 
brevity.
STATISTICAL METHODS
Sample Size Determination
The sample size for the Double-blind Phase of the study is 549 randomized subjects, based on 
determinations to provide a minimum of 80% power for the primary endpoint. The sample size 
determination includes the assumptions that the expected survival rate (percentage of subjects remaining 
relapse-free at 12 months) in the PP3M group is 85%, and that the 1-sided significance level should be 
2.5%. Given these assumptions, 549 subjects randomized in a 2:1 ratio (PP6M:PP3M) are required to 
demonstrate with 80% power that PP6M is no worse than PP3M by a noninferiority margin of 10% for 
the percentage of subjects remaining relapse-free at 12 months. This assumes that the efficacy observed in 
the PP3M group will be similar to the efficacy observed in the previous PP3M registrational Phase 3 
studies (R092670PSY3011 and R092670PSY3012).
Pharmacokinetic and Pharmacodynamic Analyses
Descriptive statistics will be calculated for the plasma concentrations of paliperidone and paliperidone 
palmitate and for the derived PK parameters, as applicable. Statistics will include sample size, mean, 
standard deviation, coefficient of variation, geometric mean, median, minimum, and maximum.
Population PK analysis of plasma concentration-time data of paliperidone will be performed using 
nonlinear mixed-effects modeling for PP6M, possibly using models previously developed from PP3M 
studies.


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Efficacy Analyses
Primary Efficacy
The primary endpoint is time to relapse in the Double-blind Phase, as described above. Subjects who meet 
at least 1 of the criteria for relapse (as also described above) during the Double-blind Phase at the time of 
study completion for the primary analysis will be considered to have had a relapse event. Subjects who do 
not have a relapse event in the Double-blind Phase will be considered as censored. The statistics to test 
the primary hypothesis are based on the percentage of subjects who remain relapse-free at Month 12 in 
the PP6M and PP3M groups per Kaplan-Meier estimate for the Double-blind Phase. The analysis will 
consider whether the lower limit of the 95% confidence interval of the difference in relapse-free rates 
between PP6M and PP3M exceeds the noninferiority margin of -10%. Further details are provided in the 
full protocol.
Secondary Efficacy
Clinically assessed secondary efficacy analyses include maintaining symptom control, functioning 
personally and socially, and achieving remission in each group (PP6M or PP3M, each sorted by dose 
level); further details about these analyses are provided in the full protocol. Subject-reported secondary 
efficacy analyses include analyses of the SPSR and the TSQM-9; further details about these analyses may
be detailed in a separate document.
Safety Analyses
Descriptive statistics, summaries, tabulations, listings, etc will be provided for each outcome as 
appropriate. Analyses will follow precedents per previous studies of PP3M and per established guidelines 
from Health Authorities.
Exploratory Analyses
Exploratory analyses are described in the full protocol, but are excluded from this synopsis for brevity.
END OF STUDY
A subject will be considered as having completed the study if he or she has had a relapse during the 
Double-blind Phase and has completed all End-of-Study Visit assessments, or has remained relapse-free 
during the Double-blind Phase and has completed all End-of-Study Visit assessments. The study is 
considered completed with the last visit for the last subject participating in the study. 


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TIME AND EVENTS SCHEDULES
A.
Screening, Transition, and Maintenance Phases
A.i.
Subjects With Prestudy PP1M or PP3M Stability
Phase Screening
Maintenance Phase:
PP1M or PP3M
EOP s
Visit Number (of Study)
1
2
3
4
5
6
7a s
Day (of Phase), if Maintenance Phase is PP3M
-28 to -2
1
3
15
30
60
90
Day (of Phase), if Maintenance Phase is PP1M
-28 to -2
1
3
8
15
22
30
Visit Window, ±Days
n/a
-1 to +2
±3
±3
±3
±3
Screening/administrative
Main ICF a
X
Optional ICF for caregiver
X
Inclusion/exclusion criteria b
X
X
Medical history and demographics
X
Pregnancy test c
X
X
X
Prestudy therapy
X d
Concomitant therapy
- - - - - - - - - - - Continuous - - - - - - - - - - -
Concomitant substance testing e,f and questions
X
X
X
Dosing
PP3M (after prestudy PP3M stability)
X g
PP3M (after prestudy PP1M stability, before PP3M prerandomization
target)
X g
PP1M (after prestudy PP1M stability, after PP3M prerandomization 
target)
X g
Safety assessments
Physical examinations h
X
X
Vital signs i
X
X
12-lead ECGs j
X X
X
X
Assessments of injection site k
X
X
X
X k
EPS assessments (AIMS, BARS, SAS) l
X
X
X
X
Suicidality (C-SSRS Baseline/Screening) f,m
X
Suicidality (C-SSRS Since Last Visit) f,m
X
X
X
X
Adverse events
- - - - - - - - - - - Continuous - - - - - - - - - - -
Efficacy assessments
Full PANSS f + CGI-S f
X
X
X
X
Abbreviated PANSS n + CGI-S
X
X
PSP
X
X
X
Collection of biofluids
Blood for hematology and serum chemistry
X o
X o
Urinalysis
X
X
Blood for pharmacokinetics f,p
X q
X
X
X
X
X
Additional exploratory assessments
HRU questionnaire, r IEQ, r SQLS
X
X


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A.ii.
Subjects Without Prestudy PP1M or PP3M Stability
Phase Screening
Transition Phase
Maintenance Phase:
PP1M or PP3M
EOP s
Visit Number (of Study)
1
2a
2b
2c
2d
2ez
2f
3
4
5
6
7a s
Day (of Phase), if Maintenance Phase is PP3M
-28 to -2
1
8
36
64
92
1 u
3
15
30
60
90
Day (of Phase), if Maintenance Phase is PP1M
-28 to -2
1
8
36
64
92
1 u
3
8
15
22
30
Visit Window, ±Days
n/a
±3
±7
±7
± 7
±3
-1 to +2
±3
±3
±3
±3
Screening/administrative
Main ICF a
X
Optional ICF for caregiver
X
Inclusion/exclusion criteria b
X
X
Medical history and demographics
X
Pregnancy test c
X
X
X
Prestudy therapy
X d
Concomitant therapy
- - - - - - - - - - - - - - - - - - - - Continuous - - - - - - - - - - - - - - - - - - - -
Concomitant substance testing e,f and questions
X
X
X
Oral tolerability test
X or n/a
Dosing: Transition Phase v
PP1M (after prestudy oral antipsychotic)
X
X
X
X
X
n/a
PP1M (after prestudy injectable risperidone)
n/a
X
X
X
X
n/a
PP1M (after 2 prestudy PP1M injections)
n/a n/a
X
X
X
n/a
PP1M (after 3 prestudy PP1M injections)
n/a n/a n/a
X
X
n/a
PP1M (after ≥4 prestudy PP1M injections)
n/a n/a n/a n/a
X
n/a
Dosing: Maintenance Phase
PP3M (before PP3M prerandomization target)
n/a
X g
PP1M (after PP3M prerandomization target)
n/a
X g
Safety assessments
Physical examinations h
X
X
Vital signs i
X
X
12-lead ECGs j
X X
X, once before first dose
X
X
Assessments of injection site k
X, after every dose
X
X
X
X k
EPS assessments (AIMS, BARS, SAS) l
X
X, once before first dose
X
X
X
Suicidality (C-SSRS Baseline/Screening) f,m
X
Suicidality (C-SSRS Since Last Visit) f,m
X
X
X
X
Adverse events
- - - - - - - - - - - - - - - - - - - - Continuous - - - - - - - - - - - - - - - - - - - -
Efficacy assessments
Full PANSS f + CGI-Sf
X
X, once before first dose
X
X
X
Abbreviated PANSS n + CGI-S
X
X
PSP
X
X, once before first dose
X
X
Subject-reported: TSQM-9 and SPSR t
X
X
Collection of biofluids
Blood for hematology and serum chemistry
X o
X o
Urinalysis
X
X
Blood for pharmacokinetics f,p
X q
X
X
X
X
X
Additional exploratory assessments
HRU questionnaire, r IEQ, r SQLS, and IMR scale 
t
X
X


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B.
Double-blind Phase (12 Months)
Phase
Double-blind Phase (12 Months): PP3M or PP6M
Visit Number (of Study) 7b s
8
9
10
11
12
13
14
15
16
17
18
19
20 to 32
EOP/33a-
Day (of Phase)
1
3
22
29
36
60
92
120 148 155 162 169 176
183 to 358
365
Visit Window, ±Days ±3
-1 to 
+3
±3
±3
±3
±7
±7
±7
±3
±3
±3
±3
±3
Same as Previous 6-Month Cycle
±7Error! 
Reference source 
not found.
Screening/administrative
Pregnancy test c
X
Same as previous 6-month cycle
X
Concomitant therapy
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Concomitant substance testing e,f and questions
X
X
Same as previous 6-month cycle
X
Dosing
PP3M & PP3M, or PP6M & placebo
X w
X x
Same as previous 6-month cycle
Safety assessments
Physical examinations h and vital signs i
X
X
Same as previous 6-month cycle
X
12-lead ECGs j
X
X
Same as previous 6-month cycle
X
Assessments of injection site k
X
X
X
X
X
Same as previous 6-month cycle
X k
EPS assessments (AIMS, BARS, SAS) l
X
X
X
X
X
Same as previous 6-month cycle
X
Suicidality (C-SSRS Since Last Visit) f,m
X
X
X
X
X
X
Same as previous 6-month cycle
X
Adverse events
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Efficacy assessments
Full PANSS f + CGI-S f + PSP
X
X
Same as previous 6-month cycle
X
Abbreviated PANSS n + CGI-S
X
X
X
X
X
X
X
X
Same as previous 6-month cycle
Subject-reported: TSQM-9, SPSR t
X
X
Same as previous 6-month cycle
X
Collection of biofluids
Blood for hematology and serum chemistry
X o
X y
Xy
X y
Same as previous 6-month cycle
X o
Urinalysis
X
Same as previous 6-month cycle
X
Blood for pharmacokinetics f,p
X q
X
X
X
X
X
X q
X
X
X
X
X
X
Same as previous 6-month cycle
X
Additional exploratory assessments
HRU questionnaire, r IEQ, r SQLS, and IMR scale t
X
X
Same as previous 6-month cycle
X


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C.
Follow-up Phase (for Subjects Who Discontinue, Withdraw, or Relapse During the Double-blind Phase)
Phase
Follow-up Phase
Visit Number (of Study)
Varies Per Subject
Month (of Phase)
Quarterly (Every 3 Months) After the Subject's
Last Double-blind Injection
Visit Window, ±Weeks
±1
Concomitant therapy
X
Adverse events
X
Full PANSS + CGI-S + PSP
X
Note: The Follow-up Phase is applicable only to subjects who have received at least 1 dose of double-blind study drug but then have relapsed or have met other relevant conditions for 
withdrawal or discontinuation, as described in Section 10.2 (Discontinuation of Study Drug / Withdrawal From the Study). For relevant subjects, participation in the Follow-up Phase 
is encouraged but not required. The first visit of the Follow-up Phase should be scheduled to match the nearest equivalent quarterly assessment in the Double-blind Phase. Visits 
thereafter should be quarterly (every 3 months) until 12 months after the subject's first double-blind injection, For example, a subject who withdraws from the Double-blind Phase on 
Day 29 / Month 1 (and completes an EOP / Early Withdrawal Visit on that day) should, if willing, have the first visit of the Follow-up Phase on the equivalent of Day 92 / Month 3, 
and then 3 quarterly visits thereafter, for a total of 4 Follow-up Phase visits. If a possible relapse is detected per PANSS criteria, as described in Section 2.1.2.2 (Relapse Criteria), then 
the investigator should ask the subject to visit the clinical site 3 to 7 days later for a PANSS reassessment, if possible.


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D.
Keys and Footnotes (for All Time and Events Schedules)
Keys: AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-S = Clinical Global Impression-Severity; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; EOP = End-of-Phase (Visit), which may be conducted as an End-of-Study Visit or an Early Withdrawal Visit when relevant (see Section 10 [Subject Completion / 
Discontinuation of Study Drug / Withdrawal From the Study); EPS = extrapyramidal symptoms; HRU = Healthcare Resource Utilization; ICF = Informed Consent Form; IEQ = Involvement 
Evaluation Questionnaire; IMR = Illness Management and Recovery; n/a = not applicable; PANSS = Positive and Negative Syndrome Scale; PP1M = paliperidone palmitate 1-month (product); 
PP3M = paliperidone palmitate 3-month (product); PP6M = paliperidone palmitate 6-month (product); PSP = Personal and Social Performance (scale); SAS = Simpson Angus Scale; 
SPSR = Satisfaction With Participation in Social Roles (scale); SQLS = Schizophrenia Quality of Life Scale; TSQM-9 = abbreviated 9-item Treatment Satisfaction Questionnaire for Medication.
Footnotes:
a.
The main ICF must be signed before the first study-related activity; the day that the main ICF is signed is considered to be the first day of the Screening Phase.
b.
The minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4 (Source Documentation). Check clinical status again before the first 
dose of study drug.
c.
The pregnancy test is applicable only to women of childbearing potential. It will be a highly sensitive serum test at screening (via central laboratory) and a urine test at all other time points (via 
local testing), and must be confirmed negative before study drug is administered at the marked visits.
d.
If subjects had been taking oral antipsychotics in addition to their PP1M or PP3M, then the oral antipsychotics should be tapered and discontinued during the Screening Phase, with the last oral 
dose swallowed on or before Day -1. If the prestudy therapy was PP1M or PP3M, then the next injection must be due within 28 days of the first screening (or first rescreening) visit.
e.
These tests for concomitant substances are an alcohol breath test and a urine drug screen for illicit substances, including marijuana (even where legal). Alcohol and illicit substances are 
strongly discouraged but are not exclusionary and are not cause for withdrawal from the study. For any subject with a positive result for alcohol or illicit substances, the study-site personnel 
should administer the relevant test again at subsequent visits (even if not marked) until a negative result is obtained. After a negative result is obtained, the subject can resume testing at the 
standard frequency as indicated in these schedules.
f.
In addition to the indicated visits, suspected relapses during the Double-blind Phase should prompt all of the following assessments at all associated clinic visits, even if not designated on these 
schedules: a pharmacokinetics (PK) sample, a full PANSS assessment, a CGI-S assessment, a C-SSRS assessment, and testing for concomitant substances (both an alcohol breath test and a 
urine drug screen for illicit substances). If a possible relapse is detected per PANSS criteria, as described in Section 2.1.2.2 (Relapse Criteria), then the investigator should ask the subject to 
visit the clinical site 3 to 7 days later for a PANSS reassessment (if no such visit is already scheduled). The EOP visit is to occur as soon as possible after relapse confirmation (preferably the 
same day).
g.
For subjects who enter the study with previous PP1M or PP3M stability, the dose in the Maintenance Phase should be administered with timing appropriate to the subject's last prestudy dose 
(ie, 30±7 days after the last prestudy PP1M dose, or 90±14 days after the last prestudy PP3M dose). For subjects who enter the study without previous PP1M or PP3M stability, the dose in the 
Maintenance Phase should similarly be administered with timing appropriate to the subject's last dose in the preceding Transition Phase (ie, 28±3 days after previous PP1M dose). For all 
subjects, the dose in the Maintenance Phase may be in the deltoid or gluteal muscle, but may not be in the left gluteal muscle (because of the anticipated left gluteal injection at the beginning of 
the Double-blind Phase, as shown in Table 5).
h.
Physical examinations include weight, waist circumference, and abnormalities at all marked visits, plus height at screening only. (Height is used in calculations of body mass index.)
i.
Vital sign assessments will include blood pressure (first supine, then standing), pulse/heart rate, respiratory rate, and temperature. Vital signs should be measured before any blood draws. See 
additional instructions in Section 9.4.4 (Vital Signs).
j.
For ECGs, see Section 9.4.3 (Electrocardiograms). Note:
Before the first dose: 2 ECGs need to be assessed during the Screening Phase, at least 24 hours apart. The first ECG may be from prior medical record within the past year, and the 
second ECG must be completed by the study site on or before Day -2 of the study (and assessed by the central reader before the first dosing day of the study). Therefore, double Xs are 
shown in the Screening Phase column. Another ECG is completed by the study site on Day 1 of the relevant phase, prior to the first dose of study drug. All 3 of these ECG results should 
be compared with the exclusion criteria.
After the first dose: if any clinically significant ECG abnormality is observed during the study, then the study-site personnel should add ECG assessments for that subject at subsequent 
visits (even if not marked) until the abnormality is resolved.
At any visit: if blood sampling or vital sign measurement is scheduled for the same time point as ECG recording, then the procedures should be performed in the following order: ECGs, 
vital signs, blood draw.


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k.
Both the subject and the investigator assess the injection site at each marked time point, unless noted otherwise below.
The subject completes a Visual Analog Scale (VAS) to assess pain within 30 minutes after each injection as the VAS-Acute and at the time points marked days or weeks later as the 
VAS-Residual. The subject does not complete a VAS at the EOP Visit.
The investigator or subinvestigator (but not other study-site personnel) assesses the injection site for tenderness, erythema/redness, and induration/swelling, and should not review the 
subject's VAS rating of the injection site pain. The investigator/subinvestigator should complete these assessments within 30 minutes after the injection and at all marked visits 
thereafter; for any characteristic still rated mild, moderate, or severe at the last marked visit, the investigator/subinvestigator should add injection site assessments at subsequent visits 
(even if not marked) until all of the characteristics are rated absent. At the EOP Visit, the investigator assesses the site of the most recent injection. See Section 9.4.8.2 (Injection Site 
Evaluations and Follow-up by Investigators) for additional details.
l.
For antiparkinsonism medications, initiations or changes should be preceded by an AIMS, BARS, and SAS (even if not designated in these schedules). If beta-adrenergic blockers or 
benzodiazepines are given for akathisia, then initiations or changes should be preceded by a BARS (even if not designated per these schedules).
m.
At the patients first study visit, the C-SSRS Baseline/Screening Form will be used; for all other visits, the C-SSRS Since Last Visit Form will be used.
n.
An abbreviated PANSS consists of the positive-symptom items P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behavior), P6 (suspiciousness/persecution), and P7 (hostility),
and the general-psychopathology item G8 (uncooperativeness). If the abbreviated PANSS indicates worsening since the last full PANSS assessment or if the subject meets one or more 
symptom criterion for relapse (as described in Section 2.1.2.2 [Relapse Criteria]), then the full PANSS should be administered.
o.
Subjects should be in fasted state (overnight or for at least 8 hours) for these clinical laboratory blood samples.
p.
In addition to PK sampling time points indicated in these schedules, sites should collect PK samples (even if unscheduled) at time points associated with serious or severe adverse events, and 
may collect other unscheduled PK samples at the investigator's discretion for other adverse events (even if the event is not serious or severe).
q.
These PK samples are collected before the dose is administered that day.
r.
The HRU questionnaire and the IEQ are both administered as the baseline assessment versions during the Screening Phase and as the postbaseline assessment versions at all subsequent visits.
The HRU questionnaire is administered by study-site personnel; see details in Section 9.6.1 (Healthcare Resource Utilization Questionnaire).
The IEQ is completed by an unpaid caregiver if available; see details in Section 9.6.2 (Involvement Evaluation Questionnaire).
s.
At the end of the Maintenance Phase, subjects who are ineligible to proceed to the Double-blind Phase will complete the EOP Visit as an Early Withdrawal Visit. For subjects who are eligible 
to proceed, the EOP Visit in the Maintenance Phase (Visit 7a) is the same as the first visit of the Double-blind Phase (Visit 7b).
t.
The TSQM-9, SPSR, and IMR scale results will only be analyzed for subjects who entered the study on an oral antipsychotic. For consistency of practice in the Screening Phase, these scales 
are also administered to subjects who entered the study on injectable risperidone, even if the data will not be analyzed. For consistency of practice in the Double-blind Phase, these scales are 
administered to all subjects, even if the data will not be analyzed. For subjects that require translation of the SPSR into their local language, the collection of the SPSR is optional until the final, 
approved translation is available.
u.
The duration between the last visit of the Transition Phase (applicable only to subjects with reason to change or stabilize their previous antipsychotic) to the first visit of the Maintenance Phase 
is 28 days.
v.
Subjects previously treated with injectable risperidone or previously initiated but not on a stable regimen with PP1M are not required to attend the visits marked "n/a" in the Transition Phase.
For these subjects, the first visit in the Transition Phase should be scheduled for the day when the subject would have received the next injectable risperidone dose (14±3 days) or next PP1M 
dose (30±7 days). See Table 3 and Table 4 for more information about dosing and dose-related eligibility in the Transition Phase.
w.
This dose is active drug (PP3M or PP6M) in both treatment groups. Subjects are randomly assigned to their treatment group before dosing at Visit 7b. See Table 5 for more information.
x.
This dose is active drug in the PP3M treatment group and placebo (to maintain the blind) in the PP6M treatment group. See Table 5 for more information.
y.
These laboratory samples are for prolactin only and do not require fasting.
z.
After the PP3M prerandomization target is met, subjects who entered the study at Visits 2a, 2b, 2c, or 2d, will skip Visit 2e and proceed to Visit 2f if the subject is eligible to enter the 
Maintenance Phase (see Section 4.3, Criteria for Entry Into the Maintenance Phase). If not eligible to enter the Maintenance Phase, the subject will be withdrawn from the study. Visit 2e 
remains available for subjects with ≥4 prestudy PP1M injections but do not have dose stability.


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ABBREVIATIONS AND TERMS
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
BMI
body mass index
CGI-S
Clinical Global Impression - Severity
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DB
double blind
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
eCRF
electronic Case Report Form
EPS
extrapyramidal symptoms
ER/PR
extended-release/prolonged-release
F013
a formulation of paliperidone palmitate, used in PP1M
FDA
Food and Drug Administration
G[x]
a general-psychopathology item of the PANSS scale, where x is the number of the item
GCP
Good Clinical Practice
HRU
Healthcare Resource Utilization
ICF
Informed Consent Form
ICH
International Conference on Harmonisation / International Council for Harmonisation
IEC
Independent Ethics Committee
IEQ
Involvement Evaluation Questionnaire
IMR
Illness Management and Recovery 
IRB
Institutional Review Board
IWRS
Interactive Web Response System
LAI
long-acting injectable
MedDRA
Medical Dictionary for Regulatory Activities
mg eq.
(paliperidone palmitate) milligrams equivalent (to paliperidone)
N[x]
a negative-symptom item of the PANSS scale, where x is the number of the item
NIMH
National Institute of Mental Health
P[x]
a positive-symptom item of the PANSS scale, where x is the number of the item
PANSS
Positive and Negative Syndrome Scale
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP1M
paliperidone palmitate 1-month (product)
PP3M
paliperidone palmitate 3-month (product)
PP6M
paliperidone palmitate 6-month (product)
PQC
Product Quality Complaint
PSP
Personal and Social Performance (scale)
Q3
every 3 months
QTc
QT interval, corrected
QTcB
QT interval, corrected according to Bazett's formula
QTcF
QT interval, corrected according to Fridericia's formula
QTcLD
QT interval, corrected according to the linear-derived formula
SAP
statistical analysis plan
CCI


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SAS
Simpson Angus Scale
SCI-PANSS
Structured Clinical Interview - PANSS
SPSR
Satisfaction With Participation in Social Roles (Short Form 8a)
SQLS
Schizophrenia Quality of Life Scale
SUSAR
suspected unexpected serious adverse reaction
TSQM-9
abbreviated 9-item Treatment Satisfaction Questionnaire for Medication
US
United States
VAS
Visual Analog Scale
Investigational Medicinal Products (IMPs):

Test product: PP6M

Comparator product: PP3M

Placebo: 20% Intralipid® (200 mg/mL) injectable emulsion.
Noninvestigational Medicinal Products (NIMPs):

Rescue medications: Anti-EPS medications/ Benzodiazepines (Section 8.2: Concomitant 
Therapy)

Pretreatment medications: Oral antipsychotics including risperidone, paliperidone ER; 
injectable risperidone, PP1M and PP3M


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1.
INTRODUCTION
Paliperidone is a monoaminergic antagonist that exhibits the characteristic dopamine Type 2 and 
serotonin Type 2A antagonism of the newer, or second-generation, atypical antipsychotic 
medications. Paliperidone is the active metabolite of risperidone and is available as a daily-dose 
oral formulation. Paliperidone palmitate is an ester of paliperidone, and is available for 
intramuscular injection in the paliperidone palmitate 1-month (PP1M) product as the 
F013 formulation and the paliperidone palmitate 3-month (PP3M) product as the 
F015 formulation. To further improve adherence and convenience, a paliperidone palmitate 
6-month (PP6M) product is now under development.
 
 
(ie, PP3M may be administered into either the 
deltoid or the gluteal muscle, but the larger volume associated with a PP6M dose requires 
injection into the larger gluteal muscle).
Doses can be expressed in milligrams of paliperidone palmitate or in milligrams equivalent 
(mg eq.) to paliperidone. Conversions between products and between units are described in 
Table 1.
Table 1:
Conversions Between Doses of the 1-, 3-, and 6-Month Formulations of Paliperidone 
Palmitate; Study R092670PSY3015
PP1M Dose
PP3M Dose
PP6M Dose
mg
mg eq.
mg
mg eq.
mg
mg eq.
Lowest-dose groups a
78 mg
50 mg eq.
Not used in this study
- - - - Not available - - - -
Lower-dose groups
117 mg
75 mg eq.
Not used in this study
- - - - Not available - - - -
Moderate-dose groups
156 mg
100 mg eq.
546 mg
350 mg eq.
1092 mg
700 mg eq.
Higher-dose groups
234 mg
150 mg eq.
819 mg
525 mg eq.
1560 mg
1000 mg eq.
Key: mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); PP1M = paliperidone palmitate 1-month 
(product); PP3M = paliperidone palmitate 3-month (product); PP6M = paliperidone palmitate 6-month (product).
a
Some countries may also have an ultralow dose of PP1M (below the lowest dose stated here), but the ultralow dose is not 
used in this study.
1.1.
Background
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.
All of the material in this "Background" section about the approved paliperidone and 
paliperidone palmitate products (oral paliperidone, PP1M, and PP3M) is summarized from the 
Investigator's Brochure, unless otherwise indicated. Statements about the investigational PP6M 
product may not yet be included in the Investigator's Brochure and/or may evolve with time. For 
the most comprehensive nonclinical and clinical information regarding paliperidone and 
paliperidone palmitate, always refer to the latest version of the Investigator's Brochure.
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Nonclinical Studies
Pharmacologic Profile
Paliperidone is a racemic mixture. Binding affinities are similar between risperidone and 
paliperidone for serotonin Type 2A receptors, dopamine Type 2 receptors, alpha-adrenergic 
receptor subfamilies Type 1 and 2, and histamine Type 1 receptors. In vitro, paliperidone was 
equipotent to risperidone in reversing the dopamine-induced suppression of prolactin release 
from anterior pituitary cells and had similar effects on human platelet function, plasma 
coagulation, and fibrinolysis. Paliperidone is devoid of antimuscarinic activity.
Toxicology
The nonclinical profile of paliperidone has been extensively evaluated during the development of 
the approved products. Paliperidone is associated with toxicologic effects that are typical of 
dopamine Type 2 receptor antagonists. Two 12-week studies in minipigs indicated that the 
toxicological profiles of PP1M and PP3M were comparable when tested up to the maximum 
dose levels for humans (150 mg eq. for PP1M and 525 mg eq. for PP3M). The Sponsor is now 
conducting a 6-month local tolerability study in minipigs for 
 
 
to be tested in the current clinical study. 
 is administered 
unilaterally or bilaterally and yields a dose up to 141 mg eq./kg if tested in a (for example) 15-kg 
minipig, which is approximately 8-fold the highest dose on a mg eq./kg basis that will tested in 
the current clinical study (1000 mg eq., or 16.7 mg eq./kg in a [for example] 60-kg subject). The 
results of the minipig study now available in an addendum to the Investigator's Brochure.
Clinical Studies
Exposure
Beyond extensive studies of oral paliperidone and PP1M, the Sponsor completed 3 registrational 
clinical studies of PP3M, 
. A total of 1,191 subjects 
received at least 1 dose of PP3M (F015) in 1 registrational Phase 1 study (R092670PSY1005) 
and 2 registrational Phase 3 studies (R092670PSY3011 and R092670PSY3012), with 
319 subjects receiving at least 48 weeks of treatment with PP3M in the Phase 3 studies.7 The 
combined exposure to PP3M was 567.6 subject-years.7 No studies of 
 have been conducted 
in humans using the mass and volume of the dose (and the resultant dosing interval) that 
characterize PP6M.
Pharmacokinetics
After injection, paliperidone palmitate dissolves slowly 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), 3 months (PP3M), or
now potentially 6 months (PP6M); the duration depends on the particle size, concentration, and 
injection volume.
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The Sponsor developed a population pharmacokinetic (PK) model to describe the time course of 
plasma paliperidone concentrations after administration of PP3M, using data from Studies 
R092670PSY1005 and R092670PSY3012. The model was subjected to external evaluations, 
extensive model diagnostics, and validations using data from Study R092670PSY3011. The 
Sponsor used this population PK modeling for PP3M to guide dose selection for PP6M, 
 
Efficacy
In addition to extensive studies of oral paliperidone and PP1M, the efficacy of PP3M in the 
maintenance treatment in adults with schizophrenia was established in the 2 registrational 
Phase 3 studies:

Study R092670PSY3012 was a double-blind, placebo-controlled, long-term, randomized 
withdrawal study designed to determine whether PP3M was more effective than placebo in 
delaying the time to relapse of the symptoms of schizophrenia. Subjects progressed, as 
eligible, through a 17-week open-label PP1M treatment period (n=506), a 12-week open-
label PP3M maintenance period (n=379), then were randomized to continue PP3M (n=160) 
or to switch to placebo (n=145) during the double-blind period. Relapses occurred in 3 times 
as many subjects in the placebo group (29.0%) as in the PP3M group (8.8%). The hazard 
ratio of relapse of schizophrenia symptoms was 3.81 (95% confidence interval: 2.08 to 6.99) 
times higher for a subject switching to placebo than for a subject continuing to receive 
PP3M, indicating a 74% decrease in relapse risk associated with continued PP3M treatment. 
The time to relapse was significantly different (p<0.001) in favor of PP3M over placebo; the 
median estimated time to relapse was not estimable for subjects in the PP3M group but was 
395 days for subjects who switched to placebo. The long time to relapse in subjects who 
switched from PP3M to placebo, in combination with their PK results, indicates that many 
subjects had sufficiently therapeutic paliperidone plasma concentrations beyond their last 
PP3M dose.

Study R092670PSY3011 was a double-blind, parallel-group, noninferiority study comparing 
the PP1M and PP3M formulations in subjects with schizophrenia. Subjects progressed, as 
eligible, through a 17-week open-label PP1M treatment period (n=1,429) and then were 
randomized to receive PP1M (n=512) or PP3M (n=504) during a 48-week double-blind 
period. Relapse rates were low, occurring in 8.1% of PP3M subjects and 9.2% of PP1M 
subjects. The lower bound of the 95% confidence interval (-2.7%) was greater than the 
prespecified noninferiority margin of -15%, thus demonstrating that PP3M was noninferior 
to PP1M.
Overall, the previous efficacy outcomes with PP3M support the plans for this current study with 
PP6M, with the longer duration of efficacy to be provided by higher doses 
 
Safety
In addition to extensive studies of oral paliperidone and PP1M, the safety profile of PP3M was 
established in the 3 registrational studies. The head-to-head comparison of PP3M and PP1M in 
Study R092670PSY3011 showed no clinically meaningful differences in their safety profiles. In 
particular, results were similar between PP3M and PP1M in the types and incidences of adverse 
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events, adverse drug reactions, and injection site reactions. Across the development program for 
PP3M, no safety signals were detected that related specifically to the PP3M (F015) formulation.
Neither of the registrational Phase 3 studies of PP3M was designed to assess dose-related safety, 
since the investigators adjusted doses of PP1M for each subject based on his or her tolerability 
and efficacy; those flexible doses then were converted to a corresponding dose of PP3M. 
Therefore, any conclusions about dose-related PP3M safety results during the double-blind
periods may be confounded by the ability or inability of individual subjects to tolerate PP1M in 
the preceding open-label periods. Still, selected exploratory analyses of safety outcomes 
stratified by optimized PP3M dose levels in the double-blind periods of these studies did not 
show higher overall rates of adverse events related to extrapyramidal symptoms (EPS) at the 
highest dose level relative to the lower dose levels, and did not show any evidence for a dose-
related effect on the investigators' or subjects' ratings of the injection sites.
Adverse events of special interest with PP3M were investigated as follows: EPS-related adverse 
events; diabetes mellitus and hyperglycemia-related adverse events; potentially prolactin-related 
adverse events; suicidality; aggression and agitation; somnolence and sedation; seizures and 
convulsions; neuroleptic malignant syndrome; cardiac arrhythmias; orthostatic hypotension; and 
adverse events suggestive of (or related to) proarrhythmic potential, ischemia, rhabdomyolysis, 
overdose, weight gain, tachycardia, injection site reactions, QT prolongation, and acute kidney 
injury.8 Investigations for adverse events of special interest will be similar for PP6M and will be 
further elaborated in the Statistical Analysis Plan (SAP).
Overall, the previous safety and tolerability outcomes with PP3M support the plans for this 
current study with PP6M, with acceptable safety and tolerability expected to be possible 
 
1.2.
Overall Rationale for the Study
Adherence to any medication regimen can be difficult for any patient, and can be especially 
problematic for patients with schizophrenia. With currently available oral antipsychotics for 
schizophrenia, full nonadherence occurs in approximately 40% to 50% of patients,23 and partial 
adherence occurs in approximately 90% of patients.36 One analysis found that treatment gaps of 
as little as 1 to 10 days could double the odds of hospitalization (p=0.004).36 In contrast to oral 
formulations, the reliable drug delivery associated with long-acting injectable (LAI) 
antipsychotics has yielded a reduced risk of relapse and hospitalization and an improved quality 
of life.16 Because LAI antipsychotics are administered by a healthcare provider, LAIs offer 
transparency with respect to medication adherence, alerting healthcare professionals to the 
occurrence of nonadherence, and ensuring that patients with chronic psychotic illness receive a 
known quantity of medication at appropriate dosing intervals.
Despite the advantages of LAI formulations over short-acting oral formulations, the development 
of antipsychotics has not achieved the same durations as some other medications. Many LAI 
antipsychotics are available with treatment intervals of 2 to 4 weeks,32 and one LAI antipsychotic 
(PP3M) is available with a treatment interval of 3 months, but no LAI antipsychotics are 
available with longer treatment intervals. This unmet medical need stands in contrast to other 
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injectable or implantable medications for long-term use, such as 6-month and 1-year treatments 
for prostate cancer, a 1-year treatment for osteoporosis, and a 3-year treatment as hormonal 
contraception.32
The 6-month dosing interval with PP6M offers convenience to stably treated schizophrenia 
populations (for those who prefer a longer dosing interval) and offers benefits to underserved 
schizophrenia populations (for those with limited access to healthcare, with geographic or 
economic problems in coordinating transportation to clinic visits for injections, or with treatment 
access problems associated with homelessness). The current study is therefore designed to 
evaluate the efficacy, safety, tolerability, and PK profile of PP6M versus PP3M.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective

The primary efficacy objective is to demonstrate that injection cycles consisting of a single 
administration of PP6M (700 or 1000 mg eq.) are not less effective than 2 sequentially 
administered injections of PP3M (350 or 525 mg eq.) for the prevention of relapse in
subjects with schizophrenia previously stabilized on corresponding doses of PP1M (100 or 
150 mg eq.) or PP3M (350 or 525 mg eq.).
Secondary Objectives

To evaluate the safety and tolerability of PP6M (700 or 1000 mg eq.) in subjects with 
schizophrenia who have switched from corresponding doses of PP1M (100 or 150 mg eq.) 
or PP3M (350 or 525 mg eq.).

To assess the pharmacokinetic (PK) profile of PP6M (700 or 1000 mg eq.) administered in 
the gluteal muscle in subjects with schizophrenia who have switched from corresponding 
doses of PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

To evaluate the clinically assessed efficacy of PP6M (700 or 1000 mg eq.) versus PP3M 
(350 or 525 mg eq.) in maintaining symptom control, functioning personally and socially,
and achieving or sustaining remission in subjects with schizophrenia who were previously 
stabilized on corresponding doses of PP1M (100 or 150 mg eq.) or PP3M (350 or 
525 mg eq.).

To evaluate the subject-reported efficacy outcomes of PP6M (700 or 1000 mg eq.) or PP3M 
(350 or 525 mg eq.) compared with treatment with previous oral antipsychotics in terms of 
satisfaction with medication and with participation in social roles.
Exploratory Objectives

To evaluate healthcare resource utilization during treatment with PP6M or PP3M versus
previous treatment.

To assess changes over time in use of nicotine-containing products.


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
To evaluate the perspectives of subjects during treatment with PP6M or PP3M versus 
previous treatment with oral antipsychotics in terms of their ability to manage their illness 
and achieve their personal goals.

To evaluate the caregiver's burden during the recipient's treatment with PP6M or PP3M 
versus previous treatment.

To evaluate health-related quality of life during treatment with PP6M or PP3M versus 
previous treatment.
2.1.2.
Endpoints
2.1.2.1.
Primary Endpoint
The primary endpoint is time to relapse during the Double-blind Phase. This noninferiority 
primary endpoint will be based on the difference in Kaplan-Meier 12-month estimate of survival 
(ie, percentage of subjects remaining relapse-free) between PP6M and PP3M.
2.1.2.2.
Relapse Criteria
Relapse is defined as 1 or more of the following:

Psychiatric hospitalization (involuntary or voluntary admission to a psychiatric hospital for 
decompensation of the subject’s schizophrenic symptoms), or

For Positive and Negative Syndrome Scale for Schizophrenia (PANSS) total score:
The subject has an increase of 25% in total PANSS score from randomization for 2 consecutive 
assessments separated by 3 to 7 days if the score at randomization was >40, or
The subject has a 10-point increase in the total PANSS score from randomization for 
2 consecutive assessments separated by 3 to 7 days if the score at randomization was ≤40, or

The subject inflicts deliberate self-injury or exhibits violent behavior resulting in suicide, 
clinically significant injury to him/her self or another person, or significant property 
damage, or 

The subject has suicidal or homicidal ideation and aggressive behavior that is clinically 
significant (in frequency and severity) in the investigator’s judgment, or

For PANSS items P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory 
behavior), P6 (suspiciousness/persecution), P7 (hostility), and G8 (uncooperativeness):
The subject has a score of ≥5 after randomization for 2 consecutive assessments separated by 
3 to 7 days on any of the above items if the maximum score for the above PANSS items was ≤3 
at randomization, or
The subject has a score of ≥6 after randomization for 2 consecutive assessments separated by 
3 to 7 days on any of the above items if the maximum score for the above PANSS items was 4 at 
randomization.
The date of the relapse will be the date of the first assessment for symptoms of relapse (not the 
date of confirmation).


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The above criteria for relapse in this study are the same as the criteria in the Sponsor's pivotal 
studies of PP3M.8,9
Refer to Section 9 (Study Evaluations) for evaluations related to endpoints. See Attachment 2 for 
the correct calculation of percentage change in full PANSS total scores relevant to relapse 
criteria.
2.1.2.3.
Secondary Endpoints
The secondary efficacy endpoints include the changes from baseline during the 12 months of the 
Double-blind Phase in the following scales: the PANSS total score and subscale scores, the 
Clinical Global Impression - Severity (CGI-S), and the Personal and Social Performance (PSP) 
scale. Additionally, the proportion of subjects during the Double-blind Phase who meet criteria 
for symptomatic remission will be summarized; the definition of remission is provided in 
Section 11.3.2 (Secondary Efficacy Analyses).
The secondary PK endpoint is plasma paliperidone exposure.
The secondary endpoints for satisfaction with medication and with participation in social roles 
are abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) and Satisfaction 
with Participation in Social Roles (SPSR), respectively.
The secondary endpoints that measure safety and tolerability include physical examinations, vital 
signs, adverse events, electrocardiograms (ECGs), the Columbia Suicide Severity Rating Scale
(C-SSRS Baseline/Screening and C-SSRS Since Last Visit), the Abnormal Involuntary 
Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Simpson Angus Scale 
(SAS), clinical laboratory assessments (in full [including prolactin] at some time points, or for 
prolactin only at other time points), and injection site evaluations.
2.2.
Hypothesis
The primary hypothesis is that the efficacy of PP6M is noninferior to PP3M for preventing 
relapse in subjects with schizophrenia who were previously stabilized on corresponding doses of 
PP1M or PP3M. See Section 11.3.1 (Primary Hypothesis and Efficacy Analyses).
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, active-controlled, multicenter, interventional, parallel-group
study. All eligible subjects who progress without relapse will participate in a Screening Phase (of 
up to 28 days), a Maintenance Phase that includes 1 injection cycle with either PP1M or PP3M 
(yielding a phase duration of 1 or 3 months, accordingly), and a Double-blind Phase (of 
12 months). The Double-blind Phase is designed to include at least 2 injection cycles of PP6M 
(investigational drug with alternating placebo) or 4 injection cycles of PP3M (active control). In 
addition to standard participation as described above, further conditional/additional participation 
is possible as follows:


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
Before the Maintenance Phase, some subjects will participate in a Transition Phase, with 
1 to 5 injections of PP1M, if they entered the study on an oral antipsychotic, on injectable 
risperidone, or on PP1M previously initiated but not yet stabilized).

The planned closure will be 12 months after the last subject has been randomized in the 
Double-blind Phase.

If a subject has already received at least 1 dose of double-blind study drug but then has 
relapsed or has met other relevant conditions for withdrawal or discontinuation, then the 
subject should enter a Follow-up Phase. The Follow-up Phase ends 12 months after the 
subject's first double-blind injection. The Follow-up Phase collects supplementary poststudy 
data from willing affected subjects, in an effort to document minimum safety information
(ie, adverse events) and minimum efficacy information (ie, relapse status) for at least 
6 months after a possible PP6M injection. The Follow-up Phase is designed to be as low-
burden and noninvasive as possible, in order to encourage participation by the affected 
subjects.
The duration of exposure to study drug (ie, the number of injections) and the duration of study 
participation are variable based on a subject's flow through treatment types, on participation in 
conditional phases or parts as described in the 3 bullet points above, and on whether a subject
experiences a relapse during the study:

For subjects without relapse,

The longest expected duration is for a subject who enters the study on an oral 
antipsychotic and who enrolls early enough to be assigned to PP3M during the 
Maintenance Phase and then to participate in 12 months in the Double-blind Phase. 
Such a subject could have ~ 19 months of participation with exposure to paliperidone 
palmitate (4 months during the Transition Phase, 3 months during the Maintenance 
Phase, 12 months of the Double-blind Phase.

The shortest expected duration for a subject who enters the study with stability on 
PP1M will be ~13 months of participation with exposure to paliperidone palmitate 
(1 month during the Maintenance Phase and 12 months during the Double-blind Phase).

For subjects with relapse, the duration of exposure and participation would be shorter and 
would depend on the timing of the relapse. For example, a subject might receive a first study 
injection providing 1 month of treatment in the Maintenance Phase and a second study 
injection at the beginning of the Double-blind Phase; if a relapse occurred a few weeks 
thereafter, then the subject would receive no further study drug injections, but would have 
an End-of-Study Visit associated with the confirmation of the relapse, and would contribute 
poststudy Follow-up Phase data if willing for the remainder of the yearly cycle.
Due to the long-acting nature of the study drugs, exposure to residual yet potentially 
subtherapeutic levels of paliperidone is expected to continue past the last study assessment, as 
addressed in the eligibility criteria, prohibitions, and restrictions that are relevant to the poststudy 
period (see Section 4 [Subject Population]).
The approximate participation targets are 903 subjects entering the Screening Phase, 
approximately 840 subjects entering the Transition/Maintenance Phase, and 549 subjects
entering the Double-blind Phase.
Of subjects entering the Double-blind Phase, the 


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prerandomization targets are approximately one-half entering from a PP3M group, and one-half
entering from a PP1M group. The Sponsor will inform sites when enrollment targets have been 
met and when no further subjects should be enrolled; the subjects who are already enrolled at 
that point may continue in the study until the Sponsor gives instructions to the sites about how to 
begin closing the study. The Sponsor also will inform sites when phase-specific targets or limits 
have been met, as follows: when the PP3M prerandomization target has been met in the 
Maintenance Phase (see Section 6.1.3 [Maintenance Phase]), and when the pathway to 
enrollment that includes the Transition Phase is closed (see Section 6.1.2 [Transition Phase]).
At the start of the Double-blind Phase,

Subjects in the moderate-dose baseline groups (who had achieved stability before or during 
the study with a PP1M dose of 100 mg eq. or a PP3M dose of 350 mg eq.) will be 
randomized in a 2:1 ratio (with dose level as a stratification factor) to receive either the 
investigational PP6M at a 700 mg eq. dose or the active control PP3M at a 350 mg eq. dose.

Subjects in the higher-dose baseline groups (who had achieved stability before or during the 
study with a PP1M dose of 150 mg eq. or a PP3M dose of 525 mg eq.) will be randomized 
in a 2:1 ratio (with dose level as a stratification factor) to receive either the investigational 
PP6M as a 1000 mg eq. dose or the active control PP3M as a 525 mg eq. dose.
Safety, efficacy, and pharmacokinetics are monitored throughout the study, as specified in the 
Time and Events Schedules.
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview; Study R092670PSY3015


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Key: mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); PP1M = paliperidone palmitate 1-month (product); PP3M = paliperidone palmitate 3-month (product); 
PP6M = paliperidone palmitate 6-month (product).
a
During the Transition Phase, the dose levels and the number of injections will depend first on a subject's previous treatment and then on his or her individual efficacy and tolerability 
results, as described in Section 6.1.2 (Transition Phase). See Figure 2 for more details.
b
Entry to the Maintenance Phase requires eligibility as specified in Section 4.3 (Criteria for Entry Into the Maintenance Phase). Each subject's Maintenance Phase dose will be matched 
by straightforward progression (PP1M to PP1M, or PP3M to PP3M) or will be matched by established conversion (PP1M to PP3M) from the same dose that they had been receiving 
during the Screening Phase or at the end of the Transition Phase, as applicable. See Figure 3 and Figure 4 for more details.
c
Randomization will occur on the day of the first double-blind injection (ie, 1 month after the Maintenance Phase injection of PP1M, or 3 months after the Maintenance Phase injection 
of PP3M). Only subjects who are eligible as specified in Section 4.4 (Criteria for Entry Into the Double-blind Phase) will be randomized.
d
The Double-blind Phase includes 4 injections for all treatment groups. The active control groups receive 1 injection of PP3M every 3 months. The investigational drug groups receive 
1 injection every 3 months in the following sequence: PP6M → placebo → PP6M → placebo. The planned closure will be 12 months after the last subject to be randomized and 
remain in the study completes 12 months of the Double-blind Phase, which will be marked by completion of Visit 33a The Sponsor will inform the sites when the study is closing and 
no further dosing should be conducted in the Double-blind Phase.
Note: This figure does not show the Follow-up Phase, which is applicable only to subjects who have received at least 1 dose of double-blind study drug but then have relapsed or have met 
other relevant conditions for withdrawal or discontinuation, as described in Section 10.2 (Discontinuation of Study Drug / Withdrawal From the Study). The Follow-up Phase ends 
12 months after the subject's first double-blind injection, 


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3.2.
Study Design Rationale
Blinding and Control
An active control (PP3M) will be used to determine the sensitivity of the clinical endpoints in 
this study. 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. Double-blinded 
treatment will be used to reduce potential bias during data collection and evaluation of clinical 
endpoints.
Additional special blinding conditions are as follows:

The Sponsor and all study-site personnel will be blinded to the results of PK measurements
(as described in Section 9.3.1 [Pharmacokinetic Evaluations]) and prolactin measurements
(as described in Section 9.4.2 (Clinical Laboratory Tests).

The Sponsor and all study-site personnel except for the study drug administrator will be 
blinded to the administration of the study drug during the Double-blind Phase, as described 
in Section 5 (Treatment Allocation and Blinding). 

An investigator/subinvestigator who evaluates an injection site should not review the 
subject's Visual Analog Scale (VAS) ratings of pain associated with the injection site, as 
described in Section 9.4.8.2 (Injection Site Evaluations and Follow-up by Investigators).

Cardiologists at the central electrocardiogram (ECG) facility will be blinded to the treatment 
group assignments of subjects, as described in Section 9.4.3 (Electrocardiograms).

The Sponsor will be blinded to the interim PK analysis, as described in Section 11.4
(Pharmacokinetic and Pharmacodynamic Analyses).
Study Phases
The phases in this study are similar to phases in the Sponsor's pivotal studies of PP3M 
(R092670PSY3011 and R092670PSY3012), with incorporation of lessons learned from those 
studies and feedback from Health Authorities. The early phases of this PP6M study (Screening, 
Transition, and Maintenance) are similar to Study R092670PSY3012,9 but with added flexibility 
(and therefore added complexity) to allow either PP1MPP6M or PP1MPP3MPP6M 
treatment pathways. The Double-blind Phase of this PP6M
study is
similar to 
Study R092670PSY3011,9 but with more intensive safety assessments around potential peak 
plasma paliperidone concentrations and more intensive efficacy assessments around potential 
trough plasma paliperidone concentrations. For a subset of subjects with relapses, study 
withdrawals, or treatment discontinuations during the Double-blind Phase, a subsequent Follow-
up Phase is applicable. The Follow-up Phase in this PP6M study is similar to the Follow-up Visit 
in Study R092670PSY3011,9 but with additional visits and assessments to attempt to collect 
minimum safety data (ie, adverse events) and minimum efficacy data (ie, relapse status) until
12 months after the first double-blind injection, In this way, the Follow-up Phase can provide 
information about the primary efficacy endpoint for 12 months after a subject's first possible 


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PP6M injection (see Section 11.3.1.1.3 [Sensitivity Analyses for Primary Efficacy]) and can 
provide minimum information about efficacy and safety for at least 6 months after a subject's last 
possible PP6M injection (see Section 10.4 [Process for Planned Study Closure]).
Dose Levels of Paliperidone Palmitate for Eligibility
To be eligible for randomization, subjects must have stability with either PP1M as 100 or 
150 mg eq. or PP3M as 350 or 525 mg eq., as described in the inclusion criteria. Both products 
are available in lower dose levels; the eligible dose levels represent the second-highest and 
highest available doses of each product. These dose levels are the ones that have been most 
commonly prescribed in postmarketing experience,11 and are the ones that were most commonly 
selected by clinical investigators to achieve stabilization for subjects in the Sponsor's pivotal 
studies of PP3M (Studies R092670PSY3011 and R092670PSY3012).8,9 Both pivotal PP3M 
studies included open-label, flexible-dose, lead-in, 17-week periods with PP1M; the doses of 
PP1M from those open-label periods then were converted to doses of PP3M for the subsequent 
double-blind periods. In those studies, the final open-label doses of PP1M were 150 mg eq. for 
~40% to ~50% of subjects, 100 mg eq. for ~40% to ~50% of subjects, 75 mg eq. for ≤9% of 
subjects, and 50 mg eq. for ≤3% of subjects. The large percentages for PP1M as 100 or 150 mg 
eq. in the open-label periods resulted in similarly large percentages for PP3M as 350 or 525 mg 
eq. in the double-blind periods. Given the frequent use of these moderate-dose and higher-dose 
levels in clinical studies and in postmarketing experience, the Sponsor selected these dose levels 
for eligibility in the current study.
Dose Levels of Paliperidone Palmitate for Investigation
The conversion of doses of PP1M or PP3M in the Maintenance Phase to doses of PP6M in the 
Double-blind Phase was based on population PK simulations. 
 
 
 
The population PK model that describes the time course of plasma paliperidone concentrations 
after
PP3M administration was
developed by using
data from a
Phase 1 study 
(R092670PSY1005) and a Phase 3 study (R092670PSY3012).7 This model was internally and 
externally evaluated, not only by performing extensive model diagnostics at the model building 
stage, but also by successfully validating the model using data from another Phase 3 study 
(R092670PSY3011). Using that previously developed and validated population PK model for 
PP3M, new population PK simulations were performed to project the optimal dose levels for 
PP6M that would correspond to similar trough paliperidone concentrations of the PP3M dose 
levels of 350 and 525 mg eq., while remaining at or below the recommended maximum 5.0-mL 
volume for aqueous intramuscular injections.10 The results indicated that investigational PP6M 
dose levels should be 700 and 1000 mg eq.
Population PK modeling was used to compare the investigational PP6M dosages against the 
highest and lowest approved dosages of other products that contain paliperidone or risperidone.
CCI


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
The higher investigational PP6M dosage is 1000 mg eq. The highest approved dosage of 
oral risperidone in the United States and some other countries is 16 mg/day (as 8 mg twice a 
day).a The maximum plasma concentration of paliperidone associated with PP6M as 
1000 mg eq. was calculated to be lower than the maximum plasma concentration of active 
moiety associated with oral risperidone 16 mg/day (as 8 mg twice a day), and in line with 
the maximum plasma concentration associated with oral risperidone 6 mg/day (as 3 mg 
twice a day).

The lower investigational PP6M dosage is 700 mg eq. The lowest approved dosage of the 
oral paliperidone extended-release/prolonged-release (ER/PR)b formulation in the United 
States and some other countries is 3 mg/day.c The minimum plasma concentration of PP6M 
as 700 mg eq. was calculated to be higher than the minimum plasma concentration of oral 
paliperidone ER/PR formulation as 3 mg/day.
Site of Administration
Although PP1M and PP3M are approved for administration into either the deltoid or the gluteal 
muscle, the larger volume associated with a PP6M dose requires injection into the larger gluteal 
muscle. The PP6M product will be provided in a syringe prefilled with 700 mg eq. (3.5 mL) or 
1000 mg eq. (5.0 mL). These volumes are expected to be well tolerated as gluteal injections, for 
the following reasons:

The maximum volume is aligned with the guidance in "Intramuscular injections: a review of 
best practice for mental health nurses," which states that "relatively large doses up to 5 mL 
can be given."10

The Sponsor's previous Study R092670PSY1005 indicated no clinically meaningful 
difference in tolerability of the largest-volume dose of PP3M (2.625 mL) versus the smaller 
doses, by randomly assigned PP3M dose level. Most pain ratings were below 10 mm on a 
100-mm scale.

Paliperidone palmitate is provided as an aqueous suspension, unlike early oil-based LAI 
antipsychotic formulations that were that were often associated with pain after injection.6,28
Benefit-risk Assessment
To consider all endpoints that may have an appreciable effect on the benefit-risk balance, the 
benefits and risks of PP6M will be assessed using a structured approach to benefit-risk 
assessment following the principles described both in the Benefit-risk Action Team Framework, 
                                                
a
RISPERDAL® [United States Prescribing Information]. Titusville, NJ: Janssen Research & Development. 
www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020272. 
Accessed 19 June 2017.
b
The terminology for ER versus PR varies by country; therefore, both terms are used together in this protocol.
c
INVEGA® [United States Prescribing Information]. Titusville, NJ: Janssen Research & Development. 
www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021999. 
Accessed 19 June 2017.


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a general platform for benefit-risk assessment,25,26 and in the relevant guideline from the 
International Conference on Harmonisation / International Council for Harmonisation (ICH).d
Timing of PK Samples
The PK profile of PP3M has been well characterized. After a single intramuscular injection of 
PP3M over the dose range of 175 to 525 mg eq., the plasma concentrations of paliperidone 
gradually rose to a maximum at approximately 30 to 33 days.7 Similarly, the Sponsor's modeling 
for PP6M has indicated that the maximum plasma paliperidone concentration at steady state 
should occur approximately 1 month after injection of PP6M. Therefore, PK sampling (and the 
associated safety evaluations) are scheduled in this study at weekly time points (ie, more 
intensive) near the expected peak. Thereafter, the PK sampling is conducted at monthly time 
points (ie, less intensive) throughout the elimination phase. Finally, the PK sampling (and the 
associated efficacy evaluations) resumes weekly time points (ie, more intensive) when 
approaching the end of the 6-month dosing interval.
Overall Study Evaluations
The efficacy, safety, pharmacokinetic, pharmacodynamic, benefit-risk, and exploratory 
evaluations for PP6M in this study are similar to evaluations for PP3M in the Sponsor's pivotal
studies (R092670PSY3011 and R092670PSY3012), with incorporation of lessons learned from 
those studies. The study evaluations have also incorporated feedback from Health Authorities.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within the period from 28 to 2 days before the 
first administration of the study drug.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate Sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
If a subject does not meet all inclusion criteria (is a screen failure) with respect to dose level, 
dose duration, or dose timing of prestudy treatment with paliperidone palmitate or injectable 
risperidone, but at some point in the future is expected to meet these inclusion criteria, then the 
subject may be rescreened on 1 occasion. Subjects who are rescreened will be assigned a new 
subject number, will undergo the informed consent process, and then will restart the Screening 
Phase. Conditions that are permissible for rescreening include the following:
                                                
d
ICH. ICH Harmonized Tripartite Guideline M4E(R2): Revision of M4E guideline on enhancing the format and 
structure of benefit-risk information in ICH.
www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4E_R2_Efficacy/M4E_R2__Step_4.pdf. 
Dated 15 June 2016. Accessed 19 June 2017.


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
Duration/stability of prestudy dosing. For example, if a potential subject has not been treated 
with the same dose for the minimum amount of time, then the potential subject may return 
for rescreening after the minimum duration as specified in the inclusion criteria.

Strength/level of prestudy dosing. For example, if a potential subject is being treated with a 
dose that is too low for eligibility, but insufficient efficacy with a lower dose means that a 
higher dose is already planned, then the subject may return for rescreening after being 
treated with an eligible dose level for the minimum duration as specified in the inclusion 
criteria.

Timing of the last prestudy dose. For example, if the last prestudy dose was not within the 
appropriate window, then the potential subject may return for rescreening at an appropriate 
time.
If a subject meets any exclusion criteria (is a screen failure) with respect to safety parameters,
then rescreening is not allowed. However, retesting may be permitted for results (eg, laboratory 
or ECG values) that may be transient or inaccurate in the opinion of the investigator. This 
exceptional and limited retesting of abnormal screening values that lead to exclusion is allowed 
only once using an unscheduled visit during the Screening Phase, to reassess eligibility.
Rescreening is permitted with the medical monitor’s approval for subjects who were withdrawn 
during the Transition Phase or Maintenance Phase due to an incomplete injection or an 
unintended dosing or administration of a study drug.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
May be either male or female.
2.
Must be 18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place) to 70 years of age, inclusive, at the time of informed consent.
3.
Must meet the diagnostic criteria for schizophrenia according to Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) for at least 6 months before screening.


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4.
Must be receiving treatment with paliperidone palmitate (as either the PP1M or PP3M 
formulation), or injectable risperidone, or any oral antipsychotic.
a. If the treatment is paliperidone palmitate, then:
1) The dose strength must be PP1M as 100 or 150 mg eq. or PP3M as 350 or 525 mg eq.
2) The dose timing must fit the study schedule. The next injection must be due within 
28 days of the first screening (or first rescreening) visit.
b. If the treatment is injectable risperidone, then the dose strength must be 50 mg, the 
dosing cycle must be every 2 weeks, the efficacy and tolerability must have been 
established as adequate with the same strength and frequency for at least 3 injection 
cycles before screening, and the subject must have a preference for a longer-acting 
injectable medication.
c. If the treatment is an oral antipsychotic, then the subject must have a valid reason to 
discontinue the previous treatment, such as problems with efficacy, safety, or 
tolerability, or preference for a long-acting injectable medication.
5.
Must be able, in the opinion of the investigator, to discontinue any antipsychotic 
medication other than PP1M or PP3M during the Screening Phase.
6.
Must have a full PANSS score of <70 points at screening.
7.
Must have a body mass index (BMI) between 17 and 40 kg/m2 (inclusive) and must have a 
body weight of at least 47 kg at screening.
8.
Must be willing to receive gluteal injections of medication during the Double-blind Phase.
9.
Must, if a woman of childbearing potential, have a negative highly sensitive serum 
(-human chorionic gonadotropin) at screening.
10.
Criterion modified per Amendment 1
10.1 Must use contraception consistent with local regulations for subjects participating in 
clinical studies. Before receiving study drug, a woman must be either:
a. Not of childbearing potential, defined as being either postmenopausal or permanently 
sterile, as follows:


R092670 (paliperidone palmitate)
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o
Postmenopausal: A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) 
level (>40 IU/L or mIU/mL) in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy, however in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.
o
Permanently sterile: Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and 
bilateral oophorectomy.
b. Of childbearing potential, but meeting the contraception requirements as follows:
o
Practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly). Examples of highly effective 
contraceptives include the following:
User-independent 
methods: 
Implantable 
progestogen-only 
hormone 
contraception associated with inhibition of ovulation; intrauterine device 
(IUD); intrauterine hormone-releasing system; vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study drug; the reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject).  
User-dependent methods: combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation: oral, 
intravaginal, and transdermal; progestogen-only hormone contraception 
associated with inhibition of ovulation: oral and injectable.
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the use of 
contraceptive methods for subjects participating in clinical studies.
o
Agreeing to remain on a highly effective method throughout the study and for at 
least 12 months after the last dose of study drug. A woman using oral 
contraceptives should use an additional birth control method (see inclusion 
criterion text in the sub-bullet above).
Note: If the childbearing potential changes after start of the study or the risk of pregnancy 
changes (eg, a woman who is not heterosexually active becomes active), a woman must 
consent to starting a highly effective method of contraception after a negative pregnancy 
test. If the subject declines consent for start of a highly effective method of contraception, 
the subject must be withdrawn from the study.


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11.
Criterion modified per Amendment 3
11.1 Must, if a man, agree that during the study and for a minimum of 12 months after 
receiving the last dose of study drug, his female partner(s) will use a highly effective 
method of contraception as described above, and:

He must, if being sexually active with a woman of childbearing potential, use a barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository).

He must, if being sexually active with a woman who is pregnant, use a condom.

He must agree not to donate sperm.
12.
Must sign an informed consent form (ICF) indicating that he or she understands the 
purpose of, and procedures required for, the study and is willing to participate in the study; 
and must be able to provide his or her own consent (ie, consent cannot be provided by a 
legal representative of the subject).
13.
Must have a stable place of residence for the previous 3 months prior to screening and in 
the foreseeable future.
14.
Must be fluent in the language of the investigator, study staff, and raters.
15.
Criterion deleted per Amendment 2.
16.
Must have an identified support person (eg, family member, social worker, caseworker, or 
nurse) considered reliable by the investigator in providing support to the subject to ensure 
compliance with study treatment, outpatient visits, and protocol procedures, including 
alerting trial staff to any signs of impending relapse.
4.2.
Exclusion Criteria
1.
Must not be receiving any form of involuntary treatment, such as involuntary psychiatric 
hospitalization, parole-mandated treatment, or court-mandated treatment.
2.
Must not have attempted suicide within 12 months before screening and must not be at 
imminent risk of suicide or violent behavior, as clinically assessed by the investigator at 
the time of screening.
3.
Must not have a DSM-5 diagnosis of moderate or severe substance use disorder (except 
for nicotine and caffeine) within 6 months of screening; however, acute or intermittent 
substance use prior to screening is not exclusionary, depending upon the clinical 
judgment of the investigator.
4.
Must not have a history of neuroleptic malignant syndrome or tardive dyskinesia.


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5.
Must not have a history of intolerability or severe reactions to moderate or higher doses 
of antipsychotic medications and must not have any other factors that would, in the 
judgment of the investigator, indicate that treatment with moderate or higher doses of 
paliperidone palmitate would be intolerable or unsafe. 
6.
Criterion modified per Amendment 3
6.1 Must not have been treated with long acting injectable formulations of neuroleptic 
drugs based on active ingredients other than risperidone or paliperidone (eg, haloperidol 
decanoate, fluphenazine decanoate, etc) during the 6 months before screening.
7.
Criterion modified per Amendment 1
7.1 Must not have a clinically significant and unstable medical illness in history or at 
screening, including (but not limited to) cardiac arrhythmias or other cardiac disease, 
hematologic disease, coagulation disorders (including any abnormal bleeding or blood 
dyscrasias), significant pulmonary disease including bronchospastic respiratory disease, 
diabetes mellitus (poorly controlled or requiring insulin), hepatic insufficiency, thyroid 
disease (poorly controlled based on recent thyroid stimulating hormone [TSH] level), 
neurologic or other psychiatric disease (except schizophrenia), infection, cancer, or any 
other illness that the investigator considers should exclude the subject or that could 
interfere with the interpretation of the efficacy or safety measurements.
8.
Must not have a primary, active DSM-5 diagnosis other than schizophrenia (eg, 
dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective 
disorder, schizophreniform disorder, autistic disorder, primary substance-induced 
psychotic disorder) and must not have dementia-related psychosis.
9.
Must not have clinically significant abnormal values during screening for hematology, 
serum chemistry (including aspartate aminotransferase or alanine aminotransferase 
greater than 2 times the upper limit of normal), or urinalysis, as deemed appropriate by
the investigator.
10.
Must not have clinically relevant abnormality in the physical examination, vital signs, or 
12-lead electrocardiogram (ECG) during screening, as deemed appropriate by the 
investigator.
11.
Must not have known allergies, hypersensitivity, or intolerance to paliperidone palmitate, 
paliperidone, risperidone, Intralipid (the placebo), or any excipients (refer to the 
Investigator's Brochure for details) of the formulations, which include soybean oil, egg 
yolk, phospholipids, and glycerol.


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12.
Criterion modified per Amendment 1
12.1 Must not have a history of treatment resistance, defined as failure to respond to 
2 adequate trials with adequate doses of different antipsychotic medications (where an 
adequate trial is defined as a minimum of 4 weeks at a therapeutic dosage), based on the 
available medical records. Final determination of eligibility is based on investigator 
judgment.
13.
Must not have been treated in the last 2 months with clozapine for treatment-resistant or 
treatment-refractory illness.
14.
Must not have a history of unresponsiveness to (lack of efficacy with) any risperidone or 
paliperidone products.
15.
Must not have a history of intolerance to doses ≥9 mg/day of oral paliperidone or 
≥6 mg/day of oral risperidone, where the intolerance was treatment-limiting (ie, leading 
to discontinuation or reduction of dose).
16.
Must not have a history or presence of circumstances that may increase the risk of the 
occurrence of torsade de pointes and/or sudden death in association with the use of drugs 
that prolong the QTc interval, including:
a.
Heart rate <50 bpm, based on 12-lead ECG and/or vital signs, on repeated occasions 
(2 or more times) during the screening and before the first dosing day of the study.
b.
Prolonged QTc interval corrected according to Fridericia's formula (QTcF) 
>450 msec, based on 12-lead ECG, on repeated occasions (2 or more times) during 
screening or from prior medical record within the past year).
c.
Cardiac conditions as follows: bradycardia, sick sinus syndrome, complete 
atrioventricular block, congestive heart failure, or polymorphic ventricular 
tachycardia.
d.
Electrolyte conditions as follows: clinically relevant hypocalcemia, hypokalemia, or 
hypomagnesemia.
e.
Concomitant use of drugs that prolong the QTc interval, such as Class IA 
antiarrhythmics (eg, disopyramide, quinidine, or procainamide) and Class III 
antiarrhythmics (eg, amiodarone or sotalol); some antihistamines; some antibiotics 
(eg, fluoroquinolones like moxifloxacin or ciprofloxacin); some antimalarials (eg, 
mefloquine); and some antipsychotics (eg, chlorpromazine or ziprasidone).
f.
Congenital prolongation of the QT interval (Romano-Ward syndrome or Jervell and 
Lange-Nielsen syndrome).


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17.
Must not concomitantly use any inducers of proteins involved in the metabolism of 
paliperidone (ie, cytochrome P450 3A4) or the excretion of paliperidone (ie, 
p-glycoprotein), such as rifampicin, carbamazepine, oxcarbazepine, barbiturates, 
phenytoin, troglitazone, or St. John's Wort, within 14 days prior to the first screening 
visit.
18.
Must not have any primary movement disorders (such as Parkinson's disease, 
Huntington's disease, or others) that could, in the investigator's judgment, affect the 
safety or tolerability for the subject or affect the results of the study.
19.
If an oral tolerability test is required (ie, if the subject has no documented tolerability to 
any oral or injectable risperidone or paliperidone formulations), then the subject must not 
have a history of any severe pre-existing gastrointestinal narrowing (pathologic or 
iatrogenic) or inability to swallow oral paliperidone ER/PR tablets whole with the aid of
water.
20.
Must not have received an investigational drug or have used an invasive investigational 
medical device within 3 months or within a period less than 5 times the drug's half-life, 
whichever is longer, before the planned first dose of study drug. This criterion does not 
apply if the prestudy investigational drug was PP1M or PP3M.
21.
Must not, if a woman, be pregnant, breastfeeding, or planning to become pregnant while 
enrolled in this study or within 12 months after the last dose of study drug.
22.
Must not, if a man, have plans to father a child while enrolled in this study or within 
12 months after the last dose of study drug.
23.
Must not have plans for a surgery or procedures that would interfere with the conduct of 
the study.
24.
Must not be 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.
25.
Must not have any condition for which, in the opinion of the investigator, participation 
would not be in the best interest of the subject (eg, compromise the well-being) or that 
could prevent, limit, or confound the protocol-specified assessments.
26.
Must not have moderate to severe renal impairment (ie, those with creatinine clearance as 
estimated by Cockcroft-Gault of <60 mL/min).


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27.
Subjects must not have the following:
-
Electroconvulsive therapy (ECT) within 60 days before screening
-
Nonselective/irreversible monoamine oxidase inhibitors (MAOI) antidepressants 
within 30 days before screening
-
Other antidepressants unless at a stable dosage for 30 days before screening (If 
the dosage has been stable for less than 30 days and the subject does not require 
the antidepressant, it can be washed out by the baseline visit; if the dosage has 
been stable for less than 30 days and the subject requires antidepressant treatment, 
the subject should not be included in this study)
28.
Must not be concomitantly treated with mood stabilizers including lithium, or valproate, 
or other antiepileptics/anticonvulsants within 14 days of the first screening visit.
29.
Must not have been treated with a dopamine agonist (eg, ropinirole or pramipexole) 
within 90 days of the first screening visit.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 9.1 (Study Procedures), describes options for retesting. 
Section 17.4 (Source Documentation) describes the required documentation to support meeting 
the enrollment criteria.
4.3.
Criteria for Entry Into the Maintenance Phase
1.
On Day 1 of the Maintenance Phase, subjects must have a full PANSS total score of 
<70 points.
2.
Criterion modified per Amendment 2
2.1. For subjects proceeding from the Transition Phase to the Maintenance Phase, the 
PP1M dose prior to entering the Maintenance Phase must have been 100 or 150 mg eq.
and, in the investigator’s judgment, the subject should continue on the same dose level (ie,
either the equivalent PP3M dose [before the PP3M prerandomization target is met] or the 
same PP1M dose [after the PP3M prerandomization target is met]).


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3.
For subjects proceeding from the Transition Phase to the Maintenance Phase, they must 
not have during the Transition Phase:
a.
required psychiatric hospitalization (involuntary or voluntary admission to a 
psychiatric hospital for decompensation of the subject’s schizophrenic symptoms), 
or 
b. inflicted deliberate self-injury or exhibited violent behavior resulting in suicide, 
clinically significant injury to him/her self or another person, or significant 
property damage, or
c.
had suicidal or homicidal ideation and aggressive behavior that is clinically 
significant (in frequency and severity) in the investigator’s judgment
4.
For subjects proceeding from the Screening Phase directly to the Maintenance Phase, the 
PP1M dose or PP3M dose must not be planned for adjustment in the foreseeable future and 
must have been unchanged in the recent past (as described in "a" and "b" below). The 
specific dose stability criteria are as follows:
a.
For PP1M, at least 3 months of injections with the last 2 doses being the same 
strength before the Screening Phase.
b. For PP3M, at least 1 injection cycle before the Screening Phase.
Subjects who do not meet the criteria above will be withdrawn from the study, will undergo End-
of-Phase Visit / Early Withdrawal Visit procedures, and will be treated thereafter according to 
clinical judgment for acceptable standard of care. If withdrawal is due to an incomplete injection 
or an unintended dosing or administration of a study drug, rescreening is permissible with the 
medical monitor’s approval.
4.4.
Criteria for Entry Into the Double-blind Phase
Eligibility to enter the Double-blind Phase requires all of the following:
1.
For the last 2 assessments before randomization (ie, at Visit 6 and Visit 7a/b), subjects 
must have a PANSS total score of <70 points.
2.
For the last 2 assessments before randomization (ie, at Visit 6 and Visit 7a/b), subjects 
must have scores of ≤4 points for PANSS items P1 (delusions), P2 (conceptual 
disorganization), 
P3 (hallucinatory 
behavior), 
P6 (suspiciousness/
persecution), 
P7 (hostility), G8 (uncooperativeness), and G14 (poor impulse control).
3.
Subjects must not, per investigator judgment, have significant EPS despite adequate 
treatment with anti-EPS medications, based on standard clinical evaluation and 
information from the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia, the 
Barnes Akathisia Rating Scale (BARS) for akathisia, and the Simpson Angus Scale (SAS)
for parkinsonism.
4.
Subjects must not have received any oral antipsychotic supplementation during the 
Maintenance Phase.


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5.
Subjects must not have during the Maintenance Phase:
a.
required psychiatric hospitalization (involuntary or voluntary admission to a 
psychiatric hospital for decompensation of the subject’s schizophrenic symptoms), 
or 
b. inflicted deliberate self-injury or exhibited violent behavior resulting in suicide, 
clinically significant injury to him/her self or another person, or significant 
property damage, or
c.
had suicidal or homicidal ideation and aggressive behavior that is clinically 
significant (in frequency and severity) in the investigator’s judgment
Subjects who do not meet the criteria above for entry into the Double-blind Phase will be 
withdrawn from the study, will undergo End-of-Phase Visit / Early Withdrawal Visit procedures, 
and will be treated thereafter according to clinical judgment for acceptable standard of care.
These subjects do not need to enter the Follow-up Phase, since they do not receive any double-
blind treatment. If withdrawal is due to an incomplete injection or an unintended dosing or 
administration of a study drug, rescreening is permissible with the medical monitor’s approval.
4.5.
Prohibitions, Restrictions, and Strong Recommendations
Prohibitions and Restrictions
Potential 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:
1.
Must follow Section 8.3 (Prohibited Concomitant Medications), regarding prohibited and 
restricted therapy during the study.
2.
Must agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Must, if a woman of childbearing potential, continue using an appropriate method of 
contraception, as described in Section 4.1 (Inclusion Criteria), during participation in the 
study and for at least 12 months after the last dose of study drug. (Women who have a 
positive pregnancy test during the study will be withdrawn from the study.)
4.
Must, if a man, continue using the measures described in Section 4.1 (Inclusion Criteria) to 
prevent women from being exposed to his sperm or conceiving his child during the study 
and for 12 months after receiving the last dose of study drug.
Strong Recommendations
Potential subjects should also be willing and able to adhere to the following strong 
recommendations (which are not strict prohibitions or restrictions) during the course of the 
study:


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1.
Should not donate blood for at least 6 months after completion of the study.
2.
Should not participate in an investigational drug study for at least 6 months after 
completion of the study.
3.
Should not use alcohol, illicit substances, or recreational marijuana (even where legal) 
during the entire study. (Recreational marijuana is a strong recommendation, but medical 
marijuana is a prohibition; see Section 8.3 [Prohibited Concomitant Medications]).
4.
Criterion modified per Amendment 3.
4.1. Should not eat before blood laboratory full panel sampling. (Nonfasting exceptions 
should be noted; fasted states are overnight or for at least 8 hours).
5.
Deleted per Amendment 3.
6.
Deleted per Amendment 2. 
5.
TREATMENT ALLOCATION AND BLINDING
See also the "Blinding and Control" subheading under Section 3.2 (Study Design Rationale).
Treatment Allocation: Procedures for Randomization and Stratification
At entry into the Double-blind Phase, subjects who had received a moderate dose in the 
Maintenance Phase will be randomly assigned to 1 of 2 treatment groups (active control or 
investigational drug as moderate doses) and subjects who had received a higher dose in the 
Maintenance Phase will be randomly assigned to 1 of 2 treatment groups (active control or 
investigational drug as higher doses), based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the Sponsor. The randomization 
(2:1 ratio, PP6M:PP3M) will be balanced by using randomly permuted blocks and will be 
stratified by study site and by moderate or high dose in the Maintenance Phase. Based on this 
randomization code, the study drug will be packaged and labeled for each subject. Medication kit 
numbers will be preprinted on the study drug labels and assigned as subjects qualify for the 
Double-blind Phase and are randomly assigned to treatment.
Central randomization will be implemented in this study. The Interactive Web Response System 
(IWRS) will assign a unique treatment code, which will dictate the treatment assignment and 
matching study drug kit for the subject. The requestor must use his or her own user identification 
and personal identification number when contacting the IWRS, and will then give the relevant 
subject details to uniquely identify the subject. Details regarding use of the IWRS will be 
provided in the IWRS Manual.
Unblinded Study Drug Administrator
Special precautions will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints. Differences in syringe sizes for PP3M versus PP6M pose a potential for the 


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study drug administrator to become unblinded to the subject's treatment assignment. The subject 
and study staff, other than the study drug administrator, should not be allowed to view the 
syringe or needle or to observe the injection. (The subject must be instructed to look away during 
the injection and related steps before and after.) To minimize the potential for unblinding, the 
study drug administrator will be allowed to perform only the following study-related procedures: 
preparing injections, administering injections, contacting IWRS, receiving subject medication kit 
numbers, and keeping drug administration and accountability information. The study drug 
administrator will not be allowed to perform any other study-related procedures (including 
efficacy, safety, or other study evaluations) or to communicate subject-related information to 
study-site personnel, including the investigator. If the subject informs the study drug 
administrator of any adverse events that occurred since the last injection, the subject should be 
instructed to provide the same information to other study staff. The investigator must explain to 
the subjects that the only subject-facing role for the study drug administrator is to administer the 
injections.
In exceptional circumstances, where an assigned study drug administrator is not available to 
administer study drug, another adequately trained investigational staff member may administer 
study drug during the Maintenance Phase only. As with the study drug administrator, any other 
person responsible for study drug administration will not be allowed to perform any other study-
related procedures (including efficacy, safety, or other study evaluations) or to communicate 
subject-related information to study-site personnel, including the investigator.
Blinding: Investigational Staff
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, study drug serum concentrations
or prolactin levels) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and unblinding.
The investigator/subinvestigator who assesses the injection site for tenderness, erythema/redness, 
and induration/swelling should not review the subject's VAS rating of the injection site pain. 
(This is not applicable to other study-site personnel.)
Intentional Unblinding
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment or emergent course of action would be dictated by knowing the treatment 
status of the subject. In such cases, the investigator or designee may in an emergency determine 
the identity of the treatment by contacting the IWRS. It is recommended that the investigator 
contact the Sponsor or its designee if possible to discuss the particular situation, before breaking 


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the blind. Telephone contact with the Sponsor or its designee will be available 24 hours per day, 
7 days per week. In the event the blind is broken, the Sponsor must be informed as soon as 
possible. The date, time, and reason for the unblinding must be documented in the appropriate 
section of the electronic Case Report Form (eCRF) and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner. Subjects who have had their treatment 
assignment unblinded should be withdrawn from the study.
6.
DOSAGE AND ADMINISTRATION
6.1.
Dosage
6.1.1.
Screening Phase
During the Screening Phase, subjects must have already been receiving PP1M at 100 or 
150 mg eq., PP3M at 350 or 525 mg eq., injectable risperidone at 50 mg, or an oral antipsychotic 
at any dosage with a reason to change, as described in Section 4.1 (Inclusion Criteria).
If subjects have no documented tolerability to any oral or injectable risperidone or paliperidone
formulations, then an oral tolerability test should be conducted. To demonstrate oral tolerability, 
paliperidone ER/PR 6 mg tablets or risperidone 3 mg/day (dose may be divided) will be given 
during the Screening Phase for 4 to 6 consecutive days with the last dose swallowed on or before 
Day -1. The recommended dose is paliperidone ER/PR of 6 mg/day or risperidone 3 mg/day 
(dose may be divided), but higher doses of paliperidone or risperidone may be used if clinically 
indicated, based on investigator judgment. Oral tolerability testing may be concurrent with any 
required washout of other medications. Tapering of oral tolerability medication during this 
period is not required. Subjects should be instructed not to chew, divide, dissolve, or crush the 
paliperidone ER/PR tablets, since an effect on the release profile is possible. The oral tolerability 
test will allow the investigator to assess possible problems with tolerability (including allergic or 
hypersensitivity reactions) that may be related to paliperidone. Examples of problems that would 
lead to exclusion of the subject would include intolerable sedation, clinically symptomatic 
orthostatic hypotension, torticollis or other severe EPS, or evidence of an allergic reaction.
For subjects with previously established tolerability to at least 1 oral or injectable risperidone or 
paliperidone formulation, the appropriate documentation may include medical or pharmacy 
records, a letter from a previous provider, or a written statement by the investigator of a credible 
report from the subject or subject's identified support person. These records must be filed in the 
source documents.
6.1.2.
Transition Phase
The Transition Phase is applicable only to subjects who entered the Screening Phase without 
previous PP1M or PP3M stability. These subjects may have been previously treated with oral 
antipsychotics, injectable risperidone, or a moderate or higher dose of PP1M with previous 
initiation but without previous stabilization (where stabilization is defined is at least 3 months of 
injections with the last 2 doses being the same strength), as shown in Figure 2 and as described 
below. In order to appropriately balance study groups at the Double-blind Phase baseline and to 


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complete the study in a timely manner, the pathway to study enrollment that includes the 
Transition Phase will be open for only a limited time. The Sponsor will inform the sites when 
this pathway and this phase have closed to enrollment.
See also Section 6.2.1 (Administration During the Open-label Phases).


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Figure 2:
Schematic Overview, Showing Additional Details for the Screening Phase and Transition Phase; Study R092670PSY3015
Key: mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); PP1M = paliperidone palmitate 1-month (product); PP3M = paliperidone palmitate 
3-month (product); PP6M = paliperidone palmitate 6-month (product).
a
If subjects in this group have no documented tolerability to any oral or injectable risperidone or paliperidone formulations, then an oral tolerability test should be 
conducted during the Screening Phase.
b
After meeting the PP3M prerandomization target.
c
Before meeting the PP3M prerandomization target.
Note: See Figure 1 for other relevant explanatory notes.


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Transition Phase: Subjects Previously Treated With Oral Antipsychotics
In the Transition Phase, subjects previously treated with oral antipsychotics will receive PP1M as
150 mg eq. on Day 1 and 100 mg eq. on Day 8. Thereafter, the PP1M doses on Days 36, 64, 
and 92 will be flexible (as 50, 75, 100, or 150 mg eq.), based on clinical judgment and shared 
decision-making. Days 1, 8, 36, 64, and 92 correspond to Visits 2a, 2b, 2c, 2d, and 2e, 
respectively (see Table 3 and Table 4). Administration should be in the deltoid muscle on Days 1 
and 8 and may be either in the deltoid or gluteal muscles on Days 36, 64, and 92, as shown in 
Table 3 and Table 4.
After the PP3M prerandomization target is met, these subjects will skip Visit 2e and proceed to 
Visit 2f if the subject is eligible to enter the Maintenance Phase (see Section 4.3, Criteria for 
Entry Into the Maintenance Phase). If not eligible to enter the Maintenance Phase, the subject 
will be withdrawn from the study.  
If a subject was previously treated with oral paliperidone ER/PR tablets and had acceptable 
efficacy and tolerability, then the Day 36 dose of PP1M may be based on the conversion 
provided in Table 2. If the previous dosage of oral paliperidone had insufficient efficacy, then 
the investigator may consider a higher dosage of PP1M. If the previous dosage of oral 
paliperidone caused problems with intolerability, then the investigator may consider a lower 
dosage of PP1M.
Table 2:
Doses of Paliperidone ER/PR Tablets and PP1M Needed to Attain Similar Steady-state 
Paliperidone Exposure
Previous Paliperidone ER/PR Tablet, Once Daily
PP1M Injection, Once Every 4 Weeks
12 mg
150 mg eq.
9 mg
100 mg eq.
6 mg
75 mg eq.
3 mg
50 mg eq.
Key: ER/PR = extended-release/prolonged-release; mg eq. = (paliperidone palmitate) milligrams equivalent 
(to paliperidone); PP1M = paliperidone palmitate 1-month (product).
Source: Adapted from the United States Prescribing Information for PP1M.e the lowest dose of PP1M is 
omitted because it is not relevant to this study.
Transition Phase: Subjects Previously Stabilized on Injectable Risperidone (Biweekly –
Risperdal CONSTA™ formulation, also named as RISPERDAL CONSTA 50 mg powder 
and solvent for prolonged-release suspension for injection formulation in certain countries)
In the Transition Phase, subjects previously stabilized on injectable risperidone 50 mg are not 
required to attend the Day 1 visit. On the Day 8 visit, when the subject's next planned injectable 
risperidone dose would have been administered (ie, 14±3 days after the last prestudy dose),
PP1M 100 mg eq. is administered instead. (This conversion scheme is established in the 
                                                
ee
INVEGA SUSTENNA® [United States Prescribing Information]. Titusville, NJ: Janssen Research & Development. 
www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=022264. Accessed 19 June 2017.


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prescribing information of some countries.f) Thereafter, the PP1M doses on Days 36, 64, and 92
will be flexible (50, 75, 100, or 150 mg eq.), based on clinical judgment and shared decision-
making. Administration should be in the deltoid muscle on Day 8 and may be either in the 
deltoid or gluteal muscles on Days 36, 64, and 92, as shown in Table 3 and Table 4.
After the PP3M prerandomization target is met, these subjects will skip Visit 2e and proceed to 
Visit 2f, if eligible to enter the Maintenance Phase (see Section 4.3, Criteria for Entry Into the 
Maintenance Phase). If not eligible to enter the Maintenance Phase, the subject will be 
withdrawn from the study.
Transition Phase: Subjects Previously Initiated (But Not on a Stable Regimen) With 
Moderate or Higher Doses of PP1M (Invega Sustenna ™ or Xeplion ™ formulation)
In the Transition Phase, subjects who entered the study on PP1M as 100 or 150 mg eq., but who 
do not yet meet criteria for stabilization with those doses, are treated with additional doses of 
PP1M during the Transition Phase, as shown in Table 3 and Table 4.
After the PP3M prerandomization target is met, subjects previously initiated on PP1M (but not 
on a stable regimen) who enter the study at Visit 2c or 2d will skip Visit 2e and proceed to Visit 
2f, if eligible to enter the Maintenance Phase (see Section 4.3, Criteria for Entry Into the 
Maintenance Phase). Subjects with ≥4 prestudy PP1M injections with the last 2 doses being the 
same strength will enter the study at Visit 2f. Subjects with ≥4 prestudy PP1M injections with 
the last 2 doses being different (ie, do not have dose stability) will enter the study at Visit 2e. If 
not eligible to enter the Maintenance Phase, the subject will be withdrawn from the study.
Owing to potential differences in release characteristics, only subjects who are taking Invega 
Sustenna ™ or Xeplion ™ PP1M formulations will be permitted to enter this phase of the study. 
Subjects who are taking non-branded formulations of once monthly paliperidone LAI or other 
once monthly LAIs will not be permitted to enter this phase.
                                                
f
XEPLION® [European Union Product Information]. Beerse, Belgium: Janssen-Cilag International. 
www.ema.europa.eu/ema/index.jsp%3Fcurl%3Dpages/medicines/human/medicines/002105/human_med_001424.jsp. 
Accessed 19 June 2017.


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Table 3:
Dosage and Administration Schedule for PP1M During the Transition Phase (Before Meeting the PP3M Prerandomization Target);
Study R092670PSY3015
Phase
Screening
Transition; PP1M
Visit Number (of Study)
1
2a
2b
2c
2d
2e
Day (of Phase) a
-28 to -2
1
8
36 or EW
64 or EW
92 or EW b
Visit Window, ±Days
n/a
±3
±7
±7
±7
PP1M after prestudy oral antipsychotic
   Treatment/dose
Last prestudy dose of oral 
antipsychotic
150 mg eq.
100 mg eq. 
50,c 75, 100,
or 150 mg eq.
50,d 75,d 100,
or 150 mg eq.
50,d 75,d 100,
or 150 mg eq.
   Injection site
not applicable
D
D
D or G
D or G
D or G
   Day (of participation) a
-28 to -2
1st
8th
36th
64th
92nd
PP1M after prestudy injectable risperidone
   Treatment/dose
Last prestudy dose of injectable 
risperidone, 50 mg
Skip
100 mg eq.
50, 75, 100,
or 150 mg eq.
50,d 75,d 100,
or 150 mg eq.
50,d 75,d 100,
or 150 mg eq.
   Injection site
D or G
Skip
D
D or G
D or G
D or G
   Day (of participation) a
-14 to -2
Skip
1st e
29th
57th
85th
PP1M after 2 prestudy PP1M injections
   Treatment/dose
Last prestudy dose of PP1M, 
100 or 150 mg eq.
Skip
Skip
100 or 150 mg eq. 
100 to 150 mg eq. 
100 to 150 mg eq.
   Injection site
D or G
Skip
Skip
D or G
D or G
D or G
   Day (of participation) a
-28 to -2
Skip
Skip
1st f
29th
57th
PP1M after 3 prestudy PP1M injections
   Treatment/dose
Last prestudy dose of PP1M, 
100 or 150 mg eq.
Skip
Skip
Skip
100 or 150 mg eq.
100 or 150 mg eq.
   Injection site
D or G
Skip
Skip
Skip
D or G
D or G
   Day (of participation) a
-28 to -2
Skip
Skip
Skip
1st f
29th
PP1M after ≥4 prestudy PP1M injections g
   Treatment/dose
Last prestudy dose of PP1M, 
100 or 150 mg eq.
Skip
Skip
Skip
Skip
100 or 150 mg eq.
   Injection site
D or G
Skip
Skip
Skip
Skip
D or G
   Day (of participation) a
-28 to -2
Skip
Skip
Skip
Skip
1st f
(See Keys below Table 4)


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Table 4:
Dosage and Administration Schedule for PP1M During the Transition Phase (After Meeting the PP3M Prerandomization Target); 
Study R092670PSY3015
Phase
Screening
Transition; PP1M
Visit Number (of Study)
1
2a
2b
2c
2d
2e
Day (of Phase) a
-28 to -2
1
8
36 or EW
64 or EW
92 or EW b
Visit Window, ±Days
n/a
±3
±7
±7
±7
PP1M after prestudy oral antipsychotic
   Treatment/dose
Last prestudy dose of oral 
antipsychotic
150 mg eq.
100 mg eq. 
50,c 75, 100,
or 150 mg eq.
50,d 75,d 100,
or 150 mg eq.
   Injection site
not applicable
D
D
D or G
D or G
   Day (of participation) a
-28 to -2
1st
8th
36th
64th
Skip
PP1M after prestudy injectable risperidone
   Treatment/dose
Last prestudy dose of 
injectable risperidone, 50 mg
Skip
100 mg eq.
50, 75, 100,
or 150 mg eq.
50,d 75,d 100,
or 150 mg eq.
   Injection site
D or G
Skip
D
D or G
D or G
   Day (of participation) a
-14 to -2
Skip
1st e
29th
57th
Skip
PP1M after 2 prestudy PP1M injections
   Treatment/dose
Last prestudy dose of PP1M, 
100 or 150 mg eq.
Skip
Skip
100 or 150 mg eq. 
100 to 150 mg eq. 
   Injection site
D or G
Skip
Skip
D or G
D or G
   Day (of participation) a
-28 to -2
Skip
Skip
1st f
29th
Skip
PP1M after 3 prestudy PP1M injections
   Treatment/dose
Last prestudy dose of PP1M, 
100 or 150 mg eq.
Skip
Skip
Skip
100 or 150 mg eq.
   Injection site
D or G
Skip
Skip
Skip
D or G
   Day (of participation) a
-28 to -2
Skip
Skip
Skip
1st f
Skip
PP1M after ≥4 prestudy PP1M injections g
   Treatment/dose
Last prestudy dose of PP1M, 
100 or 150 mg eq.
Skip
Skip
Skip
Skip
Skip or 100 or 
150 mg eq.
   Injection site
D or G
Skip
Skip
Skip
Skip
D or G
   Day (of participation) a
-28 to -2
Skip
Skip
Skip
Skip
1st f


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Keys for Table 3 and Table 4: D = deltoid muscle; EW = Early Withdrawal; G = gluteal muscle; mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); 
PP1M = paliperidone palmitate 1-month (formulation).
a
Because some subjects skip visits during the Transition Phase, the day of the phase will not match the day of a subject's participation in all cases, as shown in this table.
b
Dose flexibility is permitted at this visit in order to accommodate individual needs for efficacy and tolerability, but if the dose at Day 92 is not the same as the dose at Day 64, then the 
subject will later be ineligible to proceed to the next phase, as described in Section 4.3 (Criteria for Entry Into the Maintenance Phase). If the dose at Day 92 is not the same as the dose 
at Day 64, then study-site personnel should anticipate the future ineligibility of the subject and should conduct the Day 92 visit as an Early Withdrawal Visit. See Section 10.2
(Discontinuation of Study Drug / Withdrawal From the Study).
c
The 50 mg eq. dose is permitted at this visit in order to accommodate individual needs for efficacy and tolerability, but use of the 50 mg eq. dose at this visit shows that a subject is 
unlikely to later achieve the 100 or 150 mg eq. dose required for eligibility to proceed to the next phase, as described in Section 4.3 (Criteria for Entry Into the Maintenance Phase). If 
the 50 mg eq. dose is administered, then study-site personnel should anticipate the future ineligibility of the subject and should conduct the visit as an Early Withdrawal Visit. See 
Section 10.2 (Discontinuation of Study Drug / Withdrawal From the Study).
d
The 50 and 75 mg eq. doses are permitted at these visits in order to accommodate individual needs for efficacy and tolerability, but use of these doses at these visits shows that subjects 
will later be ineligible to proceed to the next phase, as described in Section 4.3 (Criteria for Entry Into the Maintenance Phase). If these doses are administered, then study-site 
personnel should anticipate the future ineligibility of the subject and should conduct the visit as an Early Withdrawal Visit. See Section 10.2 (Discontinuation of Study Drug /
Withdrawal From the Study).
e
This visit should be scheduled to match the subject's next planned injectable risperidone dose (ie, 14±3 days after the last prestudy dose).
f
This visit should be scheduled to match the subject's next planned PP1M dose (ie, 30±7 days after the last prestudy dose).
g
Subjects with ≥4 prestudy PP1M injections may be eligible to skip the Transition Phase and proceed from the Screening Phase directly to the Maintenance Phase, if they have already 
achieved dose stability as described in Section 4.3 (Criteria for Entry Into the Maintenance Phase). If they have not, then the dose in this Transition Phase can be used to establish dose 
stability.


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6.1.3.
Maintenance Phase
For all subjects, the Maintenance Phase includes only 1 dose of PP1M as 100 or 150 mg eq. or 
PP3M as 350 or 525 mg eq. Each subject's Maintenance Phase dose will be matched by 
straightforward progression (PP1M to PP1M, or PP3M to PP3M) or will be matched by 
established conversion (PP1M to PP3M) to the same dose that they had been receiving during 
the Screening Phase or at the end of the Transition Phase. Progression versus conversion will 
depend on prestudy treatment types and on the need to balance the PP1M and PP3M groups in 
the Maintenance Phase, as described below.
To properly characterize outcomes when switching to PP6M from either PP1M or PP3M, 
adequate numbers of subjects treated with either PP1M or PP3M must be available during the 
Maintenance Phase for randomization to the Double-blind Phase. However, low enrollment of 
subjects previously treated with PP3M is expected. To address this issue, some subjects (after 
appropriate treatment with PP1M) will be switched to PP3M during the Maintenance Phase. This 
will occur early in the course of the study, until the target of approximately one-half of the total 
Maintenance Phase sample is treated with PP3M. In this document, the target is referred to as the 
"PP3M prerandomization target." The process is described in more detail below and is shown in 
Figure 3 and Figure 4.

Throughout the study, subjects who were receiving PP3M as 350 or 525 mg eq. before the 
study will receive the same formulation and strength in the Maintenance Phase.

Early in the study (before the PP3M prerandomization target is met), subjects with 
PP1M stability achieved before the study or during the Transition Phase will be converted to 
PP3M in the Maintenance Phase in accordance with the approved prescribing information. 
That is, subjects who were receiving PP1M as 100 or 150 mg eq. will receive PP3M as 
350 or 525 mg eq. See Figure 3. The Sponsor will inform sites when they should stop using 
this pathway.

Later in the study (after the PP3M prerandomization target is met), subjects with PP1M 
stability achieved before the study or during the Transition Phase will progress with PP1M
in the Maintenance Phase. That is, subjects who were receiving PP1M as 100 or 150 mg eq. 
will again receive PP1M as 100 or 150 mg eq. See Figure 4 The Sponsor will inform sites 
when they should start using this pathway.
For subjects who enter the study with previous PP1M or PP3M stability, the dose in the 
Maintenance Phase should be administered with timing appropriate to the subject's last prestudy 
dose (ie, 30±7 days after the last prestudy PP1M dose, or 90±14 days after the last prestudy 
PP3M dose). In order to appropriately balance the number of PP1M and PP3M subjects in the 
Maintenance Phase and to complete the study in a timely manner, the pathway to study 
enrollment that includes subjects who enter the study with previous PP3M stability will be open 
for only a limited time. The Sponsor will inform the sites when this pathway has closed to 
enrollment.


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For subjects who enter the study without previous PP1M or PP3M stability, the dose in the 
Maintenance Phase should similarly be administered with timing appropriate to the subject's last 
dose in the preceding Transition Phase (ie, 28±3 days after previous PP1M dose).
See also Section 6.2.1 (Administration During the Open-label Phases).


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Figure 3:
Schematic Overview, Showing Additional Details for the Maintenance Phase (Before Meeting the PP3M Prerandomization Target); 
Study R092670PSY3015
Key: mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); PP1M = paliperidone palmitate 1-month (product); PP3M = paliperidone palmitate 3-month 
(product); PP6M = paliperidone palmitate 6-month (product).
Note: See Figure 1 and Figure 2 for other relevant explanatory notes.
Note: The grayed-out treatment pathway in the Maintenance Phase is not applicable before the meeting the PP3M prerandomization target, but is shown here for consistency 
with other figures, especially Figure 4. Of subjects entering the Double-blind Phase, the prerandomization targets are approximately one-half entering from a PP3M group, 
and one-half entering from a PP1M group.


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Figure 4: Schematic Overview, Showing Additional Details for the Maintenance Phase (After Meeting the PP3M Prerandomization Target); 
Study R092670PSY3015
Key: mg eq. = (paliperidone palmitate) milligrams equivalent (to paliperidone); PP1M = paliperidone palmitate 1-month (product); PP3M = paliperidone palmitate 
3-month (product); PP6M = paliperidone palmitate 6-month (product).
Note: See Figure 1 and Figure 2 for other relevant explanatory notes.
Note: Of subjects entering the Double-blind Phase, the prerandomization targets are approximately one-half entering from a PP3M group, and one-half entering from a 
PP1M group.


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6.1.4.
Double-blind Phase
The PP1M and PP3M dose levels that were administered in the Maintenance Phase will be 
converted to PP3M or PP6M dose levels for the Double-blind Phase as follows:

For the active control group,
The open-label PP1M doses (100 or 150 mg eq.) will be converted to double-blind PP3M doses 
(350 or 525 mg eq.) in accordance with the approved prescribing information for PP3M.
The open-label PP3M doses (350 or 525 mg eq.) will continue at the same double-blind dose 
level.

For the investigational drug group,
The open-label 100 mg eq. PP1M and 350 mg eq. PP3M doses will be converted to double-blind 
700 mg eq. PP6M doses.
The open-label 150 mg eq. PP1M and 525 mg eq. PP3M doses will be converted to double-blind 
1000 mg eq. PP6M doses.
To maintain the blind, the subjects who are assigned to treatment with PP6M will receive 
injections of placebo at the 3-month time points between their 6-month doses of investigational
drug. The placebo is 20% Intralipid® (200 mg/mL) injectable emulsion. Therefore, the 12 month 
Double-blind Phase should include a total of 4 doses at 3-month intervals, no matter which 
treatment group.
Conversions between doses are summarized in Table 1. The actual dates and times of each study 
drug administration will be recorded in the eCRF.
6.1.5.
Treatment After the Study or in the Follow-up Phase
See Section 10.3 (Antipsychotic Therapy After the Study or in the Follow-up Phase). Such 
treatments are nonstudy treatments and therefore are not described here.
6.2.
Administration
For each dose, a study-site personnel member must shake the syringe vigorously with the tip 
facing up and with a loose wrist for at least 15 seconds to ensure a homogeneous suspension. The 
shaken dose must then be administered within 5 minutes after shaking. If more than 5 minutes 
pass after shaking but before injection, then a study-site personnel member must shake the 
syringe vigorously again for at least 15 seconds to resuspend the dose. The full content is to be 
administered in one injection, using only the supplies provided in the study drug kit.
6.2.1.
Administration During the Open-label Phases
During the Transition Phase and Maintenance Phase, injections will be in the deltoid or gluteal 
muscles in accordance with the prescribing information for PP1M or PP3M, and will use 
injection kits equivalent to commercially available kits. For the Transition Phase, see also 
Table 3 and Table 4 for more information about sites (deltoid or gluteal). For the Maintenance 
Phase, the injection may be in the deltoid or gluteal muscle (note: Day 1 injection should not be 


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administered at the same site as the last injection), but may not be in the left gluteal muscle 
(because of the anticipated left gluteal injection at the beginning of the Double-blind Phase, as 
shown in Table 5).
6.2.2.
Administration During the Double-blind Phase
During the Double-blind Phase, injections will be in the gluteal muscles only, will use study-
specific injection kits, and will rotate across sides of the body as described in Table 5.
Table 5:
Administration of Study Agent During the Double-blind Phase; Study R092670PSY3015
Time Point in
Double-blind Phase
Day 1
Day 92
Day 183
Day 274
Double-blind Injection
First
Second
Third
Fourth
Active Control Groups
   Agent
PP3M
PP3M
PP3M
PP3M
   Body side
Left
Right
Right
Left
Investigational Groups 
   Agent
PP6M
Placebo
PP6M
Placebo
   Body side
Left
Right
Right
Left
Key: PP3M = paliperidone palmitate 3 month (product); PP6M = paliperidone palmitate 6 month (product).
Note: All administrations are gluteal during the Double-blind Phase.
See Attachment 1 for more details about administration during the Double-blind Phase.
7.
TREATMENT COMPLIANCE
The study drug administrator will administer the injections throughout the study and will record 
the date/time of dosing as well as the injection site (right or left side, and deltoid or gluteal 
muscle) in the eCRF.
8.
PRESTUDY AND CONCOMITANT THERAPY
8.1.
Prestudy Medical Therapy and Psychotherapy
Except as described in Section 4.2 (Exclusion Criteria), Section 4.5 (Prohibitions and 
Restrictions), Section 8.2 (Concomitant Therapy), and Section 8.3 (Prohibited Concomitant 
Medications), medications that are ongoing and stable at screening may be allowed to continue
thereafter into the study. Ongoing psychotherapy and other psychosocial interventions are 
allowed to continue. For psychiatric medications of special interest at study entry:

Antipsychotics: Other than PP1M or PP3M, no concomitant antipsychotic medications being 
used at screening are allowed to continue. Oral antipsychotics, including those being taken 
concomitantly with PP1M or PP3M, should be tapered and discontinued during the 
Screening Phase, with the last oral dose swallowed on or before Day -1. The appropriate
tapering and washout schedule is at the discretion of the treating physician. Note that 
subjects who enter the study on oral antipsychotic(s) alone (without PP1M or PP3M being 
used concomitantly) must have a valid reason to discontinue the oral antipsychotic(s), such 


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as problems with efficacy, safety, or tolerability, or preference for a LAI medication, as 
described in Section 4.1 (Inclusion Criteria).

Other psychiatric medications: Other medications taken for the treatment of psychiatric 
conditions are allowed at screening and to continue thereafter.
It is preferable that no changes have been made to any treatments (for psychiatric or other 
medical conditions) in the 30 days before screening.
8.2.
Concomitant Therapy
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) administered and/or used within 90 days of the first study drug dose, at 
entry, and throughout the study must be recorded in the eCRF. For subjects with prior PP3M 
stability, the date of the last prestudy dose would be 90±14 days prior to the first study drug 
dose, so its last date of administration must be recorded, even if >90 days from the first study 
drug dose. The study drug is not recorded as concomitant therapy in the eCRF. Recorded 
information will include a description of the type of drug, start and end dates of treatment, dosing 
regimen, and indication. Modification of an effective pre-existing therapy should not be made for 
the explicit purpose of entering a subject into the study.
Except as listed in Section 4.2 (Exclusion Criteria) and Section 8.3 (Prohibited Concomitant 
Medications), concomitant medications may be initiated during the study for medical or 
psychiatric reasons. New psychotherapies and psychosocial treatments may be started.

Anti-EPS medications: For antiparkinsonism medications, initiations or changes should be 
preceded by an AIMS, BARS, and SAS (even if not designated per Time and Events
Schedules). If beta-adrenergic blockers or benzodiazepines are given for akathisia, then 
initiations or changes should be preceded by a BARS (even if not designated per Time and 
Events Schedules). See Section 9.4.6 (Extrapyramidal Symptoms). The use of anti-EPS 
medications should be re-evaluated at regular intervals, and investigators and subjects 
should work together to lower and discontinue doses if clinically indicated.

Benzodiazepines: For the control of agitation, anxiety, akathisia, etc, lorazepam is the 
preferred benzodiazepine because of its low potential for drug-drug interactions and its 
relatively short half-life. If lorazepam is unavailable, then another equivalent short-acting 
benzodiazepine may be used; examples of allowed types and dosages are shown in Table 6, 
and others are similarly allowed per clinical judgment. Long-acting benzodiazepines
(specifically, chlordiazepoxide, flurazepam, diazepam, and clorazepate) are prohibited. 
Investigators are encouraged to use the lowest dose of benzodiazepine that is clinically 
necessary. Benzodiazepines must not be used in the 8 hours preceding any scheduled 
efficacy assessment or rating scale. If clinically needed, an injectable (intramuscular or 
intravenous) dose of lorazepam may be given through the first 4 weeks of study 
participation.
If benzodiazepines were used regularly during the Screening Phase, then the benzodiazepine 
treatment should be tapered in accordance with the maximum dosages stated in Table 6. Use 
of benzodiazepine dosages higher than the stated in the table must be approved by the 
medical monitor prior to dose increase.


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Table 6:
Maximum Allowable Benzodiazepine Daily Dosages; Study R092670PSY3015
Benzodiazepine
Approximate 
Equivalent 
Oral Dose, mg
Maximum Daily Dosage (mg/day)
Screening Phase and 
First 4 Weeks of 
Study Participation
Second 4 Weeks 
of Study 
Participation
After 8 Weeks of Study 
Participation, Through 
End-of-Study Visit
Preferred
  Lorazepam
6
6
3
2
Other
  Clonazepam
3
3
1.5
1
  Temazepam
90
90
45
30
If benzodiazepines are being initiated or changed for the treatment of akathisia, then a 
BARS should be conducted first (even if unscheduled), as described in Section 9.4.6.2
(Barnes Akathisia Rating Scale).

Sleep aids: For insomnia or sleep-related difficulties, subjects may use zolpidem, zaleplon,
zopiclone, or eszopiclone at dosages in accordance with the locally approved prescribing 
information. The frequency should not exceed once daily and the duration should not exceed 
7 consecutive days without reassessment. Sleep aid medications should not be used in the
8 hours preceding any scheduled efficacy assessment or rating scale.
8.3.
Prohibited Concomitant Medications

The concomitant medications described below may not be used during the study.
Concomitant oral and injectable antipsychotics are prohibited as follows:
After the Screening Phase, oral or injectable risperidone formulations and supplementary oral or 
injectable paliperidone formulations are prohibited.
During the Maintenance Phase, if any oral antipsychotic is required, then the subject is not 
eligible to continue to randomization.
During the Double-blind Phase, if any oral antipsychotic is required, then the subject should be 
evaluated according to parameters in Section 2.1.2.2 (Relapse Criteria).
During any phase (including the Screening Phase, during determination of eligibility), injectable
formulations of neuroleptic drugs based on active ingredients other than risperidone or 
paliperidone (eg, haloperidol decanoate, fluphenazine decanoate, etc) are prohibited.
Concomitant antipsychotics are prohibited even if they are used for nonpsychotic indications (eg, 
nausea, sleep, depression, etc).
Although concomitant antipsychotics are prohibited during the study as described above, these
medications may be initiated at the discretion of the investigator if considered necessary for the 
safety or wellbeing of the subject. If a concomitant antipsychotic is initiated, then:
o
Section 2.1.2.2 (Relapse Criteria) is relevant if the subject is completing the study 
related to the need for an antipsychotic, or
o
Section 10.2 (Discontinuation of Study Drug / Withdrawal From the Study) is 
relevant if the subject is withdrawing from the study related to the need for an 
antipsychotic.


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
Medicinal products known to prolong the QT interval - such as Class IA antiarrhythmics 
(eg, disopyramide, quinidine, or procainamide) and Class III antiarrhythmics (eg, 
amiodarone or sotalol); some antihistamines; some antibiotics (eg, fluoroquinolones like 
moxifloxacin or ciprofloxacin);
some antimalarials (eg, mefloquine); and some 
antipsychotics (eg, chlorpromazine or ziprasidone) and tricyclic anti-depressants are 
prohibited. (All concomitant antipsychotics are prohibited for reasons related to assessment 
of efficacy as described in the bullet points above, but antipsychotics that prolong the QT 
interval are specifically restated here due to relevance to safety.)

Inducers of proteins involved in the metabolism of paliperidone (ie, cytochrome P450 3A4) 
or the excretion of paliperidone (ie, p-glycoprotein) - such as rifampicin, carbamazepine, 
oxcarbazepine, barbiturates, phenytoin, troglitazone, and St. John's Wort - are prohibited.

Systemic antifungals are prohibited.

Antineoplastic agents are prohibited.

Medical marijuana is prohibited.

Long-acting benzodiazepines (specifically, chlordiazepoxide, flurazepam, diazepam, and 
clorazepate) are prohibited.

Mood stabilizers and anticonvulsants including, but not limited to: lithium, valproate, 
lamotrigine, carbamazepine, phenytoin, and gabapentin.

Antidepressants not taken at a stable dosage for 30 days before screening, and all 
nonselective/irreversible MAOIs. Throughout the study, an antidepressant (other than a 
nonselective MAOI) may be initiated in rare circumstances only after consultation with the 
Medical Monitor.

Any prescription, herbal, or over-the-counter agents with psychotropic actions, including 
any substances with stimulant and cognitive-enhancing properties.

Dopamine agonists, including, but not limited to: ropinirole, pramipexole, pergolide, 
cabergoline, lisuride and amantadine.

Nonantipsychotic dopamine antagonists, including, but not limited to, antiemetic 
medications with dopamine-blocking activity.
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
Overview
The Time and Events Schedules summarize the frequency and timing of measurements 
applicable to this study. If multiple assessments are scheduled for the same visit, then ECG and 
vital signs should be collected prior to blood sample collections (eg, PK, and/or laboratory tests) 
and blood sample collections should be collected prior to study drug injection. Evaluations of the 
injection site occur after study drug injection, as described in Section 9.4.8. Actual dates and 
times of assessments will be recorded in the source documentation.


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Beyond timing specified in the Time and Events Schedules, additional serum or 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.
For any 6 months of participation in the study, the total blood volume to be collected from each 
subject is expected to be less than 400 mL. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
Screening Phase
Screening procedures are outlined in the Time and Events Schedules and in associated text 
descriptions. For exclusion criteria relating to safety parameters, rescreening is not allowed, but 
retesting may be permitted, as described in Section 4 (Subject Population). For inclusion criteria 
related to prestudy medication parameters, rescreening is permitted once, as described in 
Section 4 (Subject Population).
Transition Phase
The Transition Phase is applicable only to subjects who entered the Screening Phase without 
previous PP1M or PP3M stability. These subjects may have been previously treated with oral 
antipsychotics, injectable risperidone, or a moderate or higher dose of PP1M with previous 
initiation but without previous stabilization (where stabilization is defined is at least 3 months of 
injections with the last 2 doses being the same strength). During this phase, subjects will be 
initiated and/or stabilized on PP1M, as shown in the relevant Time and Events Schedule and in 
associated text descriptions. At the end of this phase, subjects with adequate efficacy and 
tolerability on PP1M as 100 or 150 mg eq. may be eligible to continue to the Maintenance Phase
(see Section 4.3 [Criteria for Entry Into the Maintenance Phase]); subjects receiving PP1M as 
50 or 75 mg eq. will exit the study. If possible, the subject's identified support person should 
accompany the subject to the first visit in this phase.
Maintenance Phase
The procedures for the Maintenance Phase are outlined in the Time and Events Schedules and in 
associated text descriptions. At the end of this phase, subjects who do not meet the criteria for 
randomization (see Section 4.4 [Criteria for Entry Into the Double-blind Phase]) must withdraw 
from the study and have End-of-Phase Visit / Early Withdrawal Visit assessments performed, as 
outlined in the Time and Events Schedules. For subjects who did not take part in the Transition 
Phase, the subject's identified support person should accompany the subject to the first visit in 
this phase, if possible.
Double-blind Phase
The procedures for the Double-blind Phase are outlined in the Time and Events Schedules and in 
associated text descriptions. During this phase, investigators should ask subjects to return to the 
clinical site for unscheduled visits as required for any assessment of symptom worsening or 
possible adverse events. If a possible relapse is detected per PANSS criteria at a scheduled or 
unscheduled visit, as described in Section 2.1.2.2 (Relapse Criteria), then the investigator should 


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ask the subject to visit the clinical site 3 to 7 days later for a PANSS reassessment (if no such 
visit is already scheduled). Suspected relapses should prompt all of the following assessments at 
all associated clinic visits, even if not designated on the Time and Events Schedules:

A PK sample, per Section 9.3.1 (Pharmacokinetic Evaluations),

A full PANSS assessment, per Section 9.2.2 (Positive and Negative Syndrome Scale),

A CGI-S assessment, per Section 9.2.3 (Clinical Global Impression - Severity), 

A Columbia Suicide Severity Rating Scale (C-SSRS) assessment, per Section 9.4.7
(Columbia Suicide Severity Rating Scale), and

Testing for concomitant substances (both an alcohol breath test and a urine drug screen for 
illicit substances), per Section 9.4.2 (Clinical Laboratory Tests).
The EOP visit is to occur as soon as possible after relapse confirmation (preferably the same 
day).
Follow-up Phase
The procedures for the Follow-up Phase are outlined in the Time and Events Schedules and in 
associated text descriptions. The Follow-up Phase, when applicable, is supplementary after study 
completion. For relevant subjects, participation in the Follow-up Phase is encouraged but not 
required. No protocol deviations or violations are applicable during this phase. The Follow-up 
Phase is designed to be as low-burden and noninvasive as possible, in order to encourage 
participation by the affected subjects while still collecting minimal safety and efficacy data.
Accordingly during the Follow-up Phase, suspected relapses do not prompt the additional 
breadth of assessments (as described for the Double-blind Phase above), but should prompt the 
additional frequency of assessments if relevant (ie, if PANSS scores indicate potential relapse, 
then PANSS assessments should repeated 3 to 7 days later to confirm a relapse event).
9.2.
Efficacy Evaluations
9.2.1.
Qualified Raters
Only a qualified rater may administer the PANSS, CGI-S, and PSP scales. If possible, for a given 
subject, the same rater should administer the scales at all visits.
A qualified rater must be locally licensed to practice, alone or under supervision, in one of the 
following disciplines:

Psychiatry (eg, MD or DO), or

Senior Psychiatry Resident (eg, MD or DO) who fulfills the other requirements, or

Psychology (eg, PhD), or

Clinical specialty (at least a Master's degree; eg, MS or PhD) where patient care is a central 
component (eg, social work, counseling, psychology, nurse practitioner) and the practitioner 
is independently licensed.


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In addition, the qualified rater must have had:

Recent experience in performing PANSS ratings in psychiatry clinical studies,g and

At least 3 years of experience in evaluating patients with schizophrenia in an inpatient or 
outpatient setting, and

Qualification training in performing PANSS assessments (per certification by the Sponsor) 
and CGI-S assessments (per training by the Sponsor), and

Overall completion of the Sponsor's rater training.
9.2.2.
Positive and Negative Syndrome Scale
Full PANSS
The neuropsychiatric symptoms of schizophrenia will be assessed using the 30-item PANSS 
scale,20 which provides a total score (sum of the scores for all 30 items) and scores for 
3 subscales: the 7-item positive-symptom (P) subscale, the 7-item negative-symptom (N) 
subscale, and the 16-item general-psychopathology symptom (G) subscale. Each item is rated on 
a scale from 1 (absent) to 7 (extreme). A trained clinician experienced in the treatment of 
subjects with schizophrenia will administer the PANSS. An example of a full PANSS is 
provided in the Manual of Assessments. A full PANSS score should be administered at the time 
points indicated in the Time and Events Schedules, and at any clinic visit associated with a 
suspected relapse; see Section 2.1.2.2 (Relapse Criteria). The full PANSS should be administered 
using the Structured Clinical Interview (SCI-PANSS) format, or using an equivalent structured 
interview format to be provided by the Sponsor.
Abbreviated PANSS
At some time points (indicated in the Time and Events Schedule), an abbreviated form of the 
PANSS will be used to assess for change in symptoms. An abbreviated PANSS consists of the 
positive-symptom items P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory 
behavior), P6 (suspiciousness/persecution), and P7 (hostility), and the general-psychopathology
item G8 (uncooperativeness). If the abbreviated PANSS indicates worsening since the last full 
PANSS assessment or if the subject meets one or more symptom criterion for relapse, then the 
full PANSS should be administered (as the SCI-PANSS). For abbreviated PANSS assessments, 
raters should use the relevant questions from the SCI-PANSS or equivalent format.
9.2.3.
Clinical Global Impression - Severity
The CGI-S is included in the Early Clinical Development Evaluation Unit Assessment Manual 
that was published by the US National Institute of Mental Health (NIMH).13 This study uses a 
version of the CGI-S that is slightly modified from the original (to be more specific to psychosis, 
not general for mental illness), as was done in the Sponsor's other studies.8,9 This modified 
                                                
g
If a rater meets all criteria except the experience requirement, and is a subinvestigator at a study site where an
investigator does meet the experience requirement, then the experience requirement can be waived for the 
subinvestigator, in order to facilitate training of raters.


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CGI-S poses a single question to the investigator, to consider his or her total clinical experience 
with this particular population, and to rate the severity of the subject's psychotic disorder on a 
scale from 1 = not ill to 7 = extremely severe, as shown in the Manual of Assessments. A CGI-S 
score should be recorded at the time points indicated in the Time and Events Schedules, and at 
any clinic visit associated with a suspected relapse.
9.2.4.
Personal and Social Performance Scale
The PSP scale assesses the degree of dysfunction a subject exhibits 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 from 1 to 100 points, which can be interpreted in 10-point intervals as excellent 
functioning (91 to 100 points), good functioning (81 to 90 points), mild difficulties (71 to 
80 points), etc, as shown in the Manual of Assessments. Scores from 31 to 70 points indicate 
varying degrees of difficulty, and scores below 30 points indicate functioning so poor that 
intensive support or supervision is needed.29 Individual domain items of the PSP will be 
collected and recorded in the eCRF.
9.2.5.
Satisfaction With Participation in Social Roles
The Patient-Reported Outcomes Measurement Information System (PROMIS) group developed 
and evaluated the Satisfaction With Participation in Social Roles Short Form 8a (SPSR) with 
funding from the US National Institutes of Health (NIH) and other academic and research 
grants.14 A study in a diverse clinical population demonstrated the SPSR's responsiveness to 
change.14 The SPSR asks subjects to consider the past 7 days and to rate 8 items on 5-point 
Likert scales, with higher scores representing higher satisfaction. An example of the SPSR is 
provided in the Manual of Assessments.
Note: For subjects that require translation of the SPSR into their local language, the collection of 
the SPSR is optional until the final, approved translation is available.
9.2.6.
Abbreviated Treatment Satisfaction Questionnaire for Medication
The 9-item abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) was 
found to be a reliable and valid measure to assess treatment satisfaction in naturalistic study 
designs.5 Items are scored on 5- or 7-point Likert scales, with higher scores representing higher 
satisfaction. Subjects are asked to consider the time frame of the last 2 to 3 weeks, or since the 
last time the medication was used. An example of the TSQM-9 is provided in the Manual of 
Assessments.
9.3.
Pharmacokinetic and Pharmacodynamic Evaluations
9.3.1.
Pharmacokinetic Evaluations
Venous blood samples of approximately 4 mL will be collected to obtain approximately 2 mL of 
plasma, for measurement of plasma concentrations of paliperidone (and on selected samples, 
paliperidone palmitate) at the time points indicated in the Time and Events Schedules. During 
the study, the nominal sample collection times may be changed by the Sponsor with clear 


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communication to the investigator, but the total number of samples will not increase without a 
formal protocol amendment. The exact dates and times of blood sample collection must be 
recorded on the laboratory requisition form. Information about the collection, handling, and 
shipment of biological (PK) samples will be provided in a Laboratory Manual. Genetic analyses 
will not be performed on these PK samples. Subject confidentiality will be maintained.
The aim of the PK evaluations will be to characterize the time course of plasma paliperidone 
concentrations and PK parameters such as maximum and minimum plasma concentrations and 
timing. Therefore, 3 PK samples are scheduled weekly around the expected paliperidone peak at 
approximately 1 month after the PP6M dose, and 6 PK samples are scheduled weekly when 
approaching the end of the 6-month dosing interval. For paliperidone palmitate, PK evaluations 
will be performed on samples collected 2 days after the injections indicated in the Time and 
Events Schedules, to check for any prodrug in the bloodstream from possible partial 
intravascular injections.
In addition to PK sampling time points indicated in the Time and Events Schedules, sites should 
collect unscheduled PK samples associated with important efficacy or safety events, as follows:

If a relapse event occurs or is suspected, as defined in Section 2.1.2.2 (Relapse Criteria),
then a PK sample should be collected in association with this efficacy outcome.

If a serious or severe adverse event occurs, then a PK sample should be collected in 
association with this safety outcome.

At the investigator's discretion, an unscheduled PK sample related to an adverse event 
may be collected even if the event is not serious or severe.
To preserve the treatment blind, the results of any PK samples will not be revealed to the 
Sponsor or the study-site personnel (until use by the internal independent analyst for the 
Sponsor-blinded interim PK analysis and then by the Sponsor in the final analyses after database 
lock).
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of paliperidone at all indicated 
time points (and paliperidone palmitate at 2 days after injections) using a validated, specific, and 
sensitive method (eg, liquid chromatography with tandem mass spectrometry), by or under the 
supervision of the Sponsor. If deemed necessary to explain the study results, drug concentrations 
may be determined for paliperidone palmitate (at time points in addition to 2 days after 
injections), for paliperidone enantiomers, or for other antipsychotics (such as risperidone).
9.3.3.
Pharmacokinetic Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of paliperidone will be derived 
using population PK modeling. Baseline covariates (eg, body weight, age, sex, creatinine 
clearance, race) may be included in the model, if relevant. The PK analyses will be detailed in 


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one or more separate methods plans (outside the standard SAP) and one or more separate results 
reports (outside the standard Clinical Study Report [CSR]).
9.3.4.
Pharmacodynamic Evaluations
Samples collected for PK evaluations may also be used for pharmacodynamic (PD) evaluations. 
For safety outcomes, pharmacokinetic-pharmacodynamic (PK-PD) relationships may be 
evaluated in terms of any potential clustering of adverse events around the time of the maximum
plasma paliperidone concentration after a dose of PP6M. For efficacy outcomes such as relapse, 
PK-PD relationships may be evaluated, if appropriate. Any PK/PD analyses would be performed 
after database lock. The PK-PD analyses may be detailed in one or more separate methods plans 
(outside the standard SAP) and one or more separate results reports (outside the standard CSR).
9.4.
Safety Evaluations
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF. 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 evaluations of safety and tolerability as described below and according to 
the time points provided in the Time and Events Schedules.
9.4.1.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12 (Adverse Event Reporting).
9.4.2.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and urine samples for urinalysis will be 
collected. The investigator must review the laboratory results, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. The laboratory reports (except for prolactin results, which are blinded to study-site 
personnel and Sponsor) must be filed with the source documents.
The tests below will be performed by the central laboratory. For full panels, subjects should be in 
fasted state overnight or for at least 8 hours (and nonfasting exceptions should be noted). For the 
prolactin-only samples, fasting is not required. Information about the collection, handling, and 
shipment of biological (laboratory test) samples will be provided in a Laboratory Manual.


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
Hematology Panel
- hemoglobin
- red blood cell count
- hematocrit
- white blood cell count with differential
- platelet count
- hemoglobin A1c (only during the Screening 
Phase and the Double-blind Phase)

Serum Chemistry Panel
- sodium
- bilirubin
- potassium
- alkaline phosphatase
- chloride
- creatine phosphokinase
- bicarbonate
- lactic acid dehydrogenase
- blood urea nitrogen
- uric acid
- creatinine
- calcium
- glucose
- phosphate
- aspartate aminotransferase
- albumin
- alanine aminotransferase
- total protein
- gamma-glutamyltransferase
- magnesium
 
- prolactin, which will be blinded to the study-site personnel and Sponsor; some samples 
will be for prolactin only (not the other analytes listed above), as designated in the Time 
and Events Schedules.
- thyroid stimulating hormone.

Urinalysis
Dipstick
Sediment (performed if dipstick result is abnormal)
- specific gravity
- red blood cells
- pH
- white blood cells
- glucose
- epithelial cells
- protein
- crystals
- blood*
- casts
- ketones
- bacteria
- bilirubin
- any other findings
- urobilinogen
- nitrite*
- leukocyte esterase*
*If the dipstick result is abnormal, then flow cytometry or microscopy 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.
CCI


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
Additional Tests
For women of childbearing potential, highly sensitive serum pregnancy testing (for (-human 
chorionic gonadotropin) will be conducted during the Screening Phase, and urine pregnancy tests 
will be provided for local testing during the subsequent phases.
To facilitate confirmation of postmenopausal status as described in Section 4.1 (Inclusion 
Criteria), study-site personnel may order an FSH test if desired (per clinical judgment). For 
postmenopausal status, the FSH test can only be confirmatory, and cannot replace the associated 
requirement for 12 months of amenorrhea.
Urine drug screen kits (for illicit substances, including marijuana, even where legal) and alcohol 
breath tests will be provided for local use at the time points specified in the Time and Events 
Schedules. For any subject with a positive result for alcohol or illicit substances, the study-site 
personnel should administer the relevant test again at subsequent visits (even if not marked in the 
Time and Events Schedules) until a negative result is obtained. After a negative result is 
obtained, the subject can resume testing at the standard frequency as indicated in the Time and 
Events Schedules. These tests should also be administered whenever a relapse is suspected. 
Alcohol and illicit substances are strongly discouraged but are not exclusionary and are not cause
for withdrawal from the study.
9.4.3.
Electrocardiograms
Specific procedures for the 12-lead ECGs will be provided in a separate manual. Blinded 
cardiologists at a central ECG laboratory will read all ECGs in this study.
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, then the 
procedures should be performed in the following order: ECGs, vital signs, blood draw.
During the Screening Phase, the 2 required ECGs should be recorded at least 24 hours apart. The 
first ECG may be from prior medical record within the past year. The second ECG should be 
scheduled in a timely manner to ensure the cardiologist-read report is available before Visit 2; 
therefore, the Time and Events Schedules show the Screening Phase to extend through Day -2 
(not Day -1), to allow at least a day for ECG reading and reporting. On Day 1 of the relevant 
phase for the subject (ie, the first day of the Transition Phase for subjects without prestudy PP1M 
or PP3M stability, or the first day of the Maintenance Phase for subjects with prestudy PP1M or 
PP3M stability), a third ECG should be recorded and compared against the exclusion criteria 
before the first dose of study medication is administered; see Section 4.2 (Exclusion Criteria).
If any clinically significant ECG abnormality is observed during the study, then the study-site 
personnel should add ECG assessments for that subject at all subsequent visits (even if not 
marked in the Time and Events Schedules) until the abnormality is resolved.
A printout of all ECG recordings must be filed in the source document. Any clinically relevant 
changes that occur during the study must be recorded on the Adverse Event section of the eCRF.


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9.4.4.
Vital Signs
Vital signs include temperature, pulse/heart rate, respiratory rate, and blood pressure. Vital signs 
should be recorded before any invasive tests, such as blood draws. Blood pressure and 
pulse/heart rate measurements should be preceded by at least 5 minutes of rest in a quiet setting 
without distractions (eg, television, cell phones).
At each scheduled time point, blood pressure and pulse/heart rate measurements will be assessed 
twice (first after at least 5 minutes rest in supine position and then after 2 minutes standing, if 
possible) with a completely automated device. Pulse/heart rate will be measured each time for a 
full minute to minimize the effects of variability. The automated device should consist of an 
inflatable cuff and an oscillatory detection system. All values should be registered on a built-in 
recorder so that measurements are observer-independent. Manual techniques will be used only if 
an automated device is not available. Whether automated or manual, appropriately-sized blood 
pressure cuffs should be used for accurate reading of blood pressure. The same arm should be 
used for both supine and standing measurements.
If a subject is unable to stand up or is unable to remain standing for 2 minutes as a result of 
symptoms of orthostatic hypotension, then the blood pressure should be measured immediately 
after standing is discontinued, while the subject is in a sitting or supine position. Attendants 
should protect subjects from falling during the evaluations.
All vital sign measurements will be recorded on the eCRF.
9.4.5.
Physical Examinations
Physical examinations at the time points designated on the Time and Events Schedules include 
weight, waist circumference, and abnormalities. Height should also be measured at screening
only, in order to facilitate calculations of BMI (weight/height² as kg/m²).
9.4.6.
Extrapyramidal Symptoms
The scales to assess EPS will be the AIMS for dyskinesia, the BARS for akathisia, and the SAS 
for parkinsonism, at the visits noted in the Time and Events Schedules. Particular attention is 
given to assessing EPS around the expected timing of the maximum plasma paliperidone 
concentration after a PP6M dose.
In addition to scheduled AIMS, BARS, and SAS assessments, unscheduled assessments of these 
scales should be conducted before initiating or changing any antiparkinsonism drugs (all 
3 scales) or any beta-adrenergic blockers or benzodiazepines for akathisia (BARS only), as 
described in Section 8.2 (Concomitant Therapy).
9.4.6.1.
Abnormal Involuntary Movement Scale
The AIMS is included in the Early Clinical Development Evaluation Unit Assessment Manual 
from the US NIMH.13 The AIMS rates 9 items about dyskinesia on scale as 0 = none, 
1 = minimal, 2 = mild, 3 = moderate, and 4 = severe. It rates 1 item about the subject's awareness 
of abnormal movements as 0 = no awareness; 1 = aware, no distress; 2 = aware, mild distress; 


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3 = aware, moderate distress; and 4 = aware, severe distress. It has 2 yes/no questions about 
dental status. An example of the AIMS is provided in the Manual of Assessments.
9.4.6.2.
Barnes Akathisia Rating Scale
The BARS assesses akathisia via 1 objective rating and 2 subjective ratings (awareness of 
restlessness and reported distress related to restlessness); each is scored from 0 to 3 points.3 It 
also assesses akathisia via 1 global clinical rating scored from 0 to 5 points. For all items, 
anchors are provided for each value and higher scores indicate worse akathisia. An example of 
the BARS is provided in the Manual of Assessments.
9.4.6.3.
Simpson Angus Scale
The SAS is led by signs (rather than by symptoms) to measure drug-induced parkinsonism.34
This study uses a version of the SAS that is slightly modified from the original (where the "head 
dropping" item was changed to "head rotation," to avoid injury to the cervical spine), as was 
done in the Sponsor's other studies.8,9 This modified SAS contains 10 items: 6 items for rigidity 
(arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, and head 
rotation); 1 compound item for gait (incorporating gait, posture, and loss of arm swing), and 
3 items for tremor, glabellar tap, and salivation. An example of the SAS is provided in the 
Manual of Assessments.
9.4.7.
Columbia Suicide Severity Rating Scale
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed in a US NIMH study to assess severity and track suicidal events through any 
treatment, and is the prospective counterpart to the system developed by Columbia University 
investigators for the US FDA in their analysis of the association between suicidality and 
medication.31 The C-SSRS is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present. It can also be used during treatment to monitor for clinical 
worsening. The C-SSRS Baseline Version assesses suicidal behavior and ideation over a 
lifetime, and the C-SSRS "Since Last Visit" Version assesses those parameters over an interval. 
The appropriate version of the C-SSRS should be administered at the time points indicated in the 
Time and Events Schedules, and at any clinic visit associated with a suspected relapse. Examples 
of the C-SSRS (Baseline/Screening Version and "Since Last Visit" Versions) are provided in the 
Manual of Assessments.
9.4.8.
Evaluations of the Injection Site
9.4.8.1.
Injection Site Evaluations by Subjects
The VAS to measure pain has been widely used in diverse adult populations.15 The VAS is a 
continuous scale on a horizontal or vertical line, usually 100-mm long, and anchored by 2 verbal 
descriptors (1 for each symptom extreme).15 The instructions, time period for reporting, and 
verbal descriptor anchors have varied widely in the literature depending on the intended use of 
the scale.15 In some settings, test-retest reliability and ability to detect change have been 
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In this study, subjects will be asked about the pain associated with the injection by means of a 
100-mm VAS, scaled from "no pain at all" to "unbearably painful." (Similar VAS assessments 
were used in previous studies of PP3M.8,9) The VAS-Acute will assess pain once within 
30 minutes after each injection. The VAS-Residual will assess pain at the time points days or 
weeks later as indicated in the Time and Events Schedules; the subject does not complete a VAS 
at the End-of-Phase Visit. The VAS is scored by measuring the distance (in millimeters) from the 
left (indicating no pain) to the place mark made by the subject.
9.4.8.2.
Injection Site Evaluations and Follow-up by Investigators
Investigators or subinvestigators (but not other study-site personnel) will evaluate the injection 
sites for tenderness, erythema/redness, and induration/swelling, at the same time points as the 
VASs completed by the subject, plus at the End-of-Study Visit or at the time of early withdrawal. 
The characteristics will be scored as 0 = absent, 1 = mild, 2 = moderate, or 3 = severe, in 
accordance with the anchor points that are provided in the Manual of Assessments. For 
erythema/redness, a score of 0 is used for a measurement of <2.5 cm, a score of 1 is used for 2.5-
5 cm, a score of 2 is used for 5.1-10 cm, and a score of 3 is used for >10 cm. Two dimensions of 
induration/swelling are assessed: measurement and impact on function. The dimension yielding 
the higher score will be the one selected for this assessment. Measurement scores are the same as 
those used for erythema/redness (ie, 0 = <2.5 cm, 1 = 2.5-5 cm, 2 = 5.1-10 cm, 3 = >10 cm). 
Functional scores are as follows: 0 and 1 = no interference with the subject’s usual activities, 2 = 
interferes with (but does not prevent) one or more of the subject’s usual activities, 3 = prevents 
one or more of the subject’s usual activities. Tenderness ratings are as follows: 0 = no 
tenderness, 1 = mild discomfort to touch, 2 = discomfort with movement, 3 = significant 
discomfort at rest. The scales and anchors are a hybrid from the Sponsor's previous studies of 
PP3M,8,9 and from a US FDA guidance.h The results will be recorded on the eCRF. The 
investigator/subinvestigator should complete these assessments within 30 minutes after the 
injection and at all visits marked in the Time and Events Schedules thereafter; for any 
characteristic
still rated mild, moderate, or severe at the last marked visit, the 
investigator/subinvestigator should add assessments at subsequent visits (even if not marked) 
until all of the characteristics are rated absent. Clinical sites should make efforts to have the same 
individual perform all injection site evaluations for a particular subject. This individual should 
not review the subject's VAS rating of the injection site pain.
                                                
h
US FDA. Guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in 
preventive vaccine clinical trials. www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm091977.pdf. Issued September 2007. 
Accessed 14 April 2017.


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If a subject has an injection site adverse event that is rated as moderate or severe (see 
Section 12.1.3 [Severity Criteria]) and that is accompanied by objective findings (eg, tenderness, 
erythema/redness, and induration/swelling), then the clinical site should perform or refer for 
ultrasonography of the injection site and should refer the subject to a specialist for further 
evaluation.

For ultrasonography, the goal is to identify phlegmonous processes that might evolve to 
overt abscesses of the gluteus and to differentiate real granulomatous reactions from less 
relevant topical reactions.

For referrals, considerations are as follows:
Suspected cellulitis or abscess should be referred to a dermatologist or surgeon for consideration 
of incision and drainage procedure along with tissue microbiological samples.
Nodule, fibroma, furuncle or other noninfectious reaction with a severity assessment of either 
moderate or severe should be referred to a dermatologist or surgeon for consideration of fine 
needle aspiration and/or tissue biopsy.
The investigator should follow any clinically significant abnormalities persisting at the end of the 
study until resolution or until reaching a clinically stable endpoint.
9.5.
Benefit-risk Evaluations
Evaluations already defined for efficacy and safety will be used for the benefit-risk assessment. 
Benefit will be evaluated as described in Section 2.1.2.2 (Relapse Criteria), and will include 
relapse per all causes, relapse per psychiatric hospitalization, or relapse per PANSS total score. 
Risk will be evaluated as described in Section 9.4 (Safety Evaluations), and will include the 
following: adverse events overall; adverse events of special interest (eg, from the list in 
Section 1.1 [Background]); adverse events that are serious or that lead to discontinuation; clinical 
laboratory tests (for risk of hyperprolactinemia or hyperglycemia); ECGs (for risk of QTcF 
increase >60 milliseconds); and physical examinations (for risk of weight gain ≥7%). The 
benefit-risk evaluations may also include other unexpected clinically relevant adverse events that 
occur during the Double-blind Phase, or that are a consequence of a pre-existing condition that 
has worsened since the start of the Double-blind Phase.
9.6.
Other Exploratory Evaluations
9.6.1.
Healthcare Resource Utilization Questionnaire
The Healthcare Resource Utilization (HRU) questionnaire was designed to assess utilization of 
the following resources: hospitalization (refers to ≥1 night stay), emergency room visits without 
hospitalization, day or night clinic stays, outpatient treatment, as well as daily living conditions 
and productivity of the subject.24 The questionnaire will be used in this study as an exploratory 
tool and has been modified with recall periods appropriate to the study. Study-site personnel will 
administer the questionnaire. If possible, for a given subject, the same person should administer 
this scale at all visits. The subject will be the primary provider of the information, but additional 
outside information should also be included as available, including information from any
caregivers. Any resource utilization that is required by the protocol should not be captured on the 


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questionnaire. Examples of the HRU questionnaires (baseline assessment and postbaseline 
assessment) are provided in the Manual of Assessments.
9.6.2.
Involvement Evaluation Questionnaire
The Involvement Evaluation Questionnaire (IEQ) was designed to measure levels of caregiver 
consequences among family members and friends of subjects with schizophrenia.35 The version 
of the IEQ to be used in this study will contain 5 questions about the demographics of the 
caregiver, and will pose the 31 standard items in the IEQ, and will exclude the "supplementary" 
questions. The 31 standard questions are answered on 5-point Likert response scales to address 
consequences among 4 dimensions (tension, supervision, worrying, and urging). Data are 
available to support its reliability.35 The IEQ should be completed by a designated caregiver for 
the subject. The designated caregiver who will be completing the questionnaire is someone who 
is mutually agreed upon between the subject and the investigator, should not be a paid caregiver 
but may be a family member, significant other, or friend who provides at least 1 hour of support 
to the subject per week. The same individual should complete the questionnaire throughout the 
study and should attend study visits when the IEQ is scheduled to be completed. In order to 
support the interpretation of the data and further explore the impact of caregiving, supplemental 
questions about the sociodemographics, time spent caregiving, and health care utilization of the 
caregiver will be collected from the designated caregiver at the times the IEQ is administered 
according to the Time and Events Schedules. This IEQ may be completed by mail or telephone 
or may be performed one month before or after the visit, based on availability of the caregiver. If 
a subject has no caregiver providing at least 1 hour of support per week, then the IEQ may be 
omitted. Examples of the IEQ (baseline assessment and postbaseline assessment) are provided in 
the Manual of Assessments; along with the comments about the IEQ recall periods.
9.6.3.
Concomitant Substances Questions
Use of nicotine will be questioned as indicated in the Time and Events Schedules. Examples of 
the questions are provided in the Manual of Assessments.
9.6.4.
Illness Management and Recovery Scale
The Illness Management and Recovery (IMR) scale (client self-report version) for schizophrenia 
and other severe mental illnesses was developed as part of the US National Implementing 
Evidence-based Practices Project and is made available by the US Substance Abuse and Mental 
Health Services Administration.30 The IMR scale asks subjects to consider the past 3 months and 
to rate 15 items about personal goals, knowledge of mental illness, involvement with significant 
others, impaired functioning, symptoms, stress, coping, relapse prevention, hospitalization, 
medication, and use of drugs and alcohol. The response range for each item is from 1 to 5 points, 
with higher scores indicating better outcomes. An example of the IMR scale (client self-report 
version) is provided in the Manual of Assessments. This study uses a version of the IMR that is 
slightly modified from the original, to make the recall periods more appropriate to the study.


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9.6.5.
Schizophrenia Quality of Life Scale (Revision 4)
The Schizophrenia Quality of Life Scale (SQLS) was initially developed using items generated 
from in-depth patient interviews (ie, the perspective of patients was used to develop the SQLS).27
Thereafter, the SQLS was further developed and revised to improve its psychometric properties. 
The most recent version (Revision 4) has been translated into dozens of languages through 
standardization procedures.22
The SQLS (Revision 4) has 33 items covering topics such as psychosocial feelings and vitality. 
Response options are never, rarely, sometimes, often, or always. Scoring algorithms yield a 0 to 
100 scale, with higher scores indicating lower quality of life. The factor structure and internal 
reliability have been verified in patients with schizophrenia in the Netherlands and further 
replicated in patients with schizophrenia in the United Kingdom and Taiwan.22,27
An example of the SQLS (Revision 4) is provided in the Manual of Assessments.
10.
SUBJECT COMPLETION / DISCONTINUATION OF STUDY DRUG /
WITHDRAWAL FROM THE STUDY
An End-of-Phase Visit (as outlined in the Time and Events Schedules) may be conducted as an 
Early Withdrawal Visit if a subject is unable to complete a phase before reaching randomization, 
or unable to progress between phases before reaching randomization, or unable to complete the 
Double-blind Phase. An End-of-Phase Visit (as outlined in the Time and Events Schedules) may 
be conducted as an End-of-Study Visit if a subject is completing the Double-blind Phase (see 
Section 10.1 [Completion]). 
10.1.
Completion
A subject will be considered as having completed the study if he or she has had a relapse during 
the Double-blind Phase and has completed all End-of-Study Visit assessments, or has remained 
relapse-free during the Double-blind Phase and has completed all End-of-Study Visit 
assessments. The definition for completing the Double-blind Phase is the same as for completing 
the study. The Follow-up Phase, when applicable, is supplementary after study completion.
10.2.
Discontinuation of Study Drug / Withdrawal From the Study
Discontinuation of Study Drug
A subject will not be automatically withdrawn from the study if he or she discontinues treatment 
before the end of the treatment regimen. A subject's study drug must be discontinued if the 
investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it is in the 
best interest of the subject to discontinue study drug, or if the subject becomes pregnant.

If a subject discontinues after receiving at least 1 dose of open-label study drug but before 
receiving any double-blind study drug, then End-of-Study Visit assessments should be 
obtained and no Follow-up Phase is applicable.

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If possible, the scheduled assessments (including PK samples) should be continued through the 
relevant 6-month cycle of assessments (Visits 7 to 20, or Visits 20 to 33) . If the subject has not 
completed at least 1 year of the Double-blind Phase, then either:
o
The subject may, if preferred, continue with assessments (but without study drug 
administration) until Visit 33a (the End-of-Study Visit), or
o
The subject may, if preferred, complete Visit 20 as an End-of-Study Visit, and then 
enter the Follow-up Phase until the full year of data have been collected after the 
first double-blind injection.
In any case, the last assessment of the relevant 6-month cycle (ie, Visit 20 or 33) should 
be conducted as an End-of-Study Visit. 
o
If it is not feasible for scheduled assessments to be continued through the relevant 
6-month cycle of assessments, then End-of-Study assessments should be obtained 
as soon as possible. The subject should then, if willing, enter the Follow-up Phase 
until 12 months of data have been collected after the first double-blind injection.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal of consent.

The blind is broken by the investigator.

Treatment with concomitant antipsychotic medication when relapse criteria are not met but, 
in the investigator's judgment, a concomitant antipsychotic medication is necessary for the 
subject's wellbeing, and viable alternatives are either not available or have been exhausted.

The subject fails to meet criteria for entry to Maintenance Phase.

The subject fails to meet criteria for entry to Double-blind Phase.

For subjects in the Transition Phase:

If the dose at Visit 2e is different than the dose at Visit 2d.

If the dose at Visit 2d or 2e is <100 mg eq.

If the dose is 50 mg eq. at any time.

For subjects in the Maintenance Phase:

If the dose at Visit 2f is different from the preceding dose or is not a dose equivalent of 
the preceding dose.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF 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.


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
If a subject withdraws from the study after receiving at least 1 dose of open-label study drug 
but before receiving any double-blind study drug, then End-of-Study Visit assessments 
should be obtained if the subject is willing to complete that visit.

If a subject withdraws from the study after receiving at least 1 dose of double-blind study 
drug but before the end of the Double-blind Phase, then End-of-Phase Visit / Early 
Withdrawal Visit assessments should be obtained if the subject is willing to complete that 
visit, even if the subject is withdrawing consent to complete any other visits. Thereafter:
If the subject is withdrawing consent, then the subject's study participation is complete.
If the subject is withdrawing for a reason unrelated to consent, then the subject should enter the 
Follow-up Phase.
Loss to Follow-up
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.
10.3.
Antipsychotic Therapy After the Study or in the Follow-up Phase
Open-label Treatment: Poststudy
If a subject discontinues or withdraws from the study in the Transition Phase or Maintenance 
Phase, then he or she may be considered for poststudy treatment with PP1M, PP3M, or another 
LAI antipsychotic at an interval appropriate to the open-label identity of the last study dose, as 
described in the approved prescribing information. Oral antipsychotic medications, if 
appropriate, may be restarted regardless of the timing of the last study injection. However, 
consideration should be given to the long-acting nature of paliperidone palmitate when the oral 
antipsychotic medication and dose(s) are selected. At the End-of-Phase Visit / Early Withdrawal 
visit and thereafter, the poststudy treatment after open-label treatment is at the discretion of the 
subject's physician; the study no longer follows these subjects.
Double-blind Treatment: Poststudy or Follow-up Phase
After discontinuation, withdrawal, or completion of the study in the Double-blind Phase, 
investigators/treating physicians may choose to continue treatment with paliperidone palmitate, 
switch to treatment with a different LAI antipsychotic treatment, or switch to oral antipsychotic 
treatment. Treatment selection is at the discretion of the subject's physician and is not a study 
medication. However, given the double-blind conditions and durations of activity expected from 
PP6M and PP3M, recommendations (not requirements) for poststudy or Follow-up Phase 
treatment schedules are provided in Figure 5 and Table 7 and Table 8 below.


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Figure 5:
Post Study Medication Algorithm
Risperidone or
Paliperidone
Another oral
PP1M or PP3M
Another LAI
Timing: find row in 
Table 7 that 
corresponds to 
timing of last study 
medication injection
Oral 
supplementation: 
per investigator 
judgment
1
Dose: per 
investigator 
judgment
LAI
ORAL
Dosing per 
investigator 
judgment.
1
Timing of starting 
oral at discretion of 
investigator. 
Dose 
recommendations 
in Table 8.
1
Double Blind 
Phase
Transition or 
Maintenance Phase 
(Open Label)
When Did Subject Discontinue?
Follow 
instructions per 
local label
What is desired post-
study medication?
1: Given the prolonged half-life of PP6M/3M/1M, 
oral medication dosing should be titrated up/down 
depending on investigator judgment and timing of 
the last injection.
Timing: find row in Table 7 that 
corresponds to timing of last 
study medication injection
Oral supplementation: 
supplement with oral RIS/PALI 
until next injection. See Table 8 
for oral dose.
1
Dose: Dose for first post double-
blind injection of PP1M/3M see 
Table 8.


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Table 7:
Timing of Resumption of PP1M/3M after the Double-blind Study or in Follow-Up Phase
Visit #
Day1
Study 
Medication 
Injection
Time to wait 
until next 
PP1M/PP3M 
injection 
(days)2
Visit #
Day1
Study 
Medication 
Injection
Time to wait 
until next 
PP1M/PP3M 
injection 
(days)2
7b
1
PP6M or 
PP3M
180
21
185
178
8
3
177
22
204
159
9
22
158
23
211
152
10
29
151
24
218
145
11
36
144
25
242
121
12
60
120
26
274
Placebo or 
PP3M
89
13
92
Placebo or 
PP3M
88
27
302
61
14
120
60
28
330
33
15
148
32
29
337
26
16
155
25
30
344
19
17
162
18
31
351
12
18
169
11
32
358
5
19
176
4
33
365
0
20
183
PP6M or 
PP3M
0
Footnotes: 1: Does not include visit window 2: Timing 
of resumption of oral antipsychotic may be at any time 
depending on investigator judgment
Table 8:
Switching Conversion Table (Oral and LAI Paliperidone and Oral Risperidone)
PP1M
PP3M
PP6M
Oral 
Paliperidone 
Oral 
Risperidone
Moderate Dose Group:
100 mg eq.
350 mg eq.
700 mg eq.
9 mg/day
3-4 mg/day 
Higher Dose Group: 
.
150 mg eq.
525 mg eq.
1000 mg
eq.
12 mg/day 
5-6 mg/day
Footnote: this provides a suggested starting dose of oral medications. The timing of 
the last injection must be taken into account, and oral dose adjusted as clinically 
warranted. 
10.4.
Process for Planned Study Closure
The calendar date of the end of Study R092670PSY3015 will be determined when a sufficient 
number of subjects have been randomized to the Double-blind Phase. To ensure that subjects can 
be assessed for 6 months after their last potential PP6M injection but cannot have End-of-Study
Visits after the calendar date that marks the end of the study, subjects will not receive injections 
that are potentially PP6M after the last subject randomized receives his or her last potential 
PP6M injection. The process for determining the calendar date of the end of the study and further 
explanation of the timing of End-of-Study Visits is described below.
Throughout the study, the Sponsor will monitor the number of subjects in the Transition, 
Maintenance, and Double-blind Phases. The Sponsor will notify all sites to close screening and 


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enrollment activities when an adequate number of subjects have been enrolled to achieve the 
target number (549 randomized) needed for participation in the Double-blind Phase. Subjects 
already participating in the Transition and Maintenance Phases will continue to progress through 
the study as described in the Time and Events Schedules, including progress into the Double-
blind Phase if eligibility criteria are met as described in Section 4.4 (Criteria for Entry Into the 
Double-blind Phase). Study R092670PSY3015 will conclude when the last subject to be 
randomized and remain in the study completes 12 months of the Double-blind Phase, which will 
be marked by completion of Visit 33a
During the Double-blind Phase, only the odd-numbered (ie, 1st, 3rd) injections are potentially 
PP6M.
11.
STATISTICAL METHODS
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the SAP.
11.1.
Subject Information
The populations for efficacy analyses, the double-blind intent-to-treat analysis population and the 
per-protocol analysis population, are described in Section 11.3 (Efficacy Analyses). Other 
analysis populations will be defined in a manner similar to a previous study of PP3M,8 and may 
include sets such as the following: the open-label intent-to-treat analysis population, the all 
randomized analysis population, and the safety analysis population. Full details will be provided 
in the SAP.
11.2.
Sample Size Determination
The sample size for the Double-blind Phase of the study is 549 randomized subjects, based on 
determinations to provide a minimum of 80% power for the primary endpoint. The sample size 
determination includes the assumptions that the expected survival rate (percentage of subjects 
remaining relapse-free at 12 months) in the PP3M group is 85%, and that the 1-sided 
significance level should be 2.5%. Given these assumptions, 549 subjects randomized in a 
2:1 ratio (PP6M:PP3M) are required to demonstrate with 80% power that PP6M is no worse than 
PP3M by a noninferiority margin of 10% for the percentage of subjects remaining relapse-free at 
12 months. This assumes that the efficacy observed in the PP3M group will be similar to the 
efficacy observed in the previous PP3M registrational Phase 3 studies (R092670PSY3011 and 
R092670PSY3012). The noninferiority margin of 10% and statistical methods for this analysis
were selected based on the Sponsor's previous studies and on advice from experts and health 
authorities, as follows:

In the Sponsor's previous placebo-controlled relapse prevention studies with oral 
paliperidone ER/PR, PP1M, and PP3M,9,18,21 a Kaplan-Meier estimate indicated that the 
meta-analytic estimate of treatment benefit of paliperidone over placebo was 42.1% (95% 
confidence interval: 28.4% to 55.8%).19


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
A panel of experts in the field of schizophrenia relapse prevention studies was convened to 
obtain recommendations for the clinical noninferiority margin to be used in this study. Using 
a modified Delphi approach, the mean value obtained after anonymous voting for the 
noninferiority margin was 13.4% (median 13.0%; range 10% to 20%).19 This clinical 
judgment based on expert opinion thus provided guidance on the largest loss of efficacy that 
could be considered clinically acceptable; in accordance with the relevant US FDA 
guidance,i the maximum was therefore set at 13.0%.19

Prior scientific advice from the Committee for Medicinal Products for Human Use had 
recommended a noninferiority margin of 10%.19

For all of the above reasons, an effect of 10% was chosen as the margin.
Further details are available in a separate statistical support document.19
The study design assumes discontinuation rates during the Transition and Maintenance Phases of 
20% for subjects who entered the study with previous PP1M or PP3M stability and 40% for 
subjects who entered the study without previous PP1M or PP3M stability. The study design also 
assumes a dropout rate of 10% during the Double-blind Phase (where the dropout rate also 
accounts for subjects excluded due to protocol violations). Given these assumptions for
discontinuation, 
the 
study 
targets 
approximately 
840 
subjects
to 
enter
the 
Transition/Maintenance Phase.
11.3.
Efficacy Analyses
11.3.1.
Primary Hypothesis and Efficacy Analyses
The primary hypothesis is that the efficacy of PP6M is noninferior to PP3M for preventing 
relapse in subjects with schizophrenia who were previously stabilized on corresponding doses of 
PP1M or PP3M.
11.3.1.1.
Double-blind Intent-to-Treat Analysis Population
11.3.1.1.1.
Primary Estimand
1.
The population is restricted to those who are stabilized on either PP1M or PP3M during the 
Maintenance Phase and meet the inclusion/exclusion criteria.
2.
The variable is time to a relapse event, and will be defined during the Double-blind Phase if
the subject experiences a relapse during the Double-blind Phase.
3.
The intercurrent effects are none, regardless of whether or not major protocol deviations had 
occurred.
4.
The population-level summary is the difference in Kaplan-Meier estimate at Month 12 of 
relapse-free proportions between the 2 treatment groups.
                                                
i
US 
FDA. 
Non-inferiority 
clinical 
trials 
to 
establish 
effectiveness: 
guidance 
for 
industry.
www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm202140.pdf. 
Issued November 2016. Accessed 15 May 2017.


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11.3.1.1.2.
Primary Efficacy Analyses
All subjects who receive at least 1 dose of study drug during the Double-blind Phase will be 
included in the double-blind intent-to-treat population. The primary endpoint is time to relapse in 
the Double-blind Phase, as described in Section 2.1.2.1 (Primary Endpoint). Subjects who meet 
at least 1 of the criteria for relapse (see Section 2.1.2.2 [Relapse Criteria]) during the Double-
blind Phase at the time of study completion for the primary analysis will be considered to have 
had a relapse event. Subjects who do not have a relapse event in the Double-blind Phase will be 
considered as censored. The statistics to test the primary hypothesis are based on the percentage 
of subjects who remain relapse-free at Month 12 in the PP6M and PP3M groups per Kaplan-
Meier estimate for the Double-blind Phase. The analysis will consider whether the lower limit of 
the 95% confidence interval of the difference in relapse-free rates between PP6M and PP3M 
exceeds the noninferiority margin of -10%. The standard error estimates will be based on 
Greenwood's formula. The null and alternative hypotheses use a 1-sided α=0.025 level, and are 
written as follows:
Null Hypothesis:  (% relapse-free)PP6M  - (% relapse-free)PP3M ≤ -10%
Alternative Hypothesis:  (% relapse-free)PP6M  - (% relapse-free)PP3M > -10%
11.3.1.1.3.
Sensitivity Analyses for Primary Efficacy
Additional sensitivity analyses with the double-blind intent-to-treat population will be performed 
to evaluate impact of censoring for subjects who withdraw from the Double-blind Phase before
Month 12 by using the data collected from the Follow-up Phase. Consistency of effect across 
various geographic regions will also be evaluated.
11.3.1.2.
Per-protocol Analysis Population
11.3.1.2.1.
Estimand
The primary efficacy analysis will also be performed on the per-protocol analysis population. 
The estimand of the per-protocol analysis population is defined by the following components:
1.
The population is restricted to those who are stabilized on either PP1M or PP3M during the 
Maintenance Phase and meet the inclusion/exclusion criteria.
2.
The variable is time to first occurrence of a relapse event, and will be defined if a subject 
experiences a relapse during the Double-blind Phase.
3.
The intercurrent events are major protocol violations that may impact efficacy; these include 
errors in treatment assignment, errors in the delivery of active medication, or use of 
prohibited medications.
4.
The population-level summary is the difference in Kaplan-Meier estimate at Month 12 of 
relapse-free proportions between the 2 treatment groups.
11.3.1.2.2.
Analyses
The analysis performed on the per-protocol analysis population will be based on the comparison 
between 2 treatment groups in subjects without the aforementioned intercurrent events; that is, in 


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randomized subjects who receive at least 1 dose of study drug during the Double-blind Phase, 
and do not have major protocol violations that may impact efficacy such as errors in the delivery 
of active treatment, errors in treatment assignment, or use of prohibited medication. The 
noninferiority analysis with 10% noninferiority margin as specified in Section 11.3.1.1 (Double-
blind Intent-to-Treat Analysis Population) will be repeated on the per-protocol analysis 
population.
11.3.2.
Secondary Efficacy Analyses
Clinically assessed secondary efficacy analyses include maintaining symptom control, 
functioning personally and socially, and achieving remission in each group (PP6M or PP3M, 
each sorted by dose level). The secondary efficacy analyses will be conducted using the double-
blind intent-to-treat analysis population.

Maintaining Symptom Control: For the Double-blind Phase, analysis of change in PANSS 
total and factor scores and in the CGI-S scores will be made based on a mixed model for 
repeated measurement analysis that will include a random effect for subject and fixed effects 
terms for treatment, visit (as a categorical variable), country, baseline score, and treatment-
by-visit interaction. For the Maintenance Phase, descriptive summaries (sorted by PP1M or 
PP3M dose groups) will also be provided.

Functioning Personally and Socially: Analyses of the PSP scores will be similar to the 
analyses for maintaining symptom control, as described in the bullet above.

Achieving Remission: For single observations, transitory symptomatic remission is defined 
as having a simultaneous score of mild or less (≤3 points) on the following 8 items from the 
PANSS: the positive-symptom items P1 (delusions), P2 (conceptual disorganization), 
P3 (hallucinatory behavior); the negative-symptom items N1 (blunted affect), N4 (social 
withdrawal), and N6 (lack of spontaneity); and the general-psychopathology items 
G5 (mannerisms/posturing) and G9 (unusual thought content).2 For multiple observations, 
durable symptomatic remission is defined as meeting those remission criteria for a 6-month 
period.2 For each treatment group, the number and percentage of subjects achieving durable 
symptomatic remission at the end of the Double-blind Phase will be presented. The point 
estimate and 2-sided 95% confidence interval will be provided for the relative risk using a 
Mantel-Haenszel test controlling for country. The count and percentage of remission status 
at each Double-blind Phase outcome time point will be presented by treatment group for 
subjects who were in remission at Double-blind Phase baseline. Point estimates and 2-sided 
95% confidence interval will also be provided for subjects meeting the remission criteria at 
each time point (including at the end of the study). Time to remission and maintenance of 
remission for longer than the 6-month period may also be assessed.
Subject-reported secondary efficacy analyses (ie, of the SPSR and the TSQM-9 outcomes) may
be detailed in a separate report (outside the standard SAP and CSR).
11.4.
Pharmacokinetic and Pharmacodynamic Analyses
Descriptive statistics will be calculated for the plasma concentrations of paliperidone and 
paliperidone palmitate and for the derived PK parameters, as applicable. Statistics will include 
sample size, mean, standard deviation, coefficient of variation, geometric mean, median, 
minimum, and maximum. Population PK analysis of plasma concentration-time data of 


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paliperidone will be performed using nonlinear mixed-effects modeling for PP6M, possibly 
using models previously developed from PP3M studies.
Mean and/or median plasma paliperidone concentration-time profiles will be plotted. Individual 
plasma concentration-time profiles may also be plotted. Plasma paliperidone concentrations and 
summary statistics may be presented graphically as scatter plots or box plots to support subgroup 
or meta-analyses.
The study will include a Sponsor-blinded interim PK analysis of available paliperidone 
concentration data at the time when at least 6 months of double-blind treatment has been 
completed by no more than 140 (26%) of 549 randomized subjects. The objective of this interim 
analysis is to verify that the observed PK properties of PP6M are conforming to the expected PK
behavior of PP6M. The following analyses will be conducted:
1.
Assess whether the observed concentrations of paliperidone after injection of PP6M are 
consistent with previous population PK predictions;
2.
Assess whether PK sampling times need to be adjusted to fully characterize the PK behavior 
of PP6M. (These potential changes would be communicated to study sites via a protocol 
amendment.)
An internal independent analyst (not associated with the study team) or an external vendor will 
be granted access to the treatment assignment information of the subjects included in the 
analysis. The external vendor or study-independent analyst will work in a secured environment 
to ensure no accidental unblinding of the Sponsor. To further ensure no accidental unblinding of 
the Sponsor, the data transfer to the internal independent analyst or external vendor will be done 
in a blinded way by using dummy subject identifiers.
No unblinding information will be shared with the Sponsor throughout this process prior to 
locking of the database. No efficacy or safety data measures will be included in this analysis. 
However, the Sponsor-blinded PK analysis will include a selection of demographic information 
needed for evaluation of PK (eg, potential PK covariates such as body weight, age, sex, 
creatinine clearance, and race) and will include information about study drug administration 
(volume, dose, muscle site, and history of similar parameters from the Maintenance Phase). The 
procedural steps to enable the Sponsor-blinded PK analysis will follow the Sponsor's internal 
operating procedures.
In addition, a snapshot date for PK samples to be analyzed will be defined, if required, to allow a 
further Sponsor-blinded PK analysis prior to database lock. Samples collected before this date 
will be analyzed for paliperidone concentrations and will be included in the population PK 
analysis. Samples collected after the snapshot date will be analyzed at a later date, and will be 
included in a population PK re-analysis when they become available after database lock.
After database lock, PK-PD analyses may be performed. For safety outcomes, PK-PD 
relationships may be evaluated in terms of any potential clustering of adverse events around the 
timing of the maximum plasma paliperidone concentration after a dose of PP6M. For efficacy 
outcomes such as relapse, PK-PD relationships may be evaluated, if appropriate.


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The population PK analysis and the PK-PD analyses will be detailed in one or more separate 
methods plans and one or more separate results reports.
11.5.
Safety Analyses
11.5.1.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the treatment phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. In addition, 
comparisons between treatment groups will be provided if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event. Analyses of the adverse events of special interest, as described in 
Section 1.1 (Background), will be described in the SAP. Adverse events will be analyzed 
separately for the open-label phases (Transition Phase and Maintenance Phase) and for the
Double-blind Phase.
11.5.2.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed 
values and changes from baseline at each scheduled time point. A listing of subjects with any 
laboratory results outside the reference ranges will be provided. A listing of subjects with any 
markedly abnormal laboratory results will also be provided.
11.5.3.
Electrocardiograms
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values (with the prerandomization ECG used as baseline).
The ECG variables that will be analyzed include heart rate, PR interval, QRS interval, QT 
interval, and corrected QT (QTc) interval using the following correction methods: QT interval 
corrected according to the linear-derived formula (QTcLD) as the primary method, as well as 
according to Bazett's formula (QTcB) and according to Fridericia's formula (QTcF) as 
supplemental methods.4,17,33
In the Double-blind Phase, descriptive statistics of QTc intervals and changes from baseline will 
be summarized at each scheduled time point. The criteria for abnormal QTc interval values will 


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be based on the classification from the relevant ICH guidelinej (normal as ≤450 milliseconds, or 
elevated as >450, >480, or >500 milliseconds). Similarly, the percentage of subjects with 
increases in QTc of normal as ≤30 milliseconds or elevated as 30 to 60 milliseconds or 
>60 milliseconds will also be summarized at each time point.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline 
readings will be reported.
11.5.4.
Vital Signs
Descriptive statistics of vital sign values and changes from baseline will be summarized at each 
scheduled time point. The percentage of subjects with values beyond clinically important limits 
will be summarized.
A frequency table of the occurrence of orthostatic hypotension will be presented. Orthostatic 
hypotension is defined as a decrease in systolic (>20 mm Hg) or diastolic (>10 mm Hg) blood 
pressure after standing for at least 2 minutes that is associated with an increase in pulse/heart rate 
of >15 bpm compared with supine measurements.12
11.5.5.
Physical Examinations
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made.
11.5.6.
Extrapyramidal Symptom Scales
The results of the EPS scales (AIMS, BARS, and SAS) will be summarized descriptively at each 
time point. See also Section 11.5.1 (Adverse Events) for analyses of EPS-related adverse events.
11.5.7.
Columbia Suicide Severity Rating Scale
C-SSRS Baseline/Screening Form will be used at screening. C-SSRS Since Last Visit Form will 
be used at other visits, as per Time and Events Schedules. Suicide-related thoughts and behaviors 
based on the C-SSRS scale will be summarized by treatment group in incidence and shift tables.
11.5.8.
Evaluations of the Injection Sites
The results of the evaluations by the subjects and by the investigators will be summarized 
descriptively at each time point.
                                                
j
ICH. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs. 
www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf . 
Dated 12 May 2005. Accessed 14 March 2017.


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11.5.9.
Anticipated Event Review Committee
An Anticipated Event Review Committee will be established to monitor safety data on an 
ongoing basis. The Anticipated Event Review Committee will consist of at least one medical 
expert in the relevant therapeutic area and at least one statistician. After each review meeting, the 
Anticipated Event Review Committee will make recommendations regarding reporting of 
anticipated events, as described in Section 12.3.1 (All Adverse Events) and Attachment 3.
11.6.
Benefit-risk Analyses
Efficacy and safety outcomes for the benefit-risk analysis will be considered in the Double-blind 
Phase; ie, excluding results that may arise from treatment with PP1M or PP3M during the 
Transition or Maintenance Phases. All general rules and conventions from the statistical methods 
section will be applied to the benefit-risk analyses, unless otherwise noted in the SAP.
 the benefit-risk analyses will be based on 
the efficacy and safety outcomes previously used for the PP3M formulation.7
Treatment comparisons of PP6M versus PP3M will be evaluated using the excess number of 
events between groups, where the benefits are harmful events to be prevented and the risks are 
harmful events that may be reported. The benefit-risk analyses will be based on a post-hoc 
interpretation of the excess numbers of events using clinical judgment to consider the clinical 
impact of each outcome. The excess number of events is defined as the product of the risk 
difference between PP6M and PP3M and the size of a hypothetical population (eg, 
1,000 patients). This can be interpreted as the additional number of patients in this hypothetical 
population who would experience a particular event when treated with PP6M minus that in the 
same population receiving PP3M. For benefit-risk assessment, point estimates will be shown 
with 95% confidence intervals; however, statistical tests on risk differences will not be specified.
Tabular and graphical displays of data may be created. Important benefits and risks are listed in 
Section 9.5 (Benefit-risk Evaluations).
11.7.
Other Exploratory Analyses
If applicable, exploratory analyses may be described in one or more separate methods plans 
(outside the standard SAP) and one or more separate results reports (outside the standard CSR).
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.
CCI


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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 noninvestigational) 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 noninvestigational) product, whether or not related 
to that medicinal (investigational or noninvestigational) product. (Definition per 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*
*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 paliperidone palmitate, the expectedness of 
an adverse event will be determined by whether or not it is listed in the Investigator's Brochure.


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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 (Attribution Definitions).
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).
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).


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12.2.
Special Reporting Situations
Safety events on a Sponsor study drug that may require expedited reporting or safety evaluation 
include, but are not limited to:

Overdose of a Sponsor study drug.

Suspected abuse/misuse of a Sponsor study drug.

Accidental or occupational 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).

Exposure to a Sponsor study drug from breastfeeding.

Exposure to a Sponsor study drug during pregnancy; see Section 12.3.3 (Pregnancy).
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or nonserious, 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 within 6 months after the last 
dose of study drug, 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. As permitted per local 
regulations, anticipated events will be recorded and reported as described in Attachment 3.
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 eCRF. 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 eCRF 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 
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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). For 
anticipated events reported as individual serious adverse events the Sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
Sponsor's Anticipated Event Review Committee will periodically evaluate the accumulating data 
and, when there is sufficient evidence and the Sponsor has determined there is a reasonable 
possibility that the drug caused a serious anticipated event, they will submit a safety report in 
narrative format to the investigators (and the head of the investigational institute where required). 
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. A SUSAR will be reported to 
regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded 
SUSAR summary, unless otherwise specified.
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

Any other information that is required to do an emergency breaking of the blind
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, 
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


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
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:

Study-designated hospitalizations.

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 
eCRF). 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.
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.
See also Section 9.3.1 (Evaluations) regarding collection of PK samples associated with serious 
adverse events.
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. 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 and discontinue 
further study drug.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported as noted above.
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 in 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 in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
Study drugs will be supplied in prefilled syringes, as follows:

PP1M:
50 mg eq. (78 mg) in 0.5 mL
75 mg eq. (117 mg) in 0.75 mL
100 mg eq. (156 mg) in 1.0 mL
150 mg eq. (234 mg) in 1.5 mL


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
PP3M:
350 mg eq. (546 mg) in 1.75 mL
525 mg eq. (819 mg) in 2.625 mL

PP6M:

Placebo: The placebo consists of 20% Intralipid (200 mg/mL) injectable emulsion. It has the 
same milky-white appearance as the active compound, and was used as placebo in the 
Sponsor's previous studies of PP3M.
The study drug will be manufactured and provided under the responsibility of the Sponsor. Refer 
to the Investigator's Brochure for a list of excipients.
14.2.
Packaging
The study drug will be packaged in individual subject kits. Each kit will consist of a safety 
needle, instructions for use, and a blister-packed, prefilled syringe assembled with a plunger rod.
14.3.
Labeling
Labels will contain blanks for the subject’s identification number and the investigator’s name. 
These will be filled in when the study drug is dispensed to a subject.
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study drug and matching placebo must be stored at controlled temperatures as instructed by 
the clinical label.
14.5.
Drug Accountability
The unblinded study drug administrator (see Section 5 [Treatment Allocation and Blinding]) is 
responsible for ensuring that all study drug received at the site is inventoried and accounted for 
throughout the study. The study drug administered to the subject must be documented on the 
drug accountability form. All study drug will be stored and disposed of according to the 
Sponsor's instructions. Study-site personnel must not combine contents of the study drug 
containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the Sponsor's 
study-site monitor during on-site monitoring visits. The return to the Sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
CCI
CCI


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destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form.
Potentially hazardous materials (such as used ampules, needles, syringes, and vials containing 
hazardous liquids) should be disposed immediately in a safe manner. Therefore, these will not be 
retained for drug accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the Sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following materials:

Documentation:
Investigator's Brochure
Locally approved prescribing information and patient information for the marketed study drugs 
(oral paliperidone, PP1M, and PP3M) that precede the investigational study drug (PP6M) in this 
study. Investigators should provide subjects with the appropriate patient information files that are 
relevant to their treatment paths through the study.
Manuals:
o
For assessments (ie, questionnaires and scales)
o
For ECGs
o
For biological samples (including for laboratory tests, PK samples)
o
For IWRS
o
For electronic data capture completion guidelines
Study-site investigational product binder

Supplies:
Blood collection tubes, storage tubes, preprinted labels (or tubes labeled with preprinted labels), 
and related supplies for the collection and shipment of biological samples (including for 
laboratory tests, PK samples). These supplies will be provided by the central laboratories (where 
different central laboratories may be used for different sample types, such as one for PK samples, 
etc).
Urine and routine blood collection kits
Urine pregnancy test kits
Urine drug screen test kit
Alcohol breath test


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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.
Primary study-specific ethical concerns and study-specific mitigations are as follows:

Changing medications:
For subjects with prestudy PP1M or PP3M stability, a concern may be associated with changing 
from an antipsychotic that had been providing acceptable levels of efficacy and tolerability 
before the study to a new investigational antipsychotic within the study. This risk is limited in 
the current study by changing only the formulation or dose, not the active substance, of the 
antipsychotic.
For subjects with prestudy injectable risperidone stability, the above risk is limited in the current 
study by providing an equivalently converted antipsychotic dose and by the minimal nature of 
the change in antipsychotic type (substituting the combination of parent molecule [risperidone] 
and metabolite [paliperidone] for the metabolite [paliperidone] alone).
For subjects with reason to change their prestudy oral antipsychotic, the above concern does not 
apply; they will be enrolled only per valid reason to change their previous antipsychotic 
(including problems with efficacy, safety, or tolerability, or per preference for a LAI
medication).
For all subjects, the study also allows subjects to continue taking other nonantipsychotic 
medications that they had been using at entry to the study, to initiate or make changes to 
nonantipsychotic medications during study (within some limitations), and to receive 
supplementation with oral antipsychotics during the study (within some limitations).

Long-acting formulation: A concern may be associated with the long-acting nature of the 
study drug. If an adverse event occurs during treatment with an oral antipsychotic, then dosing 
can be stopped, which results in rapid elimination from the body and often a resolution of the 
adverse event over a similar time course. If an adverse event occurs during treatment with a 
LAI antipsychotic, then the plasma concentrations may be maintained for months after the 
injection; elimination of the drug cannot be accelerated to facilitate resolution of the adverse 
event. However, many of the expected adverse events can be managed with pharmacological 
intervention (eg, beta-blockers for akathisia or anticholinergics for EPS). Moreover, eligible 
study subjects will already have been using LAI formulations before enrolling in the study; the 
study does not introduce a new risk of this nature, but only extends the duration in which the 
risk is present.

High doses: A concern may be associated with the high doses of the investigational study 
drug. The Sponsor has performed PK simulations to select these doses, and has considered the 


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acceptability of the PP6M exposures based on comparison with paliperidone and risperidone 
data from previous studies. The results indicated that exposures at the proposed PP6M dose 
levels should yield tolerability that is similar to existing paliperidone and risperidone 
formulations. Beyond those aggregate analyses, the Sponsor also considered individual cases 
of subjects who had high exposures to PP3M during previous studies, and found that high 
concentrations of paliperidone were well tolerated. Still, the current study includes extra safety 
assessments around the time of expected peak plasma paliperidone levels.

Large volumes: A concern may be associated with the large volumes of the intramuscular 
injections. The Sponsor has consulted nursing guidelines for the acceptability of these 
volumes, and has accordingly restricted the administration of PP6M into the gluteal muscle. 
The study also includes structured assessments of the injection sites and guidelines for 
handling any associated adverse events.
The volume of blood to be collected in this study is not considered to pose an ethical concern or a 
special risk. The volume to be collected over any 6-month period of the study is less than the 
volume collected in a single day (with an allowed 2-month frequency) associated with a 
charitable blood donation.1
More generally, the study also includes many safety assessments and eligibility criteria designed to 
ensure that the population is appropriate for enrollment and is carefully assessed throughout the 
study.
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


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
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, unless required locally), 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.
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 
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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
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).
16.2.3.
Informed Consent
Each subject (not a legal representative, but the subject himself or herself) 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. It also denotes that the 
subject agrees to allow his or her study physician to recontact the subject for the purpose of 
obtaining consent for additional safety evaluations, if needed.
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.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
A separate ICF will also be signed by the subject's designated unpaid caregiver (such as a family 
member, significant other, or friend, with knowledge of the subject) who is willing to complete 
the IEQ assessments and who is willing to support the investigator and subject during other study 
assessments if requested. The designated caregiver must sign the ICF prior to the first baseline 
assessment. In case no designated caregiver is available for a subject or in case the designated 


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caregiver cannot or is not willing to provide informed consent, the subject will nevertheless be 
eligible for participation upon his or her own informed consent.
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 
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.
In addition, the Sponsor cannot make decisions as to the significance of any findings resulting 
from exploratory research. Therefore, exploratory research data will not be returned to subjects 
or investigators, unless required by law or local regulations. Privacy and confidentiality of data 
generated in the future on stored samples will be protected by the same standards applicable to 
all other clinical data.
16.2.5.
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 if the need for the product persists, 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 nonacceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 


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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 
Sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (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 listed in the Contact Information page(s), which will be provided as a separate
document. 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 eCRF 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.


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
Signed and dated Clinical Trial Agreement, which includes the financial agreement.

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 (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) 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 documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
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.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 


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the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the Sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Electronic Case Report Form Completion
The eCRFs are prepared and provided by the Sponsor for each subject. All eCRF entries, 
corrections, and alterations must be made by the investigator or authorized study-site personnel. 
The investigator must verify that all data entries in the eCRF are accurate and correct. The study 
data will be transcribed by study-site personnel from the source documents onto the eCRF, if 
applicable. Study-specific data will be transmitted in a secure manner to the Sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed 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, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the electronic data capture tool. If corrections to an
eCRF are needed after the initial entry into the eCRF, this can be done in either of the following
ways:

Investigator and study-site personnel can make corrections in the electronic data capture tool 
at their own initiative or as a response to an auto-query (generated by the electronic data 
capture tool).

Sponsor or Sponsor delegate can generate a query for resolution by the investigator and 
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 eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The Sponsor will review eCRFs 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 eCRFs
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 use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study.
The Sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site 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 eCRF with the source documents (eg,
hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF 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 documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review 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 documents will 


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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.
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.
Central monitoring will take place for data identified by the Sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion (End of Study)
The study is considered completed with the last visit for the last subject participating in the 
study. Poststudy followup information, eg, as described in Section 12.3.1 (All Adverse Events),
will not be considered to be part of a "last visit" and will not be included in the study database. 
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
In addition to the planned closure at 12 months after the last subject has been randomized in the 
Double-blind Phase, 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. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 


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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.
17.11. Use of Information and Publication
All information, including but not limited to information regarding paliperidone palmitate 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, 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 paliperidone palmitate 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 CSR generated by the Sponsor and will contain data 
from all study sites that participated in the study as per protocol. Recruitment performance or 
specific expertise related to the nature and the important assessment parameters of the study will 
be used to determine a coordinating investigator. 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 
data specific to the study site 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 


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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. 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 disclose the existence of and the results of clinical studies as 
required by law.


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Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M. Medication adherence in 
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Hough D, Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens M. Paliperidone palmitate maintenance 
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Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. 
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van Wijngaarden B, Schene AH, Koeter M, et al. Caregiving in schizophrenia: development, internal 
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ATTACHMENTS
Attachment 1: Guidelines for the Intramuscular Injection of Paliperidone Palmitate or Placebo 
During the Double-blind Phase
In the Double-blind Phase, these guidelines should be used. In the Transition Phase and the Maintenance
Phase, the guidelines in the prescribing information for PP1M and PP3M should be used.
For each dose, a study-site personnel member must shake the syringe 
vigorously with the tip facing up and with a loose wrist for at least 15 
seconds to ensure a homogeneous suspension. The shaken dose must 
then be administered within 5 minutes after shaking. If more than 
5 minutes pass after shaking but before injection, then a study-site 
personnel member must shake the syringe vigorously again for at least 
15 seconds to resuspend the dose.
The full content of the syringe should be injected, slowly.
During the Double-blind Phase, injections will rotate across sides of the body (left or right), as shown in
Table 5, but the image below shows landmarks for only 1 side as an example.
Figure
Needle
1.5-inch, 20-gauge, thin-walled needle
Notes
Palpate the junction of the posterior iliac crest and sacrum. Then imagine drawing a line to the greater 
trochanter of the femur. Administer the injection in the upper-outer area bordered by this imaginary 
triangle. Injections should be administered in the dorso-gluteal injection site only. Ventrogluteal 
injections are not permitted.


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Attachment 2: Relapse Criteria for PANSS Total Score
A prespecified minimum change in PANSS total score is one of the possible qualifying criteria 
for relapse. The table below correlates a subject's score at randomization to the minimum 
posttreatment score during the Double-blind Phase that would meet the relapse criterion. If a 
subject's score during the Double-blind Phase is greater than or equal to the value in the second 
column, then the subject should be considered for relapse. The relapse should then be re-
evaluated for confirmation at a visit 3 to 7 days later (previously unscheduled, if necessary).
Criteria for Relapse According to PANSS Total Score
Score at Randomization
Relapse Criterion Score
≤40 Points
Increase of 10 points
30a
40
31
41
32
42
33
43
34
44
35
45
36
46
37
47
38
48
39
49
40
50
>40 Points
Increase of 25%
41
44
42
45
43
47
44
48
45
49
46
50
47
52
48
53
49
54
50
55
51
57
52
58
53
59
54
60
55
62
56
63
57
64
58
65
59
67
60
68
61
69
62
70
63
72
64
73
65
74
66
75
67
77
68
78
69
79
≥70 Points
Not eligible to enter study or to continue to 
Double-blind Phase
Key: PANSS = Positive and Negative Syndrome Scale.
a
A score of 30 is the lowest possible value on the PANSS.


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Criteria for Relapse According to PANSS Total Score
Note: The percent change is calculated after subtracting 30 from the Randomization 
score, as this represents the lowest score on the PANSS:
% 	

 = 		
 	
 −	
  	
	
  	 −30
× 100


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Attachment 3: Anticipated Events for Study R092670PSY3015
Anticipated Event
An anticipated event is an adverse event (serious or nonserious) 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

Substance use
Reporting of Anticipated Events
All adverse events will be recorded in the eCRF regardless of whether considered to be anticipated events 
and will be reported to the Sponsor as described in Section 12.3.1 (All Adverse Events). Any anticipated 
event that meets serious adverse event criteria will be reported to the Sponsor 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.
Anticipated Event Review Committee
An Anticipated Event Review Committee will be established to perform reviews of prespecified 
anticipated events at an aggregate level. The Anticipated Event Review Committee is a safety committee 
within the Sponsor's organization that is independent of the Sponsor's study team. The Anticipated Event 
Review Committee will meet to aid in the recommendation to the Sponsor's study team as to whether 
there is a reasonable possibility that an anticipated event is related to the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan.


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INVESTIGATOR AGREEMENT
PPD
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Approved, Date: 20 April 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
A Double-blind, Randomized, Active-controlled, Parallel-group Study of 
Paliperidone Palmitate 6-Month Formulation
Protocol R092670PSY3015; Phase 3
Amendment 3/USA-1
R092670 (paliperidone palmitate)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the Sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. 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 United States (US) Food & Drug Administration (FDA) 
Investigational New Drug (IND) regulations (21 Code of Federal Regulations [CFR] Part 312).
EudraCT Number: 2017-001941-28
Status:
Approved
Date:
20 April 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number: EDMS-RIM-32995, 1.0
Local: EDMS-ERI-130495167, 5.0
Compliance: This study will be conducted in compliance with Good Clinical Practice (GCP), and applicable regulatory 
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT03345342


R092670 (paliperidone palmitate)
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COVID-19 Appendix
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Approved, Date: 20 April 2020
PROTOCOL AMENDMENTS
DOCUMENT HISTORY
Document
Date
Amendment 3/USA-1
20 April 2020
Amendment 3
11 February 2019
Amendment 2
28 September 2018
Amendment 1
21 March 2018
Original Protocol
28 August 2017
Amendment 3/USA-1, 20 April 2020
Overall Rationale for the Amendment: To provide guidance on changes to study conduct and 
assessments due to restrictions and limitations during the COVID-19 pandemic. 
Section Number
and Name
Description of Change
Brief Rationale
COVID-19 
Appendix
Added a COVID-19 Appendix as guidance on changes to 
study conduct and assessments due to restrictions and 
limitations during the COVID-19 pandemic.
To provide guidance on study 
conduct and assessments 
during the COVID-19 
pandemic.


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3015 Amendment 3/USA-1
COVID-19 Appendix
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Approved, Date: 20 April 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, social distancing, self-isolation/quarantine 
by participants and study-site personnel; travel restrictions/limited access to public places, 
including hospitals; study site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidances to address the potential impact of COVID-19 
on the conduct of clinical trials, the sponsor is providing options for study related participant 
management in the event of disruption to the conduct of the study. This guidance does not 
supersede any local or government requirements or the clinical judgement of the investigator to 
protect the health and well-being of participants and site staff. 
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed within the allowed visit window. At each contact, 
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should 
be performed if required and as feasible. Participants will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted after consultation between the participant and investigator, and with the agreement of 
the sponsor. Missed assessments/visits will be captured in the clinical trial management system as 
protocol deviations. Discontinuations of study interventions and withdrawal from the study due to 
COVID-19 should be documented in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.  
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical monitor to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic will be summarized in the clinical 
study report.


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3015 Amendment 3/USA-1
COVID-19 Appendix
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Approved, Date: 20 April 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL:

Subject Visits/Assessments: If a subject cannot visit the research site in person, the sponsor 
recommends that any assessments that may be captured remotely for that particular visit be 
collected. This collection should be performed remotely by trained, delegated site staff. These 
remote assessments could be conducted via telephone (or videoconference, eg, Facetime, 
Skype, if possible) with subjects in their homes. Please ensure that the remote method is 
allowable per local regulations. Assessments that could be completed include a review of 
adverse events, concomitant medications, clinical interviews, evaluation of relapse criteria, 
and questionnaires. Please note, the visit windows included in the Time and Events Schedule 
are still applicable. 

Administration of study drug: All subjects in the R092670PSY3015 study have received 
all injections of study drug; therefore, there will be no interruptions in administration of 
study drug. 

Study assessments:
o
Relapse assessment: Please evaluate as many elements of the relapse criteria as 
possible. The Positive and Negative Syndrome Scale for Schizophrenia (PANSS) 
total score is the most important element for assessment of relapse. After the PANSS 
has been administered, the investigator or delegate must perform a review to 
determine if the relapse criteria have potentially been met (per Section 2.1.2.2 and 
Attachment 2). If so, a confirmation visit will need to be conducted as outlined in 
Section 2.1.2.2 and Attachment 2. The confirmation visit may be performed 
remotely.
o
Evaluation of secondary and exploratory endpoints (Personal and Social 
Performance scale, Clinical Global Impression - Severity, Columbia Suicide Severity 
Rating Scale, Healthcare Resource Utilization
Questionnaire, Involvement 
Evaluation Questionnaire, Schizophrenia Quality of Life Scale, Illness Management 
and Recovery, 9-item Treatment Satisfaction Questionnaire for Medication, 
Satisfaction With Participation in Social Roles): Many of the assessments for 
evaluation of secondary and exploratory endpoints may be collected remotely. Please 
collect as much information as possible.
o
Physical examinations, vital signs, scales to assess extrapyramidal symptoms 
(Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson 
Angus Scale), electrocardiograms, collection of pharmacokinetic/blood samples, 
pregnancy tests, and laboratory assessments may not be possible to collect as part of 
the remote visit.
o
It must be documented in the CRF if a visit occurs remotely due to COVID-19. 

Missed assessments/protocol deviations:
o
Missed assessments will be captured in the clinical trial management system as 
protocol deviations. All protocol deviations will be recorded as either major or minor
protocol deviations in the clinical trial management system using the current Major 
Protocol Deviation Criteria document.


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3015 Amendment 3/USA-1
COVID-19 Appendix
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Approved, Date: 20 April 2020
o
Remote visits, missed visits, out of window visits, and missing assessments due to 
COVID-19-related issues will be recorded as minor protocol deviations. 

Early Withdrawal: If a subject is lost to follow-up, or is unwilling to have any remote 
assessments performed, then he/she would be considered an early withdrawal. Please attempt 
to contact the subject via telephone, text message, email or through a relative, if possible. 
Consider certified mail as an option to contact a subject before declaring him/her as being lost 
to follow-up. 

COVID-19 Illness in Subjects:

If a subject in this study becomes symptomatic, the sponsor suggests that Coronavirus 
infection be confirmed with reverse transcriptase polymerase chain reaction (RT-PCR)
using diagnostic test kits. This should be performed using locally approved laboratory 
kits and reported to the local health authorities as required.

Positive test results for Coronavirus as well as any associated symptoms should be 
recorded as adverse events, and if the subject is hospitalized, the event should be captured 
as a serious adverse event. Similarly, hospitalization should be recorded on the Healthcare 
Resource Utilization Questionnaire (HRUQ) form at the next visit, if applicable.

Please notify the treating physician of the subject’s participation in Study 
R092670PSY3015, and details of the study treatments in a blinded fashion.

Monitoring: In addition to subject study visits, monitoring visits and data cleaning activities 
need to be completed prior to final database lock. On-site monitoring visits may not be 
possible due to local regulations, restrictions and guidance. In these cases, the Site Manager 
(and Independent Drug Monitor) will arrange to conduct site monitoring visits and activities 
remotely. Site closeout visits will be postponed until Site Managers and Independent Drug 
Monitors are able to return to the site to complete final closeout activities.


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3015 Amendment 3/USA-1
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Approved, Date: 20 April 2020
INVESTIGATOR AGREEMENT
PPD
PPD

SAP_001.pdf: 
1
Approved, Date: 26 May 2020
Janssen Research & Development *
Statistical Analysis Plan
A Double-Blind, Randomized, Active-controlled, Parallel-group Study of Paliperidone 
Palmitate 6-Month Formulation
Protocol R092670PSY3015; Phase 3
R092670  (paliperidone palmitate)
Revised on 26 May 2020
Status:
Approved
Date:
26 May 2020
Prepared by:
Janssen Research & Development  
Document No.: EDMS-ERI-153143529, 4.0
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.
NCT03345342


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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Approved, Date: 26 May 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 8
1.
INTRODUCTION.................................................................................................................................. 9
1.1.
Trial Objectives ................................................................................................................................ 9
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 12
2.1.
Visit Windows................................................................................................................................. 12
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 18
2.3.
Analysis Populations...................................................................................................................... 19
2.3.1.
Open Label Intent-to-Treat (OL ITT) Analysis Population, and OL Safety Population............... 19
2.3.2.
Double-blind Intent-to-Treat (DB ITT) Analysis Population ........................................................ 19
2.3.3.
All Randomized Analysis Population.......................................................................................... 19
2.3.4.
Per-Protocol Analysis Population ............................................................................................... 19
2.3.5.
Pharmacokinetics Analysis Population....................................................................................... 20
2.3.6.
Pharmacodynamics Analysis Population.................................................................................... 20
2.4.
Definition of Subgroups.................................................................................................................. 20
2.5.
Study Day and Relative Day .......................................................................................................... 21
2.5.1.
Study Day Definitions ................................................................................................................. 21
2.5.2.
Relative Day for a Visit ............................................................................................................... 22
2.6.
Baseline and Endpoint ................................................................................................................... 23
2.6.1.
Baseline Values....................................................................................................................... 23
2.6.2.
Endpoint Values ...................................................................................................................... 24
2.7.
Imputation Rules for Missing Date and Time................................................................................. 24
2.7.1.
Imputation Rules for Missing AE Date/Time of Onset/Resolution.............................................. 24
2.7.2.
Incomplete/Missing Dates of Most Recent Hospitalization for Psychosis .................................. 25
2.7.3.
Incomplete/Missing Dates of Hospitalization Collected in HRUQ .............................................. 25
2.7.4.
Incomplete/Missing Dates for Concomitant Medications............................................................ 26
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 27
4.
SUBJECT INFORMATION................................................................................................................ 27
4.1.
Demographics and Baseline Characteristics ................................................................................. 27
4.2.
Disposition Information................................................................................................................... 28
4.3.
Treatment Compliance................................................................................................................... 29
4.4.
Extent of Exposure......................................................................................................................... 29
4.4.1.
Injections..................................................................................................................................... 29
4.4.2.
Oral Tolerability Test................................................................................................................... 30
4.5.
Protocol Deviations ........................................................................................................................ 30
4.6.
Prior and Concomitant Medications ............................................................................................... 30
4.6.1.
Prior Psychotropic Medications .................................................................................................. 30
4.6.2.
Concomitant Benzodiazepines (Sedatives/Hypnotics/Anxiolytics)............................................. 31
4.6.3.
Concomitant Medications Other Than Benzodiazepines ........................................................... 32
5.
EFFICACY ......................................................................................................................................... 32
5.1.
Analysis Specifications................................................................................................................... 32
5.1.1.
Level of Significance................................................................................................................... 32
5.1.2.
Data Handling Rules................................................................................................................... 32
5.2.
Primary Efficacy Estimand ............................................................................................................. 32


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5.2.1.
Definition of Time to Relapse ..................................................................................................... 34
Definition of Relapse Event ..................................................................................................... 34
Time to Relapse During Double-Blind Phase.......................................................................... 35
5.2.2.
Primary Efficacy Analysis Performed on the Double-blind Intent-to-Treat Analysis 
Population................................................................................................................................... 35
Main Analysis........................................................................................................................... 35
Sensitivity Analysis .................................................................................................................. 36
Supplementary Analyses......................................................................................................... 36
Subgroup Analysis................................................................................................................... 37
Model Diagnostics ................................................................................................................... 38
5.2.3.
Primary Efficacy Analysis Performed on Per-Protocol Analysis Population............................... 38
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 38
5.3.1.
PANSS Total Score ................................................................................................................. 38
Definition.................................................................................................................................. 38
Analysis Methods .................................................................................................................... 39
5.3.2.
Clinical Global Impression - Severity (CGI-S) ......................................................................... 39
Definition.................................................................................................................................. 39
Analysis Methods .................................................................................................................... 39
5.3.3.
Personal and Social Performance Scale (PSP) ...................................................................... 39
Definition.................................................................................................................................. 39
Analysis Methods .................................................................................................................... 40
5.3.4.
PANSS Subscale Scores ........................................................................................................ 40
Definition.................................................................................................................................. 40
Analysis Methods .................................................................................................................... 41
5.3.5.
PANSS Response and Cumulative Response Rate ............................................................... 41
Definition.................................................................................................................................. 41
Analysis Methods .................................................................................................................... 41
5.3.6.
Symptomatic Remission.......................................................................................................... 42
Definition.................................................................................................................................. 42
Analysis Methods .................................................................................................................... 42
5.4.
Other Efficacy Variable(s) .............................................................................................................. 42
5.4.1.
Satisfaction With Participation in Social Roles (SPSR) Short Form 8a...................................... 42
Definition.................................................................................................................................. 42
Analysis Methods .................................................................................................................... 42
5.4.2.
Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9)........................... 43
Definition.................................................................................................................................. 43
Analysis Methods .................................................................................................................... 43
6.
SAFETY............................................................................................................................................. 44
6.1.
Adverse Events .............................................................................................................................. 44
6.1.1.
EPS-Related Adverse Events..................................................................................................... 45
6.1.2.
Diabetes Mellitus and Hyperglycaemia-Related Adverse Events .............................................. 46
6.1.3.
Potentially Prolactin-Related Adverse Events ............................................................................ 46
6.1.4.
Other Adverse Events of Special Interest................................................................................... 46
6.1.5.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 47
6.2.
Clinical Laboratory Tests................................................................................................................ 48
6.2.1.
Glucose Abnormalities................................................................................................................ 48
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 49
6.3.1.
Weight, Waist Circumference, and Body Mass Index ................................................................ 50
6.4.
Electrocardiogram.......................................................................................................................... 50
6.5.
Extrapyramidal Symptoms (EPS) Assessment Scales.................................................................. 52
6.5.1.
Abnormal Involuntary Movement Scale...................................................................................... 52
6.5.2.
Barnes Akathisia Rating Scale ................................................................................................... 53
6.5.3.
Simpson and Angus Rating Scale .............................................................................................. 53
6.5.4.
Extrapyramidal Symptoms Based on Rating Scales and Use of Anticholinergic 
Medication .................................................................................................................................. 53
6.6.
Injection Site Evaluations............................................................................................................... 54


R092670  (paliperidone palmitate)
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7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 54
8.
HEALTH ECONOMICS ..................................................................................................................... 54
REFERENCES............................................................................................................................................ 56
ATTACHMENTS......................................................................................................................................... 57
Attachment 1: Special Interest Adverse Events .................................................................................... 57
Attachment 2:  Criteria of Markedly Abnormal Laboratory Values...................................................... 65


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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AMENDMENT HISTORY
26 May  
2020
Change since 
Version 3.0
Section
Change
Rationale
5.2.2.3
Added one 
supplementary 
analysis S5
Evaluate the potential impact of COVID-19 related remote visits to 
the primary efficacy analysis
8 May  
2020
Change since Version 
2.0
Section
Change
Rationale
2.1
Added PSP in tables 1a and 
few notes in Tables 1a to 1f
According to Time and Events Table
2.1 
Modified text about how to 
deal with the data for five 
subjects from Turkey who 
received a Month 12 injection 
Five subjects from Turkey who received a Month 12 
injection 
2.3.4.
Added criteria of identifying 
Major Protocol Violation
Per an agreement with the FDA dated on 2Mar2020
2.4.
Replace subgroup BMI at 
Baseline (MA) by BMI 
Baseline (DB)
After screen visit, the body weight was only corrected at 
the start of DB phase  
2.5.1
Added definition of Date of 
DB Month 12 for five Turkey 
subjects who received a 
Month 12 injection
Five subjects from Turkey who received a Month 12 
injection  
5.2.2.3
Added supplementary 
Analysis S4 
Per an agreement with the FDA, to exclude 3 Mexico 
subjects who were affected by the delay of drug supply
5.3.6.1
Made the changes so it’s 
consistent with the analysis in 
Study PSY3011
Due to protocol amendment 3
5.4.1.2
Added scoring algorithm for 
SPSR
Requested by programming
5.4.2.2
Added scoring algorithm for 
TSQM-9
Requested by programming
6.2.1
Removed analysis related to 
insulin
Insulin data are not collected in the study
8
Added scoring algorithm for 
SQLS-R4
Requested by programming
Reference
Added a reference related to 
TSQM-9
The reference is needed in Section 5.4.2.2
6.1.1, 
6.1.2, 
6.1.3, and 
Attachment 
1
Changed AEDECOD for 
Special Interest AEs
Due to the new MedDRA version


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5 April 
2019
Change since 
Version 
1.0
Section
Change
Rationale
1.2, 1.4, 
2.1, 2.3.4, 
2.6.2, 6.1
Limit Double-
blind phase to 12 
months
Per Protocol Amendment 3
2.1
Summarize 
number of post-
study contacts 
Per a Missing data Prevention Plan imposed in April/May 2019
2.1 Table 
1c, and 6.4
In the analysis, 
the average 
predose ECG 
value will be 
summarized
separately for 
those who were 
on pre-study 
status categories 
(oral 
antipsychotic, on 
injectable 
risperidone, 
PP1M initiation, 
PP1M stability, 
and PP3M
stability).
Clarify analysis of ECG data
2.3.1
Way to handle 
re-screened 
subjects
Per Protocol Amendment 2
2.4
Add three sub-
groups
2.5.1
Definition of 
reference days, 
and dates for 
each phase.
Necessary for programming
2.5.1, and 
throughout 
the SAP
Define date of 
DB Month 12
Due to Protocol Amendment 3
4.1
Remove 
“alcohol” from 
analysis
Per Protocol Amendment 2
4.4.1
Define duration 
of exposure
Needed in analysis
5.2, 5.3
and their 
Based on 
protocol 
amendment 3, 
Per Protocol Amendment 3


R092670  (paliperidone palmitate)
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sub-
sections
limiting DB 
phase to 12 
Month
5.2 and its
sub-
sections
Restructure these 
sections to 
include upfront
the definition of 
the primary 
estimand, 
followed by the 
corresponding 
analyses. Clarify 
the definitions 
for the primary 
and 
supplementary 
estimands.  The 
changes made do 
not affect the 
detailed analyses 
specified in the 
previous version 
of the SAP 
finalized on 
16Mar2018. 
Per new ICH E9(R1) guidance. The guidance could be found online:
http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html#9-2
5.4.1.2 
and 
5.4.2.2
Remove 
ANCOVA 
models for SPSR 
and TSQM-9 
The data will only be summarized for subjects who entered the study 
on an oral antipsychotic.  No ANCOVA models are needed.
8
Data about Use 
of Nicotine will 
only be listed
Too many types/units for the data of use of nicotine
8
Add scoring 
algorithm for 
calculating the 
total SQLS-R4
Necessary for programming


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Statistical Analysis Plan R092670PSY3015
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ABBREVIATIONS
ADA
American Diabetes Association
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale 
ANCOVA
analysis of covariance 
BARS
Barnes Akathisia Rating Scale 
BMI
body mass index
C-SSRS
Columbia-Suicide Severity Rating Scale 
CGI-S
Clinical Global Impression-Severity
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
DB
double-blind
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
EOP
end-of-phase
EOS
end-of-study
EPS
extrapyramidal symptoms
ER
extended release
EU
European Union
FDA
Food and Drug Administration
FU
follow-up
HOMA
homeostasis model assessment
HRUQ
Health Resource Utilization Questionnaire
ICH
International Conference on Harmonization
IEQ
Involvement Evaluation Questionnaire
IMR
Illness Management and Recovery
ITT
intent-to-treat
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LOCF
last observation carried forward
LS
least-squares
MA
Maintenance 
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures
MPV
major protocol violation
OL
Open-label
PANSS
Positive and Negative Syndrome Scale for Schizophrenia
PP
per protocol
PP1M
paliperidone palmitate 1-month formulation
PP3M
paliperidone palmitate 3-month formulation
PP6M
paliperidone palmitate 6-month formulation
PSP
Personal and Social Performance Scale
PSRE
potentially suicide-related event
ROW
Rest of World
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
Simpson and Angus Rating Scale 
SD
standard deviation
SE
standard error
SPSR
Satisfaction With Participation in Social Roles (scale)
SQLS-R4
Schizophrenia Quality of Life Scale, Revision 4
TRANS
Transition
TSQM-9
abbreviated 9-item Treatment Satisfaction Questionnaire for Medication
VAS
Visual Analog Scale


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis populations, derived variables 
and statistical methods for the analysis of efficacy and safety data from study R092670PSY3015. 
1.1.
Trial Objectives
Primary Objective
The primary efficacy objective is to demonstrate that injection cycles consisting of a single
administration of PP6M (700 or 1000 mg eq.) are not less effective than 2 sequentially 
administered injections of PP3M (350 or 525 mg eq.) for the prevention of relapse in subjects with 
schizophrenia previously stabilized on corresponding doses of PP1M (100 or 150 mg eq.) or 
PP3M (350 or 525 mg eq.).
Secondary objectives
To evaluate the safety and tolerability of PP6M (700 or 1000 mg eq.) in subjects with 
schizophrenia who have switched from corresponding doses of PP1M (100 or 150 mg eq.) or 
PP3M (350 or 525 mg eq.).
To evaluate the pharmacokinetic (PK) profile of PP6M (700 or 1000 mg eq.) administered in the 
gluteal muscle in subjects with schizophrenia who have switched from corresponding doses of 
PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).
To evaluate the clinically assessed efficacy of PP6M (700 or 1000 mg eq.) versus PP3M (350 or 
525 mg eq.) in maintaining symptom control, functioning personally and socially, and achieving 
or sustaining remission in subjects with schizophrenia who were previously stabilized on 
corresponding doses of PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).
To evaluate the subject-reported outcomes of PP6M (700 or 1000 mg eq.) or PP3M (350 or 
525 mg eq.) compared with treatment with previous oral antipsychotics in terms of satisfaction 
with medication and with participation in social roles.
1.2.
Trial Design
This is a randomized, double-blind, active-controlled, multicenter, interventional, parallel-group 
study. All eligible subjects who progress without relapse will participate in a Screening Phase (of 
up to 28 days), a Maintenance Phase that includes 1 injection cycle with either PP1M or PP3M 
(yielding a phase duration of 1 or 3 months, accordingly), and a Double-blind Phase (of 12 
months). The Double-blind Phase is designed to include 2 injection cycles of PP6M 
(investigational drug with alternating placebo) or 4 injection cycles of PP3M (active control). In 
addition to standard participation as described above, further conditional/additional participation 
is possible as follows:


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Before the Maintenance Phase, some subjects will participate in a Transition Phase, with 1 to 5 
injections of PP1M, if they entered the study on an oral antipsychotic, on injectable risperidone, 
or on PP1M previously initiated but not yet stabilized.
If a subject has already received at least 1 dose of double-blind study drug but then has relapsed 
or has met other relevant conditions for withdrawal or discontinuation, then the subject should 
enter a Follow-up Phase. The Follow-up Phase ends 12 months after the subject's first double-
blind injection. The Follow-up Phase collects supplementary poststudy data from willing affected 
subjects, in an effort to document minimum safety information (ie, adverse events) and minimum 
efficacy information (ie, relapse status). The Follow-up Phase is designed to be as low-burden and 
noninvasive as possible, in order to encourage participation by the affected subjects.
The duration of exposure to study drug (ie, the number of injections) and the total duration of study 
participation are variable based on a subject's flow through treatment types, on participation in 
conditional phases or parts as described in the 3 bullet points above, and on whether a subject 
experiences a relapse during the study.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis is that the efficacy of PP6M is non-inferior to PP3M for preventing relapse 
in subjects with schizophrenia who were previously stabilized on corresponding doses of PP1M 
and/or PP3M.
1.4.
Sample Size Justification
The sample size for the Double-blind Phase of the study is 549 randomized subjects, based on 
determinations to provide a minimum of 80% power for the primary endpoint. The sample size 
determination includes the assumptions that the expected survival rate (percentage of subjects 
remaining relapse-free at 12 months) in the PP3M group is 85%, and that the 1-sided significance 
level should be 2.5%. Given these assumptions, 549 subjects randomized in a 2:1 ratio 
(PP6M:PP3M) are required to demonstrate with 80% power that PP6M is no worse than PP3M by 
a noninferiority margin of 10% for the percentage of subjects remaining relapse-free at 12 months. 
This assumes that the efficacy observed in the PP3M group will be similar to the efficacy observed 
in the previous PP3M registrational Phase 3 studies (R092670PSY3011 and R092670PSY3012). 
The noninferiority margin of 10% and statistical methods for this analysis were selected based on 
the Sponsor's previous studies and on advice from experts and health authorities, as follows:

In the JRD's previous placebo-controlled relapse prevention studies with oral paliperidone 
ER/PR, PP1M, and PP3M,[1],[2],[3] a Kaplan-Meier estimate indicated that the meta-analytic 
estimate of treatment benefit of paliperidone over placebo was 42.1% (95% confidence 
interval: 28.4% to 55.8%).[4]

A panel of experts in the field of schizophrenia relapse prevention studies was convened to 
obtain recommendations for the clinical noninferiority margin to be used in this study. Using 
a modified Delphi approach, the mean value obtained after anonymous voting for the 
noninferiority margin was 13.4% (median 13.0%; range 10% to 20%).[4] This clinical 


R092670  (paliperidone palmitate)
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judgment based on expert opinion thus provided guidance on the largest loss of efficacy that 
could be considered clinically acceptable; in accordance with the relevant US FDA 
guidance,[5] the maximum was therefore set at 13.0%.[4]

Prior scientific advice from the Committee for Medicinal Products for Human Use had 
recommended a noninferiority margin of 10%.[4]

For all of the above reasons, an effect of 10% was chosen as the margin.
Further details are available in a separate statistical support document. [4]
The study design assumes discontinuation rates during the Transition and Maintenance Phases of 
20% for subjects who entered the study with previous PP1M or PP3M stability, and 40% for 
subjects who entered the study without previous PP1M or PP3M stability. The study design also 
assumes a dropout rate of 10% during the Double-blind Phase (where the dropout rate also 
accounts for subjects excluded due to protocol violations). Given these assumptions for 
discontinuation, the study targets approximately 840 subjects to enter the Transition or 
Maintenance Phase.
1.5.
Randomization and Blinding
At entry into the Double-blind Phase, subjects who had received a moderate dose in the 
Maintenance Phase will be randomly assigned to 1 of 2 treatment groups (active control or 
investigational drug as moderate doses) and subjects who had received a higher dose in the 
Maintenance Phase will be randomly assigned to 1 of 2 treatment groups (active control or 
investigational drug as higher doses), based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the Sponsor. The randomization (2:1 ratio,
PP6M:PP3M) will be balanced by using randomly permuted blocks and will be stratified by study 
site and by moderate or high dose in the Maintenance Phase. Based on this randomization code, 
the study drug will be packaged and labeled for each subject. Medication kit numbers will be 
preprinted on the study drug labels and assigned as subjects qualify for the Double-blind Phase 
and are randomly assigned to treatment.
The randomization code and treatment code are assigned using an Interactive Web Response 
System (IWRS). The investigator will not be provided with randomization codes. To maintain the 
blind, due to differences in the syringe sizes used between PP6M and PP3M, the study drug 
administrator is not allowed to perform any other study-related procedures. The study staff, other 
than the study drug administrator, are not allowed to view the syringe or needle or observe the 
injection. 
Subjects in the PP6M treatment group will receive matched placebo injections every 3 months 
when not receiving active medication to maintain the blind.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Because subjects do not always adhere to the protocol visit schedule, the following rules are 
applied to assign visit windows to protocol-defined visits for data analysis. 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. Listed in Tables 1 are the visit windows (time points), and the 
corresponding day ranges and the target days for each protocol-defined visit. The relative days are 
with respect to the start date of Transition (Trans.), Maintenance (MA), and Double-blind phases, 
depending on which phase a visit belongs to. No data from the Follow-up phase will be considered 
with visit windows.
If a subject has 2 or more actual visits in 1 visit window [other than Screening windows, Baseline 
(OL, MA, or DB) window, and Average Pre-dose window for ECG], the visit closest to the target 
day will be used as the protocol-defined visit for that visit window. If 2 actual visits are equidistant 
from the target day within a visit window, the later visit will be 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 for that protocol visit.
PANSS scores measured at the confirmation visit (solely for the purpose of confirming relapse) 
will not be included in statistical analyses. As specified in the protocol, once relapse is confirmed
in the Double-blind phase, subject will have the EOP/Early withdrawal visit performed. PANSS 
scores measured close to (and including) the date of confirmation visit will be recorded in the 
EOP/Early withdrawal visit. Hence there won’t be information loss by discarding PANSS score 
measured at the confirmation visit. 
Final post-baseline (OL) assessment during the Open-label Phase will be used as the value for 
Baseline (DB) visit.
Based on the Amendment 3 of the protocol that was issued on 13 February 2019, the Double-blind 
(DB) phase is limited to 12 months.  However, there were five subjects from Turkey who have 
received a Month 12 injection and have data after Month 12 of the DB phase because the protocol 
amendment 3 was not approved in the country when these subjects reached Month 12.  The date 
of DB Month 12 is defined in Section 2.5.1. of the SAP.  As shown in Tables 1a to 1f, the efficacy 
and safety data collected after Month 12 of Double-blind phase (visit 33b) will not be included in 
over-time summaries, nor be considered as the End point of the DB phase.  However, all data from 
the Double-blind phase, regardless of whether the data are collected before or after the DB 
Month 12 date, will be included in data listings, subject’s profiles, and the overall summaries (eg, 
treatment exposure, AE, concomitant medication, protocol deviation, etc.) for the Double-blind 
phase.


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Table 1a: Time Intervals for Visits for Positive and Negative Syndrome Scale (PANSS), 
SPSR, PSP, Abbreviated TSQM-9, HRUQ, IEQ, SQLS, and IMR
Analysis 
Phase
Scheduled 
Visit Number
Label on Output
Time Interval
in Phase Day
Target Time in 
Phase Day
1
Screeninga
Pre-OL dose
-28 to -1 before 
OL dosing
Trans.b
2a, 2b, 2c, 2d 
or 2e
Baseline (OL.)b
≤ 1st Trans. 
injection date
1
MAc
1,2f
Baseline (OL.)d
≤ MA injection 
date
1
Baseline (MA)e
MA
MA Final 
Visit
End Point (MA)f
≥2 (MA day)
30 (PP1M) or 
90 (PP3M)
Double-blind
7b
Baseline (DB)f
1st OL injection 
date relative day 
+1 to ≤1
1
Double-blind
13
Month 3 (DB)
2 to 137
92
Double-blind
20
Month 6 (DB)
138 to 228
183
Double-blind
26
Month 9 (DB)
229 to 319
274
Double-blind
33a or 33b
Month 12 (DB)
320 to DB Dayg
of Visit 33a or 
33b if it’s ≥320
365
Double-blind
DB Final 
Visit
End Point (DB)
Last recordg
before/on Visit 
33a or 33b
a The Screening visit window is defined for PANSS, SPSR and Abbreviated TSQM-9 which 
are scheduled to be performed at Visit Number 1 (Screening). For PANSS, if there is only 1 
pre-dose assessment and it is prior to OL Study Day 1 (ie, Reference Start Date), then the 
same value will be assigned to the Screening and Baseline (MA) visit windows. 
b Trans. = Transition Phase, PANSS score only, and only applicable to those who enter 
Transition Phase. 
c MA = Maintenance Phase. Only applicable to PANSS and PSP
d Only applicable to those who do not enter Transition Phase, and only applicable to PANSS
and PSP
e Only applicable to those who enter Maintenance Phase, and only applicable to PANSS and 
PSP
f Final post-baseline (MA) assessment during the Maintenance Phase will be used as the value 
for Baseline (DB) visit.
g If the End of DB Phase visit date is after Visit 33b, use the data on or before Date of DB 
Month 12 that is defined in Section 2.5.1.
OL=Open-label, DB=Double-blind.


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Table 1b: Time Intervals for Visits for Prolactin from Laboratory Tests, and EPS (including 
AIMS, BARS, and SAS)
Analysis 
Phase
Scheduled 
Visit Number
Label on Output
Time Interval
in Phase Day
Target Time in 
Phase Day
1
Screening
Pre-OL Dose
-28 to -1 before 
OL dosing
Trans.a
2a, 2b, 2c, 2d 
or 2e
Baseline (OL.)a
≤ 1st Trans. 
injection date
1
MAb
1,2f 
Baseline (OL.)c
≤ MA injection 
date
1
Baseline (MA)d
MA
MA Final 
Visit
End Point (MA)e
2 to End of MA
30 (PP1M) or 
90 (PP3M)
Double-blind
7b
Baseline (DB)e
1st OL injection 
date relative day 
+1 to ≤1
1
Double-blind
9
Week 3 (DB) 
2 to 25
22
Double-blind
10
Week 4 (DB) 
26 to 32
29
Double-blind
11
Week 5 (DB) 
33 to 47
36
Double-blind
12
Month 2 (DB)f
48 to 121
60
Double-blind
20
Month 6 (DB) 
122 to 196
183
Double-blind
23
Month 7 (DB) 
197 to 226
211
Double-blind
25
Month 8 (DB)
227 to 303
242
Double-blind
33a or 33b
Month 12 (DB) 
304 to DB Dayg
of Visit 33a or 
33b if it’s ≥304
365
Double-blind
DB Final 
Visit
End Point (DB)
Last recordg
before/on Visit 
33a or 33b
a Trans. = Transition Phase, only applicable to those who enter the Transition Phase.
b MA = Maintenance Phase.
c Only applicable to those who do not enter the Transition Phase.
d Only applicable to all patients who enter Maintenance Phase.  For subjects who do not enter 
the Transition Phase, Baseline (MA) = Baseline (OL).
e Final post-baseline (MA) assessment during the Maintenance Phase will be used as the value 
for Baseline (DB) visit.
f Only applicable to EPS data.
g If the End of DB Phase visit date is after Visit 33b, use the data on or before Date of DB 
Month 12 that is defined in Section 2.5.1.
.
OL=Open-label, DB=Double-blind


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Table 1c: Time Intervals for Visits for CGI-S, vital signs, and ECG
Analysis 
Phase
Scheduled 
Visit Number
Label on Output
Time Interval
in Phase Day
Target Time in 
Phase Day
1
Screening
<1
-28 to -1 before 
OL dosing
Trans.a
2a, 2b, 2c, 2d 
or 2e
Baseline (OL.)a,h
≤ 1st Trans. 
injection date
1
MAb
1,2f 
Baseline (OL.)c,h
≤ MA injection 
date
1
Baseline (MA)d
MA
MA Final 
Visit
End Point (MA)e
2 to End of MA
30 (PP1M) or 
90 (PP3M)
Double-blind
7b
Baseline (DB)e
1st OL injection 
date relative day 
+1 to ≤1
1
Double-blind
10
Week 4 (DB) 
2 to 44
29
Double-blind
12
Month 2 (DB)f
45 to 75
60
Double-blind
13
Month 3 (DB)f
76 to 105
92
Double-blind
14
Month 4 (DB)f
106 to 133
120
Double-blind
15
Month 5 (DB)f
134 to 165
148
Double-blind
20
Month 6 (DB)f
166 to 196
183
Double-blind
20
Month 6 (DB)g
45 to 347
183
Double-blind
23
Month 7 (DB)f
197 to 226
211
Double-blind
25
Month 8 (DB)f
227 to 257
242
Double-blind
26
Month 9 (DB)f
258 to 287
274
Double-blind
27
Month 10 (DB)f
288 to 315
302
Double-blind
28
Month 11 (DB)f
316 to 347
330
Double-blind
33a or 33b
Month 12 (DB) 
348 to DB Dayi of 
Visit 33a or 33b if 
it is ≥348
365
Double-blind
DB Final 
Visit
End Point (DB)
Last recordi
before/on Visit 
33a or 33b
a Trans. = Transition Phase, only applicable to those who enter the Transition Phase.  For 
ECG, Baseline (OL) is the average predose ECG value that is defined as the average of all 
non-missing predose ECG results.
b MA = Maintenance Phase.
c Only applicable to those who do not enter the Transition Phase.  For ECG, Baseline (OL) is 
the average predose ECG value that is defined as the average of all non-missing predose 
ECG results.
d Only applicable to all patients who enter Maintenance Phase.  For subjects who do not enter 
the Transition Phase, Baseline (MA) = Baseline (OL).
e Final post-baseline (MA) assessment during the Maintenance Phase will be used as the value 
for Baseline (DB) visit.
f  Only applicable to CGI-S
g  Only applicable to Vital Sign and ECG
h  In the analysis, the average predose ECG value will be summarized separately for those who 
were on oral antipsychotic, on injectable risperidone, PP1M initiation, or on PP1M/PP3M 
stability at the time of entering the study.
i If the End of DB Phase visit date is after Visit 33b, use the data on or before Date of DB 
Month 12 that is defined in Section 2.5.1.
OL=Open-label, DB=Double-blind


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Table 1d: Time Intervals for Visits for Laboratory Tests (other than prolactin)
Analysis 
Phase
Scheduled 
Visit Number
Label on Output
Time Interval
in Phase Day
Target Time in 
Phase Day
1
Screening
<1
-28 to -1 before 
OL dosing
Trans.a
2a, 2b, 2c, 2d 
or 2e
Baseline (OL)a
≤ 1st Trans. 
injection date
1
MAb
1,2f 
Baseline (OL)c
≤ MA injection 
date
1
Baseline (MA)d
MA
MA Final 
Visit
End Point (MA)e
2 to End of MA
30 (PP1M) or 
90 (PP3M)
Double-blind
7b
Baseline (DB)e
1st OL injection 
date relative day 
+1 to ≤1
1
Double-blind
20
Month 6 (DB) 
2 to 273
183
Double-blind
33a or 33b
Month 12 (DB) 
274 to DB Dayf of 
Visit 33a or 33b if 
it’s ≥274
365
Double-blind
DB Final 
Visit
End Point (DB)
Last recordf
before/on Visit 
33a or 33b
a Trans. = Transition Phase, only applicable to those who enter the Transition Phase.
b MA = Maintenance Phase.
c Only applicable to those who do not enter the Transition Phase.
d Only applicable to those who enter Maintenance Phase.  For subjects who do not enter the 
Transition Phase, Baseline (MA) = Baseline (OL).
e Final post-baseline (MA) assessment during the Maintenance Phase will be used as the value 
for Baseline (DB) visit.
f If the End of DB Phase visit date is after Visit 33b, use the data on or before Date of DB 
Month 12 that is defined in Section 2.5.1.
OL=Open-label, DB=Double-blind


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Table 1e: Time Intervals for Visits for C-SSRS
Analysis Phase
Scheduled Visit 
Number
Label on Output
Time Interval
in Phase Day
Target Time in 
Phase Day
1
Screening
<1
-28 to -1 before 
OL dosing
MAa
1,2f 
Baseline (MA)b
≤ MA injection 
date
1
MA
MA Final Visit
End Point (MA)c
2 to End of MA
30 (PP1M) or 
90 (PP3M)
Double-blind
7b
Baseline (DB)c
1st OL injection 
date relative day 
+1 to ≤1
1
Double-blind
10
Week 4 (DB) 
2 to 44
29
Double-blind
12
Month 2 (DB) 
45 to 75
60
Double-blind
13
Month 3 (DB)
76 to 105
92
Double-blind
14
Month 4 (DB) 
106 to 133
120
Double-blind
15
Month 5 (DB)
134 to 165
148
Double-blind
20
Month 6 (DB) 
166 to 197
183
Double-blind
23
Month 7 (DB) 
198 to 227
213
Double-blind
25
Month 8 (DB)
228 to 257
242
Double-blind
26
Month 9 (DB) 
258 to 287
274
Double-blind
27
Month 10 (DB) 
288 to 319
302
Double-blind
29
Month 11 (DB) 
320 to 350
337
Double-blind
33a or 33b
Month 12 (DB) 
351 to DB Dayd
of Visit 33a or 
33b if it’s ≥351
365
Double-blind
DB Final Visit
End Point (DB)
Last recordd
before/on Visit 
33a or 33b
a MA = Maintenance Phase.
b Only applicable to those who enter Maintenance Phase.  For subjects who do not enter the Transition 
Phase, Baseline (MA) = Baseline (OL).
c Final post-baseline (MA) assessment during the Maintenance Phase will be used as the value for 
Baseline (DB) visit.
d If the End of DB Phase visit date is after Visit 33b, use the data on or before Date of DB Month 12 that 
is defined in Section 2.5.1.
OL=Open-label, DB=Double-blind


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Table 1f: Time Intervals for Subject Injection Site Rating VAS, and Investigator Injection Site 
Rating
Analysis 
Phase
Scheduled 
Visit Number
Label on Output
Time Interval
in Phase Day
Target Time in 
Phase Day
Trans.a
Trans. Final 
visit
End Point (Trans.)a
2 to End of Trans
MAb
MA Final 
Visit
End Point (MA)c
2 to End of MA
30 (PP1M) or 
90 (PP3M)
Double-blind
7b
Baseline (DB)c
1st OL injection 
date relative day 
+1 to ≤1
1
Double-blind
8
Day 3 (DB) 
2 to 12
3
Double-blind
9
Week 3 (DB) 
13 to 56
22
Double-blind
13
Month 3 (DB) 
57 to 105
92
Double-blind
14
Month 4 (DB) 
106 to 151
120
Double-blind
20
Month 6 (DB) 
152 to 228
183
Double-blind
26
Month 9 (DB) 
229 to 287
274
Double-blind
27
Month 10 (DB)
288 to 333
302
Double-blind
33a or 33b
Month 12 (DB) 
334 to DB Dayd
of Visit 33a or 
33b if it’s ≥334
365
Double-blind
DB Final 
Visit
End Point (DB)
Last recordd
before/on Visit 
33a or 33b
a Trans. = Transition Phase, only applicable to those who enter Transition Phase. 
b MA = Maintenance Phase.
c Final post-baseline (MA) assessment during the Maintenance Phase will be used as the value 
for Baseline (DB) visit.
d If the End of DB Phase visit date is after Visit 33b, use the data on or before Date of DB 
Month 12 that is defined in Section 2.5.1.
OL=Open-label, DB=Double-blind
Hemoglobin A1c and urinalysis testing will be summarized at baseline (MA), end point (MA), and 
end point (DB).
To prevent missing data for subjects who withdraw early in the Double-blind phase and do not 
provide the data in the Follow-up phase up to the end of Month 12 from their first Double-blind 
injection, multiple contacts to the subjects by the sites will be made to get the information 
regarding safety and information related to a relapse event.  The number of subjects who agreed 
to be contacted at the time of withdrawal will be summarized by the 2 treatment groups in the 
Double-blind phase.
2.2.
Pooling Algorithm for Analysis Centers
There will be no pooling for the study sites in the efficacy and safety analyses.


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2.3.
Analysis Populations
Four analysis populations are defined: the open-label intent-to-treat (OL ITT) analysis population, 
the double-blind intent-to-treat (DB ITT) analysis population, the all randomized analysis 
population, and the per-protocol analysis population (PP). The DB ITT analysis populations is the 
primary analysis population for the primary efficacy endpoint.
2.3.1.
Open Label Intent-to-Treat (OL ITT) Analysis Population, and OL 
Safety Population
The open-label intent-to-treat analysis population, denoted as OL ITT, includes all subjects who 
have received at least 1 dose of open-label study drug (excluding the first study participation of 
these re-screened subjects mentioned in the first paragraph), including transition and maintenance 
phases. The open-label safety analysis population (OL Safety) is the same as the OL ITT analysis 
population. 
Protocol amendment 2 permitted the withdrawal of subjects who had an incomplete injection or 
received an unintended dosing or administration of study drug during the Transitional Phase or 
Maintenance Phase, and re-screening of these subjects.  For these subjects, only data collected 
during the second study participation will be included in the data summary.  The data collected 
during the first study participation will only be listed in the subject’s profile, and would not be 
included in the summaries for the OL ITT analysis population. 
2.3.2.
Double-blind Intent-to-Treat (DB ITT) Analysis Population
The DB intent-to-treat analysis population, denoted as DB ITT, includes all subjects who are 
randomly assigned to treatment group of either PP6M or PP3M during the Double-blind Phase, 
receive at least 1 dose of double-blind study drug.  The Double-blind safety analysis population
(DB Safety) will be the same as the DB ITT population.
2.3.3.
All Randomized Analysis Population
The all randomized population includes all subjects who are randomly assigned to treatment group 
of either PP6M or PP3M during the Double-blind Phase.  
2.3.4.
Per-Protocol Analysis Population
The per-protocol analysis population includes subjects who are randomly assigned to treatment 
(PP6M or PP3M) during the Double-blind Phase and receive at least 1 dose of double-blind study 
drug. Subjects should not have Major Protocol Violations (MPV) up to Visit 33a or 33b of the 
double-blind phase (DB Month 12 date), that is, major protocol deviations that may impact 
efficacy such as violations of intended study population, errors in treatment assignment or use of 
excluded medication.   
Criteria to identify MPVs:


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The categories and examples for subjects who are considered as having had MPVs, that is, the 
subjects who are in the intent-to-treat analysis set but are excluded from the per-protocol analysis 
set (Inclusion/Exclusion/Eligibility Criteria numbers referenced below are those from Amendment 
3 of the Protocol) are listed below:
1. Violations of Inclusion and Exclusion Criteria that are deemed to affect the primary 
efficacy endpoint (time to relapse at Month 12 of the Double-blind phase).  Examples are: 
a full PANSS score ≥70 points at screen (violation of Inclusion Criteria 6), diagnosis at 
screening is not schizophrenia (violation of Inclusion Criteria 3), had attempted suicide 
within 12 months before screening (violation of Exclusion Criteria 2)
2. Subjects who should not be randomized to enter the Double-blind phase.  For example, the 
PANSS total score at the randomization (Visit 7b) is ≥70 (violation of Eligibility Criteria
1),  or have scores of > 4 points at the randomization (Visit 7b) for at least one of the 
following PANSS items P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory 
behavior), P6 (suspiciousness/ persecution), P7 (hostility), G8 (uncooperativeness), and 
G14 (poor impulse control) (violation of Eligibility Criteria 2)
3. Subjects who have errors in treatment of the Maintenance or Double-blind phases.  
Examples are: Subjects took the study medication that deviated from the assignment of the 
IWRS in the Maintenance or Double-blind phases, Study drug was not fully administrated 
at any visit in the Maintenance or Double-blind phase, Subjects took moderate dose level 
at maintenance though they were supposed to take high dose level according to the 
protocol, etc.
4. Use of excluded medication, including subjects that used excluded Long Active Injectable 
(LAI) antipsychotic during Maintenance or Double-blind phases
5. Others, for example, subjects that had no PANSS score data during the entire Double-blind 
phase
Subjects with a major deviation and/or a MPV will be determined prior to unblinding the data.
2.3.5.
Pharmacokinetics Analysis Population
The Plan of PK Analysis will be addressed in a separate document.
2.3.6.
Pharmacodynamics Analysis Population
The Plan of PK-PD Analysis will be addressed in a separate document.
2.4.
Definition of Subgroups
Subgroup
Version
Definition
Region
1
EU, US, Non-EU/Non-US
Age Group
1
18-25
26-50
51-65


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Subgroup
Version
Definition
>65
Race
1
White, Black, Non-black/Non-white
Sex
1
male, female
BMI at DB Baseline
1
normal <25 kg/m2
overweight 25-<30 kg/m2
obese ≥30 kg/m2
Stabilized PP formulation 
(PP1M or PP3M in 
Maintenance Phase, for 
primary efficacy and AE 
summary) (MAR)
1
PP1M
PP3M
Dose level: (A stratification
factor at randomization that 
based: Dose Level in 
Maintenance Phase, for 
primary efficacy and AE 
summary) (MADL)
1
This subgroup is only defined for randomized subjects:
moderate
high
Prior antipsychotic use 
(only applicable to analyses 
of ECG data)
1
Oral antipsychotic
Injectable Risperidone
PP1M initiation
PP1M stability
PP3M stability
2.5.
Study Day and Relative Day
2.5.1.
Study Day Definitions 
The study day is defined based on the phase a visit happens.  Three phases are considered when 
the study day is calculated: Transition, Maintenance, and Double-blind.  Both Transition and 
Maintenance Phases are also referred as Open-label phase.
The ‘Reference Start Date’ or ‘Start Day 1’ for a subject is the date of the first study injection
during the Open-Label Phase.  The ‘Reference End Date’ for a subject is the end-of-study (EOS) 
visit, the completion/withdrawal date, the last date of study drug administration during the study, 
or the last OL or DB evaluation date collected in QS, EG, VS, and LB data.
Date of Maintenance injection
There is only one study medication injection for the Maintenance Phase.  Date of Maintenance 
injection is the date of the exposure record for Visit 2f for subjects who enter the Transition Phase, 
and the date of exposure record for Visit 2 for subjects who enter the Maintenance directly (no 
Transition Phase) from Screen Phase.
Start and End dates of the Transition, Maintenance, and Double-blind phases

For subjects who enter the Transition Phase, the Start date of Transition Phase (Trans. Day 
1) refers to the date of first injection of the study medication (PP1M) during the Transition 
Phase; and the Transition Phase end date (denoted as ‘Trans. End Date’) is one day before 
the start date Maintenance Phase for subjects who enter the Maintenance Phase, or the trial 


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disposition date for subjects who do not enter the Maintenance Phase. The Start and end 
dates are not defined for subjects who do not enter the Transition Phase (those who enter 
the Maintenance Phase directly from Screen Phase).

For subjects who enter the Maintenance Phase, the Start date of the Maintenance Phase 
(MA Day 1) is the injection date of the Maintenance Phase; and the Maintenance Phase 
end date (denoted as “MA End Date”) is one day before the DB Day 1 for subjects who 
enter the Double-blind phase, or the trial disposition date for subjects who do not enter the 
Double-blind Phase.

For randomized subjects who receive Double-blind study medication, the Start date of the 
Double-blind Phase (DB Day 1) is the first injection date of the Double-blind Phase; and 
the Double-blind Phase end date (denoted as ‘DB End Date’) is the same as the date on the 
Double-blind treatment disposition page.  The DB Start Date and the DB End Date are not 
defined for subjects who do not receive Double-blind Phase study medication.
Data collected after the DB End Date will be allocated to phase of ‘FOLLOW-UP’.  The Start Date 
for the Follow-up Phase is one Day after the DB End Date.  The End Date for the Follow-up Phase 
is same as the ‘Reference End Day.’
Date of Double-blind Month 12 (DB Month 12)
For 5 subjects who received a Month 12 injection as mentioned in Section 2.1,  the date of Double-
blind Month 12 (DB Month 12) is defined for the primary efficacy analysis as the date of Visit 33a
or 33b from the eCRF.   For all other subjects who did not receive a Month 12 injection, their DB 
Month 12 dates will be missing. 
2.5.2.
Relative Day for a Visit
There are three types of relative days (Study Day) defined for a visit in this trial – (1) relative to 
the Date of First Open-Label injection (either in Transition phase or Maintenance Phase), (2) 
relative to the Date of Maintenance Injection, (3) relative to the DB Start Date. Relative days are 
defined with respect to the date of Maintenance injection and the DB start date. Days relative to 
the DB Start Date will only be defined for the Double-blind and Follow-up visits.
Maintenance (MA) Study Day
Days relative to the Date of Maintenance injection are defined as follows (only for subjects who 
receive Maintenance injection):
MA Study Day = visit date – the Date of Maintenance injection + 1; if visit date ≥ the Date of 
Maintenance injection;


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MA Study Day = visit date – the Date of Maintenance injection; if visit date < the Date of 
Maintenance injection.
OL Study Day
Days relative to the Date of First Open-Label (either transition or maintenance phase) injection are 
defined as follows:

If the subject receives injections in transition phase,
OL Study Day = visit date – the Date of First injection of Transition phase + 1; if visit date ≥ the 
Date of First injection in Transition phase
OL Study Day = visit date – the Date of First injection of Transition phase; if visit date < the Date 
of First injection of Transition phase.

If the subject enters maintenance directly after the screen phase (no transition phase), 
OL Study Day = MA Day.
DB Study Day
Days relative to the DB Start Date are defined as follows (only for those who receive Double-
Blind injection):
DB Study Day = visit date - the DB Start Date+ 1; if visit date ≥ the DB Start Date,
DB Study Day = visit date – the DB Start Date; if visit date < the DB Start Date.
For all types of relative days, as per the definitions above, there is no ‘Day 0’.
2.6.
Baseline and Endpoint
2.6.1.
Baseline Values
Three kinds of Baseline values are defined in the analyses: Baseline (OL), Baseline (MA), and 
Baseline (DB).
Baseline (OL):
The ‘Baseline (OL)’ value is the baseline values that will be summarized in the demographic 
tables.  The ‘baseline (OL)’ value is defined as the last value collected before administration of 
any study medication from Open-label phases (Transition and Maintenance Phases).  
For ECG, the Baseline (OL) is the average predose value defined in Section 6.4.
Baseline (MA):


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The ‘Baseline (MA)’ value for the Maintenance phase is defined as the last assessment on or before 
the Maintenance injection date. Note that the Baseline (MA) is defined for each parameter of 
interest whereas the Maintenance injection Date is defined at subject level and remains the same 
for all parameters of interest.
The ‘C-SSRS Baseline’ version is collected on the Screening visit and the ‘C-SSRS Since Last 
Visit’ version is collected on all other visits including Visit 2 (or 2a to 2f). To avoid confusion of 
the meaning of ‘baseline’, we denote assessment of C-SSRS at Visit 2 or 2f (i.e., the Maintenance
Start Date) as ‘Day 1 (MA)’ (Table 1e), instead of ‘Baseline (MA)’ because it uses the C-SSRS 
Since Last Visit version.
Baseline (DB):
The ‘Baseline (DB)’ value for the Double-blind Phase is defined as the pre-dose (Double-blind) 
assessment value measured at the day closest to (and including) the DB Start Date. It is defined 
for all efficacy variables as well as for the safety variables in the Double-blind Phase for subjects 
who enter the DB phase. 
No baseline values are needed for the Transition phase (only baseline values for Open-label phase)
and the Follow-up Phase.
2.6.2.
Endpoint Values
For each variable measured over time, the ‘End Point (MA)’ value is defined as the last assessment 
value (note that the Baseline (MA) value is excluded) during the Maintenance Phase. This value 
will be the same as the Baseline (DB) value for subjects who continue into the Double-blind Phase.  
The ‘End Point (DB)’ value is defined as the last post-baseline (DB) assessment value (note that 
the Baseline (DB) value is excluded) before or on the date of DB Month 12, or the disposition date 
of the treatment disposition if the date of DB Month 12 is missing.
2.7.
Imputation Rules for Missing Date and Time
2.7.1.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
An AE with an incomplete date will not be considered as treatment-emergent for the open-label 
phase (including Transition and Maintenance phases).
The following rules will be used to determine if an AE is treatment-emergent for the Double-blind 
phase when the AE start date is incomplete:
(1) If the month and year are known and day of the month is missing: If the DB study 
medication started during or prior to that month/year then the AE is considered treatment-
emergent for the Double-blind phase.  If the DB study medication started after that 
month/year, then the AE will not be considered treatment emergent for the Double-blind 
phase.


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(2) If the year is known and the month is missing: If the DB study medication started during 
or prior to that year then the AE is considered treatment-emergent.
(3) If the year is missing: The AE will be considered treatment emergent for the Double-blind 
phase.
2.7.2.
Incomplete/Missing Dates of Most Recent Hospitalization for 
Psychosis 
The duration (days) of the most recent hospitalization for psychosis prior to the start of the study 
will be calculated as: stop date - start date + 1. If the hospitalization start/stop date is completely 
missing or the year is missing, no imputation will be performed. If the start/stop dates of 
hospitalization are partially missing the following rules will apply:
Hospitalization start date: if only the day is missing, use the first day of the month. If only the 
month is missing, January will be used. If both the day and month are missing, the imputed date 
will be January 1. 
Hospitalization stop date will be the minimum between the day before the Screening Visit and 
the following imputed date: 
–
If only the day is missing, then the last day of the given month will be used (eg, if the 
month is April, then the missing day will be imputed as April 30); 
–
If only the month is missing, then December will be used; 
–
If both the day and the month are missing, then the imputed date will be December 31. 
2.7.3.
Incomplete/Missing Dates of Hospitalization Collected in HRUQ 
The duration (days) of the hospitalization collected in HRUQ will be calculated as: stop date - start 
date + 1. If the hospitalization start/stop date is completely missing or the year is missing, no 
imputation will be performed. If the start/stop dates of hospitalization are partially missing the 
following rules will apply:
Hospitalization start date: 
–
if only the day is missing, use the first day of the month. 
–
If only the month is missing, January will be used. 
–
If both the day and month are missing, the imputed date will be January 1. 
Hospitalization stop date will be the minimum between the day before the date of assessment 
and the following imputed date: 
–
If only the day is missing, then the last day of the given month will be used (eg, if the 
month is April, then the missing day will be imputed as April 30); 


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–
If only the month is missing, then December will be used; 
–
If both the day and the month are missing, then the imputed date will be December 31.
2.7.4.
Incomplete/Missing Dates for Concomitant Medications
No imputation of start/end dates will be done for concomitant medication reported during the 
follow-up phase, and hence, the following rules do not apply to follow-up phase.
If a partial date is reported, it is assumed medication was taken in both the Open-label and Double-
blind 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 (OL Day 1) and still ongoing at 
end of the Double-blind Phase, it is assumed medication was taken both in the Open-label Phase 
and the Double-blind Phase.
The rules for estimating an incomplete concomitant medication start date are as follows:
If the month of the concomitant medication start date is equal to the month of the start of the 
Open-label Phase, then the estimated start date is the start date of the Open-label Phase; 
If the month of the concomitant medication start date is greater than the month of the start of 
the Open-label Phase and earlier than the month of the reference end date (i.e. max (the OL End 
Date, the DB End Date)), then the estimated start date of the concomitant medication is the first 
day of the month;
If the month of the concomitant medication start date is greater than the month of the reference
end date, then no imputation will be done;
If the month and year of the concomitant medication start date are known and the OL Start Date 
is after the month of the concomitant medication start date, then no imputation will be done;
If both the month and the day of the concomitant medication start date are missing but the year 
is not, the imputed start date will be the first day of that year.
For the incomplete concomitant medication end date, the rules are: 
If the month of the concomitant medication end date is prior to the month of the reference end 
date, then the estimated the concomitant medication end date is the last day of that month;
If the month of the concomitant medication end date is during the month of the reference end 
date, then the estimated end date is the reference end date; 
If the month of the concomitant medication end date is after the reference end date, then the 
estimated end date is the last day of that month;


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If the month of the concomitant medication end date is missing but the year is not, and if the 
subject entered the Open-label Phase, then the estimated end date is the minimum of the last 
day of the year and the reference end date;
If the year is missing then the estimated end date is the reference end date;
If the concomitant medication is continuing, then the estimated end date is the reference end 
date for the purpose of duration calculation.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analyses are planned. There is no unblinded Data Monitoring Committee for this 
study.
4.
SUBJECT INFORMATION
Unless indicated otherwise, the results for subject information will be provided by treatment 
group and total subjects.
4.1.
Demographics and Baseline Characteristics
Table 2 presents the list of demographic variables and baseline characteristics and Table 3 presents 
the list of diagnosis and psychiatric history variables. Variables will be summarized for the OL 
ITT (same as OL Safety), DB ITT (same as DB Safety), and per-protocol analysis populations 
except for smoking history which will be summarized for the OL ITT analysis population only. In 
addition, these summaries will be presented for the subset of the OL ITT subjects who were not 
randomized.
The continuous variables will be summarized using descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum and maximum]). The categorical variables will be 
summarized using a frequency distribution with the number and percentage of subjects in each 
category.


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Table 2: Demographic Variables and Baseline Characteristics
Continuous Variables:
Age (years)a
Baseline (OL) weight (kg)
Baseline (OL) height (cm)
Baseline (OL) BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2
Baseline (OL) waist circumference (cm)
Categorical Variables:
Age (18-25 years, 26-50 years, 51-65 years, and >65 years)a
Sex (male, female)
Raceb (White, Black or African American, Asian (include Asian subcategories)c, 
American Indian or Alaska native, native Hawaiian or other Pacific islander, 
other, multiple, not reported, unknown)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
Country
Region (European Union, US, Non-EU/Non-US)
Baseline (OL) BMI (normal: <25 kg/m2, overweight: 25 kg/m2 to <30 kg/m2, 
obese: 30 kg/m2)
Nicotine Use at Screening (never used, current/former user)
a Age at Screening visit.
b If multiple race categories are indicated, then Race is recorded as “Multiple.”
c Asian subcategories include Chinese, Korean, Japanese, Filipino, Asian Indian, Thai, 
Malaysian, and Asian (other).
Demographic and baseline characteristics will be summarized by European Union vs. US vs. Non-
EU/Non-US, for the per-protocol analysis population.
Table 3: Diagnosis and Psychiatric History Variables at Maintenance and Double-
blind Phases
Continuous Variables:
Age at diagnosis of schizophrenia (years)
Duration of most recent hospitalization prior to study entry (years)a,b calculated 
as end date of hospitalization for psychosis-start date of hospitalization for 
psychosis + 1
Baseline (MA) and Baseline (DB) PANSS total score
Baseline (MA) and baseline (DB) PSP score
Categorical Variables:
DSM-5 diagnosis 
1)Number of prior hospitalizations for psychosis within last 24 months (0, 1, 2, 
3, 4)a
Baseline (MA) and Baseline (DB) CGI-S score  
a Excludes hospitalization at time of study entry.
b Applies only to subjects with prior hospitalizations.
4.2.
Disposition Information
Subject disposition will be summarized for both the Open-label (including Transition and 
Maintenance Phases) and Double-blind phases. For the OL ITT analysis population, the reasons 
for study discontinuation during the Open-label Phase will be summarized. In addition, the number 
of subjects continuing into the Double-blind Phase will be summarized. For the DB ITT (same as 


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DB Safety), and per-protocol analysis populations, the reasons for study completion (i.e. relapse 
during the Double-blind Phase or completion of Double-blind Phase without a relapse) and the 
reasons for study discontinuation during the Double-blind Phase will be summarized. The 
disposition information for the Double-blind Phase is recorded on the treatment disposition “of 
Double-blind Phase” CRF page.  Subjects who discontinue treatment by “disease relapse” will be 
considered as having completed the Double-blind phase by having a relapse event. 
The cumulative number of subjects in the DB ITT analysis population will be presented over time 
for those who discontinue the Double-blind treatment without a relapse event..
Subject disposition during the Double-blind Phase will also be summarized by remission status 
during the Double-blind Phase. The remission criteria are provided in Section 5.3.6.
A Kaplan-Meier plot of time to all cause discontinuation (including relapses) during the Double-
blind Phase will be presented by treatment group for the DB ITT population.
The number of screen failures will be presented. 
4.3.
Treatment Compliance
Since the study injection medication will be administered as SC injections by the study site staff, 
compliance of the injection study medication will not be included as an analysis variable.  The 
number of injections received will be summarized as part of exposure (see Section 4.4.1).
4.4.
Extent of Exposure
4.4.1.
Injections
The number and percent of subjects who receive 1, 2, 3, etc. injections of double-blind study drug 
will be summarized by treatment group, both including and excluding the placebo injections in the 
PP6M group. The number and percent of subjects at each dose level will be summarized. For each 
3 months (quarterly) during the Double-blind Phase, a frequency distribution will be presented 
showing the number of subjects who receive the injection in the gluteal muscle. The treatment 
exposure (including duration of total exposure), and mean dose (not including placebo injection)
will be presented. These summaries will be provided for the DB ITT population.
The duration of total exposure in the Double-blind phase is calculated as the total number of days 
a subject remains in the Double-blind Phase of the study, that is, 
The duration of total exposure in DB phase = treatment disposition date – the DB Start Date + 1
Similar analyses on the exposure during the Open-label Phase will be carried out for the OL ITT
analysis population.


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4.4.2.
Oral Tolerability Test
For those subjects without documented tolerability to oral or injectable risperidone or paliperidone, 
oral paliperidone ER 6 mg daily or oral risperidone 3 mg daily are to be administered for 4 to 6 
consecutive days. Tolerability testing is to occur during the Screening Phase (last dose must be 
administered by Day -1) and may be concurrent with any required washout.
The number and percent of subjects who receive 4, 5, or 6 consecutive daily doses of 
paliperidone ER as a tolerability test during the screening period will be summarized for the OL 
ITT analysis population.
4.5.
Protocol Deviations
All major protocol deviations will be summarized for the OL ITT (Same as OL Safety) population
and the DB ITT (same as DB Safety) population. Major Protocol Violations (i.e., Major Protocol 
Deviations that led to exclusion from Per-protocol population) before visits 33a or 33b (Section 
2.3.4) will be summarized for the DB ITT population.
The following list of major protocol deviations may have the potential to impact subjects’ rights, 
safety or well-being, or the integrity and/or result of the clinical study. Subjects with major 
protocol deviations will be identified prior to database lock and the subjects with major protocol 
deviations will be summarized by category.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
4.6.
Prior and Concomitant Medications
4.6.1.
Prior Psychotropic Medications
The number and percentage of subjects who received psychotropic medications prior to the OL 
Start 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 (used for Anti-
extrapyramidal symptoms [EPS] / akasthesia) : Acetylcholinesterase inhibitors, Antidepressants, 
Anti- 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 OL 
ITT (same as OL safety) and DB ITT analysis populations.
Those prior psychotropic medications received by at least 5% of the subjects in either double-blind 
treatment group will be presented for the safety analysis population.


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The number and percentage of subjects who received prior antiparkinsonian medications (beta 
blockers (used for EPS / akasthesia), anticholinergics [anti-EPS] or antihistamines) will be 
provided by the generic term category within the psychotropic group. The summary will be 
presented for the OL ITT (same as OL safety) analysis populations.
4.6.2.
Concomitant Benzodiazepines (Sedatives/Hypnotics/Anxiolytics)
The number and percentage of subjects who received benzodiazepines during the Open-label 
Phase (Transition and Maintenance phases combined) will be provided based on generic term 
category for the OL ITT (same as OL safety) analysis population. The number and percentage of 
subjects who received benzodiazepines during the Double-blind Phase will be provided based on 
generic term category for DB ITT (same as DB Safety) and per-protocol analysis populations. 
For each subject, the total duration of each benzodiazepine will be calculated. Descriptive statistics 
of the duration (days) of benzodiazepine use during the Open-label Phase for the OL ITT analysis 
population, and during the Double-blind Phase for the safety and per-protocol analysis populations 
will be presented. 
If both start and end dates for benzodiazepines are known, duration of concomitant medication is 
defined as stop date – start date +1. Otherwise stop and start dates of the concomitant medication 
during the 2 phases (OL and DB phases) are defined below.
For the summary of duration of benzodiazepines during the Open-label Phase, if the start date of 
concomitant medication is prior to the OL Start Date, the OL Start Date will be used as concomitant 
medication start date for duration calculation.  If the end date of concomitant medication is after 
the OL End Date or indicated as continuing, then the OL End Date will be used as the concomitant 
medication end date for duration calculation. 
For the summary of duration of benzodiazepines during the Double-blind Phase, if the start date 
of concomitant medication is prior to the DB Start Date, then the DB Start date will be used as 
concomitant medication start date for duration calculation.  If the end date of concomitant 
medication is after the DB End Date or indicated as continuing, then the DB End Date will be used 
as the concomitant end date in calculating duration.
Additionally, for the summary of duration of benzodiazepines during the combined open-label and 
double-blind phase, if the start date of concomitant medication is prior to the OL Start Date, then 
the OL Start date will be used as concomitant medication start date for duration calculation.  If the 
end date of concomitant medication is after the DB End Date or indicated as continuing, then the 
DB End Date will be used as the concomitant end date in calculating duration. Otherwise, duration 
in the combined phase = benzodiazepine stop date –start +1. 


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4.6.3.
Concomitant Medications Other Than Benzodiazepines
The number and percentage of subjects who receive concomitant therapies other than 
benzodiazepines during the study will be provided based on generic term category for the Open-
label Phase for the OL ITT analysis population and for the Double-blind Phase for the safety 
analysis population. Those concomitant medications, other than benzodiazepines, received by at 
least 5% of the subjects in either double-blind treatment group will be presented for the safety 
analysis population.
Note that duration in the trial is not calculated for concomitant medications other than 
benzodiazepines and prior psychotropic medications.
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Unless otherwise specified, a 2-sided significance level of 5% will be used. No adjustment for 
multiple testing will be used for the secondary efficacy analyses. 
5.1.2.
Data Handling Rules
For the efficacy scales PANSS, CGI, and PSP, both observed case (OC) and last observation 
carried forward (LOCF) values will be determined for Maintenance Visit 2 (for subjects who do 
not enter transition phase) or 2f (for subjects who enter transition phase), and double-blind Months
3, 6, 9, and so on. These imputed time points will be labeled “Month X LOCF.” Because it is 
possible for more than 1 visit to occur during the same time interval for a protocol-specified visit, 
rules for choosing the visit to use for the analysis are those given in Section 2.2. Imputed time 
points Month XX (MA) LOCF and Month XX (DB) LOCF are not needed as they are essentially 
equivalent to END POINT (MA) and END POINT (DB), respectively. 
If there are multiple visits in a time interval with non-missing values, the visit closest to the 
protocol-specified time is used as both observed case and LOCF. If there is no visit in a time 
interval with a non-missing value, then the OC value is missing and the last non-missing, post-
baseline value prior to the interval is used for LOCF. 
Individual item scores will not be carried forward for PANSS. Refer to Section 5.3.1.1 for handling 
of missing PANSS item scores.
5.2.
Primary Efficacy Estimand
The primary efficacy estimand is defined by the following components:


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The population is restricted to those who are stabilized on either PP1M or PP3M during the 
Maintenance Phase and meet the inclusion/exclusion criteria.
The variable is time to first occurrence of a relapse event during the Double-blind Phase.
The intercurrent events and corresponding strategies are the following:

Treatment discontinuation – Hypothetical Strategy: After treatment discontinuation, 
assume similar efficacy for subjects who discontinued as those subjects from the same 
treatment group who did not discontinue the treatment.

Major protocol violations – Treatment Policy Strategy: use all relapse events, regardless of 
whether or not major protocol violations had occurred.
The population-level summary is the difference in Kaplan-Meier estimate at Month 12 of relapse-
free proportions between the 2 treatment groups.
The primary analysis set is the DB ITT population (see Section 2.3.2.). For consistency to previous 
studies, same analyses will also be applied to the PP population (see Section 2.3.4.). 
Subjects who meet at least 1 of the criteria for a relapse during the Double-blind Phase before DB 
Month 12 date are considered to have had a relapse event. The definition of a relapse event is 
presented in Section 5.2.1.1. Under the primary estimand, which applies a hypothetical strategy 
for treatment discontinuation, only the relapse events occurring during the Double-blind Phase 
prior to treatment discontinuation will be counted as events in the primary analysis. The details are 
as follows:
The date of DB Month 12 has been specified in Section 2.5.1.  
(1) For a subject who stays in the DB phase up to the date of DB Month 12 without a relapse 
event, the subject would be considered as censored at the date of the DB Month 12 whether
the date is before or after Day 365;
(2) If a subject does not belong in (1), the subject must have discontinued the Double-blind phase 
before reaching DB Month 12 visit, either by premature withdrawal (i.e. treatment 
discontinuation) or by having a relapse event.

If the subject has a relapse event in the Double-blind Phase before reaching the DB 
Month 12 date, prior to treatment discontinuation, the subject is considered as having 
an event 

If the subject discontinues treatment (and therefore the Double-blind Phase) before 
Day 365 without a relapse event, the subject is considered as censored at the Day of 
discontinuation (day of treatment disposition of the Double-blind Phase).


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The definition of the time to relapse in the Double-blind Phase is presented in Section 5.2.1.2.
5.2.1.
Definition of Time to Relapse
Definition of Relapse Event
Relapse is defined as 1 or more of the following:

Psychiatric hospitalization (involuntary or voluntary admission to a psychiatric hospital for 
decompensation of the subject’s schizophrenic symptoms), or

For Positive and Negative Symptom Scale for Schizophrenia (PANSS)
o
The subject has an increase of 25% in PANSS total score from randomization for 
2 consecutive assessments separated by 3 to 7 days if the score at randomization 
was >40, where 
Percent change = DB score – randomization score   * 100
                               randomization score – 30
or,
o
The subject has a 10-point increase in the PANSS total score from randomization 
for 2 consecutive assessments separated by 3 to 7 days if the score at randomization 
was <40, or

The subject inflicts deliberate self-injury or exhibits violent behavior resulting in suicide, 
clinically significant injury to him/herself or another person, or significant property 
damage, or
o
The subject has suicidal or homicidal ideation and aggressive behavior that is 
clinically significant (in frequency and severity) in the investigator’s judgment, or

For PANSS items P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory 
behavior), P6 (suspiciousness/persecution), P7 (hostility), and G8 (uncooperativeness);
o
The subject has a score of >5 after randomization for 2 consecutive assessments 
separated by 3 to 7 days on any of the above items if the maximum score for the 
above PANSS items was < 3 at randomization, or 
o
The subject has a score of >6 after randomization for 2 consecutive assessments 
separated by 3 to 7 days on any of the above items if the maximum score for the 
above PANSS items was 4 at randomization.


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The date of relapse will be the date of the first assessment for symptoms of relapse (not the date 
of confirmation). 
Time to Relapse During Double-Blind Phase
The time to relapse during the Double-blind phase is defined as follows:
1. Relapse during the Double-blind Phase
Time to relapse = Date of Relapse - Randomization Date + 1
censoring indicator variable = “NO”
2. Early withdrawal during the Double-blind Phase
Time to relapse = Date of early withdrawal - Randomization Date + 1
censoring indicator variable = “YES”.
3. Remained relapse free in the Double-blind Phase (for subjects who received Month 12 
injection, their time to relapse will be censored at the DB Month 12 date defined in Section 
2.5.1)
Time to relapse = Date of end of Double-blind Phase - Randomization Date + 1
censoring indicator variable = “YES”.
5.2.2.
Primary Efficacy Analysis Performed on the Double-blind Intent-to-
Treat Analysis Population
Main Analysis
The hypotheses to be tested using a 1-sided α=0.025 level are: H0:p6-p3<-δ vs. H1:p6-p3>-δ; where 
p3 refers to the percentage of subjects who remain relapse free at Month 12 for the PP3M groups 
and p6 refers to the percentage of subjects who remain relapse free at Month 12 for the PP6M 
group. The Kaplan-Meier method will be used to estimate the Month 12 cumulative estimate of 
survival (ie, percentage of subjects remaining relapse-free). Standard Error (SE) estimates will be 
based upon Greenwood’s formula. 
Non-inferiority of PP6M to PP3M will be concluded if the lower limit of the 2-sided 95% 
confidence interval of the difference in the relapse-free rates between PP6M and PP3M 
exceeds -10%. If the lower limit of the 2-sided 95% confidence interval of the difference in the 
relapse-free rate between PP6M and PP3M exceeds 0%, then PP6M will be declared superior to 
PP3M.


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Sensitivity Analysis 
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 DB ITT analysis population. Specifically, it is assumed that subjects on PP6M who discontinue 
prematurely from the Double-Blind phase have a higher relapse hazard starting from the 
discontinuation time, compared with similar subjects who remain in this phase. The higher relapse 
hazard is determined by the 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 Double-Blind phase. A Kaplan-Meier
multiple imputation (KMMI) non-parametric approach will be used for the imputation of relapse 
events, as described in Taylor et al (2002)[11] and Lipkovich et al (2016)[12]. 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 PP6M group 
(i.e. subjects censored due to other reasons than the end of Double-Blind phase cut-off), starting 
with 1 (ignorable censoring) and increasing by 1 until the point when the non-inferiority condition 
is no more satisfied. For the PP3M group, the sensitivity parameter Delta will be set to one, i.e. 
maintaining the ignorable censoring assumption.
Supplementary Analyses 
Three supplementary estimands are defined to support the primary estimand. In their definitions, 
the only component that changes from the definition of the primary estimand is how the strategy 
is defined for treatment discontinuation.
For subjects who discontinue treatment during the Double-blind phase and enter the Follow up 
phase, their last day of the Follow up phase is recorded as the trial disposition date.
Supplementary Estimand S1:
Hypothetical Strategy: After treatment discontinuation (defined as treatment discontinuation plus 
91 days in the Follow-up Phase), assume similar efficacy for subjects who discontinued as those 
subjects from the same treatment group who did not discontinue the treatment.
Under the S1 supplementary estimand, all relapse events occurring 91 days (i.e. 3 months) after 
treatment discontinuation will also count as events in the analysis. Subjects who discontinue 
treatment and have no relapse event within this timeframe will be considered censored at the 91 
days threshold, or the date of trial disposition date, whichever is earlier.
Supplementary Estimand S2:
Hypothetical Strategy: After treatment discontinuation (defined as treatment discontinuation plus 
182 days in the Follow-up Phase), assume similar efficacy for subjects who discontinued as those 
subjects from the same treatment group who did not discontinue the treatment.


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Under the S2 supplementary estimand, all relapse events occurring 182 days (i.e. 6 months) after 
treatment discontinuation will also count as events in the analysis. Subjects who discontinue 
treatment and have no relapse events within this timeframe will be considered censored at the 182 
days threshold, or the date of trial disposition date, whichever is earlier.
Supplementary Estimand S3:
Treatment Policy Strategy: use all relapse events, regardless of treatment discontinuation.
Under the S3 supplementary estimand, all relapse events occurring after treatment discontinuation 
up to the DB Month 12 date will also count as events in the analysis. Subjects remaining relapse-
free at the DB Month 12 date will be censored at that date. Subjects who discontinue the study and 
do not reach the DB Month 12 will be censored at the trial disposition date.
For each of the 3 supplementary estimands, the difference between the PP6M and PP3M groups
of the percentage of subjects who remain relapse-free at end of Month 12 based on Kaplan-Meier 
estimate will be presented, together with the 95% confidence interval of the difference.  The 
analysis dataset is the DB ITT population.
Supplementary Analysis S4:
The primary efficacy analysis will be performed based on S3 estimand for the DB ITT analysis 
population by excluding 3 subjects in Mexico who were impacted by delay of drug supply. 
After changes starting in 2018 at the Ministry of Health in Mexico, new drug import licensing 
process affected shipments of PP6M.  The delays affected three subjects who had to be withdrawn 
early from the Double-blind phase.
Supplementary Analysis S5:
To evaluate the potential impact of COVID-19, this supplementary analysis is added to censor 
subjects after their last onsite visits for those who had COVID-19 related remote visits.     
A supplementary analysis will be performed based on the estimand in Section 5.2 (for primary 
efficacy estimand) for the DB ITT analysis population by censoring subjects at their last onsite 
visit. For other subjects who did not have COVID-19 remote visits, or whose end of DB visits 
were performed onsite, their time to relapse and censoring status remains the same as the analysis 
specified in Section 5.2.1.2.  
Subgroup Analysis
To evaluate the consistency of the results in various subgroups, the Kaplan-Meier estimate of time 
to relapse will be fit for each of the following subgroups: Dose level (moderate/high) in 
Maintenance Phase, Dose regimen (PP1M/PP3M) in Maintenance Phase, age group (18-25, 26-
50, 51-65, > 65 years), sex, race (White, Black, Other), Baseline (DB) BMI group, and region 


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(European Union, US, Non-EU/Non-US).   The treatment difference between PP6M and PP3M 
groups at Month 12 and its 95% confidence interval will be reported for each of the subgroups. 
A forest plot will be used to evaluate the consistency of effect across these subgroups.
In addition, subgroup analysis will also be performed using the Cox Regression model.  To adjust 
for the effect of baseline covariates, the following variables will be included in the Cox regression 
model: Dose level (moderate/high) in Maintenance Phase, Dose regimen (PP1M/PP3M) in 
Maintenance Phase, age group (18-25, 26-50, 51-65, > 65 years), sex, race (White, Black, Other), 
Baseline (DB) BMI group, region (European Union, US, Non-EU/Non-US), in addition to 
treatment.
Model Diagnostics
To assess the appropriateness of the proportional hazards assumption, a log-log survival plot of 
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.
5.2.3.
Primary Efficacy Analysis Performed on Per-Protocol Analysis 
Population
Same main analysis, sensitivity analyses and supplementary analyses specified in Section 5.2.2
will also be conducted on the PP population, defined in Section 2.3.4. The 10% non-inferiority 
margin specified in Section Error! Reference source not found.  for the DB ITT population will 
also be used for the main analysis on the PP population.
5.3.
Secondary Efficacy Endpoints
Secondary analyses will be conducted using the DB ITT analysis population. Summaries and/or 
analyses for PANSS total score, CGI-S, PSP, and PANSS subscales will also be provided for the 
per-protocol analysis population. No multiplicity adjustments will be made.
5.3.1.
PANSS Total Score
Definition
The PANSS scale consists of 30 items with a score of 1 to 7. The total score is the sum of all 30 
PANSS items and ranges from 30 to 210. Higher scores indicate more severe neuropsychiatric 
symptoms of schizophrenia. If a PANSS item is missing, it will be imputed with the closest integer 
to the average of the remaining items within the subscale (positive, negative and general 
psychopathology) at that time point and then the total will be summed. If more than 15% of the 
items are missing, i.e., if 5 or more items are missing, no imputation will be performed and the 
total score and the scores of the subscales that include these items will be left missing. Imputation 


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of item scores is performed prior to determining the LOCF for the PANSS subscale and total 
scores.
Analysis Methods
At each assessment time point during the Double-blind Phase and at end point (DB), descriptive 
statistics (mean, standard deviation, minimum and maximum) for the PANSS total score and the 
change from baseline (DB) will be provided for both the observed case and LOCF data. The 
change from baseline (DB) at each visit during the Double-blind Phase will be analyzed using an 
ANCOVA model with factors for treatment and country and baseline score as a covariate. The 
treatment effects will be estimated based upon least square means (PP6M-PP3M), and the 
accompanying 95% confidence intervals will be presented. 
In addition, descriptive statistics of the PANSS total score and the change from baseline (MA) will 
be provided for selected visits (see Section 2.1, Table 1a) during the Open-label Phase for the OL 
ITT analysis population.
5.3.2.
Clinical Global Impression - Severity (CGI-S)
Definition
The CGI-S is a categorical rating of the subject’s severity of illness on a 7-point scale (1=not ill, 
2=very mild, 3=mild, 4=moderate, 5=marked, 6=severe, 7=extremely severe). 
Analysis Methods
At each assessment time point during the Double-blind Phase and at endpoint (DB), frequency 
counts of CGI-S scores by severity label (mild, moderate, etc.) will be produced for both the 
observed case and LOCF data. At each visit, descriptive statistics (mean, standard deviation, 
minimum and maximum) of the numerical scores and change from baseline (DB) will also be 
presented. The change from baseline (DB) at each visit during the Double-blind Phase will be 
analyzed using an ANCOVA model with factors for treatment and country and baseline score as a 
covariate. The treatment effects will be estimated based upon least square means (PP6M-PP3M), 
and the accompanying 95% confidence intervals will be presented.
In addition, frequency distributions and descriptive statistics of the CGI-S score and the change 
from baseline (MA) will be provided for endpoint of the Maintenance Phase for the ITT (OL) 
analysis population.
5.3.3.
Personal and Social Performance Scale (PSP)
Definition
The PSP scale provides an overall rating of personal and social functioning on a 100-point scale 
of 1 to 100. The scale defines a continuum from grossly impaired functioning to excellent 


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functioning. A higher score represents a better level of functioning. The PSP scale assesses the 
degree of difficulty a subject exhibits over a 7-day period based on 4 domains of behavior: socially 
useful activities, personal and social relationships, self-care, and disturbing and aggressive 
behaviors.
Analysis Methods
At each assessment time point during the Double-blind Phase and at end point (DB), descriptive 
statistics (mean, standard deviation, minimum and maximum) of the PSP total score and domain 
scores and change from baseline (DB) will be provided for both the observed case and LOCF data. 
The change from baseline (DB) in PSP total score at each visit during the Double-blind Phase will 
be analyzed using an ANCOVA model with factors for treatment and country and baseline score 
as a covariate. The treatment effects will be estimated based upon least square means (PP6M-
PP3M), and the accompanying 95% confidence intervals will be presented. Shift tables 
summarizing change from Baseline (DB) in number and frequency of subjects reporting each of 
the PSP deciles, and 3 PSP categories (Poor (≤ 30), Variable (>30 - ≤ 70), Good (>70)) will be 
presented. Frequency counts, percentages, and cumulative percentages of subjects at each PSP 
domain level will be summarized for both observed data and LOCF data by treatment group.
In addition, descriptive statistics of the PSP total score and the change from baseline (MA) will be 
provided for baseline and endpoint of Maintenance Phase for the OL ITT analysis population.
5.3.4.
PANSS Subscale Scores
Definition
The sums of the item scores for the following derived subscales based on Marder et al[6] will be 
calculated: 
Positive symptoms factor (range: 8 to 56): Delusions, Hallucinatory behavior, Grandiosity, 
Suspiciousness (items 1, 3, 5 and 6 in positive subscale), Stereotyped thinking (item 7 in 
negative subscale), Somatic concern, Unusual thought content, Lack of judgment and insight 
(items 1, 9, and 12 in general psychopathology subscale);
Negative symptoms factor (range: 7 to 49): Blunted affect, Emotional withdrawal, Poor rapport, 
Passive social withdrawal, Lack of spontaneity (items 1, 2, 3, 4, and 6 in negative subscale), 
Motor retardation, Active social avoidance (items 7 and 16 in general psychopathology 
subscale);
Disorganized thoughts factor (range: 7 to 49): Conceptual disorganization (item 2 in positive 
subscale), Difficulty in abstract thinking (item 5 in negative subscale), Mannerisms and 
posturing, Disorientation, Poor attention, Disturbance of volition, Preoccupation (items 5, 10, 
11, 13, and 15 in general psychopathology subscale);


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Uncontrolled hostility/excitement factor (range: 4 to 28): Excitement, Hostility (items 4 and 7 
in positive subscale), Uncooperativeness, Poor impulse control (items 8 and 14 in general 
psychopathology subscale);
Anxiety/depression factor (range: 4 to 28): Anxiety, Guilt feelings, Tension, Depression 
(items 2, 3, 4, and 6 in general psychopathology subscale).
In addition, the following subscale scores of PANSS will be calculated:
Positive subscale (range: 7-49): sum of Items P1 to P7 in the positive subscale; 
Negative subscale (range: 7-49): sum of Items N1 to N7 in the negative subscale;
General psychopathology subscale (range: 16-112): sum of Items G1 to G16 in the general 
psychopathology subscale.
Analysis Methods
At each assessment time point during the Double-blind Phase and at end point (DB), descriptive 
statistics (mean, standard deviation, minimum and maximum) for each factor and subscale score 
and change from baseline (DB) will be provided for both the observed case and LOCF data. The 
change from baseline (DB) at each visit during the Double-blind Phase will be analyzed using an 
ANCOVA model with factors for treatment and country and baseline score as a covariate. The 
treatment effects will be estimated based upon least square means (PP6M-PP3M), and the 
accompanying 95% confidence intervals will be presented.
In addition, descriptive statistics of the score and change from baseline (MA) will be provided for 
baseline and endpoint of Maintenance Phase for the OL ITT analysis population.
5.3.5.
PANSS Response and Cumulative Response Rate
Definition
Clinical response based on the PANSS total score is defined as a ≥20% reduction from the baseline
(DB)
score. 
The 
percent 
change 
in 
PANSS 
total 
score 
is 
calculated 
as: 
100*CHANGE/(BASELINE-30), with 30 being the lowest possible value. If BASELINE is 30, 
then the percent change is missing.
In addition, a 30% and 40% responder classification will be provided.
Analysis Methods
For each treatment group, the number and percent of responders will be tabulated at each time 
point during the Double-blind Phase. At end point (DB), the point estimate and 2-sided 95% 
confidence interval will be provided for the relative risk using a Mantel-Haenszel test controlling 


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for country. The cumulative response rate, defined as the percentage of subjects experiencing at 
least a given value of percent reduction from baseline in PANSS total score, will also be presented 
graphically.
5.3.6.
Symptomatic Remission 
Definition
Remission criterion is defined as having a simultaneous score of mild or less on all 8 selected 
PANSS items (P1, P2, P3, N1, N4, N6, G5, and G9).
Symptomatic remission is defined for the last 6 months of the Double-blind phase as meeting the 
remission criterion during the last 6 months with one excursion allowed.  The duration of the last 
6 months counts back from either the date of DB Month 12 (defined in Section 2.5.1) or the 
disposition date of the Double-blind Phase, whichever is earlier.  For a subject who discontinues 
the Double-blind phase within 6 months, the subject will be considered as a non-remitter for the 
Double-blind phase.
The Baseline (DB) remission is defined as meeting the remission criterion at all the visits from the 
start of Maintenance phase to Day 1 of the DB phase, (there are 3 scheduled visits: Visits 2/2f, 6 
and 7b). The point-wise remission status at each double-blind time point is defined as meeting the 
remission criterion at that particular time point.
Analysis Methods
For each treatment group, the number and percent of subjects achieving symptomatic remission in
the Double-blind Phase will be presented. The point estimate and 2-sided 95% confidence interval 
will be provided for the relative risk using a Mantel-Haenszel test controlling for country. 
In addition, the count and frequency of remission status at each double-blind time point will be 
presented by treatment group for subjects who are Baseline (DB) remitters.
5.4.
Other Efficacy Variable(s)
5.4.1.
Satisfaction With Participation in Social Roles (SPSR) Short Form 8a
Definition
The SPSR Short Form 8a asks subjects to consider the past 7 days and to rate 8 items on 5-point 
Likert scales, with higher scores representing higher satisfaction.
Analysis Methods
As noted in the time and event table of the protocol, the SPSR scales will only be analyzed for 
subjects who entered the study on an oral antipsychotic.


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At each assessment time point during the Double-blind Phase and at end point (DB), descriptive 
statistics (mean, standard deviation, minimum and maximum) for the SPSR total score and the 
change from baseline (DB) will be provided for both the observed case and LOCF data.
In addition, descriptive statistics of the SPSR total score and the change from baseline (MA) will 
be provided for endpoint of the Maintenance Phase for the OL ITT analysis population.
PROMIS - Satisfaction with social roles and activities short form 8a
If 4 items are answered:
SPSR total score = (8*sum) /(# of items answered)
5.4.2.
Abbreviated Treatment Satisfaction Questionnaire for Medication
(TSQM-9)
Definition
The abbreviated treatment satisfaction questionnaire (TSQM-9) for medication has 9 items.  Each 
item is scored on 5- or 7-point Likert scales, with higher scores representing higher satisfaction. 
Subjects are asked to consider the time frame of the last 2 to 3 weeks, or since the last time the 
medication was used.
Analysis Methods
As noted in the time and event table of the protocol, the questionnaire will only be analyzed for 
subjects who entered the study on an oral antipsychotic.
At each assessment time point during the Double-blind Phase and at end point (DB), descriptive 
statistics (mean, standard deviation, minimum and maximum) for the abbreviated TSQM-9 
Subscale score, and the change from baseline (DB) will be provided for both the observed case 
and LOCF data.
In addition, descriptive statistics of the abbreviated TSQM-9 Subscale score and the change from 
baseline (MA) will be provided for endpoint of the Maintenance Phase for the ITT OL analysis 
set.
Subscale Scoring algorithm for TSQM-9 based on TSQM9_Atkinson_2005 paper[13]

Effectiveness = 100*[(Item 1 + Item 2 + item 3) -3]/18, 
if one item is missing, Effectiveness = 100*[Sum ( remaining 2 items ) -2]/12

Convenience = 100*[(Item 4 + Item 5 + item 6) -3]/18, 
if one item is missing, Convenience = 100*[Sum ( remaining 2 items ) -2]/12

Overall satisfaction: 
Recode item 9:  item 9_recode = (item 9 -1)*5/6
Overall satisfaction = 100*[(Item 7 + Item 8 + item 9_recode) -3]/12, 
if one item is missing, Effectiveness = 100*[Sum ( remaining 2 items ) -2]/8


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6.
SAFETY
All safety analyses and summaries will be based on the Open-label Safety (OL Safety, same as OL 
ITT) analysis population for the Open-label Phase and Double-blind safety (DB Safety, same as 
DB ITT) analysis population for the Double-blind Phase. 
6.1.
Adverse Events
Adverse events (AEs) are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 16 or later versions. 
A treatment-emergent AE 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 is to be 
considered treatment-emergent only if the severity increases after the start of medication. 
Treatment-emergent flags will be defined separately for the Open-label Phase (including 
Transition and Maintenance Phases), the Double-blind Phase, and combined Double-blind and
Follow-up Phases.
Treatment-emergent AE in the Open-label Phase are defined as the adverse events with onset date 
on or after the first study injection date and during the Open-label Phase (onset date >= the Date 
of First Study Injection and <= the OL End Date) or increase in severity during the same period.   
An event that starts prior to the first study injection and ends afterwards will be considered 
treatment emergent in the Open-label Phase only if the severity increases on or after the Date of 
First Study Injection.  
Treatment-emergent AE in the Double-blind Phase are defined as the adverse events that start after 
the initiation of the double-blind medication (onset >= the DB Start Date and <= the DB End Date) 
or increase in severity on or after the DB Start Date (onset in the Open-label Phase or even at 
Screening).  An event that starts prior to the DB Start Date and ends afterwards will be considered 
treatment-emergent in the Double-blind Phase only if the severity increases on or after the DB 
Start Date.
Because the OL End Date is the same as DB Start Date for those who entered the Double-blind 
Phase, adverse events with onset on this date will be considered to be treatment-emergent during 
the Double-blind Phase.
Treatment-emergent AE summaries will also be provided quarterly for the Double-blind phase.  
The entire Double-Blind phase will be divided as for time intervals: Double-blind days 1-91, 92-
182, 183-273, 274-end of DB.  An event that will be considered as treatment-emergent during that 
time interval, either if the event starts during that interval, or it starts before the time interval but 
the severity increases on or after the start date of the interval.    


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The number (%) of subjects with treatment-emergent AEs, treatment-emergent serious AEs 
(SAEs), treatment-emergent AEs that lead to study discontinuation, and treatment-emergent AEs 
resulting in death will be summarized separately by system organ class and preferred term. 
Treatment-emergent AEs will also be summarized by severity and relationship to study drug as 
determined by the investigator using the preferred term. Summaries will be provided for both the 
Open-label Phase and the Double-blind Phase by treatment group. AEs that have an onset date in 
the Open-label Phase and persist into the Double-blind Phase with no change in severity, and lead 
to discontinuation from the Double-blind Phase, will be counted in the Open-label Phase summary 
of treatment-emergent AE leading to discontinuation. 
Data listings will be generated for deaths, other SAEs, and discontinuations due to AEs. A listing 
of AEs with onset prior to Day 1 or post-study will be provided. A listing of AEs with onset during 
the oral tolerability test will also be provided.
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 v. 22.1 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, Reduced Facial Expression).
Dyskinesia (preferred terms: Dyskinesia, Muscle contractions involuntary, Movement disorder, 
Muscle twitching, Athetosis, Chorea, Choreoathetosis, Tardive dyskinesia, Myoclonus, 
Protrusion tongue, Rabbit syndrome, Buccoglossal syndrome.


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The incidence for each EPS subgroup will be calculated.
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, Cardiometabolic syndrome, 
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 resistant diabetes, 
Insulin-requiring type 2 diabetes mellitus, Ketoacidosis, Ketonuria, Ketosis, Latent 
autoimmune diabetes in adults, Neonatal diabetes mellitus, Pancreatogenous diabetes, Type 1 
diabetes mellitus, Type 2 diabetes mellitus, Urine ketone body present.
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, Blood prolactin, Blood prolactin abnormal, 
Breast tenderness, 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 
were classified into the following group names: 


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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, Injection-site Related, QT 
Prolongation Related, and Acute Kidney Injury Related.
6.1.5.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinical interview providing an evaluation of suicidal ideation, intent, and 
behavior. Data are collected using the C-SSRS Baseline Version at Screening, and all the post-
screening data is collected using the C-SSRS ‘Since Last Visit Version’.
Using the C-SSRS, potentially suicide-related events will be categorized using the following 
scores: 
Suicidal Ideation (1-5)
1: Wish to be dead
2: Non-specific active suicidal thoughts
3: Active suicidal ideation with any methods (not plan) without intent to act
4: Active suicidal ideation with some intent to act, without specific plan
5: Active suicidal ideation with specific plan and intent
Suicidal Behavior (6-10)
6: Preparatory acts or behavior
7: Aborted attempt
8: Interrupted attempt
9: Non-fatal suicide attempt
10: Completed suicide
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no event that can be 
assessed on the basis of C-SSRS”). 
A frequency distribution of scores (1 to 10) at each time point will be provided. Shifts from the 
screening visit to the maximum score during the Open-label Phase and the Double-blind Phase 
will be summarized.


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The maximum score assigned during the Open-label and Double-blind Phases for each subject will 
be summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal 
ideation (1-5), Suicidal behavior (6-10). Shifts from the screening visit to the maximum category 
during the Open-label Phase and the Double-blind Phase will be summarized. 
6.2.
Clinical Laboratory Tests
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be 
provided for the clinical laboratory tests at each time point, end point (MA), and end point (DB).
Changes from baseline (OL) will be summarized for the Open-label Phase and changes from 
baseline (DB) will be summarized for the Double-blind Phase. For the Double-blind Phase, 
changes from baseline (OL) will also be summarized. 
Clinical laboratory test values are to be considered “treatment-emergent markedly abnormal” 
(TEMA) using the criteria defined by the Sponsor (Janssen R&D) listed in Attachment 2. The 
identification of TEMA laboratory values is based on the postbaseline value being out of range 
while the baseline value is either missing or within the range given in Attachment 2. If postbaseline 
laboratory results are above the upper limit and the baseline value is below the lower limit, then 
the postbaseline 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.
The frequency and percent of subjects with any TEMA laboratory values during the Maintenance
Phase (relative to baseline (MA)) and the Double-blind Phase (relative to baseline (DB)) will be 
presented. For the Double-blind Phase, the TEMA values relative to baseline (MA) will also be 
summarized. Clinical laboratory tests that meet the criteria for markedly abnormal will be listed 
by subject. 
For prolactin laboratory results, values over time and treatment-emergent abnormal results based 
on the laboratory reference range will be presented by sex during the Maintenance Phase (relative 
to baseline (MA)) and the Double-blind Phase (relative to both baseline (MA) and baseline (DB)). 
Median prolactin values will be plotted over time.  To avoid potential unblinding of treatment, the 
prolactin laboratory results will not be made available to the clinical team members until the final 
database lock and study unblinding.
6.2.1.
Glucose Abnormalities
In addition to standard descriptive summaries for glucose measurements and markedly abnormal 
changes, treatment-emergent abnormal values will be identified according to guidelines from the 
American Diabetes Association (ADA) [7] (Table 4):
Table 4: Fasting Glucose Treatment-Emergent Abnormality
ADA Guidelines
Baseline
Any Postbaseline 
Glucose Tolerance
US Units
SI Units
US Units
SI Units


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Normal to high 
<100 mg/dL
<5.551 mmol/L
≥126 mg/dL
≥6.994 mmol/L
Impaired to high
≥100 mg/dL and 
<126 mg/dL
≥5.551 mmol/L and 
<6.994 mmol/L
≥126 mg/dL
≥6.994 mmol/L
Normal/impaired to high
<126 mg/dL
<6.994 mmol/L
≥126 mg/dL
≥6.994 mmol/L
≥140 mg/dL
≥7.771 mmol/L
≥200 mg/dL
≥11.102 mmol/L
≥300 mg/dL
≥16.653 mmol/L
Note: 1 mg/dL=0.05551 mmol/L.
Shift tables from baseline (MA) to the maximum postbaseline fasting glucose during the 
Maintenance Phase and from both baseline (MA) and baseline (DB) to the maximum postbaseline 
fasting glucose during the Double-blind Phase will be presented based on the ADA guidelines.
6.3.
Vital Signs and Physical Examination Findings
Continuous variables including orthostatic changes in vital sign measures (orthostatic systolic and 
diastolic blood pressure), heart rate, blood pressure, and change from baseline, will be calculated 
for each position at each assessment time point, end point (MA), and end point (DB). Changes 
from baseline (MA) will be summarized for the Open-label Phase and changes from baseline (MA)
and baseline (DB) will be summarized for the Double-blind Phase. Descriptive statistics (mean, 
standard deviation, median, minimum and maximum) will be presented.
A treatment-emergent abnormality for pulse and blood pressure is defined as a postbaseline value 
and change from baseline that meet the criteria in Table 5. If the baseline value is missing, the 
postbaseline value will be compared against the abnormally low/abnormally high criteria. The 
frequency and percent of subjects with any postbaseline treatment-emergent abnormalities during 
the Open-label Phase (relative to baseline (MA)) and the Double-blind Phase (relative to baseline 
(MA) and baseline (DB)) will be tabulated.
Table 5: Treatment-Emergent Abnormality Categories for Blood Pressure (BP) and 
Pulse Relative to Baseline (MA) or Baseline (DB)
Postbaseline value outside of normal limit if: 
Vital Sign
Abnormally low
Abnormally high
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
Pulse 
(beats/min)
A decrease from baseline of 15
to a value 50
An increase from baseline of 15
to a value 100
Orthostatic hypotension is defined as a decrease in systolic (>20 mmHg), or diastolic 
(>10 mmHg), blood pressure after standing for at least 2 minutes relative to supine position with 
an increase in pulse rate of >15 beats per minute (Table 6). The number and percentage of subjects 
who experience treatment-emergent orthostatic hypotension at any time during the Open-label 


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Phase and at any time during the Double-blind Phase and for whom the orthostatic hypotension 
was not present at baseline (MA) or baseline (DB) for the respective phases will be tabulated. 
Table 6: Abnormal Limits for Orthostatic Hypotension Parameters (Changes in Vital 
Signs in Standing Relative to Supine Position)
Vital Sign 
Outside of normal limit if difference
(standing minus supine)
(1)   Pulse (bpm)
> 15 bpm
(2a) Systolic blood pressure (mmHg) (SBP)
< -20 mmHg
(2b) Diastolic blood pressure (mmHg) (DBP)
< -10 mmHg
Note: Orthostatic hypotension requires that conditions (1) and [(2a) or (2b)] are met.
For subjects who are unable to stand and have the vital signs measured in a sitting or supine 
position instead of the standing position, the difference between standing and supine values will 
remain missing.
6.3.1.
Weight, Waist Circumference, and Body Mass Index
Body mass index (BMI) will be calculated as weight (kg)/(height (m))2, at each time point that 
body weight is measured. The screening height measurement will be used in the calculation. 
Continuous variables including weight, waist circumference, and BMI, and change from baseline 
will be summarized at each assessment time point, end point (MA) and end point (DB). Changes 
from baseline (MA) will be summarized for the Maintenance Phase and changes from both 
baseline (MA) and baseline (DB) will be summarized for the Double-blind Phase. Descriptive 
statistics (mean, standard deviation, median, minimum and maximum) will be presented.
For body weight, the incidence of increases/decreases from both Open-Label and double-blind
baselines >7% will be summarized by a frequency distribution. BMI will be categorized as normal: 
BMI <25 kg/m2, overweight: 25 kg/m2 BMI <30 kg/m2, obese: BMI 30 kg/m2. The frequency 
and percent of subjects in each category will be presented. 
6.4.
Electrocardiogram
The blinded central reader will read and analyze the 12-lead ECGs. The ECG variables that will 
be analyzed are heart rate, RR interval, PR interval, QRS interval, QT interval, and QT corrected 
(QTc) interval using the following correction methods: QTcLD (Linear Derived), QTcF 
(Fridericia), QTLc linear (Sagie) and QTcB (Bazett).
The QT corrected interval values are based on the following formulas:
Linear Derived: QTcLD(ms) = QT(ms) + b * (1-60/HR(bpm)), where b is an estimate of the 
slope, β, derived from the linear regression model QT(ms) = + * 60/HR(bpm), using all 
observations prior to treatment initiation of all subjects including screen failures;


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Fridericia: QTcF(ms) = QT(ms) * (HR(bpm)/60)1/3;
Sagie: QTLc(ms) = 1000 * (QT(sec) + .154 * (1 - 60/HR(bpm)));
Bazett: QTcB(ms) = QT(ms) * (HR(bpm)/60)1/2.
The corrected QTcF and QTcB intervals will be provided by the ECG central reader. The sponsor 
will calculate QTcLD and QTLc.
The “Average Predose” ECG value is defined as the average of all non-missing predose (prior to 
intake of study drug) ECG results. The baseline (MA) and baseline (DB) were defined in the 
Section 2.6.1 of the SAP.
The average predose ECG value will be compared between three prior antipsychotic use subgroups 
(as indicated in Section 2.4): oral antipsychotic, injectable risperidone, PP1M initiation, or
PP1M/PP3M stability at the time of entering the study.
The change from baseline (MA) and baseline (DB) will be summarized for the Maintenance and 
Double-blind Phases. The maximum postbaseline values during Maintenance phase and Double-
blind phase will be obtained. Descriptive statistics (mean, standard deviation, median, minimum 
and maximum) will be presented.
The number and percent of subjects with QTc intervals >450 ms, >480 ms, and >500 ms will be 
presented. The QTc increases relative to Baseline (MA) and relative to Baseline (DB) will be 
categorized as shown in Table 7. The criteria are based on the classification from the International 
Conference on Harmonisation (ICH) E14 Guideline (2005) [8].
The descriptive statistics will be presented by time point, for the maximum values, end point (MA), 
and end point (DB). 
QTc increase from baseline as categorized in Table 7 will be summarized for change from baseline
(MA) to maximum QTc interval during the Maintenance Phase, change from baseline (MA) to 
maximum QTc interval during the Double-blind Phase and change from baseline (DB) to 
maximum QTc interval during the Double-blind Phase.
QTc increase from baseline categories will also be presented over time, showing change from 
baseline (MA) over the Maintenance Phase, change from baseline (MA) over the Double-blind 
Phase and change from baseline (DB) over the Double-blind Phase.


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Table 7: Criteria for Abnormal QTc Values and Changes From Baseline (MA)
or Baseline (DB)
Clinically significant QTc value 
No
500
Yes
>500
QTc increase from baseline (MA) or 
Baseline (DB)
No concern
30
Concern
>30 – 60
Clear concern
>60
QTc value
Normal
450
>450
>450 – 480
>480
>480 – 500
>500
>500
Note: these criteria are based on ICH E14 Guideline
The distribution of the average predose QTcLD, baseline (DB), and the maximum QTcLD values 
in each phase will be presented graphically in a box plot. A box plot of the change from average 
predose to maximum QTcLD value in the Open-label Phase and of the change from baseline (DB) 
and baseline (MA) to maximum QTcLD value in the Double-blind Phase will also be produced.
A treatment-emergent abnormality for heart rate, PR interval, QRS interval, and QT interval is 
defined as a postbaseline value that meets the criteria in Table 8. If an open-label postbaseline 
ECG result is above the upper limit (abnormally high) and the baseline (MA) value is normal or 
below the lower limit (abnormally low), then the postbaseline abnormality will be considered 
treatment-emergent. The same applies to the postbaseline value being below the lower limit 
(abnormally low) with the baseline (MA) value being normal or above the upper limit (abnormally 
high). If the baseline (MA) value is missing, the postbaseline value will be compared against the 
abnormally low/abnormally high criteria. Similar derivations will be presented relative to 
Baseline (DB) for the Double-blind Phase.
Table 8: Potentially Clinically Important Criteria for ECG Parameters 
ECG Parameter
Abnormally Low
Abnormally High
HR (bpm)
50
100
PR interval (ms)
--
210
QRS interval (ms)
50
120
QT interval (ms)
200
500
The number and percent of subjects with any postbaseline treatment-emergent abnormalities will 
be tabulated.
6.5.
Extrapyramidal Symptoms (EPS) Assessment Scales
6.5.1.
Abnormal Involuntary Movement Scale
The AIMS rates 10 items for dyskinesia on a 5-point scale from 0 to 4, relating to facial and oral 
movements, extremity movements, trunk movements, and global judgments. Summing items 1 to 


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7 produces an AIMS total score (range: 0 to 28). No imputation will be performed for missing 
items; if any of the items 1 to 7 is not recorded the total score will not be calculated. Global 
judgment items 8 (global impression), 9 (incapacitation), and 10 (awareness) will be summarized 
separately. Higher scores indicate more severe condition (or higher awareness for item 10) in 
abnormal involuntary movements. Two additional items (11 and 12) consist of binary questions 
(0=no, 1=yes) and are related to the subject’s dental status.
Descriptive statistics for the AIMS total score will be presented at each time point, end point (MA),
and end point (DB). Changes from baseline (MA) will be summarized for the Open-label Phase 
and changes from baseline (DB) will be summarized for the Double-blind Phase. The frequency 
distribution for each item will be presented at each time point, end point (MA), and end point (DB). 
6.5.2.
Barnes Akathisia Rating Scale
The BARS [9] includes an objective rating and 2 subjective ratings (awareness of restlessness and 
reported distress related to restlessness) of symptoms of akathisia on a 4-point scale ranging from 
0 to 3, and a global clinical rating of akathisia on a 6-point scale ranging from 0 (absent) to 5 
(severe). Higher scores denote worsening akathisia.
The frequency distribution for each item will be presented at each time point, end point (OL), and 
end point (DB).
6.5.3.
Simpson and Angus Rating Scale
The SAS rates 10 items for general EPS on a 5-point scale from 0 (normal) to 4 (extreme), 
including gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, 
head rotation, Glabellar tap, tremor, and salivation. The SAS global score is the average score 
(total sum of item scores divided by the number of items) and ranges between 0 and 4. No 
imputation will be performed for missing items; if any item is left blank the global score will not 
be calculated. Higher scores denote more severe condition of EPS.
Descriptive statistics for the SAS global score will be presented at each time point, end point (MA),
and end point (DB). Changes from baseline (MA) will be summarized for the Open-label Phase 
and changes from baseline (DB) will be summarized for the Double-blind Phase. The frequency 
distribution for each item will be presented at each time point, end point (MA), and end point (DB).
6.5.4.
Extrapyramidal Symptoms Based on Rating Scales and Use of 
Anticholinergic Medication
Treatment-emergent EPS will also be assessed by various rating scales’ incidence and use of 
anticholinergic medication. The incidence of dyskinesia is defined as the percentage of subjects 
with a score ≥3 on any of the first 7 items or a score ≥2 on 2 or more of any of the first 7 items of 
AIMS at any time. The incidence of akathisia is defined as the percentage of subjects with a BARS 
global clinical rating score ≥2 at any time. The incidence of parkinsonism is defined as the 


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percentage of subjects with a SAS global score >0.3 at any time. The incidence of use of 
anticholinergic medication is defined as the use of anti-EPS medication. The identification of 
treatment-emergent is based on a value occurring after the first injection during each phase meeting 
the EPS criteria as defined above while the baseline value is either missing or does not meet the 
criteria. The frequency summary of the treatment-emergent EPS will be provided for the Open-
label Phase and the Double-blind Phase.
6.6.
Injection Site Evaluations
The investigator will evaluate the injection site for redness, swelling, and induration (0=absent,
1=mild, 2=moderate, 3=severe) and the subject will assess the intensity of the pain of the injection 
using a visual analogue scale (VAS 0-100 mm). Frequency distributions will be provided for the 
investigator evaluations of the injection site and descriptive statistics (N, mean, standard deviation, 
median, and range) will be provided for the subject evaluation of the injection pain. The results 
will be presented at each time point, end point (TRANS), end point (MA), and end point (DB).
7.
PHARMACOKINETICS/PHARMACODYNAMICS
PK/PD analysis will be documented and described in a separate analysis plan.
8.
HEALTH ECONOMICS
Descriptive statistics will be provided based on the Healthcare Resource Utilization Questionnaire
(HRUQ), Involvement Evaluation Questionnaire (IEQ), the Illness Management and Recovery 
(IMR) Scale, and the Schizophrenia Quality of Life Scale (SQLS-R4). 
As noted in the time and event table of the protocol, the IMR scale will only be analyzed for 
subjects who entered the study on an oral antipsychotic.
Out of the 31 items on the IEQ questionnaire, 27 items will be summarized into 4-distinct sub-
scales:  Tension (9 items), Supervision (6 items), Worrying (6 items), Urging (8 items) and a Sum 
Score of the 27 items [10].  The descriptive statistics for the IEQ will only apply to those subjects 
who have a designated caregiver during the study.
Additionally, demographic characteristics of the caregiver and caregiving arrangements will be 
summarized for the OL ITT and DB ITT analysis populations.
Scoring algorithm for the total SQLS-R4
The self-administered rating scale includes 33 items concerning the subject’s symptoms and well-
being over the preceding 7 days on a scale of 1 to 5.  For all items except item number 7, 12, 14 
and 26, score 1 indicates “Never” and 5 indicates “Always”.  For items 7, 12, 14 and 26, scores 
should be reversed (1 for “Always” and 5 for “Never”).  They will be reversed in the programmatic 


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calculation of total score, as those item scores were entered in the database without conversion. 
Only total score for the SQLS-R4 will be analyzed. 
Total score is calculated as a percentage from 0 to 100 with 0 indicating “no problem at all” 
and 100 indicating “the maximum level of problem”. 
The total score is calculated as:
100*Sum of scores of each item / (4*33)
If less than 25% items are missing (i.e., less than or equal to 8 items), the total score can be 
calculated by dividing the sum of scores of the valid items by the maximum possible score 
(4*number of valid items).  
Imputed score =  (Sum of scores of each valid item * 100)/(4*number of valid items)
If at least 25% of the items (i.e., more than 8 items) are missing, the total score will not be 
computed for that visit.
Observed case and LOCF values will be derived according to the rules above.
Changes from Baseline (MA) and Baseline (DB) will be calculated. The SQLS-R4 will be 
summarized descriptively for the OL ITT and DB ITT analysis populations. 


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REFERENCES
1.
Clinical Study Report R092670PSY3012. A randomized, multicenter, double-blind, relapse prevention study 
of paliperidone palmitate 3-month formulation for the treatment of subjects with schizophrenia. Janssen 
Research & Development, LLC (02 Sep 2014).
2.
Hough D, Gopal S, Vijapurkar V, et al. Paliperidone palmitate maintenance treatment in delaying the time-to-
relapse in patients with schizophrenia: A randomized, double-blind, placebo controlled study. Schizophr Res 
2010;116:107–117.
3.
Kramer M, Simpson G, Maciulis V. Paliperidone extended-release tablets for prevention of symptom 
recurrence in patients with schizophrenia. A randomized, double-blind, placebo-controlled study. J Clin 
Psychopharmacol 2007;27:6–14.
4.
Justification of Noninferiority Margin. Paliperidone palmitate 6-month product for the maintenance treatment 
of schizophrenia. Janssen Research & Development, LLC (02 Aug 2017).
5.
US FDA. Non-inferiority clinical trials to establish effectiveness: guidance for industry.
www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm202140.pdf. 
Issued November 2016. Accessed 15 May 2017.
6.
Marder SR, Davis JM, and Chouinard G. “The effects of risperidone on the five dimensions of schizophrenia 
derived by factor analysis: combined results of the North American trials”. J Clin Psychiatry, 1997; 58(12): 
538-46. Erratum in: J Clin Psychiatry 1998; 59(4): 200.
7.
American Diabetes Association, American Psychiatric Association, American Association of Clinical 
Endocrinologists, North American Association for the Study of Obesity. 2004. Consensus development 
conference on antipsychotic drugs and obesity and diabetes, Diabetes Care 27(2):596-601.
8.
International Conference on Harmonization (ICH) Tripartite Guideline E14. The clinical evaluation of QT/QTc 
interval prolongation and proarrhythmic for non-antiarrhythmic drugs. London 2005.
9.
Barnes T, “The Barnes Akathisia Rating Scale – Revisited”, J Psychopharmacology, 2003, 17(4): 365-370.
10.
van Wijngaarden B, Schene AH, Koeter M, et al. Caregiving in schizophrenia: development, internal 
consistency, and reliability of the Involvement Evaluation Questionnaire – European Version. Br J Psychiatry 
2000;177(suppl.39):s21-s27
11.
Taylor M., Murray S., Hsu C-H. Survival estimation and testing via multiple imputation.  Statistics and 
Probability letters. 2002; 58:221-232.
12.
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.
13.
Atkinson M., Kumar R., Cappelleri J., Hass S. Hierarchical Construct Validity of the Treatment Satisfaction 
Questionnaire for Medication (TSQM Version II) Among Outpatient Pharmacy Consumers.  ISOR. 2005; 8: 
S9-S24.


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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
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
ISCHAEMIA
Cerebrovascular insufficiency
ISCHAEMIA
Embolic cerebral infarction


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ISCHAEMIA
Embolic stroke
ISCHAEMIA
Haemorrhagic cerebral infarction
ISCHAEMIA
Haemorrhagic stroke
ISCHAEMIA
Ischaemic cerebral infarction
ISCHAEMIA
Ischaemic stroke
ISCHAEMIA
Subclavian steal syndrome
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
SYNCOPE
Syncope
SYNCOPE
Presyncope
SYNCOPE
Circulatory collapse
SYNCOPE
Loss of consciousness
MOVERCATAEDECOD
Overdose
Accidental overdose
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
VENTRICULAR TACHYCARDIA
Ventricular tachycardia
VENTRICULAR TACHYCARDIA
Ventricular tachyarrhythmia
VENTRICULAR FIBRILLATION AND 
FLUTTER
Cardiac fibrillation


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VENTRICULAR FIBRILLATION AND 
FLUTTER
Ventricular arrhythmia
VENTRICULAR FIBRILLATION AND 
FLUTTER
Ventricular fibrillation
VENTRICULAR FIBRILLATION AND 
FLUTTER
Ventricular flutter
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
Focal dyscognitive seizures
SEIZURES
Seizure
SEIZURES
Convulsion in childhood
SEIZURES
Neonatal seizure
SEIZURES
Convulsions local
SEIZURES
Convulsive threshold lowered
SEIZURES
Déjà vu
SEIZURES
Dreamy state
SEIZURES
Drug withdrawal convulsions
SEIZURES
Eclampsia
SEIZURES
Epilepsy
SEIZURES
Epilepsy congenital
SEIZURES
Epileptic aura
SEIZURES
Epileptic psychosis
SEIZURES
Febrile convulsion
SEIZURES
Frontal lobe epilepsy
SEIZURES
Generalised non-convulsive epilepsy
SEIZURES
Grand tonic-clonic seizure
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
Partial seizures with secondary generalisation
SEIZURES
Petit mal epilepsy
SEIZURES
Post-traumatic epilepsy


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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SEIZURES
Focal dyscognitive 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 self-injury
SUICIDALITY
Poisoning deliberate
SUICIDALITY
Self-injurious ideation
SUICIDALITY
Completed suicide
SUICIDALITY
Suicidal ideation
SUICIDALITY
Suicide attempt
SUICIDALITY
Suicidal behaviour
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
Opisthotonus
NMS
Rhabdomyolysis


R092670  (paliperidone palmitate)
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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
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


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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Approved, Date: 26 May 2020
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 increased
MINJCAT
AEDECOD
INJECTION SITE
Injection related reaction
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 exfoliation
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
INJECTION SITE
Injection site injury
INJECTION SITE
Injection site irritation


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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Approved, Date: 26 May 2020
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
Musculoskeletal 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
MQTPLCAT
AEDECOD


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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Approved, Date: 26 May 2020
QT PROLONGATION
Electrocardiogram QT interval abnormal
QT PROLONGATION
Electrocardiogram QT prolonged
QT PROLONGATION
Long QT syndrome
QT PROLONGATION
Long QT syndrome congenital
MAKICAT
AEDECOD
ACUTE RENAL FAILURE (SMQ)
ACUTE PHOSPHATE NEPHROPATHY
ACUTE RENAL FAILURE (SMQ)
ACUTE KIDNEY INJURY
ACUTE RENAL FAILURE (SMQ)
ANURIA
ACUTE RENAL FAILURE (SMQ)
AZOTAEMIA
ACUTE RENAL FAILURE (SMQ)
CONTINUOUS HAEMODIAFILTRATION
ACUTE RENAL FAILURE (SMQ)
DIALYSIS
ACUTE RENAL FAILURE (SMQ)
HAEMODIALYSIS
ACUTE RENAL FAILURE (SMQ)
HAEMOFILTRATION
ACUTE RENAL FAILURE (SMQ)
NEONATAL ANURIA
ACUTE RENAL FAILURE (SMQ)
NEPHROPATHY TOXIC
ACUTE RENAL FAILURE (SMQ)
OLIGURIA
ACUTE RENAL FAILURE (SMQ)
PERITONEAL DIALYSIS
ACUTE RENAL FAILURE (SMQ)
PRERENAL FAILURE
ACUTE RENAL FAILURE (SMQ)
RENAL FAILURE
ACUTE RENAL FAILURE (SMQ)
RENAL FAILURE NEONATAL
ACUTE RENAL FAILURE (SMQ)
RENAL IMPAIRMENT
ACUTE RENAL FAILURE (SMQ)
RENAL IMPAIRMENT NEONATAL


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670PSY3015
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Approved, Date: 26 May 2020
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
Creatinine [mol/L]
N/A
265.2
Gamma glutamyl transferase [U/L]
N/A
300
Glucose [mmol/L]
2.2
16.7
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
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.
CCI
CCI
CCI